Am J Physiol Heart Circ Physiol 288: H1028-H1036, 2005;
doi:10.1152/ajpheart.00780.2004
0363-6135/05 $8.00
8TH INTERNATIONAL SYMPOSIUM ON RESISTANCE ARTERIES
New Developments in Resistance Artery Research: From Molecular Biology to Bedside
In vivo functional NMR imaging of resistance artery control
P. G. Carlier and
D. Bertoldi
NMR Laboratory, AFM and CEA, Institute of Myology, IFR 14, Pitié-Salpêtrière University Hospital, Paris, France
Submitted 2 August 2004
; accepted in final form 22 September 2004
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ABSTRACT
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Arterial spin labeling (ASL) in combination with NMR imaging is an in vivo technique that quantifies tissue perfusion in absolute values (ml blood·min–1·g tissue–1) with high temporal (1–10 s) and spatial (0.1–3 mm) resolution. It uses the arterial water spins as endogenous freely diffusible markers of perfusion and, hence, is a totally noninvasive method. The technique has been successfully applied to quantify baseline perfusion in many organs, including the heart, in humans and animals, and results were validated by comparison with gold standards, PET and microspheres, respectively. Because of the high sampling rate of perfusion with ASL and the possibility that measurements could be obtained without harm over indefinite periods of time, the technique has the potential for use in functional investigations of microcirculation regulation and resistance artery control in vivo. We describe examples of the use of ASL to this end. With use of specific technological developments, ASL determination of perfusion can be coupled with simultaneous acquisitions of 1H and 31P NMR spectroscopy data. These protocols offer new possibilities whereby the microcirculatory control of cell oxygenation and high-energy phosphate metabolism can be explored.
arterial spin labeling; imaging; microcirculation; perfusion
AT FIRST SIGHT, NONINVASIVE in situ visualization of resistance artery lumen and wall is well beyond the technological limits of in vivo NMR imaging, which has detection limits of 0.1–3 mm (31).
However, in situ resistance vessel vasodilatory capacity, reactivity, and sensitivity to various agonists and antagonists can be studied indirectly by dynamic monitoring of tissue perfusion, provided a number of conditions are met. The technique used to measure perfusion must be strictly noninvasive in order not to disturb tissue physiology. It must be quantitative in absolute terms, i.e., in blood volume per unit time and unit tissue mass, to allow comparisons between subjects and between experimental conditions. Multiple repetitions at a high acquisition rate also represent an absolute prerequisite for dynamic evaluations of microcirculation responsiveness to stimuli. The perfusion information must be unambiguously localized in deep as well as in superficial organs, and the acquisition of high-spatial-resolution perfusion maps is a fundamental issue. The only method that meets all these criteria is an NMR imaging submodality originally proposed by Detre, Williams, and co-workers (18, 82) and known as arterial spin labeling (ASL). As such, it deserves the attention of vascular physiologists.
The aim of this brief review is to introduce ASL-NMR, its potential, still largely unexploited, for functional investigation of resistance artery behavior in vivo, and its limits. We also present an overview of the few studies that pioneered the field.
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PRINCIPLE OF PERFUSION MEASUREMENT WITH ASL
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The physics of ASL have been explained in detail (2, 12, 13, 30, 85, 86), and a mere outline is given here. The ASL methods can be divided into two subgroups: continuous and pulsed ASL. Many acronyms have been coined to identify variants of ASL methods, principally in the pulsed mode: FAIR, QUIPSS, QUIPPS2, EPICORE, FAIRER, STAR, and SATIR. Most ASL protocols realize single-slice quantitation of perfusion, but multislice, and even three-dimensional, acquisition schemes have been proposed.
Contrary to continuous ASL, pulsed ASL sequences can, in most cases, be implemented without any change in the NMR hardware. Besides other considerations in relation to the arterial transit time (86), this practical advantage led us to use and to recommend the use of pulsed ASL for physiological applications.
Briefly, in the pulsed ASL mode, the arterial spins are first magnetically tagged, typically positively or negatively, by a radio-frequency pulse, which is followed by a delay, i.e., the evolution time (T), during which perfusing spins enter the organ of interest and mix almost instantaneously with the stationary spins. The arrival of the arterial spins into the tissue induces a modulation of tissue magnetization that is proportional to perfusion (Fig. 1). This modulation is recorded by NMR imaging. In practice, for extraction of the perfusion information, at least two images with different arterial tag values are required, and, in most protocols, perfusion images are acquired in pairs (Fig. 2). This is the case with SATIR (i.e., saturation inversion recovery), the ASL variant developed in our laboratory (54), where the arterial spins are alternatively tagged positively by slice-selective (ss) inversion and negatively by nonselective (ns) inversion. For cardiac and muscle applications, during work at a high magnetic field, such as 4 T, the almost identical longitudinal relaxation rates (r1) of blood and muscle in these fields are an advantage, and perfusion can be directly quantified as follows
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Fig. 1. After negative (A) or positive (B) magnetic labeling of the arterial water spins (ASL; black arrows), perfusing spins enter the capillary network, where they exchange freely with the tissue water spins (white arrows). The result is a reduction (A) or an acceleration (B) of the apparent relaxation rate (r1 app), which is proportional to perfusion (f/ ). Acquisition of 2 images differently weighted by perfusion allows quantitative tissue perfusion.
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Fig. 2. Functional images of perfusion and the corresponding anatomic image in the leg of a 5-wk-old lean Zucker rat. A: functional perfusion image after positive ASL, obtained by imaging slice saturation (plus slice-selective inversion) via ultrafast spin echo imaging: echo spacing = 2.9 ms, image acquisition time = 60 ms with half-Fourier scheme, sequence repetition time = 8 s, field of view = 8.29 x 4 cm, acquisition matrix = 128 x 32. B: functional perfusion image after negative ASL, obtained by imaging slice saturation plus nonselective inversion. Imaging parameters are identical to those described in A. Visual comparison of A and B does not reveal perfusion information. C: difference image between acquisitions with positive (A) and negative (B) ASL reveals perfusion information. Rectangle, a typical positioning of the region of interest; circles, angiographic effects in large blood vessels, which have to be carefully excluded from the region of interest. D: high-resolution anatomic spin echo image with TE = 11 ms, TR = 800 ms, field of view = 7 x 7 cm, and acquisition matrix = 256 x 256.
