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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
METHODS
RESULTS
DISCUSSION
REFERENCES
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We tested the hypothesis that
nitric oxide (NO) inhibits endothelium-derived hyperpolarizing factor
(EDHF)-induced vasodilation via a negative feedback pathway in the
coronary microcirculation. Coronary microvascular diameters were
measured using stroboscopic fluorescence microangiography. Bradykinin
(BK)-induced dilation was mediated by EDHF, when NO and prostaglandin
syntheses were inhibited, or by NO when EDHF and prostaglandin
syntheses were blocked. Specifically, BK (20, 50, and 100 ng · kg
1 · min1 ic) caused dose-dependent
vasodilation similarly before and after administration of
NG-monomethyl-L-arginine
(L-NMMA) (3 µmol/min ic for 10 min) and indomethacin (Indo, 10 mg/kg iv). The residual dilation to BK with
L-NMMA and Indo was completely abolished by suffusion of miconazole or an isosmotic buffer containing high KCl (60 mM), suggesting that this arteriolar vasodilation is mediated by the cytochrome P-450 derivative EDHF. BK-induced dilation was
reduced by 39% after inhibition of EDHF and prostaglandin synthesis,
and dilation was further inhibited by combined blockade with
L-NMMA to a 74% reduction in the response. This suggests
an involvement for NO in the vasodilation. After dilation to BK was
assessed with L-NMMA and Indo, sodium nitroprusside (SNP,
1-3 µg · kg1 · min1
ic), an exogenous NO donor, was administered in a dose to increase the
diameter to the original control value. Dilation to BK was virtually
abolished when administered concomitantly with SNP during L-NMMA and Indo (P < 0.01 vs. before SNP),
suggesting that NO inhibits EDHF-induced dilation. SNP did not affect
adenosine- or papaverine-induced arteriolar dilation in the presence of
L-NMMA and Indo, demonstrating that the effect of SNP was
not nonspecific. In conclusion, our data are the first in vivo evidence
to suggest that NO inhibits the production and/or action of EDHF in the
coronary microcirculation.
endothelium-derived hyperpolarizing factor; endothelium-dependent dilation; coronary microcirculation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE VASCULAR
ENDOTHELIUM synthesizes and releases vasodilators such as nitric
oxide (NO), prostaglandins (22), and endothelium-derived hyperpolarizing factor (EDHF) (11). In vitro studies have
shown that EDHF-induced dilation tends to be more important in small resistance arteries than in large vessels, where NO-induced dilation is
dominant (23), although we are compelled to mention that some of the original observations of EDHF were made in epicardial coronary arteries (24, 26). Recent
studies suggest that EDHF plays a role in the physiological regulation
of tissue blood flow (11) and that its action mimics
cytochrome P-450 metabolites (6). However, most
conclusions about the role of EDHF have been made after inhibition of
endothelial NO synthase (eNOS). NO normally accounts almost entirely
for agonist-induced dilation in porcine epicardial coronary arteries,
but after NO synthase inhibition EDHF produces considerable dilation
(20). If NO exerts feedback inhibition on EDHF production,
an obvious implication is that the quantitative contribution of EDHF on
endothelium-dependent vasodilation would be overestimated after
inhibition of eNOS. Indeed, this proposition is suggested by results
demonstrating that under combined blockade of NO synthase and
cyclooxygenase, EDHF-mediated vasodilation in rabbit carotid and
porcine artery was significantly attenuated by a NO donor
(3). Such a feedback pathway could also explain why
N
-nitro-L-arginine
(L-NNA)-resistant, acetylcholine-induced vasodilation in
small coronary arterioles was completely abolished by the addition of
cytochrome P-450 inhibitor, but L-NNA alone did
not affect acetylcholine-induced vasodilation (31). We
propose a negative feedback of NO on EDHF as the center role in this
redundant vasodilator mechanism. Importantly, it is unknown whether a
similar negative feedback scheme, NO-induced inhibition of EDHF-induced
dilation, operates in vivo in the coronary microcirculation. This
question is physiologically important, because these small vessels are the dominant resistance vessels in the coronary circulation, and the
contribution of EDHF in endothelium-dependent dilation appears greater
in small vessels than in large conductance vessels (23).
