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Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Increases in shear stress promote coronary vasodilation by stimulating the production of nitric oxide (NO). Whether shear stress-induced NO production also limits vasoconstriction in the coronary microcirculation in vivo is unknown. Accordingly, we measured microvascular diameter and flow velocity in the beating heart along with estimated blood viscosity to calculate shear stress during vasoconstriction with endothelin or vasopressin. Measurements were repeated in the presence of NG-monomethyl-L-arginine (L-NMMA) to inhibit NO production and BQ-788 to block NO-linked endothelin type B receptors. BQ-788 did not augment steady-state constriction to endothelin, suggesting that NO production via activation of this receptor is inconsequential. L-NMMA potentiated constriction to both agonists, particularly in small arteries (inner diameter >120 µm). Shear stresses in small arteries were elevated during constriction and further elevated during constriction after L-NMMA. These observations suggest that NO production limits vasoconstriction in the coronary microcirculation and that the principal stimulus for this governance is elevated shear stress. The degree of shear stress moderation of constriction is heterogeneously distributed, with small arteries displaying a higher degree of shear stress regulation than arterioles. These results provide the strongest evidence to date that shear stress-mediated production of NO exerts a "braking" influence on constriction in the coronary microcirculation.
endothelin; coronary circulation; nitric oxide synthase
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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FACTORS THAT DETERMINE coronary perfusion remain to be unequivocally identified. Although chemical factors associated with cardiac metabolism undoubtedly play a major role, physical factors, notably shear stress, also contribute to the active regulation of microvascular resistance. Shear stress is determined by three variables: blood velocity, blood viscosity, and vascular diameter. When vessel diameter is reduced, or when blood velocity or viscosity is elevated, the shear stress imposed on the endothelium is increased (8). An increase in shear stress stimulates a variety of physiological pathways, most notably the generation of nitric oxide (NO). NO is a potent vasodilator, and thus tends to normalize shear stress and facilitate coronary vascular perfusion.
Because shear stress is inversely related to diameter, vasoconstriction may also promote the production of NO, which would act as a brake to limit reductions in diameter. Thus the shear stress-induced production of NO may prevent excessive vasoconstriction and, when operative, protect the heart during conditions such as coronary vasospasm. Such a mechanism could explain why the effects of vasoconstrictors are often exacerbated by NO inhibition (5, 12). The extent to which shear stress-induced production of NO limits vasoconstriction in the coronary microcirculation in vivo remains unknown.
The objective of this study was to test the hypothesis that shear stress-induced production of NO limits coronary microvascular constriction to the potent agonist endothelin. We measured constriction to endothelin at multiple levels of the coronary microvasculature with and without inhibition of NO synthase. These measurements were correlated with measurements of shear stress in the coronary microcirculation. Because endothelin also activates endothelin type B (ETB) receptors on the endothelium that stimulate the production of NO (13, 23), we also measured steady-state constriction in the presence and absence of the ETB receptor antagonist N-[N-[N-[(2,6-dimethyl-1-piperidinyl) carbonyl]-4-methyl-L-leucyl-1-(met-hoxycarbonyl)-D-tryptophyl]-D-norleucine monosodium (BQ-788). To demonstrate that the ameliorating effect of NO on constriction was applicable to other agonists, constriction to vasopressin as well as the effects on shear stress were also examined. To further show the importance of flow, and thus shear stress, in the NO-dependent modulation of coronary microvascular diameter, we measured the effect of NO synthase inhibition on the constriction of isolated coronary arterioles in the absence of flow.