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where f is perfusion (ml·s–1·ml tissue–1), T is evolution time between inversion and acquisition, is blood-tissue partition coefficient, and M is tissue signal intensity in the tagged images.
At lower magnetic field, a correction algorithm for the difference between blood and tissue r1 values can be applied.
Arterial blood may contaminate the perfusion signal but can be eliminated at acquisition by gradient crushing or by postprocessing. Sequences have been introduced to accelerate the ASL temporal resolution to seconds, but some assumptions with regard to arterial time are required. To minimize the risk of quantitation bias, we prefer to apply, when possible, whole body radio-frequency excitation and let blood magnetization recover between scans.
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ASL ASSESSMENT OF TISSUE PERFUSION
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The capacity of ASL methods to quantify perfusion has been demonstrated in various organs, principally the brain (1, 18, 35, 48, 50, 57, 66, 80, 87), but also the heart (4, 15, 23, 49, 52, 55, 73–75, 77, 83), skeletal muscle (20, 26, 39, 44, 54, 65, 69), kidney (33, 45, 58, 78, 84), lungs (42, 43), ovaries (67, 68), and testis (53).
Because the ASL method relies on the fast exchange between perfusing water spins and the tissue stationary spins, it is not appropriate for determination of perfusion in fat tissue. The blood-brain barrier is an obstacle to the fast exchange condition, but only at very high cerebral blood flow, which will then be underestimated by ASL. For identical reasons, ASL is insensitive to arteriovenous shunts and evaluates the real perfusion, not the blood flow to the organ, and this interesting feature has been overlooked.
Validation studies were performed vs. 15O PET or hydrogen clearance for the brain (40, 51, 88), microsphere for the heart (77), and venous occlusion plethysmography for skeletal muscle (54).
However, ASL combined with NMR imaging combines the advantages of all other techniques available for in vivo measurement of perfusion. The microsphere method, the accepted gold standard of tissue perfusion quantitation in animal models, is in essence a single-time-point measurement, requiring an injection and a blood reference sample and, even when repeated, is at risk of missing the peak of perfusion in dynamic processes. In contrast, ASL combined with NMR imaging requires no surgical procedures or injections and is indefinitely repeatable, with a resolution on the order of seconds, making it ideally suited to the study of the dynamics of perfusion.
Venous occlusion plethysmography has provided noninvasive, highly temporally resolved measurements of limb perfusion, defined as the initial slope of the increase in limb volume, since the 18th century (16). However, it offers no information on spatial distribution of perfusion. On the contrary, ASL provides high-resolution perfusion maps of whole limbs or organs. Indeed, at least in highly perfused organs, information can even be obtained on perfusion heterogeneity. This opens interesting perspectives for the evaluation of the impact of perfusion heterogeneity on tissue metabolism and function (3, 56), an area that remains largely to be explored.
The laser-Doppler method estimates perfusion noninvasively and repeatably but is only semiquantitative and requires a reference measurement (17) and the penetration of light in the tissue and restricts the measurement of perfusion to relatively superficial layers (70).
In recent years, it has been shown that, with microbubbles as an exogenous marker of perfusion, echography can assess perfusion with an excellent temporal resolution (22), but it is minimally invasive, and the quantitation of the measurement can be achieved only if the arterial input function of the exogenous tracer is known, which is rarely the case. This same constraint exists for another NMR modality of perfusion measurement, i.e., NMR imaging of Gd chelates by first passage (81), and also for PET, which uses H215O as a marker of perfusion, with the first-pass method of the tracer (5) or by constant infusion of the tracer (79). Of these, PET is more quantitative when a well-defined arterial input function is recorded and offers the ability to evaluate perfusion and metabolism with use of the 15O-radiolabeled tracer. However, PET of short-lived radiotracers such as 15O requires the proximity of a producing cyclotron and is invasive. Repeated determinations of perfusion implies multiple radiotracer injections, which can be highly irradiative. A PET examination is far more expensive than an NMR examination, and PET cannot compete with ASL in terms of temporal or spatial resolution.
Because of the fundamental characteristics of ASL, namely, full noninvasiveness, repeatability, high sampling rate of perfusion, quantitative measurements, and ability to map perfusion in superficial and internal organs, the technique has a tremendous potential for in vivo investigation of vasomotion control in most organs in many physiological and pathological conditions. The use of ASL to determine perfusion has been rather limited in this particular research context. Among the explanations for this somewhat paradoxical situation are the relatively small number and poor availability of in vivo NMR systems dedicated to clinical and animal research, the complexity and contraintuitivity of the ASL method, the need for fine tuning of the acquisition sequence, and the low contrast-to-noise ratio of the perfusion data. Most of these obstacles are being progressively overcome. Increasing numbers of NMR spectrometers, including systems dedicated to small animals, are being delivered and are in operation in academic research facilities, with the main mission of phenotyping genomic manipulations in rodents. Ready-to-use and robust ASL protocols are becoming available and should be included in standard NMR imaging packages in the near future. Automated processing algorithms are being developed and will accelerate data analysis while minimizing operator intervention (28). Slowly but surely, the awareness of the existence of ASL and of its advantages is growing among potential end users and, in particular, among physiologists.
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ASL DETECTION LIMIT
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Perfusion alters tissue apparent longitudinal NMR relaxation of water marginally. The consequence is a low perfusion weighting of the ASL images. Typically, perfusion on the order of 100 ml·min–1·100 g–1, as can be found in humans in highly irrigated organs such as the heart and brain or during heavy exercise of some muscle groups, induces a 1% change in the ASL image signal intensity. Modern NMR imaging platforms offer sufficient instrumental stability to monitor such perfusion levels with a 10- to 20-dB contrast-to-noise ratio at an acquisition rate of one measurement per 2–3 s. In the same technical conditions, the quantitation of a low perfusion state, such as 5 ml·min–1·100 g–1 in a skeletal muscle at rest, will be imprecise, with a contrast-to-noise ratio of –3 to 7 dB, if the same 2- to 3-s temporal resolution is maintained. In this situation, the measurement precision can be maintained only by multiplying the number of acquisitions by the square of the perfusion ratio, 400 in this example. This will drastically prolong the acquisition time, but a 12- to 20-min temporal resolution will probably remain acceptable for subtle regulation processes. For instance, a still-debated question is how disturbances of skeletal muscle vasomotion control contribute to the abnormal nonoxidative disposal of glucose in Type 2 diabetes (63). In this context, 10- to 15-min maps of skeletal muscle perfusion will be appropriate and fully compatible with the time frame of metabolic investigations, such as glucose-insulin clamps and 13C NMR spectroscopy of glycogen synthesis.