In this study, we tested the hypothesis that NO exerts an inhibitory influence on EDHF-induced vasodilation in the coronary microcirculation in vivo. Our observations suggest that in vivo there is feedback inhibition of NO on EDHF-mediated dilation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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General Preparation
Surgical preparation. The experimental preparation has been described in previous studies (10, 27). In brief, adult mongrel dogs (8-12 kg) were anesthetized with pentobarbital sodium (35 mg/kg iv), intubated, and ventilated with room air. A catheter was inserted into the carotid artery and advanced into the left ventricle (LV) for measurement of LV pressure and the change in pressure over time (dP/dt). The heart was exposed via a left thoracotomy, and a pericardial cradle was produced. The proximal left circumflex or anterior descending coronary artery was isolated, and then a 24-gauge Teflon catheter was placed immediately distal to it for measurements of coronary arterial pressure and intracoronary administration of drugs.
High-frequency jet ventilation. After these procedures, the animal was ventilated with a high-frequency jet ventilator (supplemented with 100% O2 at a pressure of 9-12 psi) synchronized to the cardiac cycle. A pressure regulator connected to a solenoid valve was triggered from the LV dP/dt and remained open for 30-40 ms each cardiac cycle. This results in low tidal volume ventilation once per cardiac cycle, at the same point during the cardiac cycle, for only a short period of time. The advantage of this procedure is that respiratory influences on cardiac motion are eliminated. Arterial blood gases and pH were monitored throughout the study and were maintained within normal limits.
Microvascular Preparation
The microvasculature was visualized using fluorescence video microscopy. The resolution of this configuration was 2 µm. Illumination of the epicardial surface of the LV was accomplished with a xenon stroboscopic light source synchronized with the cardiac cycle. A computer received input from the LV dP/dt and subsequently triggered the strobe at the same point in time (late diastole) per cardiac cycle. With jet ventilation, the microvasculature appear to be "fixed," simply because the epicardium is in view for a short instant (15-25 µs) at the same time in each cardiac cycle.The coronary microvasculature was visualized using fluorescence video microscopy. Small bolus injections of fluorescein isothiocyanate-labeled dextran were made via the coronary catheter. Measurement of microvascular caliber during fluorescence microscopy provides data on the internal diameter of the blood vessel. The existence of a well-defined anatomical landmark (branching point, etc.) was the major criteria used in the selection of a blood vessel. Video images were analyzed with a Power Mac computer utilizing NIH Image.
Protocols
Protocol 1: verification that NG-monomethyl-L-arginine/indomethacin-resistant bradykinin-induced dilation is mediated by EDHF. Unequivocal information on EDHF-mediated responses is best accomplished by measurement of membrane potentials or K+-channel conductance, which is not technically feasible in the beating heart. Thus, to verify that the component of bradykinin (BK)-induced dilation resistant to NG-monomethyl-L-arginine (L-NMMA)/indomethacin (Indo) blockade is caused by EDHF, we made two measurements. First, we determined whether this residual dilation is blocked by a cytochrome P-450 antagonist (miconazole, Mico), which is consistent with the consensus in the literature that EDHF is produced by this enzyme family (6). Second, we observed whether the dilation resistant to L-NMMA/Indo was blocked by suffusion of buffered isotonic solution containing 60 mM KCl, which inhibits membrane hyperpolarization (and thus the vasodilatory actions of a hyperpolarizing factor) by clamping membrane potentials in a depolarized state.
In four animals, microvascular diameter was measured under control conditions and during BK infusion (100 ng · kg1 · min1 ic for 5 min). Ten
minutes after this measurement, Indo (10 mg/kg iv) and
L-NMMA (3 µmol/min ic for 10 minutes) were administered. Thirty minutes after Indo injection, the diameter measurements to BK
were repeated. After these measurements, Mico (30 µM, cytochrome P-450 inhibitor) was suffused on the epicardial surface in
the microscopic field of view for 20 min in the presence of inhibition of NO and PGI2. BK was readministered, and the measurements
were repeated during the last 5 min of Mico suffusion.
In an additional four animals, the same protocol was repeated with Mico
replaced by a high-K suffusion (60 mM KCl for 20 min). Microvascular
responses to papaverine (2 mg bolus ic) were then measured to verify
that endothelium-independent dilation was not affected by the interventions.
Protocol 2: Mico/Indo-resistant BK-induced dilation is mediated
by NO.
To verify that BK causes arteriolar vasodilation via NO in addition to
EDHF and that this NO-mediated vasodilation is blocked with
L-NMMA, we made the following measurements in four animals: 1) during administration of BK (100 ng · kg1 · min1 ic for 5 min);
2) during administration of BK after Mico (suffusion for 20 min) and Indo; 3) during administration of BK during
infusion of L-NMMA, in the presence of Mico and Indo; and
4) during papaverine administration (2 mg ic). The
doses of Mico, L-NMMA, and Indo were the same as in the
protocol 1. This protocol was designed to show that a
component of BK-induced dilation is mediated by NO, by showing that the
vasodilation resistant to Indo and Mico can be antagonized by
L-NMMA.