We observed that constriction of coronary microvessels to both endothelin and vasopressin is enhanced by inhibition of NO production. In the presence of NG-monomethyl-L-arginine (L-NMMA), shear stress is markedly elevated relative to untreated constrictor conditions. In the absence of flow, the in vitro endothelin-induced constriction was unaffected by NO synthase inhibition. Thus augmentation of constriction appears to reflect the loss of flow-mediated or shear stress-induced production of NO rather than ETB receptor-stimulated production. Taken together, these findings support the hypothesis that NO modulates vasoconstriction in the coronary circulation in a manner consistent with shear stress-induced regulation.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Coronary Microvascular Preparation
Adult mongrel dogs (5-15 kg) were anesthetized with pentobarbital sodium (Nembutal; 30 mg/kg iv). A core body temperature of 37°C was maintained by placing the animals on a homeothermic blanket. The right femoral artery and vein were cannulated for measurements of aortic pressure and arterial blood gases and the administration of drugs, respectively. A 5-Fr fluid-filled catheter was advanced into the left ventricle (LV) from the left carotid artery to measure LV pressure. The first derivative of the LV pressure trace (LV dP/dt) was obtained by an on-line differentiator. Hemodynamic data were acquired continuously using ACODAS data acquisition software from Dataq (Akron, OH). A tracheotomy was performed, and ventilation was performed by high-frequency jet ventilation. With the use of the maximum LV dP/dt as a timing reference, a solenoid connected to a pressure source (100% O2, 6-12 psi) was triggered to open for 20-35 ms at the same time in each cardiac cycle. The small tidal volume minimizes respiratory movement, which occurs at the same frequency as the heartbeat. Arterial pH and blood gases were monitored frequently and maintained within the following ranges by adjustment of the tracheal catheter or by administration of sodium bicarbonate: PCO2 25-40 mmHg, PO2 100-200 mmHg, and pH 7.35-7.45. All animals routinely received propranolol (1 mg/kg), indomethacin (10 mg/kg), and the H1-histamine receptor antagonist diphenhydramine (1 mg/kg) to limit tissue motion, reduce inflammatory reactions, and prevent anaphylactic reactions to the high-molecular-weight dextrans, respectively.To visualize the epicardial surface, the heart was exposed by a left thoracotomy at the fifth intercostal space and stabilized in a partial pericardial cradle. A large coronary artery (left anterior descending or circumflex artery) was exposed, and a 24-gauge cannula was inserted to allow the measurement of coronary artery pressure and the administration of microspheres, intracoronary drugs, and fluorochromes. After an area of easily visible epicardial microvessels was identified, four 22-gauge pins were passed horizontally through the LV to minimize vertical cardiac motion. Neither maneuver appears to compromise coronary tone because resting blood flow or vasodilator reserve are unaffected in each case.
Measurement of Coronary Microvascular Diameter
To measure coronary microvascular diameter, the cardiac surface was illuminated by a stroboscope (100 W xenon arc, Chadwick-Helmuth; El Monte, CA), which was triggered by the maximum LV dP/dt signal to flash once for 20-30 µs at the same point during each cardiac cycle. The strobe trigger signal was monitored in relation with LV pressure for a precise determination of the position of the strobe in the cardiac cycle. The combined use of low-tidal volume jet ventilation and brief epicardial illumination both synchronized to the cardiac cycle cause the surface coronary microvessels to appear virtually motionless when viewed through an intravital microscope (Leitz Ploemopak). The microscope objectives used were the Leitz EF4 (×4, numerical aperture 0.22) and the Leitz L10 (×10, numerical aperture 0.22).To illuminate the inner diameters of the microvessels, 50- to 100-µl
aliquots of fluoroscein isothiocyanate-dextran (25 mg/ml) in 0.9%
saline (mol wt 500,000) were injected through the coronary cannula.
Representative measurements are shown in Fig.
1. A Leitz H2 excitation-barrier filter
was used to activate the fluoroscein and receive the emitted light.
Each injection causes arterial and venous vessels to fluoresce
sequentially for 5-10 s. The anatomic landmarks of a particular
vessel were identified, and five to eight were images obtained over a
period of <1 min using a Cohu silicon-intensified tube video camera
[Cohu intensified charged-coupled devide (CCD) camera]. The images
were digitized directly from the camera by a frame digitizer (Scion
Image, National Institutes of Health) and transferred to a Macintosh
computer (Apple Computer) for diameter measurements using appropriate
software (Image 2.18, National Institutes of Health Research Services
Branch). Diameters were measured by aligning cursors at the vessel
edges. Measurements in pixels were converted to micrometers using a
conversion factor determined from a micrometer grid. Typically,
microvascular measurements over each image acquisition period vary by
less than ±3% from the average value. Vessels were excluded from
analysis if control microvascular diameters after interventions varied
from the prior baseline by >10%.