To determine whether ASL can assess low tissue blood flow in very small target organs, we decided to measure the baseline perfusion of gastrocnemius muscles in adult mice (6, 7). Using SATIR, the ASL variant developed in our laboratory, we were able to measure perfusion at rest of 17.6 ± 10.7 ml·min–1·100 g–1 with 5-min acquisition windows. It was difficult to compare these results with literature data obtained with other techniques. This fact alone illustrates the novelty and the power of the ASL determination of perfusion. We found only one report of mouse skeletal muscle perfusion data at rest obtained with microsphere injection (38). The published results were similar to the ASL values. The major difference between the two methods is the difficulty in repeating the microsphere measurements, mainly because of the need to draw an arterial blood reference sample each time. This is a real issue in small animals, whereas the ASL determinations, because of their noninvasive nature, can be repeated indefinitely.
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IN VIVO STUDY OF MICROCIRCULATION DYNAMICS USING ASL COUPLED TO NMR IMAGING
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Because of the novelty of the technique and, even more, its application to the dynamics of microcirculation in skeletal muscle, literature on the subject is very scarce, and examples taken from recent studies to illustrate how ASL coupled to NMR imaging can be used to investigate resistance artery control in vivo are from our own group. In a protocol conducted in elite athletes, we compared endurance-trained runners with sprinters (20). After exercise bouts consisting of ischemic plantar flexions, there was a considerable difference in calf muscle reperfusion patterns as determined by ASL between the two groups (Fig. 3). Early muscle reperfusion was higher in the endurance-trained runners, peak perfusion occurred earlier, and perfusion values returned toward baseline level faster than in the sprinters. In large part, these findings are likely to reflect an increased vasodilatory responsiveness of the muscle arteriolar bed associated with endurance training compared with force training (32, 62). The increased capillary density in endurance-trained muscles (11, 46) may also contribute somewhat to the high perfusion observed in this group. Also, the maximum perfusion achieved in the activated muscles was identical in both groups, suggesting the absence of structural differences in the arteriolar beds. Finally, despite specific temporal patterns of reperfusion, the postexercise perfusion integrals, or the volume returned to the muscles, did not differ between the two groups. Such observations had not been reported previously, probably simply because of lack of appropriate technology. They illustrate the richness and diversity of information on vasodilation dynamics and control that can be derived from ASL determination of skeletal muscle perfusion.
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Fig. 3. Kinetics of postischemic exercise calf reperfusion in elite endurance runners (ER) and sprinters (SR). Because of its noninvasiveness and high temporal resolution, ASL determination of perfusion identified very different patterns of microcirculatory control in ER and SR. P < 10–4, ER vs. SR over entire data set.
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Using ASL sequences specially adapted to small target organs, we also studied skeletal muscle reperfusion in animal models. Even with a simple paradigm of ischemia-reperfusion of the rat or the mouse leg, original data were obtained. We observed that the duration of the hyperemic response was highly dependent on the duration of the ischemic stress itself (Fig. 4) (8). The high temporal resolution of ASL revealed the diverse and rapid fluctuations of skeletal muscle perfusion in these experimental conditions. With more standard technology, such as the microsphere method, only a few measurements would have been possible per animal, and the dynamics of the vasodilatory response would have been heavily truncated. Any attempt to identify the mechanisms responsible for the postischemic hyperemia and, more importantly, for the differential responses in relation to ischemia duration will require the high temporal resolution that is offered only by ASL. A large number of metabolites (19, 21, 34, 41, 47, 61, 64, 89) have been identified as playing a role in postexercise or postischemic hyperemia: nitric oxide, bradykinin, various prostaglandins, ATP, ADP, adenosine and other purinergic derivatives, endothelium-derived hyperpolarizing factor, catecholamines, lactate, K+, and H+. The challenge is to quantify their contributions, which in addition may vary over time and will then need to be evaluated at several time points in the course of the hyperemic response. For instance, to identify and quantify the contribution of nitric oxide to reactive hyperemia after ischemia of various durations, experiments are underway that imply acute and chronic administration of nitro-L-arginine methyl ester before the ischemic insult, on the one hand, and the study of animals overexpressing nitric oxide synthase, on the other hand.
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Fig. 4. Time course of reactive hyperemia in a rat leg after 5 min (A) or 30 min (B) of ischemia. Very different reperfusion patterns were detected. Their mechanisms remain to be determined.
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Furthermore, ASL determination of perfusion may be directed toward the identification of yet unresolved manifestations of abnormal control of resistance arteries. It was established decades ago that chronic arterial hypertension is associated with elevated peripheral arterial resistance and decreased maximal vasodilation in most, if not all, organs (24, 25, 60). In a recent study in calf muscles from old spontaneously hypertensive rats, postischemic reperfusion profiles measured by ASL-NMR confirmed these two fundamental features. In addition, we discovered that, in contrast to the normotensive Wistar-Kyoto rats, aged hypertensive animals were unable to maintain skeletal muscle vasodilation over prolonged periods after 30 min of ischemia (Fig. 5). The mechanisms responsible for the abnormal regulation of the resistance artery tone are unknown but cannot be a mere consequence of the hypertensive structural changes. The failure of chronically hypertensive animals to depress arteriolar resistance over extended periods of time is perhaps of highly functional significance, because it may be one of the mechanisms that make hypertensive target organs more sensitive to ischemia (27, 37, 59). That such an observation had not been made previously, despite the abundant literature on hypertensive disease, is highly indicative of the new possibilities offered by ASL methods for the functional investigation of resistance arteries in vivo.
