AJP - Heart Calcium Transients and Cell-Sarcomere
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 284: H2405-H2411, 2003. First published February 21, 2003; doi:10.1152/ajpheart.00879.2002
0363-6135/03 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
284/6/H2405    most recent
00879.2002v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (9)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Farouque, H. M. O.
Right arrow Articles by Meredith, I. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Farouque, H. M. O.
Right arrow Articles by Meredith, I. T.
Vol. 284, Issue 6, H2405-H2411, June 2003

Relative contribution of vasodilator prostanoids, NO, and KATP channels to human forearm metabolic vasodilation

H. M. Omar Farouque and Ian T. Meredith

Cardiovascular Research Centre, Monash Medical Centre and Monash University, Melbourne 3168, Victoria, Australia


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Isolated ATP-sensitive K+ (KATP) channel inhibition with glibenclamide does not alter exercise-induced forearm metabolic vasodilation. Whether forearm metabolic vasodilation would be influenced by KATP channel inhibition in the setting of impaired nitric oxide (NO)- and prostanoid-mediated vasodilation is unknown. Thirty-seven healthy subjects were recruited. Forearm blood flow (FBF) was assessed using venous occlusion plethysmography, and functional hyperemic blood flow (FHBF) was induced by isotonic wrist exercise. Infusion of NG-monomethyl-L-arginine (L-NMMA), aspirin, or the combination reduced resting FBF compared with vehicle (P < 0.05). Addition of glibenclamide to L-NMMA, aspirin, or the combination did not further reduce resting FBF. L-NMMA decreased peak FHBF by 26%, and volume was restored after 5 min (P < 0.05). Aspirin reduced peak FHBF by 13%, and volume repaid after 5 min (P < 0.05). Coinfusion of L-NMMA and aspirin reduced peak FHBF by 21% (P < 0.01), and volume was restored after 5 min (P < 0.05). Addition of glibenclamide to L-NMMA and aspirin did not further decrease FHBF. Vascular KATP channel blockade with glibenclamide does not affect resting FBF or FHBF in the setting of NO and vasodilator prostanoid inhibition.

blood flow; exercise hyperemia; ion channels; vasoregulation


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

DESPITE MANY YEARS OF STUDY, the control mechanisms underlying skeletal muscle blood flow at rest and with exercise are not clearly understood. Early investigators proposed that local muscle metabolites and ions, including lactate, adenine nucleotides, and K+, were important but that other determinants, such as decreased tissue O2 tension and pH, increased CO2 tension, and osmolarity, may also modulate blood flow (34). Methodological advances, including development of pharmacological modulators and analytic techniques, have enabled us to gain further insights. Specifically, there is a growing body of evidence implicating endothelium-derived vasoactive factors and ion channels in the regulation of vascular tone (12, 13, 19, 20, 29, 37). It is apparent that multiple factors are involved, but their relative roles may vary between species, vascular beds, and the nature of the exercise stimulus.

The ATP-sensitive K+ (KATP) channel is a distinct type of K+ channel that is metabolically regulated and has a ubiquitous distribution (38). It has been found in the vascular smooth muscle cells of a variety of mammalian species, including humans (23). The activity of KATP channels is determined by many factors, including the intracellular metabolic milieu. In this way, KATP channels provide a potential link between cellular metabolism and vascular tone through their effects on membrane potential. Recently, we demonstrated that isolated vascular KATP channel blockade does not attenuate resting blood flow or exercise-induced hyperemia in the human forearm (17). These findings suggest that vascular KATP channels in the human forearm may not play a critical role in exercise-induced hyperemia under optimal conditions. However, it remains possible that "upregulation" of parallel vasodilator systems may have compensated for KATP channel inhibition, leading to maintenance of blood flow, as has been described in the canine coronary circulation (29). Accordingly, this study was undertaken to examine the interplay between KATP channels and endothelium-derived vasoactive factors in the control of forearm skeletal muscle blood flow by sequential inhibition of vasodilator prostanoids, nitric oxide (NO), and KATP channels.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects

A total of 37 healthy subjects (mean age 24 ± 5 yr, 19 male and 18 female) were recruited for the study. Baseline characteristics are displayed in Table 1. Subjects were asked to refrain from alcohol and caffeine for 24 h before the procedure, and none were taking vasoactive medication. The study was approved by the Southern Health Human Research Ethics Committee, and written informed consent was obtained from all subjects.

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Clinical characteristics of study population

General Methods

Plethysmographic studies were performed in a climate-controlled vascular research laboratory after an overnight fast. Brachial arterial cannulation was performed under local anesthesia. Physiological solutions (0.9% saline or 5% dextrose) were infused at 0.4 ml/min through a 20-gauge, 5-cm polyethylene catheter (Cook, Brisbane, Australia) by computerized syringe pump (Terumo, Tokyo, Japan) for >= 30 min before the first blood flow recording. Intra-arterial blood pressure was monitored throughout the study.