Protocol 3: negative feedback effects of NO on EDHF-induced
vasodilation.
In seven animals, the following measurements were made: 1)
during administration of BK (20, 50, and 100 ng · kg1 · min1 ic for 5 min);
2) during administration of BK after L-NMMA and Indo; and 3) during concomitant administration of BK and
sodium nitroprusside (SNP) in the presence of L-NMMA and
Indo. For the third set of measurements, SNP, an exogenous NO donor,
was infused at the rate of 1-3 µg · kg1 · min1 ic for 15 min. Before the
administration of SNP, combined administration of L-NMMA
and Indo produced 9 ± 2% decrease in diameter. The dose of SNP
was selected because it had little effect on the systemic hemodynamics
and because it returned diameter to the control value in the absence of
any drugs. Ten minutes after the start of SNP infusion, the diameter
measurements to BK were repeated. Microvascular responses to papaverine
(2 mg, bolus ic) were then measured in the absence of SNP to verify
that endothelium-independent dilation was intact at the end of this
protocol. The doses of L-NMMA and Indo were the same as
those in protocol 1.
Protocol 4: dilation to adenosine and papaverine in presence of
L-NMMA and Indo, and SNP.
In four animals, the microvascular diameter to adenosine (20 µg
· kg1 · min1 ic for 5 min) was
measured during control conditions, after L-NMMA and Indo,
and finally during SNP with L-NMMA and Indo. We performed this protocol to determine whether the effects of SNP are nonspecific, i.e., to insure that SNP does not inhibit vasodilation to an
endothelium-independent dilator (adenosine). At the end of this
protocol, the microvascular responses to papaverine (2 mg bolus ic)
were measured with SNP along with inhibition of NO synthase and
cyclooxygenase to again confirm vasodilator reserve.
Drugs
BK, adenosine, and papaverine were prepared in 0.9% saline. Indo was dissolved in 95% ethanol and made into a 5-10 mg/ml solution in 0.9% saline. Indo was prepared as a 0.27 mg/ml solution in 0.9% saline brought to a physiological pH (between 7.3 and 7.5) by the addition of small aliquots of 1 M NaOH immediately before use. Krebs solution (in mM: 142 NaCl, 5.4 KCl, 2.0 CaCl2, 1.2 MgCl2, 11.0 dextrose, and 18 bicarbonate) and high-KCl solution (in mM: 102 NaCl, 45.4 KCl, 2.0 CaCl2, 1.2 MgCl2, 11.0 dextrose, and 18 bicarbonate) were bubbled with 20% O2-5% CO2-75% N2. Mico was initially dissolved in 100% ethanol and was subsequently dissolved into the Krebs perfusate to provide a final concentration of 30 µM. All drugs were obtained from Sigma Chemical.Statistical Analysis
Microvascular diameters to BK were calculated as a percent change from the data before each intervention. Thus +% and
%
indicate dilation and constriction, respectively. Two-way repeated
measures of ANOVA were used to assess differences in dilation to BK
during each condition. To show significant vasodilation to BK, the
percent changes in diameter were compared with zero using a paired
t-test. The data are presented as means ± SE.
P values <0.05 were considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Mean aortic blood pressure and heart rate did not change
significantly during any of the interventions, except during SNP where
the mean aortic pressure decreased slightly but significantly (Table 1).
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Protocol 1: Verification that L-NMMA/Indo-Resistant BK-induced Dilation Is Mediated by EDHF
Figure 1 shows the percent change in diameter to BK (100 ng · kg1 · min1) under control conditions and during
L-NMMA+Indo, L-NMMA+Indo+Mico, and
L-NMMA+Indo+KCl (KCl solution). Baseline
diameters decreased by 5 ± 1% (P < 0.05) after L-NMMA+Indo. Additional administration of
Mico did not affect the diameter, but KCL caused a further 4 ± 1% vasoconstriction (P < 0.05).
L-NMMA+Indo did not affect BK-induced dilation. This
residual dilation to BK was completely abolished by additional
administration of Mico (22 ± 5% before vs. 5 ± 1% after
Mico, P < 0.05, 11 vessels, control diameters = 99 ± 5 µm, range ~66-150 µm) or KCl suffusion (19 ± 4% before vs. 6 ± 1% after KCl, P < 0.05, 12 vessels, control diameters = 93 ± 11 µm, range ~54-126
µm). These data strongly suggest that during inhibition of NO and
PGI2 production, BK-induced vasodilation in coronary
arterioles is mainly mediated by a cytochrome P-450 derivative and is a hyperpolarizing factor.