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MYOCARDIAL PERFUSION AND CORONARY RESERVE
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The evaluation of myocardial perfusion at rest and under maximal vasodilation is of paramount importance in clinical cardiology, because it reveals the functional significance of atherosclerotic stenoses in coronary patients. This area is a major potential field of application for the ASL technique. However, progress in this specific direction has been slow. When it is not taken into account properly, cardiac contractility itself generates spurious results in pulsed ASL, the only ASL mode technically applicable to this organ. A basic constraint in pulsed ASL stipulates that the slice-selective tag must coincide strictly with the imaging slice. When the acquisition sequence is well designed, this condition is automatically met for organs that remain still. Because of cardiac contraction or relaxation, depending on the cardiac phase at the time of the ASL and at the time of image acquisition, the slice-selective tag can be shifted very significantly from the imaging slice. If the position of the tag is not controlled, the displacement can result in changes in ASL image signal intensity that may easily exceed the perfusion modulation by one order of magnitude. Failure to recognize and handle this specificity of cardiac ASL has been the cause of some aberrant myocardial perfusion values (23, 73, 74). Extremely high myocardial perfusion values (220–850 ml·min–1·100 g–1) were measured in humans at rest. Furthermore, inasmuch as contractility and perfusion are closely matched, conditions known to alter perfusion had a similar impact on contractility and, consequently, on the intensity of the pseudo-ASL contractility artifact. These changes were, in turn, falsely interpreted as a validation of this erroneous methodological approach (73). Poncelet et al. (52) proposed a solution in the form of a double synchronization of the sequence. The ASL and the imaging modules were triggered by the ECG, with an identical delay after the R wave. The procedure ensured the required spatial superimposition of the selective ASL slab and the imaging slice. An ultrafast echoplanar imaging sequence was used to measure the expected myocardial perfusion values in human volunteers and in pigs, where the method was validated against the microsphere gold standard. Using the same double trigger but working with single-shot fast spin echo imaging, which is less sensitive to magnetic susceptibility artifacts, we obtained similar results during breath-hold acquisitions (15). In a preliminary study, we showed that cardiac ASL could detect relatively small changes in coronary reactivity, such as those induced by a cold pressor test (15).
Because myocardial perfusion is four to five times higher in rats than in humans, adaptation of cardiac ASL has been simplified in this species. On the basis of the determination of the apparent T1 recovery curve using fast gradient echo imaging, a number of studies demonstrated the feasibility of measuring myocardial perfusion in rats (4, 75–77). In a recent publication, very convincing perfusion maps were generated with an optimized version of the same approach (36).
Most importantly, there is evidence that coronary reserve can be quantified with ASL after administration of coronary vasodilator or cardiac inotropic drugs (36, 75, 77). The main limitation seems to pertain more to difficulties of inducing maximal coronary vasodilation in anesthetized animals than to the ASL technique itself.
Absolute quantitation of myocardial perfusion as provided by ASL coupled to NMR imaging will be of particular interest in conditions that diffusely affect the heart, such as dilated and concentric cardiomyopathies, but also in diseases such as diabetes and hypertension, all situations where it would be difficult to express results relative to a normal myocardial segment.
Now that the problems specific to cardiac ASL have been identified and viable solutions proposed, one may expect the technique to play a role as a noninvasive functional tool to investigate the coronary microcirculation in vivo.
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COUPLING ASL DETERMINATION OF PERFUSION WITH IN VIVO NMR SPECTROSCOPY OF TISSUE METABOLISM
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The NMR signal of a living tissue is a complex function controlled by a great number of parameters in relation to tissue composition, including its viscoelastic properties, as well as arterial blood flow velocity, blood volume, perfusion, blood and tissue oxygenation, capillary permeability, diffusion, and temperature (31). Specific metabolites that play a role in energy and intermediary metabolism can also be detected and quantified with NMR spectroscopy, mainly 1H, 31P, and 13C (29). It is a primary role of sequence programming to extract more-or-less specifically and, ideally, very specifically the desired information, such as ASL modules extract for perfusion. In the classical use of NMR, for each parameter under scrutiny, one NMR experiment is run at each time. In many cases, there is, however, no theoretical obstacle to combining the collection of different parameters during one single experiment by rapid interleaving of data acquisitions with different specific pulse sequences. To achieve this, modifications to the NMR spectrometer configuration are required. Because of the simultaneity or quasi-simultaneity of data acquisitions, subtle interactions between parameters may be attempted; this justifies the methodological efforts.
This concept, referred to as multiparametric functional (mpf) NMR, has become a powerful tool for dynamic investigation of skeletal muscle function and metabolism in animal models and in humans (9, 10, 14, 20, 39, 71). In parallel with the ASL evaluation of muscle perfusion, it is possible to monitor intramyocytic oxygenation using 1H NMR spectroscopy of myoglobin and high-energy phosphate distribution using 31P NMR spectroscopy. A complete set of mpf-NMR data can be acquired in 1.5–2 s. This high data sampling rate allows a detailed description of dynamic processes such as postexercise recovery.
In the study of elite athletes mentioned above, the mpf-NMR acquisitions identified complex relations between early reperfusion, myoglobin concentration, and mitochondrial ATP production (20). In situations where mitochondrial energy production is impaired, which can be demonstrated by an abnormally long creatine rephosphorylation time constant calculated from postexercise 31P NMR spectra, simultaneous evaluation of muscle reperfusion and reoxygenation can help determine the reasons for the defective ATP production (Fig. 6). Whether the main factor is insufficient oxygen and substrate supply, abnormal oxygen transport, or intrinsic mitochondrial dysfunction will be revealed by the comparison of the reperfusion, myoglobin resaturation, and creatine rephosphorylation time curves, as illustrated by these two clinical cases of peripheral arterial disease and mitochondrial diabetes.
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Fig. 6. Examples of multiparametric functional (mpf) NMR studies performed in a patient with peripheral artery disease (A) and another with mitochondrial diabetes (B). After a plantar flexion ischemic bout, calf muscle perfusion (top), myoglobin resaturation (middle), and creatine rephosphorylation (bottom) were simultaneously monitored using ASL imaging and 1H and 31P NMR spectroscopy, respectively. In both conditions, creatine rephosphorylation rate, an indicator of mitochondrial ATP production, was abnormally low. In A, mitochondrial dysfunction was clearly attributable to a blunted functional hyperemia (top) and a dramatically slow muscle reoxygenation (middle). In B, postexercise reperfusion and myoglobin resaturation were within normal ranges, indicating an intrinsic defect of mitochondrial function.
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In animal models, comparison of ASL perfusion and 31P-NMR spectroscopy data is possible. In a peripheral arterial disease model, this approach revealed that spontaneous angiogenesis developed until normalization of mitochondrial ATP production but not until full restoration of the vasodilation reserve in the rat leg (72).
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CONCLUSION
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Functional imaging of perfusion is possible with ASL combined with NMR imaging. Because of several intrinsic characteristics, the technique offers the physiologist a new noninvasive tool for the study of resistance artery control in vivo. Unexplored facets of microcirculatory regulation mechanisms are becoming accessible to investigation, in particular, the dynamics of vasomotion, perfusion heterogeneity, microcirculatory control of tissue oxygenation, and energy metabolism.