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Measurement of Coronary Microvascular Velocity
A procedure similar to that designed by Nellis et al. (15) was utilized to measure flow velocities in the epicardial coronary microcirculation in vivo. The strobe was triple-flashed during a single video frame (33 ms for one complete video image); thus three images, separated in time (8 ms between flashes), are captured on the same video frame. The fluorescent particles appear three times in each image, and the velocity was calculated as the quotient of the distance moved by the microspheres and the time interval between strobe flashes. Fluorescent microspheres (10 µm, Fluoresbrite YG plain microspheres, Polyscience) suspended in a mixture of dilute fluorescein solution-0.9% saline were injected into the coronary artery, and images during a fixed interval of the cardiac cycle were obtained.Calculation of Shear Stress
Shear stress (tw) was calculated from measurements of the microvascular flow velocity (v), blood viscosity (
), and radius of the microvessel (r) by the formula
tw = (4 × v × )/r. Viscosity was estimated from an arterial blood
hematocrit and shear rate using the relationship described by Brooks et
al. (1). According to this relationship, when shear rates
exceed 50-100 s
1, variations in the hematocrit
observed in these studies have negligible effects on viscosity. Because
shear rates in this study exceeded this level even in the basal state,
we assumed that variations between the systemic and microvascular
hematocrits would have no significant effect on shear stress calculations.
Experimental Protocols
Experiments were divided into five separate protocols. In each experiment, the preparation was allowed to stabilize 15-30 min and basal diameters of each vessel were obtained. All animals were treated with indomethacin to eliminate potential effects of prostanoid production stimulated by endothelin (21, 22, 24). Animals were then introduced into one of the following protocols.Endothelin.
After baseline data were acquired, endothelin (2 ng · kg1 · min1 ic) was
infused for 45 min. Diameter measurements and hemodynamic data were
obtained at 15, 30, and 45 min. In a subset of experiments, shear-stress measurements were made at the 30 min time point.
Endothelin with L-NMMA.
After baseline measurements were acquired, L-NMMA (300 µg · kg1 · min1) was
infused for 20 min. Endothelin was then infused, and diameter measurements and hemodynamic data were obtained at 15, 30, and 45 min.
In a subset of experiments, shear stress measurements were made at the
30 min time point.
Endothelin with BQ-788. After baseline measurements were acquired, BQ-788 (25 µg/kg iv) was administered. Endothelin was then infused, and diameter measurements and hemodynamic data were obtained at 15, 30, and 45 min.
Vasopressin.
To demonstrate that the effects of L-NMMA on constriction
and shear stress were applicable to other agonists, vasopressin was
administed at a rate of 1 µg · kg1 · min1 ic.
Diameter measurements and hemodynamic data were obtained at 15 and 30 min. In a subset of experiments, shear stress measurements were made at
the 30 min time point. Measurements were taken in the presence and
absence of L-NMMA.
Elevated aortic pressure without endothelin.
After baseline measurements were acquired, aortic pressure was
increased by 40 mmHg (consistent with results from previous experiments; see Table 1) with an aortic
snare. Coronary microvascular diameter measurements and hemodynamic
data were obtained at 15 and 30 min.
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Isolate Arterioles
Coronary arterioles were isolated as previously described (10) and placed in ice-cold physiological saline solution (PSS) of the following composition (in mM): 145.0 NaCl, 4.7 KCl, 2.0 CaCl2, 1.17 MgSO4, 1.2 NaH2PO4, 5.0 glucose, 2.0 pyruvate, 0.02 EDTA, and 3.0 MOPS; the solution was buffered to pH 7.4 at 4°C and filtered (dissection buffer). A section of the myocardium was placed under a dissection microscope in a 4°C chamber, and vessels were carefully dissected free from the surrounding myocardial tissue and placed in dissection buffer containing 1% bovine serum albumin. The vessels were cannulated on both ends with micropipettes (outer diameter ~50 µm) connected to pressurized reservoirs filled with PSS buffered at pH 7.4 at 37°C. The height of these reservoirs was varied to obtain the desired intraluminal pressure (60 mmHg). Vessels that failed to maintain pressure were excluded from analysis. Internal diameter of coronary microvessel was measured under a CCD Camera (Sony CCD-IRIS) using a video-caliper system. The vessel was slowly warmed up to 37°C and allowed to develop spontaneous tone. Diameter changes in response to endothelin-1 (1010-108 M) were
measured in the absence or presence of L-NMMA (300 µM). Data are expressed as a percentage of the resting diameter.