Hemodynamic Measurements

Bilateral forearm blood flow (ml · 100 ml-1 · min-1) was measured by venous occlusion plethysmography using calibrated mercury-in-Silastic strain gauges (D. E. Hokanson, Bellevue, WA). Hand blood flow was prevented by inflation of a wrist cuff to a pressure of 200 mmHg during forearm blood flow recordings. Resting blood flow was measured for >= 2 min, and an average of at least five stable recordings was used for analysis. Forearm metabolic vasodilation (functional hyperemia) was induced by 2 min of rhythmic nonischemic wrist flexion-extension exercise at 45 cycles per minute, in time with a metronome, as previously described (12, 17). We previously showed that this form of exercise induces reproducible hyperemic responses (12). Forearm blood flow was measured for 5 min after cessation of exercise, allowing construction of a flow vs. time curve. Peak functional hyperemic blood flow (FHBF) was determined, and the volume repaid to the forearm at 1 and 5 min was estimated from the area under the flow vs. time curve. The absolute increase in peak FHBF (Delta peak FHBF) and volumes repaid were calculated by subtraction of resting forearm blood flow immediately before exercise from peak FHBF and total volume restored at 1 and 5 min. The absolute values were calculated to account for variations in baseline forearm blood flow. Forearm blood flow was expressed as milliliters per 100 ml of forearm tissue per minute, and forearm vascular resistance (mmHg · ml-1 · 100 ml forearm tissue-1 · min) was calculated by dividing mean arterial pressure by forearm blood flow.

Drug Infusion Protocols

Glibenclamide lyophilisate (kindly supplied by Aventis Pharma Deutschland) was dissolved in isotonic saline and infused into the brachial artery at 15 µg/min. This agent has been used in similar infusion regimens to inhibit vascular KATP channels in the human forearm (4, 18). Aspirin (Aspisol, Bayer) was diluted in dextrose and infused at 3 mg/min to inhibit cyclooxygenase. It was expected, on the basis of previous work from our laboratory, that this dose would reduce net forearm prostacyclin production in the resting state by ~70% and resting forearm blood flow by ~20% (13). NG-monomethyl-L-arginine (L-NMMA; Clinalfa), an NO synthase inhibitor, was infused at 2 mg/min, as in previous studies (21, 37). All drugs were infused at 0.4 ml/min by computerized syringe pump.

Experimental Protocols

To examine the relative contributions of KATP channels, the vasodilator prostanoids, and NO to resting forearm blood flow and metabolic vasodilation, three experimental protocols were devised (Fig. 1). All drugs were administered for >= 10 min before the first blood flow measurement was recorded. Drug infusions were continued during forearm exercise and the assessment of functional hyperemia. Fasting blood samples were taken for measurement of serum glucose, insulin, and C-peptide levels before and after glibenclamide infusion. In experimental protocols 1, 2, and 3, a sample size of 16, 9, and 7 subjects, respectively, would provide 80% power to detect a 30% change in 5-min hyperemic volume at the 5% significance level.


View larger version (19K):
[in this window]
[in a new window]
  		Fig. 1.   Outline of protocols 1-3. A: protocol 1; B: protocol 2; C: protocol 3. Blood flow was measured at rest and after isotonic forearm exercise [functional hyperemic blood flow (FHBF)] during saline infusion (vehicle). An identical series of measurements was performed during drug infusions. L-NMMA, NG-monomethyl-L-arginine.

Protocol 1 (n = 17). To assess the effect of KATP channel blockade on forearm blood flow after inhibition of local prostanoid synthesis, resting blood flow and functional hyperemia were measured after vehicle infusion, aspirin infusion, and, finally, the combination of aspirin and glibenclamide.

Protocol 2 (n = 10). The effect of KATP channel blockade on forearm blood flow after inhibition of NO synthesis was examined by measuring basal blood flow and FHBF after vehicle, L-NMMA infusion, and the combination of L-NMMA and glibenclamide.

Protocol 3 (n = 10). The effect of KATP channel blockade on forearm blood flow after inhibition of prostacyclin and NO synthesis was examined by measuring basal blood flow and FHBF after vehicle, coinfusion of L-NMMA and aspirin, and then infusion of aspirin, L-NMMA, and glibenclamide.