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Protocol 2: Verification that Mico/Indo-Resistant BK-induced Dilation Is Mediated by NO
Figure 2 shows the percent change in diameter (9 vessels, control diameter = 88 ± 7 µm, range ~56-143 µm) to BK (100 ng · kg1 · min1 ic for 5 min) under
control conditions, during Mico+Indo, and during
Mico+Indo+L-NMMA. Baseline diameters did not change after Mico+Indo, but L-NMMA caused a 6 ± 1% reduction in
baseline diameter (P < 0.05). BK-induced dilation
decreased significantly from 24 ± 4% in the absence of
inhibitors to 16 ± 3% in the presence of Mico+Indo
(P < 0.05). This residual dilation was further
inhibited by additional administration of L-NMMA to 7 ± 1% (P < 0.05 vs. before). These data indicate that
BK causes vasodilation of coronary microvessels via NO following
administration of Mico and Indo.
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Protocol 3: Negative Feedback Effects of NO on EDHF-induced Vasodilation
Figure 3 shows a scatter plot of changes in diameter (10 vessels, control diameter = 112 ± 12 µm) to the highest dose of BK (100 ng · kg1
· min1 ic) under control conditions, during
L-NMMA+Indo, and during L-NMMA+Indo+SNP. After
L-NMMA and Indo, BK increased the diameter to a similar
extent as to that without the antagonists. However, this
residual dilation to BK is severely depressed by the additional administration of SNP. Figure 4 shows the
average data to each dose of BK. During control conditions, BK
increased diameters in a dose-dependent manner (6 ± 1, 13 ± 2, and 19 ± 2% at doses of 20, 50, and 100 ng · kg1 · min1 ic, respectively).
L-NMMA and Indo produced a significant decrease in baseline
diameter (112 ± 15 to 98 ± 13 µm, P < 0.05), but did not affect the dilation to BK (5 ± 2, 10 ± 1, and 17 ± 3%, not significant vs. control response).
Administration of SNP increased the diameter to the original control
value (112 ± 15 µm at control vs. 106 ± 13 µm after
SNP, not significant). During SNP infusion with L-NMMA and
Indo, BK-induced vasodilation was virtually abolished (0 ± 0, 2 ± 1, and 3 ± 1%, P < 0.01 vs. before
SNP). Papaverine caused a 14 ± 4% increase in diameter of
microvessels at the end of this protocol, showing that the vessels were
capable of responding to a vasodilatory stimulus.
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Protocol 4: Effects of SNP on Papaverine- or Adenosine-induced Dilation in the Presence of L-NMMA and Indo
Under control conditions, adenosine increased the diameter by 21 ± 2%. Baseline diameter decreased 5 ± 1% after L-NMMA+Indo (P < 0.05). Adenosine-induced dilation was not changed after L-NMMA+Indo or after L-NMMA+Indo+SNP (21 ± 2% vs. 16 ± 2%, respectively, not significant vs. control, 10 vessels, control diameter = 86 ± 8 µm, range ~46-132 µm). Papaverine-induced dilation was also maintained (19 ± 2%) in the presence of L-NMMA, Indo, and SNP.| |
DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The most important finding we have made is that NO inhibits EDHF-mediated coronary microvascular vasodilation in vivo. This is consistent with the view that NO exerts negative feedback on EDHF-induced dilation. Our data have important implications about the effects of EDHF on vascular relaxation after blockade of NO production, because the role of EDHF may be overestimated if measurements are obtained after inhibition of NO synthase. Relevant to these conclusions are several issues concerning the limitations of the methodology, possible mechanism(s) for the interaction between NO and EDHF, and significance of the findings.