Drugs
All drugs except indomethacin were dissolved in 0.9% saline solution. Indomethacin was dissolved in 95% ethanol and raised to a pH of 8.5 with 1 NaOH. The final concentration was diluted to 10 mg/ml with 0.9% saline. Propranolol, indomethacin, endothelin, and all buffer components were purchased from Sigma. BQ-788 and L-NMMA were purchased from RBI.Statistics
All statistics were performed on StatView software for Macintosh computers (Abacus Concepts; Berkeley, CA). Differences in shear stress, vascular diameter, and microvascular velocity were evaluated by ANOVA with Fisher's post hoc least significant difference test as the post hoc multiple comparison test. Data are presented as means ± SE and reported at the 30-min time point after endothelin infusion or occlusion of the aortic snare. Significance was accepted at P
0.05 in all experiments.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Preliminary Studies
To identify a vasoconstrictor concentration, endothelin was infused at rates of 2.5, 10, and 25 µg · kg1 · min1 ic. Doses
of 10 or 25 µg · kg1 · min1 produced
substantial reductions in coronary microvascular diameter, with spasm
of many vessels, ventricular tachycardia, and cardiac fibrillation. An
endothelin infusion of 2.5 µg · kg1 · min1 produced
a reduction in vascular diameter of ~10% at 30 min. This dose was
used in all studies to produce measureable constriction without the
complications of excessive vasoconstriction (e.g., loss of the animal).
Additional preliminary experiments assessed the reversibility of endothelin constriction. After 30 min of endothelin infusion, microvascular diameter decreased by 10 ± 3% (n = 3). The infusion was terminated, and vascular diameter was monitored for an additional 90 min. Despite 90 min of potential recovery, coronary microvessels remained constricted. This finding is consistent with the well-known tenacity of endothelin-induced constriction (3, 4, 19). On the basis of this observation, studies were performed in an unpaired fashion to avoid the effects of confounding changes in basal tone by previous doses of endothelin.
Effect of Experimental Treatments on Hemodynamics
The effects of the experimental interventions on heart rate and aortic pressure are shown in Table 1. None of the interventions affected heart rate, but aortic pressure was significantly increased during each infusion of endothelin. To account for this increase, we evaluated the effects of increasing aortic pressure at a constant heart rate on microvascular tone.Effect of Endothelin on Microvascular Diameter
The effects of endothelin on coronary microvascular tone are shown in Fig. 2. Endothelin caused progressive constriction over the duration of the experiment (45 min). Both the time course and degree of constriction were similar in arterioles (inner diameter <120 µm, 11 ± 3%) and small arteries (inner diameter >120 µm, 8 ± 3%).
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Effect of L-NMMA on Endothelin-Induced Vasoconstriction in Vivo
The effects of L-NMMA (300 µg · kg1 · min1 ic) on
endothelin-induced constriction in the coronary microcirculation are
shown in Fig. 3. L-NMMA (in
the presence of indomethacin) reduced baseline diameter by 15 ± 3 and 16 ± 2% in arterioles and small arteries (inner diameter
>120 µm), respectively. Data are expressed as percent
constriction from baseline with L-NMMA to account for the change in baseline conditions. After L-NMMA treatment,
the constrictor effect of endothelin was significantly enhanced in small arteries (32 ± 4 vs. 8 ± 3%, P < 0.0001) and arterioles (21 ± 7 vs. 11 ± 3%,
P < 0.005). The effect of L-NMMA on
endothelin-induced constriction was greater in small arteries versus
arterioles (P < 0.01).
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Effect of Vasopressin on Microvascular Diameter
The effects of vasopressin on coronary microvascular tone are shown in Fig. 4. Vasopressin elicited constriction in all calibers of vessel examined, and this constriction was augmented by L-NMMA (9 ± 3 vs 17 ± 3% at 30 min, P < 0.05).