Statistical Analysis

Baseline characteristics are presented as means ± SD. Other data are expressed as means ± SE. Repeated-measures analysis of variance with robust standard errors was used to compare physiological data during vehicle and drug (single and combined) infusions. The paired Student's t-test was used to compare biochemical data. Statistical significance was accepted if P < 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Effect of Aspirin and Glibenclamide on Forearm Blood Flow

Intra-arterial infusion of aspirin reduced resting forearm blood flow by 22% (from 2.3 ± 0.2 to 1.8 ± 0.2 ml · 100 ml-1 · min-1, P < 0.05; Table 2). There was an associated 36% increase in forearm vascular resistance (P < 0.05). Coinfusion of glibenclamide did not result in any additional change in resting forearm blood flow or vascular resistance (Table 2).

                              
View this table:
[in this window]
[in a new window]
  		Table 2.   Effect of aspirin and combination of aspirin and glibenclamide on exercise hemodynamics

Aspirin infusion produced a 13% reduction in peak FHBF, which remained significant after the decrease in basal forearm blood flow was taken into account (P < 0.05; Table 2). There was a corresponding 16% increase in minimum forearm vascular resistance (P < 0.05). A trend to reduction in total and absolute hyperemic volume at 1 min was noted; it attained significance by 5 min.

Addition of glibenclamide to aspirin did not further alter exercise blood flow parameters (Table 2). Glibenclamide did not alter serum glucose levels (5.1 ± 0.1 and 5.1 ± 0.1 mmol/l), but insulin increased by 51% (from 6.1 ± 0.7 to 9.2 ± 1.0 mU/l, P < 0.0001) and C-peptide by 16% (from 0.6 ± 0.1 to 0.7 ± 0.1 nmol/l, P = 0.001). Contralateral forearm blood flow and mean arterial blood pressure did not change significantly during drug infusions.

Effect of L-NMMA and Glibenclamide on Forearm Blood Flow

Infusion of L-NMMA decreased resting forearm blood flow by 37% (from 2.7 ± 0.4 to 1.7 ± 0.2 ml · 100 ml-1 · min-1, P < 0.05; Table 3) and increased basal forearm vascular resistance by 60% (from 40.8 ± 6.3 to 65.9 ± 9.4 mmHg · ml-1 · 100 ml-1 · min, P < 0.05). When glibenclamide was combined with L-NMMA, no further reduction in resting forearm blood flow was noted compared with L-NMMA alone (Table 3). The mean value after combined infusion was not significantly different from that after L-NMMA alone.

                              
View this table:
[in this window]
[in a new window]
  		Table 3.   Effect of L-NMMA and combination of L-NMMA and glibenclamide on exercise hemodynamics

L-NMMA reduced peak FHBF by 26% (from 17.0 ± 2.3 to 12.6 ± 1.0 ml · 100 ml-1 · min-1) and increased minimum forearm vascular resistance by 23% (from 6.4 ± 0.9 to 7.9 ± 0.7 mmHg · ml-1 · 100 ml-1 · min, P < 0.05 for both parameters; Table 3). L-NMMA significantly reduced total hyperemic volume at 1 and 5 min by 22 and 30%, respectively.

Coinfusion of glibenclamide and L-NMMA did not further attenuate functional hyperemia (Table 3). Glibenclamide did not significantly alter serum glucose (5.0 ± 0.1 and 4.8 ± 0.1 mmol/l) but did increase insulin by 49% (from 5.0 ± 0.7 to 9.1 ± 1.2 mU/l, P = 0.002) and C-peptide by 23% (from 0.6 ± 0.1 to 0.8 ± 0.1 nmol/l, P = 0.01). Systemic hemodynamic parameters did not change significantly during the study.

Effect of Triple Drug Infusion on Forearm Blood Flow

Compared with vehicle infusion, the combination of L-NMMA and aspirin reduced resting forearm blood flow by 28% (from 1.8 ± 0.1 to 1.3 ± 0.1 ml · 100 ml-1 · min-1) and increased basal forearm vascular resistance by 28% (from 52.1 ± 3.5 to 72.2 ± 5.6 mmHg · ml-1 · 100 ml-1 · min, P < 0.05 for both parameters; Table 4). Addition of glibenclamide to the combination of aspirin and L-NMMA did not result in any additional change in these resting parameters (Table 4).

                              
View this table:
[in this window]
[in a new window]
  		Table 4.   Effect of aspirin and L-NMMA and combination of L-NMMA, aspirin, and glibenclamide on exercise hemodynamics

Infusion of L-NMMA with aspirin reduced peak FHBF by 21% (from 14.1 ± 1.2 to 11.2 ± 0.6 ml · 100 ml-1 · min-1, P < 0.05; Table 4) and increased minimum forearm vascular resistance by 19% (from 6.5 ± 0.7 to 8.0 ± 0.6 mmHg · ml-1 · 100 ml-1 · min, P < 0.05). There was a trend to reduction in total hyperemic volume at 1 min; it was significant by 5 min.