Until now, classical experiments on resistance artery control were to be performed on isolated vessels, on perfused organs, or on hindquarters and, hence, were destructive and final. Because it is noninvasive, quantitative, spatially localized, and repetitive, ASL-NMR imaging of tissue perfusion allows similar experiments to be conducted in vivo in intact animals. Therefore, ASL-NMR imaging is not just another method to measure tissue perfusion. When the potential of the technique is fully appreciated, physiologists will have the opportunity to construct dose-response curves of agonist and antagonist actions on arterial tone in different organs in vivo, including in humans, and to assess in the same group of subjects the arteriolar response changes with aging or with the progression of diseases.
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GRANTS
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D. Bertoldi is the recipient of an Association Francaise contre les Myopathies research fellowship.
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ACKNOWLEDGMENTS
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The authors thank colleagues and former colleagues from the NMR Laboratory at the Institute Myology, in particular S. Duteil, A. Leroy-Willig, J. S. Raynaud, G. Vidal, and C. Wary, who have been instrumental in the realization of several of the studies.
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FOOTNOTES
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Address for reprint requests and other correspondence: P. G. Carlier, Laboratoire de RMN AFM-CEA, Institut de Myologie, Bat. Babinski, CHU Pitié-Salpêtrière, 83, Bd de l'Hôpital, 75651 Paris Cedex 13, France (E-mail: p.carlier{at}myologie.chups.jussieu.fr)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES
|
|---|
- Alsop DC and Detre JA. Multisection cerebral blood flow MR imaging with continuous arterial spin labeling. Radiology 208: 410–416, 1998.[Abstract/Free Full Text]
- Barbier EL, Lamalle L, and Decorps M. Methodology of brain perfusion imaging. J Magn Reson Imaging 13: 496–520, 2001.[CrossRef][ISI][Medline]
- Bauer WR, Hiller KH, Galuppo P, Neubauer S, Kopke J, Haase A, Waller C, and Ertl G. Fast high-resolution magnetic resonance imaging demonstrates fractality of myocardial perfusion in microscopic dimensions. Circ Res 88: 340–346, 2001.[Abstract/Free Full Text]
- Belle V, Kahler E, Waller C, Rommel E, Voll S, Hiller KH, Bauer WR, and Haase A. In vivo quantitative mapping of cardiac perfusion in rats using a noninvasive MR spin-labeling method. J Magn Reson Imaging 8: 1240–1245, 1998.[ISI][Medline]
- Bergmann SR, Fox KA, Rand AL, McElvany KD, Welch MJ, Markham J, and Sobel BE. Quantification of regional myocardial blood flow in vivo with H215O. Circulation 70: 724–733, 1984.[Abstract/Free Full Text]
- Bertoldi D and Carlier PG. Letter to the editor. J Magn Reson Imaging 18: 515–516, 2003.[CrossRef][ISI][Medline]
- Bertoldi D, Von Euw D, Fromes Y, Wary C, and Carlier PG. Determination of skeletal muscle perfusion in mouse leg at rest with SATIR arterial spin labeling sequence. Proc 11th Meeting Int Soc Magn Reson Med, Toronto, 2003, p. 1519.
- Bertoldi D, Von Euw D, Fromes Y, Wary C, Leroy-Willig A, and Carlier PG. Different patterns of post-ischemic hyperemia identified by arterial spin labeling in mouse skeletal muscle (Abstract). MAGMA 16: S161, 2003.
- Brillault-Salvat C, Giacomini E, Jouvensal L, Wary C, Bloch G, and Carlier PG. Simultaneous determination of muscle perfusion and oxygenation by interleaved NMR plethysmography and deoxymyoglobin spectroscopy. NMR Biomed 10: 315–323, 1997.[CrossRef][ISI][Medline]
- Brillault-Salvat C, Giacomini E, Wary C, Peynsaert J, Jouvensal L, Bloch G, and Carlier PG. An interleaved heteronuclear NMRI-NMRS approach to non-invasive investigation of exercising human skeletal muscle. Cell Mol Biol (Noisy-le-grand) 43: 751–762, 1997.
- Brodal P, Ingjer F, and Hermansen L. Capillary supply of skeletal muscle fibers in untrained and endurance-trained men. Am J Physiol Heart Circ Physiol 232: H705–H712, 1977.[Abstract/Free Full Text]
- Buxton RB. Arterial spin labelling techniques. In: Introduction to Functional Magnetic Resonance Imaging Principles and Techniques. New York: Cambridge University Press, 2002, p. 351–387.
- Buxton RB, Frank LR, Wong EC, Siewert B, Warach S, and Edelman RR. A general kinetic model for quantitative perfusion imaging with arterial spin labeling. Magn Reson Med 40: 383–396, 1998.[ISI][Medline]
- Carlier PG. Multiparametric functional NMR of skeletal muscle: application to in vivo investigations of oxygen metabolism. MAGMA 14: 164–166, 2002.
- Carlier PG, Parzy E, Wary C, Richer C, Gilles RJ, Fromes Y, Vignaux O, Leroy-Willig A, and Le Roux P. Myocardial perfusion imaging using arterial spin labeling and optimized single-shot fast spin echo (SSFSE) in humans and in rats: first results. MAGMA 15: 104, 2002.