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Effect of ETB Receptor Antagonism on Endothelin-Induced Vasoconstriction
To account for the direct stimulation of NO production by endothelial ETB receptors, steady-state coronary microvascular responses were observed in the presence of the ETB antagonist BQ-788. The results are shown in Fig. 5. BQ-788 caused a small constriction of both small arteries (7 ± 4%) and arterioles (6 ± 3%) under basal conditions. However, neither the time course nor the magnitude of endothelin-induced constriction was affected by inhibition of the ETB receptor.
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Effect of Elevated Aortic Pressure on Coronary Microvascular Diameter
A potential confounding variable in these experiments is the increase in aortic pressure with endothelin. Theoretically, this may lead to an autoregulatory constriction of the vessels. The effects of increasing aortic pressure by aortic snaring are shown in Fig. 6. Substantial dilation was observed during this procedure. This indicates that the vasoconstriction induced by endothelin in these studies reflects a direct action of endothelin on the vessels and not an indirect effect of elevated perfusion pressure.
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Effect of Vasoconstriction on Coronary Microvascular Shear Stress
The effects of the experimental conditions on microvascular shear stress are shown in Fig. 7. Vessels in each group ranged from an inner diameter of 120 to 180 µm to focus on the caliber of vessels in which augmented constriction was the most pronounced. Basal velocity and shear stress were 5.5 ± 1 mm/s and 9.7 ± 2 dyn/cm2, respectively (n = 8). Microvascular velocity was 13 ± 2 mm/s during endothelin infusion and 11 ± 2 mm/s after L-NMMA [n = 4, P = not significant (NS)]. Velocity during vasopressin infusion was 12 ± 2 mm/s before L-NMMA and 11 ± 3 mm/s after L-NMMA (n = 4, P = NS). Microvascular shear stress during vasoconstriction was significantly elevated with microvascular vasoconstriction (endothelin = 21 ± 3 dyn/cm2 and vasopressin = 21 ± 4 dyn/cm2, n = 4, P < 0.05 vs. basal in each). After L-NMMA treatment, a higher level of shear stress was observed during the vasoconstriction (endothelin = 30 ± 3 dyn/cm2 and vasopressin = 29 ± 3 dyn/cm2, n = 4, P < 0.05 vs. control infusions). These findings suggest that during vasoconstriction, the increase in shear stress induces the production of NO, mitigating the magnitude of the constriction. When NO production is inhibited, the ensuing constriction is augmented.
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Effect of L-NMMA on Endothelin-Induced Vasoconstriction in Vitro
The effect of inhibiting NO production on microvascular constriction to endothelin is shown in Fig. 8. Pretreatment with L-NMMA had no effect on the response to endothelin in either small arteries (Fig. 8A) or arterioles (Fig. 8B). At the end of each protocol, flow was elevated by generating a perfusion pressure difference of 10 mmHg (mean pressure = 60 mmHg). Vessels without L-NMMA dilated by 39 ± 11% to flow, but those treated with L-NMMA did not show dilation.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Our study provides the first evidence to date that shear stress-induced production of NO modulates vasoconstriction in the coronary microcirculation in vivo. This conclusion is based on the following findings: 1) endothelin- and vasopressin-induced constrictions are mitigated by shear stress-dependent NO production in coronary microvessels; 2) in the absence of flow, inhibition of NO production has no effect on endothelin-induced constriction; and 3) endothelin activation of ETB receptors plays no perceptible role in moderating coronary microvascular constriction to endothelin. There are some issues that bear on these findings and the attendant conclusion, including the methodology, regulation of tone by shear stress, and clinical implications.
Critique of Methodology
A number of caveats must be considered when assessing the results of this study. First, we studied epicardial microvessels exclusively. While cognizant of this limitation, we feel its impact on the current study is minimal for two reasons. Although differences in reactivity between endocardial and epicardial vessels have been reported (16-18), these differences are mainly a function of sensitivity and not signaling. Second, the goal of these studies was to determine whether shear stress induced production of NO regulated coronary vasoconstriction. To meet this objective, constriction is needed and, in this regard, both vasopressin and endothelin are effective in epicardial arterioles. We therefore feel that studies of the epicardial circulation are applicable to other portions of the coronary circulation.Another potential limitation is that we used only a single dose of the constrictors that produce moderate constriction. Higher doses than those used in these studies produce constriction of such vigor that the preparation becomes unstable or induces changes in blood pressure due to coronary overflow of the constrictor. Therefore, it is impractical to complete a full dose-response curve to endothelin or vasopressin. Moreover, to study potentiation of constriction after inhibition of NO synthase, a less than maximal dose of agonist is mandatory. Therefore, despite this potential limitation, we are confident in the conclusions.