Addition of glibenclamide did not decrease functional hyperemia to a greater extent than the combination of L-NMMA and aspirin (Table 4). There was no change in serum glucose (4.9 ± 0.2 and 4.9 ± 0.1 mmol/l), but insulin increased by 28% (from 7.6 to 9.8 mU/l, P = 0.047) and C-peptide by 13% (from 0.6 ± 0.1 to 0.7 ± 0.1 nmol/l, P = 0.12). Mean arterial blood pressure and contralateral forearm blood flow did not change significantly during the study.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

In this study, we demonstrate that brachial arterial infusion of aspirin and L-NMMA, alone or in combina tion, produces a decrease in resting forearm blood flow and exercise-induced functional hyperemia. However, addition of glibenclamide to aspirin or L-NMMA, or a combination thereof, did not result in a greater reduction of resting forearm blood flow or functional hyperemia. These findings imply that vascular KATP channels do not contribute to exercise-induced functional hyperemia in the forearm circulation after inhibition of NO and prostanoid synthesis. Furthermore, our observations confirm that NO and the vasodilator prostanoids are important participants in regulation of forearm blood flow.

Basic Mechanisms of Vasodilation

In a previous report from our laboratory, isolated KATP channel inhibition did not decrease forearm blood flow (17). We hypothesized that parallel vasodilator systems may have compensated for KATP channel inhibition, resulting in maintenance of forearm blood flow at rest and during metabolic vasodilation. The other vasodilator pathways examined in this study were those leading to the synthesis of NO and the vasodilator prostanoids. The primary physiological action of NO is through activation of the cytosolic soluble guanylate cyclase, leading to an increase in cGMP and smooth muscle cell relaxation. In contrast, the vasodilator prostanoids (primarily prostacyclin) produce smooth muscle cell relaxation by receptor-mediated activation of adenylate cyclase, leading to an elevation of intracellular cAMP. Thus both of these important vasoactive substances lead to vasorelaxation through different signaling pathways. K+ channel activation is thought to represent the third fundamental mechanism of vasorelaxation by causing smooth muscle cell membrane hyperpolarization (25). A number of vasodilator substances may lead to hyperpolarization by opening KATP channels, including NO and prostacyclin in some instances (10, 30, 43). For these reasons, we chose to inhibit the activity of these three distinct vasodilator pathways to examine their contribution to vascular tone.

Concept of "Redundant" Vasodilator Pathways

It is apparent that several independent vasodilator pathways contribute to the maintenance of vascular tone and blood flow to cardiac and skeletal muscle. The existence of parallel systems is likely to be advantageous in the regulation of organ blood flow. Specifically, activation of a parallel or backup system to ensure continuity of vasomotor control may compensate for the malfunction of one system due to disease (9). Similar considerations may apply in the experimental setting when the contribution of these pathways to blood flow regulation is assessed. Inhibition of a single regulatory mechanism may lead to erroneous conclusions, inasmuch as increased activation or upregulation of alternative vasodilator systems may obscure the role of the inhibited pathway (34).

There are many examples of such interactions. In a canine model, the isolated inhibition of NO synthesis did not reduce basal coronary blood flow (29). However, in the setting of KATP channel inhibition and adenosine receptor blockade, inhibition of NO synthesis reduced resting coronary blood flow. These results suggest that NO may contribute to basal coronary blood flow regulation in dogs when the activities of other vasodilator systems are impaired. In further experiments by this group of investigators, the blockade of KATP channels alone did not limit exercise-induced coronary vasodilation in dogs. However, the subsequent addition of adenosine receptor blockade, alone or in combination with an NO synthase inhibitor, resulted in attenuation of exercise-induced metabolic vasodilation (14, 29). Along similar lines, a greater dependency on prostanoid-induced vasodilation has been noted in NO synthase knockout mice (8, 22). Other studies have shown that NO may inhibit the production of an endothelium-derived hyperpolarizing factor (2, 39). Thus, in the presence of impaired NO synthesis, vasodilator function may be maintained by endothelium-derived hyperpolarizing factor.

Relative Contribution of KATP Channels to Forearm Blood Flow

Our data suggest that vascular KATP channels do not contribute to resting blood flow or functional hyperemia in the forearm under conditions of impairment in NO- and prostanoid-dependent vasodilation. There are several potential explanations for these findings. Inadequate inhibition of alternative vasodilator pathways could explain the lack of impact of glibenclamide infusion on forearm blood flow. However, the dose of L-NMMA used in this study (2 mg/min) is known to attenuate acetylcholine-induced hyperemia (12), a commonly used measure of NO-related vasodilation. Furthermore, the observed fall in resting forearm blood flow during L-NMMA infusion attests to the reduction in bioavailability of NO. Previous work from our laboratory indicates that aspirin as administered in this study (3 mg/min) reduces production of 6-ketoprostaglandin F1alpha (a stable metabolite of prostacyclin) in association with a fall in forearm blood flow (13). These data, in addition to the reduction noted in basal forearm blood flow with aspirin infusion, indicate adequate inhibition of vasodilator prostanoid synthesis.