- Corbally MT and Brennan MF. Noninvasive measurement of regional blood flow in man. Am J Surg 160: 313–321, 1990.[ISI][Medline]
- Couffinhal T, Silver M, Zheng LP, Kearney M, Witzenbichler B, and Isner JM. Mouse model of angiogenesis. Am J Pathol 152: 1667–1679, 1998.[Abstract]
- Detre JA, Leigh JS, Williams DS, and Koretsky AP. Perfusion imaging. Magn Reson Med 23: 37–45, 1992.[ISI][Medline]
- Duffy SJ, New G, Tran BT, Harper RW, and Meredith IT. Relative contribution of vasodilator prostanoids and NO to metabolic vasodilation in the human forearm. Am J Physiol Heart Circ Physiol 276: H663–H670, 1999.[Abstract/Free Full Text]
- Duteil S, Bourilhon C, Raynaud JS, Wary C, Richardson RS, Leroy-Willig A, Jouanin JC, Guezennec CY, and Carlier PG. Metabolic and vascular support for the role of myoglobin in humans: a multiparametric NMR study. Am J Physiol Regul Integr Comp Physiol 287: R1441–R1449, 2004.[Abstract/Free Full Text]
- Engelke KA, Halliwill JR, Proctor DN, Dietz NM, and Joyner MJ. Contribution of nitric oxide and prostaglandins to reactive hyperemia in human forearm. J Appl Physiol 81: 1807–1814, 1996.[Abstract/Free Full Text]
- Feinstein SB. The powerful microbubble: from bench to bedside, from intravascular indicator to therapeutic delivery system, and beyond. Am J Physiol Heart Circ Physiol 287: H450–H457, 2004.[Abstract/Free Full Text]
- Fidler F, Wacker CM, Dueren C, Weigel M, Jakob PM, Bauer WR, and Haase A. Myocardial perfusion measurements by spin-labeling under different vasodynamic states. J Cardiovasc Magn Reson 6: 509–516, 2004.[CrossRef][ISI][Medline]
- Folkow B. The haemodynamic consequences of adaptive structural changes of the resistance vessels in hypertension. Clin Sci 41: 1–12, 1971.[ISI][Medline]
- Folkow B, Grimby G, and Thulesius O. Adaptive structural changes of the vascular walls in hypertension and their relation to the control of the peripheral resistance. Acta Physiol Scand 44: 255–272, 1958.[ISI][Medline]
- Frank LR, Wong EC, Haseler LJ, and Buxton RB. Dynamic imaging of perfusion in human skeletal muscle during exercise with arterial spin labeling. Magn Reson Med 42: 258–267, 1999.[CrossRef][ISI][Medline]
- Frohlich ED. Local hemodynamic changes in hypertension: insights for therapeutic preservation of target organs. Hypertension 38: 1388–1394, 2001.[Abstract/Free Full Text]
- Frouin F, Duteil S, Raynaud JS, Carlier PG, and Herment A. Automated extraction of muscular perfusion from NMR imaging with arterial spin labeling. MAGMA 15: 23, 2002.
- Gillies RJ. NMR in Physiology and Biomedicine. San Diego, CA: Academic, 1994.
- Golay X, Hendrikse J, and Lim TC. Perfusion imaging using arterial spin labeling. Top Magn Reson Imaging 15: 10–27, 2004.[CrossRef][Medline]
- Haacke EM, Brown RW, Thompson MR, and Venkatesan R. Magnetic Resonance Imaging. Physical Principles and Sequence Design. New York: Wiley-Liss, 1999.
- Hepple RT, Babits TL, Plyley MJ, and Goodman JM. Dissociation of peak vascular conductance and
O2 max among highly trained athletes. J Appl Physiol 87: 1368–1372, 1999.[Abstract/Free Full Text]
- Karger N, Biederer J, Lusse S, Grimm J, Steffens J, Heller M, and Gluer C. Quantitation of renal perfusion using arterial spin labeling with FAIR-UFLARE. Magn Reson Imaging 18: 641–647, 2000.[CrossRef][ISI][Medline]
- Kilbom A and Wennmalm A. Endogenous prostaglandins as local regulators of blood flow in man: effect of indomethacin on reactive and functional hyperaemia. J Physiol 257: 109–121, 1976.[Abstract/Free Full Text]
- Kim SG. Quantification of relative cerebral blood flow change by flow-sensitive alternating inversion recovery (FAIR) technique: application to functional mapping. Magn Reson Med 34: 293–301, 1995.[ISI][Medline]
- Kober F, Iltis I, Izquierdo M, Desrois M, Ibarrola D, Cozzone PJ, and Bernard M. High-resolution myocardial perfusion mapping in small animals in vivo by spin-labeling gradient-echo imaging. Magn Reson Med 51: 62–67, 2004.[CrossRef][ISI][Medline]
- Koyanagi S, Eastham CL, Harrison DG, and Marcus ML. Increased size of myocardial infarction in dogs with chronic hypertension and left ventricular hypertrophy. Circ Res 50: 55–62, 1982.[Free Full Text]
- Kubis N, Richer C, Domergue V, Giudicelli JF, and Levy BI. Role of microvascular rarefaction in the increased arterial pressure in mice lacking the endothelial nitric oxide synthase gene (eNOS3pt–/–). J Hypertens 20: 1581–1587, 2002.[CrossRef][ISI][Medline]
- Lebon V, Brillault-Salvat C, Bloch G, Leroy-Willig A, and Carlier PG. Evidence of muscle BOLD effect revealed by simultaneous interleaved gradient-echo NMRI and myoglobin NMRS during leg ischemia. Magn Reson Med 40: 551–558, 1998.[ISI][Medline]
- Liu HL, Kochunov P, Hou J, Pu Y, Mahankali S, Feng CM, Yee SH, Wan YL, Fox PT, and Gao JH. Perfusion-weighted imaging of interictal hypoperfusion in temporal lobe epilepsy using FAIR-HASTE: comparison with H215O PET measurements. Magn Reson Med 45: 431–435, 2001.[CrossRef][ISI][Medline]
- Lott ME, Hogeman CS, Vickery L, Kunselman AR, Sinoway LI, and MacLean DA. Effects of dynamic exercise on mean blood velocity and muscle interstitial metabolite responses in humans. Am J Physiol Heart Circ Physiol 281: H1734–H1741, 2001.[Abstract/Free Full Text]
- Mai VM, Hagspiel KD, Altes T, Goode AR, Williams MB, and Berr SS. Detection of regional pulmonary perfusion deficit of the occluded lung using arterial spin labeling in magnetic resonance imaging. Magn Reson Imaging 11: 97–102, 2000.[CrossRef][ISI][Medline]
- Mai VM, Hagspiel KD, Christopher JM, Do HM, Altes T, Knight-Scott J, Stith AL, Maier T, and Berr SS. Perfusion imaging of the human lung using flow-sensitive alternating inversion recovery with an extra radiofrequency pulse (FAIRER). Magn Reson Imaging 17: 355–361, 1999.[CrossRef][ISI][Medline]
- Marro KI and Kushmerick MJ. Skeletal muscle perfusion measurements using adiabatic inversion of arterial water. Magn Reson Med 38: 40–47, 1997.[ISI][Medline]
- Martirosian P, Klose U, Mader I, and Schick F. FAIR true-FISP perfusion imaging of the kidneys. Magn Reson Med 51: 353–361, 2004.[CrossRef][ISI][Medline]