It should also be noted that all studies were performed in the presence of cyclooxygenase inhibition with indomethacin. This intervention likely eliminated the contribution of shear stress-induced production of vasodilator prostaglandins in these experiments. In conjunction with NO, prostaglandins may play an important role in determining the effect of shear stress on vascular tone (9). Clearly, the role of prostanoids in this response warrants future study. Nonetheless, the results of these studies demonstrate that NO plays a critical role in modulating vasoconstriction in the coronary microcirculation.
Shear Stress-Induced Regulation of Coronary Vasoconstriction
The modulation of endothelin-induced vasoconstriction by NO is a well-documented phenomenon in the coronary circulation (6, 11). Conventionally, two distinct potential explanations existed in the literature before our study: 1) the concomitant activation of ETA and ETB receptors, of which the latter can augment production of NO directly or 2) by increased shear stress, and thus NO production caused by vasoconstriction. Our results allow resolution between these two possibilities.Blockade of ETB receptors during administration of endothelin did not augment steady-state constriction. Also, blockade of NO production in the absence of flow in vitro did not potentiate endothelin-induced constriction. On the basis of these observations, we conclude that the ETB receptor-stimulated production of NO is not the source of NO modulating endothelin-induced constriction in vivo.
Alternatively, our results support the idea that endothelin- or vasopressin-induced vasoconstriction increases shear stress, which then stimulates NO production to "brake" the constriction. It follows that blockade of endothelial NO synthase unfetters the vasoconstrictor response because the increase in shear stress no longer increases NO production. Indeed, we observed that vasoconstriction increased shear stress and that the increase was exacerbated after blockade of NO synthesis. Small arteries constricted to a greater degree than arterioles. This is consistent with the pattern of shear-stress regulation that we (20) reported previously, in which regulation of shear stress in vivo occurs to a much larger extent in small arteries than in coronary arterioles. Taken together, these observations support the concept that the effect of vasoconstrictors on coronary microvessels in vivo is the balance of direct constriction and shear stress-induced NO-mediated vasodilation.
Clinical Implications
Coronary artery disease is associated with impaired NO production. Interestingly, the diseased coronary circulation displays augmented responses to several vasoconstrictor stimuli including the cold pressor test (14),
-adrenergic stimulation (7), serotonergic stimulation (2), and endothelin
administration (11). These observations suggest that the
progression of coronary disease is associated with increased
constriction and impaired NO production. Our results suggest that
coronary vasoconstriction is opposed by shear stress-induced production
of NO. This mechanism is not a function of the vasoconstrictor itself
but a response to the increasing shear stress resulting from reductions
in diameter. By linking modulation of constriction to shear stress, the
heart employs a mechanism that allows a broad spectrum of protection, which, when impaired by the progression of vascular disease, may increase the risk of spastic interruptions in coronary blood flow.
Taken together, these studies suggest that the source of NO opposing coronary vasoconstriction of resistance vessels is not secondary to receptor stimulation but is primarily due to NO production caused by elevations in shear stress. These studies provide the strongest evidence to date that shear stress moderates vasoconstriction in the coronary microcirculation in vivo.
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ACKNOWLEDGEMENTS |
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The authors are grateful for the expert technical assistance of Deron W. Jones in the completion of these experiments.
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FOOTNOTES |
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Support was provided by an American Heart Association grant-in-aid (to D. W. Stepp and to Y. Nishikawa) and by National Heart, Lung, and Blood Institute Grant HL-32788 (to W. M. Chilian).
Address for reprint requests and other correspondence: D. W. Stepp, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: dstepp{at}mcw.edu).
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.
Received 8 August 2000; accepted in final form 5 April 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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4 animals in each group).