The effects of adenosine and endothelium-derived hyperpolarizing factor were not inhibited in this study. Intra-arterial aminophylline and potassium chloride infusions have been used previously to examine the role of these mediators in the forearm (24, 35). In theory, the added inhibition of one or the other of these vasoactive substances may have altered our results. However, aminophylline and potassium chloride are not ideal pharmacological tools, inasmuch as they have nonspecific effects that may complicate interpretation of the results (24, 35). Glibenclamide caused small increases in insulin levels in all study protocols. The vasodilator action of insulin may have offset any vasoconstriction induced by KATP channel inhibition. This is, however, unlikely, inasmuch as its vasodilator effects are mediated by NO (41), which was also inhibited by infusion of L-NMMA in protocols 2 and 3. The levels of insulin in the present study were in the low physiological range and unlikely to have produced vasoactive effects. Moreover, in previous forearm studies, we found no correlation between baseline insulin levels and resting or exercise-induced forearm blood flow responses (unpublished observations).

Resting Blood Flow

Our observations indicate that vasodilator prostanoids and NO contribute to resting skeletal muscle blood flow and exercise-induced functional hyperemia in healthy humans. The early investigations assessing the role of prostanoids in forearm blood flow regulation used orally administered cyclooxygenase inhibitors (5, 6, 32). These studies did not support a role for prostaglandins in the control of basal forearm blood flow. Recent studies have employed brachial arterial infusion of cyclooxygenase inhibitors and have demonstrated significant reductions in basal blood flow of 12-30%, most likely related to more effective blockade of local prostanoid synthesis than in earlier studies (13, 45). These findings are also consistent with data from animal studies examining resting skeletal muscle blood flow (3, 46).

The involvement of NO is also in keeping with the results of experimental studies in resting skeletal muscle (16) and previous investigations conducted in the human forearm (21). These studies demonstrate consistent reductions in blood flow of 25-50% after brachial arterial L-NMMA infusion. However, adenosine does not appear to play an important role in regulating resting skeletal muscle blood flow in animals (33) or in the forearm of healthy humans (5).

Functional Hyperemia

The findings of this study indicate that endothelium-mediated vascular control mechanisms are important during functional hyperemia in human skeletal muscle vasculature. The endothelium is able to release a number of paracrine vasodilator factors, such as NO and prostacyclin. The release of these mediators may be stimulated by forces exerted by flowing blood acting on the endothelium (shear stress) or in response to neurohumoral influences such as acetylcholine, adenine nucleotides, and bradykinin (7).

In this study, infusion of aspirin reduced the initial and sustained phases of functional hyperemia. Peak forearm blood flow was reduced by 13% and blood volume repaid after 5 min by 13%. These changes remained significant when the fall in basal forearm blood flow was taken into account. The magnitude of reduction was slightly less than with L-NMMA infusion, although this may in part be a dose-related phenomenon. These changes are in line with results of previous human studies (12, 32, 42, 45). Prostaglandin-like substances have been found in the venous effluent of exercising muscle in dogs and appear to contribute to hyperemia during and after exercise (26). However, contrary findings have been reported from other canine studies (3, 46). Several (12, 15, 21, 31, 42), but not all (44), previous reports indicate that NO is an important mediator of exercise-induced hyperemia in the forearm of healthy humans. There is also supportive experimental evidence that NO-mediated vasodilation in skeletal muscle contributes to exercise hyperemia (27, 28, 36). Our observations are consistent with these reports. There was a significant 25% reduction in peak FHBF and a 30% decrease in blood volume restored at 5 min after NO synthase inhibition. The magnitude of reduction is consistent with that reported in previous studies using the same methodology (11, 12, 42). When the decrease in resting blood flow was taken into account, the changes in functional hyperemia were no longer significant but did show a trend to reduction at 5 min. This was most likely due to the relatively small number of subjects recruited in this protocol. The persistent hyperemia after aspirin and L-NMMA infusion indicates that factors in addition to NO and vasodilator prostanoids are involved in the maintenance of FHBF under normal conditions.