- Masuda K, Okazaki K, Kuno S, Asano K, Shimojo H, and Katsuta S. Endurance training under 2,500-m hypoxia does not increase myoglobin content in human skeletal muscle. Eur J Appl Physiol 85: 486–490, 2001.[CrossRef][ISI][Medline]
- Meredith IT, Currie KE, Anderson TJ, Roddy MA, Ganz P, and Creager MA. Postischemic vasodilation in human forearm is dependent on endothelium-derived nitric oxide. Am J Physiol Heart Circ Physiol 270: H1435–H1440, 1996.[Abstract/Free Full Text]
- Mildner T, Trampel R, Moller HE, Schafer A, Wiggins CJ, and Norris DG. Functional perfusion imaging using continuous arterial spin labeling with separate labeling and imaging coils at 3 T. Magn Reson Med 49: 791–795, 2003.[CrossRef][ISI][Medline]
- Nahrendorf M, Hiller KH, Theisen D, Hu K, Waller C, Kaiser R, Haase A, Ertl G, Brinkmann R, and Bauer WR. Effect of transmyocardial laser revascularization on myocardial perfusion and left ventricular remodeling after myocardial infarction in rats. Radiology 225: 487–493, 2002.[Abstract/Free Full Text]
- Parkes LM, Rashid W, Chard DT, and Tofts PS. Normal cerebral perfusion measurements using arterial spin labeling: reproducibility, stability, and age and gender effects. Magn Reson Med 51: 736–743, 2004.[CrossRef][ISI][Medline]
- Pell GS, King MD, Proctor E, Thomas DL, Lythgoe MF, Gadian DG, and Ordidge RJ. Comparative study of the FAIR technique of perfusion quantification with the hydrogen clearance method. J Cereb Blood Flow Metab 23: 689–699, 2003.[CrossRef][ISI][Medline]
- Poncelet BP, Koelling TM, Schmidt CJ, Kwong KK, Reese TG, Ledden P, Kantor HL, Brady TJ, and Weisskoff RM. Measurement of human myocardial perfusion by double-gated flow alternating inversion recovery EPI. Magn Reson Med 41: 510–519, 1999.[CrossRef][ISI][Medline]
- Pretorius ES and Roberts DA. Continuous arterial spin-labeling perfusion magnetic resonance imaging of the human testis. Acad Radiol 11: 106–110, 2004.[CrossRef][ISI][Medline]
- Raynaud JS, Duteil S, Vaughan JT, Hennel F, Wary C, Leroy-Willig A, and Carlier PG. Determination of skeletal muscle perfusion using arterial spin labeling NMRI: validation by comparison with venous occlusion plethysmography. Magn Reson Med 46: 305–311, 2001.[CrossRef][ISI][Medline]
- Reeder SB, Atalay MK, McVeigh ER, Zerhouni EA, and Forder JR. Quantitative cardiac perfusion: a noninvasive spin-labeling method that exploits coronary vessel geometry. Radiology 200: 177–184, 1996.[Abstract/Free Full Text]
- Richardson RS, Haseler LJ, Nygren AT, Bluml S, and Frank LR. Local perfusion and metabolic demand during exercise: a noninvasive MRI method of assessment. J Appl Physiol 91: 1845–1853, 2001.[Abstract/Free Full Text]
- Roberts DA, Detre JA, Bolinger L, Insko EK, and Leigh JS Jr. Quantitative magnetic resonance imaging of human brain perfusion at 1.5 T using steady-state inversion of arterial water. Proc Natl Acad Sci USA 91: 33–37, 1994.[Abstract/Free Full Text]
- Roberts DA, Detre JA, Bolinger L, Insko EK, Lenkinski RE, Pentecost MJ, and Leigh JS Jr. Renal perfusion in humans: MR imaging with spin tagging of arterial water. Radiology 196: 281–286, 1995.[Abstract/Free Full Text]
- Schalla S, Wendland MF, Higgins CB, Ebert W, and Saeed M. Accentuation of high susceptibility of hypertrophied myocardium to ischemia: complementary assessment of gadophrin-enhancement and left ventricular function with MRI. Magn Reson Med 51: 552–558, 2004.[CrossRef][ISI][Medline]
- Sexton WL, Korthuis RJ, and Laughlin MH. Vascular flow capacity of hindlimb skeletal muscles in spontaneously hypertensive rats. J Appl Physiol 69: 1073–1079, 1990.[Abstract/Free Full Text]
- Shoemaker JK, Halliwill JR, Hughson RL, and Joyner MJ. Contributions of acetylcholine and nitric oxide to forearm blood flow at exercise onset and recovery. Am J Physiol Heart Circ Physiol 273: H2388–H2395, 1997.[Abstract/Free Full Text]
- Snell PG, Martin WH, Buckey JC, and Blomqvist CG. Maximal vascular leg conductance in trained and untrained men. J Appl Physiol 62: 606–610, 1987.[Abstract/Free Full Text]
- Steinberg HO and Baron AD. Vascular function, insulin resistance and fatty acids. Diabetologia 45: 623–634, 2002.[CrossRef][ISI][Medline]
- Street D, Bangsbo J, and Juel C. Interstitial pH in human skeletal muscle during and after dynamic graded exercise. J Physiol 537: 993–998, 2001.[Abstract/Free Full Text]
- Streif JU, Hiller KH, Waller C, Nahrendorf M, Wiesmann F, Bauer WR, Rommel E, and Haase A. In vivo assessment of absolute perfusion in the murine skeletal muscle with spin labeling MRI. Magnetic resonance imaging. J Magn Reson Imaging 17: 147–152, 2003.[CrossRef][ISI][Medline]
- Talagala SL, Ye FQ, Ledden PJ, and Chesnick S. Whole-brain 3D perfusion MRI at 3.0 T using CASL with a separate labeling coil. Magn Reson Med 52: 131–140, 2004.[CrossRef][ISI][Medline]
- Tempel C and Neeman M. Perfusion of the rat ovary: application of pulsed arterial spin labeling MRI. Magn Reson Med 41: 113–123, 1999.[CrossRef][ISI][Medline]
- Tempel C and Neeman M. Spatial and temporal modulation of perfusion in the rat ovary measured by arterial spin labeling MRI. J Magn Reson Imaging 9: 794–803, 1999.[CrossRef][ISI][Medline]
- Toussaint JF, Kwong KK, MKF, Weisskoff RM, LaRaia PJ, and Kantor HL. Interrelationship of oxidative metabolism and local perfusion demonstrated by NMR in human skeletal muscle. J Appl Physiol 81: 2221–2228, 1996.[Abstract/Free Full Text]
- Tyml K and Ellis CG. Simultaneous assessment of red cell perfusion in skeletal muscle by laser Doppler flowmetry and video microscopy. Int J Microcirc Clin Exp 4: 397–406, 1985.[ISI][Medline]
- Vanderthommen M, Duteil S, Wary C, Raynaud JS, Leroy-Willig A, Crielaard JM, and Carlier PG. A comparison of voluntary and electrically induced contractions by interleaved 1H- and 31P-NMRS in humans. J Appl Physiol 94: 1012–1024, 2003.[Abstract/Free Full Text]
- Vidal G, Giacomini E, Wary C, Juvet P, Emmanuel F, and Carlier PG. Combined ASL perfusion imaging, BOLD imaging and 31P NMR spectroscopy of the leg in a rat model of peripheral arteriopathy. Proc 11th Meeting Int Soc Magn Reson Med, Toronto, 2003, p. 1692.