KATP Channels and Vasoregulation

The present findings suggest that KATP channels may not be active in the vasculature of the human forearm at rest or during functional hyperemia. However, this may not be the case in other circulatory beds. We recently demonstrated that KATP channels may be involved in the regulation of coronary blood flow in humans at rest and during metabolic vasodilation (19, 20). These observations indicate that there are differences in the importance of vascular regulatory mechanisms between peripheral and coronary circulations. Although similarities may exist in cellular mechanisms of vascular regulation within skeletal and cardiac muscle, each tissue and associated vascular bed clearly has unique characteristics. Recent data suggest that KATP channels exhibit structural heterogeneity in terms of their molecular composition (40). The implications of these observations for channel function are unknown, but it is conceivable that unique subtypes of KATP channels with different functional characteristics are expressed in the coronary compared with the skeletal muscle circulation. There is also evidence to suggest that the density of sulfonylurea receptors, a component of the KATP channel, is greater in some tissues than in others (1).

Conclusion

The data suggest that vascular KATP channels in forearm skeletal muscle vasculature of healthy subjects do not modulate basal blood flow or exercise-induced hyperemia in the setting of impaired prostanoid- and NO-mediated vasodilation. These findings imply that KATP channels do not appear to play an important role in regulation of forearm blood flow during functional hyperemia. The results of this study also indicate that NO and vasodilator prostanoids are significant contributors to the regulation of forearm blood flow; however, additional mechanisms are clearly involved.


    ACKNOWLEDGEMENTS

The authors thank Michael Zhang and Mauro Baldi for technical assistance.


    FOOTNOTES

H. M. O. Farouque was supported by a National Heart Foundation of Australia Medical Postgraduate Research Scholarship.

Address for reprint requests and other correspondence: I. T. Meredith, Cardiovascular Research Centre, Monash Medical Centre, 246 Clayton Rd., Clayton, Melbourne 3168, Victoria, Australia (E-mail: ian.meredith{at}med.monash.edu.au).

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.

First published February 21, 2003;10.1152/ajpheart.00879.2002

Received 4 October 2002; accepted in final form 6 February 2003.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Ashcroft, SJ, and Ashcroft FM. The sulfonylurea receptor. Biochim Biophys Acta 1175: 45-59, 1992[Medline].

2.   Bauersachs, J, Popp R, Hecker M, Sauer E, Fleming I, and Busse R. Nitric oxide attenuates the release of endothelium-derived hyperpolarizing factor. Circulation 94: 3341-3347, 1996[Abstract/Free Full Text].

3.   Beaty, O, III, and Donald DE. Contribution of prostaglandins to muscle blood flow in anesthetized dogs at rest, during exercise, and following inflow occlusion. Circ Res 44: 67-75, 1979[Abstract/Free Full Text].

4.   Bijlstra, PJ, Lutterman JA, Russel FG, Thien T, and Smits P. Interaction of sulphonylurea derivatives with vascular ATP-sensitive potassium channels in humans. Diabetologia 39: 1083-1090, 1996[Web of Science][Medline].

5.   Carlsson, I, Sollevi A, and Wennmalm A. The role of myogenic relaxation, adenosine and prostaglandins in human forearm reactive hyperaemia. J Physiol 389: 147-161, 1987[Abstract/Free Full Text].

6.   Carlsson, I, and Wennmalm A. Effect of different prostaglandin synthesis inhibitors on post-occlusive blood flow in human forearm. Prostaglandins 26: 241-252, 1983[Web of Science][Medline].

7.   Celermajer, DS. Endothelial dysfunction: does it matter? Is it reversible? J Am Coll Cardiol 30: 325-333, 1997[Abstract].

8.   Chataigneau, T, Feletou M, Huang PL, Fishman MC, Duhault J, and Vanhoutte PM. Acetylcholine-induced relaxation in blood vessels from endothelial nitric oxide synthase knockout mice. Br J Pharmacol 126: 219-226, 1999[Web of Science][Medline].

9.   Chilian, WM, and Koshida R. EDHF and NO: different pathways for production---similar actions. Circ Res 89: 648-649, 2001[Free Full Text].

10.   Corriu, C, Feletou M, Edwards G, Weston AH, and Vanhoutte PM. Differential effects of prostacyclin and iloprost in the isolated carotid artery of the guinea-pig. Eur J Pharmacol 426: 89-94, 2001[Web of Science][Medline].

11.   Duffy, SJ, Castle SF, Harper RW, and Meredith IT. Contribution of vasodilator prostanoids and nitric oxide to resting flow, metabolic vasodilation, and flow-mediated dilation in human coronary circulation. Circulation 100: 1951-1957, 1999[Abstract/Free Full Text].

12.   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].

13.   Duffy, SJ, Tran BT, New G, Tudball RN, Esler MD, Harper RW, and Meredith IT. Continuous release of vasodilator prostanoids contributes to regulation of resting forearm blood flow in humans. Am J Physiol Heart Circ Physiol 274: H1174-H1183, 1998[Abstract/Free Full Text].

14.   Duncker, DJ, van Zon NS, Pavek TJ, Herrlinger SK, and Bache RJ. Endogenous adenosine mediates coronary vasodilation during exercise after KATP channel blockade. J Clin Invest 95: 285-295, 1995[Web of Science][Medline].

15.   Dyke, CK, Proctor DN, Dietz NM, and Joyner MJ. Role of nitric oxide in exercise hyperaemia during prolonged rhythmic handgripping in humans. J Physiol 488: 259-265, 1995[Abstract/Free Full Text].

16.   Ekelund, U, and Mellander S. Role of endothelium-derived nitric oxide in the regulation of tonus in large-bore arterial resistance vessels, arterioles and veins in cat skeletal muscle. Acta Physiol Scand 140: 301-309, 1990[Web of Science][Medline].

17.   Farouque, HMO, and Meredith IT. Effects of inhibition of ATP-sensitive potassium channels on metabolic vasodilation in the human forearm. Clin Sci (Lond) 104: 39-46, 2003[Medline].

18.   Farouque, HMO, and Meredith IT. Inhibition of vascular ATP-sensitive K+ channels does not affect reactive hyperemia in human forearm. Am J Physiol Heart Circ Physiol 284: H711-H718, 2003[Abstract/Free Full Text].

19.   Farouque, HMO, Worthley SG, Meredith IT, Skyrme-Jones RA, and Zhang MJ. Effect of ATP-sensitive potassium channel inhibition on resting coronary vascular responses in humans. Circ Res 90: 231-236, 2002[Abstract/Free Full Text].

20.   Farouque, HMO, Worthley SG, Zhang MJ, Baldi MA, and Meredith IT. The contribution of ATP-sensitive potassium channels to metabolic coronary vasodilation in the human (Abstract). Circulation 104: II-151, 2001.

21.   Gilligan, DM, Panza JA, Kilcoyne CM, Waclawiw MA, Casino PR, and Quyyumi AA. Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation. Circulation 90: 2853-2858, 1994[Abstract/Free Full Text].

22.   Godecke, A, Decking UK, Ding Z, Hirchenhain J, Bidmon HJ, Godecke S, and Schrader J. Coronary hemodynamics in endothelial NO synthase knockout mice. Circ Res 82: 186-194, 1998[Abstract/Free Full Text].

23.   Gollasch, M, Bychkov R, Ried C, Behrendt F, Scholze S, Luft FC, and Haller H. Pinacidil relaxes porcine and human coronary arteries by activating ATP-dependent potassium channels in smooth muscle cells. J Pharmacol Exp Ther 275: 681-692, 1995[Abstract/Free Full Text].

24.   Halcox, JP, Narayanan S, Cramer-Joyce L, Mincemoyer R, and Quyyumi AA. Characterization of endothelium-derived hyperpolarizing factor in the human forearm microcirculation. Am J Physiol Heart Circ Physiol 280: H2470-H2477, 2001[Abstract/Free Full Text].

25.   Heistad, DD, and Harder DR. Experimental biology 1996: potassium channels in blood vessels (Abstract). Clin Exp Pharmacol Physiol 23: 1068, 1996.

26.   Herbaczynska-Cedro, K, Staszewska-Barczak J, and Janczewska H. Muscular work and the release of prostaglandin-like substances. Cardiovasc Res 10: 413-420, 1976[Web of Science][Medline].

27.   Hester, RL, Eraslan A, and Saito Y. Differences in EDNO contribution to arteriolar diameters at rest and during functional dilation in striated muscle. Am J Physiol Heart Circ Physiol 265: H146-H151, 1993[Abstract/Free Full Text].

28.   Hirai, T, Visneski MD, Kearns KJ, Zelis R, and Musch TI. Effects of NO synthase inhibition on the muscular blood flow response to treadmill exercise in rats. J Appl Physiol 77: 1288-1293, 1994[Abstract/Free Full Text].

29.   Ishibashi, Y, Duncker DJ, Zhang J, and Bache RJ. ATP-sensitive K+ channels, adenosine, and nitric oxide-mediated mechanisms account for coronary vasodilation during exercise. Circ Res 82: 346-359, 1998[Abstract/Free Full Text].

30.   Jackson, WF, Konig A, Dambacher T, and Busse R. Prostacyclin-induced vasodilation in rabbit heart is mediated by ATP-sensitive potassium channels. Am J Physiol Heart Circ Physiol 264: H238-H243, 1993[Abstract/Free Full Text].