- Wacker CM, Bock M, Hartlep AW, Beck G, van Kaick G, Ertl G, Bauer WR, and Schad LR. Changes in myocardial oxygenation and perfusion under pharmacological stress with dipyridamole: assessment using T*2 and T1 measurements. Magn Reson Med 41: 686–695, 1999.[CrossRef][ISI][Medline]
- Wacker CM, Fidler F, Dueren C, Hirn S, Jakob PM, Ertl G, Haase A, and Bauer WR. Quantitative assessment of myocardial perfusion with a spin-labeling technique: preliminary results in patients with coronary artery disease. J Magn Reson Imaging 18: 555–560, 2003.[CrossRef][ISI][Medline]
- Waller C, Hiller KH, Albrecht M, Hu K, Nahrendorf M, Gattenlohner S, Haase A, Ertl G, and Bauer WR. Microvascular adaptation to coronary stenosis in the rat heart in vivo: a serial magnetic resonance imaging study. Microvasc Res 66: 173–182, 2003.[CrossRef][ISI][Medline]
- Waller C, Hiller KH, Kahler E, Hu K, Nahrendorf M, Voll S, Haase A, Ertl G, and Bauer WR. Serial magnetic resonance imaging of microvascular remodeling in the infarcted rat heart. Circulation 103: 1564–1569, 2001.[Abstract/Free Full Text]
- Waller C, Kahler E, Hiller KH, Hu K, Nahrendorf M, Voll S, Haase A, Ertl G, and Bauer WR. Myocardial perfusion and intracapillary blood volume in rats at rest and with coronary dilatation: MR imaging in vivo with use of a spin-labeling technique. Radiology 215: 189–197, 2000.[Abstract/Free Full Text]
- Wang JJ, Hendrich KS, Jackson EK, Ildstad ST, Williams DS, and Ho C. Perfusion quantitation in transplanted rat kidney by MRI with arterial spin labeling. Kidney Int 53: 1783–1791, 1998.[CrossRef][ISI][Medline]
- Weber B, Westera G, Treyer V, Burger C, Khan N, and Buck A. Constant-infusion H215O PET and acetazolamide challenge in the assessment of cerebral perfusion status. J Nucl Med 45: 1344–1350, 2004.[Abstract/Free Full Text]
- Weber MA, Gunther M, Lichy MP, Delorme S, Bongers A, Thilmann C, Essig M, Zuna I, Schad LR, Debus J, and Schlemmer HP. Comparison of arterial spin-labeling techniques and dynamic susceptibility-weighted contrast-enhanced MRI in perfusion imaging of normal brain tissue. Invest Radiol 38: 712–718, 2003.[ISI][Medline]
- Wilke N, Jerosch-Herold M, Stillman AE, Kroll K, Tsekos N, Merkle H, Parrish T, Hu X, Wang Y, Bassingthwaighte J, et al. Concepts of myocardial perfusion imaging in magnetic resonance imaging. Magn Reson Q 10: 249–286, 1994.[ISI][Medline]
- Williams DS, Detre JA, Leigh JS, and Koretsky AP. Magnetic resonance imaging of perfusion using spin inversion of arterial water. Proc Natl Acad Sci USA 89: 212–216, 1992. [Corrigenda. Proc Natl Acad Sci USA 89: 1 May 1992, p. 4220.][Abstract/Free Full Text]
- Williams DS, Grandis DJ, Zhang W, and Koretsky AP. Magnetic resonance imaging of perfusion in the isolated rat heart using spin inversion of arterial water. Magn Reson Med 30: 361–365, 1993.[ISI][Medline]
- Williams DS, Zhang W, Koretsky AP, and Adler S. Perfusion imaging of the rat kidney with MR. Radiology 190: 813–818, 1994.[Abstract/Free Full Text]
- Wong EC, Buxton RB, and Frank LR. Quantitative perfusion imaging using arterial spin labeling. Neuroimaging Clin N Am 9: 333–342, 1999.[ISI][Medline]
- Wong EC, Buxton RB, and Frank LR. A theoretical and experimental comparison of continuous and pulsed arterial spin labeling techniques for quantitative perfusion imaging. Magn Reson Med 40: 348–355, 1998.[ISI][Medline]
- Yang Y, Frank JA, Hou L, Ye FQ, McLaughlin AC, and Duyn JH. Multislice imaging of quantitative cerebral perfusion with pulsed arterial spin labeling. Magn Reson Med 39: 825–832, 1998.[ISI][Medline]
- Ye F, Berman K, Ellmore T, Esposito G, van Horn J, Yang Y, Duyn J, Smith A, Frank J, Weinberger D, and McLaughlin A. H215O PET validation of arterial spin tagging measurements of cerebral blood flow in humans (Abstract). Proc Int Soc Magn Reson Med 1: 598, 1999.
- Zhao S, Snow RJ, Stathis CG, Febbraio MA, and Carey MF. Muscle adenine nucleotide metabolism during and in recovery from maximal exercise in humans. J Appl Physiol 88: 1513–1519, 2000.[Abstract/Free Full Text]
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ABSTRACT
PRINCIPLE OF PERFUSION...
), spontaneously hypertensive rats (solid lines) were unable to maintain a prolonged muscle vasodilation. *P 
0.05 between groups.