31.   Katz, SD, Krum H, Khan T, and Knecht M. Exercise-induced vasodilation in forearm circulation of normal subjects and patients with congestive heart failure: role of endothelium-derived nitric oxide. J Am Coll Cardiol 28: 585-590, 1996[Abstract].

32.   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].

33.   Klabunde, RE, Laughlin MH, and Armstrong RB. Systemic adenosine deaminase administration does not reduce active hyperemia in running rats. J Appl Physiol 64: 108-114, 1988[Abstract/Free Full Text].

34.   Laughlin, HM, Korthuis RJ, Duncker DJ, and Bache RJ. Control of blood flow to cardiac and skeletal muscle during exercise. In: Handbook of Physiology. Exercise: Regulation and Integration of Multiple Systems. Bethesda, MD: Am. Physiol. Soc, 1996, sect. 12, chapt. 17, p. 705-769.

35.   Leuenberger, UA, Gray K, and Herr MD. Adenosine contributes to hypoxia-induced forearm vasodilation in humans. J Appl Physiol 87: 2218-2224, 1999[Abstract/Free Full Text].

36.   Maxwell, AJ, Schauble E, Bernstein D, and Cooke JP. Limb blood flow during exercise is dependent on nitric oxide. Circulation 98: 369-374, 1998[Abstract/Free Full Text].

37.   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].

38.   Nelson, MT, and Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol Cell Physiol 268: C799-C822, 1995[Abstract/Free Full Text].

39.   Nishikawa, Y, Stepp DW, and Chilian WM. Nitric oxide exerts feedback inhibition on EDHF-induced coronary arteriolar dilation in vivo. Am J Physiol Heart Circ Physiol 279: H459-H465, 2000[Abstract/Free Full Text].

40.   Pountney, DJ, Zhuo-Qian S, Porter LM, Nitabach MN, Nakamura TY, Holmes D, Rosner E, Kanako M, Manaris T, Holmes TC, and Coetzee WA. Is the molecular composition of KATP channels more complex than originally thought? J Mol Cell Cardiol 33: 1541-1546, 2001[Web of Science][Medline].

41.   Scherrer, U, Randin D, Vollenweider P, Vollenweider L, and Nicod P. Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest 94: 2511-2515, 1994[Web of Science][Medline].

42.   Skyrme-Jones, RAP, O'Brien RC, and Meredith IT. Vasodilator prostanoids, but not nitric oxide, may account for skeletal muscle hyperaemia in type 1 diabetes mellitus. Clin Sci (Lond) 99: 383-392, 2000[Medline].

43.   Tare, M, Parkington HC, and Coleman HA. EDHF, NO and a prostanoid: hyperpolarization-dependent and -independent relaxation in guinea-pig arteries. Br J Pharmacol 130: 605-618, 2000[Web of Science][Medline].

44.   Wilson, JR, and Kapoor S. Contribution of endothelium-derived relaxing factor to exercise-induced vasodilation in humans. J Appl Physiol 75: 2740-2744, 1993[Abstract/Free Full Text].

45.   Wilson, JR, and Kapoor SC. Contribution of prostaglandins to exercise-induced vasodilation in humans. Am J Physiol Heart Circ Physiol 265: H171-H175, 1993[Abstract/Free Full Text].

46.   Young, EW, and Sparks HV. Prostaglandins and exercise hyperemia of dog skeletal muscle. Am J Physiol Heart Circ Physiol 238: H191-H195, 1980[Abstract/Free Full Text].

Am J Physiol Heart Circ Physiol 284(6):H2405-H2411
0363-6135/03 $5.00 Copyright © 2003 the American Physiological Society


This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
F. Harel, J. Dupuis, A. Benelfassi, N. Ruel, and J. Gregoire
Radionuclide plethysmography for noninvasive evaluation of peripheral arterial blood flow
Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H258 - H262.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
J. M. Lockwood, M. P. Pricher, B. W. Wilkins, L. A. Holowatz, and J. R. Halliwill
Postexercise hypotension is not explained by a prostaglandin-dependent peripheral vasodilation
J Appl Physiol, February 1, 2005; 98(2): 447 - 453.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
J. Dupuis, A. Arsenault, B. Meloche, F. Harel, C. Staniloae, and J. Gregoire
Quantitative hyperemic reactivity in opposed limbs during myocardial perfusion imaging: A new marker of coronary artery disease
J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1473 - 1477.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
S. Fazel, R. D. Weisel, and S. Verma
A novel technique to assess flow-mediated vasodilation
J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1478 - 1480.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
284/6/H2405    most recent
00879.2002v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (9)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Farouque, H. M. O.
Right arrow Articles by Meredith, I. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Farouque, H. M. O.
Right arrow Articles by Meredith, I. T.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2003 by the American Physiological Society.