Limitation of the Methodology
Although electrophysiological measurements provide unequivocal information about EDHF-mediated responses, it is not technically feasible to make these measurements in microvessels of the beating heart. The chemical nature of EDHF remains obscure. The uncertainty of the identity of EDHF makes it difficult to show evidence of EDHF-induced dilation in vivo. However, a recent study has suggested that EDHF activity is an epoxyeicosatrienoic acid, which is formed from arachidonic acid by the action of cytochrome P-450 (6, 28). Epoxyeicosatrienoic acids increase the opening of the Ca2+-activated potassium (KCa) channels in coronary arterial smooth muscle (2, 15, 24), causing hyperpolarization and vasodilation. These data suggest that the activation of KCa channels plays a role in EDHF-mediated vascular dilation. In our study, we show that the component of BK-induced dilation that occurs after inhibition of NO and prostanoid synthesis is completely blocked by an inhibitor of cytochrome P-450 enzymes. Moreover, this residual dilation to BK is also blocked by suffusion of the KCl buffer, which clamps membrane potential in a depolarized state, and prevents membrane hyperpolarization. Therefore, our data strongly suggest that EDHF mediates BK-induced residual dilation after inhibition of NO and PG synthesis.Because SNP blocked BK-induced vasodilation in the presence of L-NMMA+Indo, we tested the possibility that the NO donor would affect vasodilation to other vasodilators. However, adenosine-induced dilation was not changed before and during SNP administration. In addition, the dilation to papaverine was preserved after administration of SNP in the presence of L-NMMA+Indo. Thus our data clearly suggest that the inhibitory effect of NO donor on EDHF-induced dilation is specific to this agonist under these conditions.
Another critical aspect of our study is that our interpretations depend on efficacious antagonism of NO synthase by L-NMMA and cyclooxygenase by Indo. One could argue that the reason we observed dilation to these two enzymes, and the complete inhibition we observed after administration of Mico, L-NMMA, and Indo, may be related to an additive effect of the three antagonists. However, our data argue against this possibility. Specifically, we observed that arteriolar dilation to BK was inhibited in the presence of L-NMMA and Indo, when given in conjunction with the NO donor SNP. This supports the concept that the antagonism of the production of NO and prostanoids was effective, and our results are best explained by a negative feedback interaction of NO on EDHF.
Comparison of BK- and Acetylcholine-induced Vasodilation
We have previously shown (27) that acetylcholine-induced vasodilation after L-NMMA and Indo is completely blocked by clamping the resting potentials by suffusion of high-K buffer solution, implying a role for EDHF in dilation to acetylcholine. We used BK instead of acetylcholine as an agonist for endothelium-dependent dilation, because vasodilation to acetylcholine is inhibited by 50-70% after inhibition of NO and PG production. In contrast, we found that BK-induced dilation after L-NMMA and Indo was not different from the control response in the absence of antagonists. These observations, compatible with previous reports (17, 18, 26, 30), indicate that unlike acetylcholine, EDHF plays a dominant role in endothelium-dependent dilation to BK in vivo in the coronary microcirculation. The percent change of diameter in response to BK did not differ before and after L-NMMA/Indo administration. This observation does not necessarily mean that NO does not contribute to BK-induced vasodilation. Because NO inhibits the action or release of EDHF, L-NMMA increases the contribution of this factor in BK-mediated vasodilation. Indeed, we demonstrated that BK-induced vasodilation in the presence of Mico and Indo was significantly inhibited by additional administration of L-NMMA, suggesting that vasodilation to BK in the presence of Mico and Indo occurred via NO. Lamping (21) recently reported that coronary arteriolar vasodilation by BK was mediated almost exclusively by NO. We cannot readily explain this discrepancy between Lamping (21) and our and other results (17, 18, 26, 30), but we believe that BK produces coronary dilation by producing NO, EDHF, and possibly prostaglandins.Possible Mechanism(s) for the Interaction between NO and EDHF
One explanation for the interaction of NO and EDHF comes from evidence for an inhibitory effect of NO on cytochrome P-450. EDHF appears to be synthesized by one of the cytochrome P-450 enzymes (2, 13, 27); therefore, inhibition of the enzymes would impair production of the hyperpolarizing factor. Possible effects of NO on cytochrome P-450 have been suggested from the observation that endotoxin shock, characterized by a large amount of NO production, is known to result in inhibition of hepatic cytochrome P-450-dependent metabolism (8, 29). This inhibitory effect of NO on cytochrome P-450 may partly account for the hypoactivity to vasodilator agents observed in endotoxin-treated animals (14). In vitro treatment of hepatic microsomes with NO substantially suppressed cytochrome P-450-dependent oxygenation reactions (19). Taken together, these data support the concept that cytochrome P-450 enzyme activity may be inhibited by NO. Thus, in the absence of NO, cytochrome P-450 activity could increase and induce production of EDHF.A study in human endothelial cells pretreated with L-NNA showed that C87-3786, a NO donor, attenuated the increase in intracellular Ca2+ produced by BK (3). Considering that EDHF formation and liberation of arachidonic acid from phospholipid by phospholipase A2 is strictly dependent on an increase in the intracellular concentration of Ca2+ ([Ca2+]i) (4, 9), a NO-mediated decrease in [Ca2+]i could also inhibit EDHF synthesis.
Clinical Significance and Conclusions
In rats, EDHF-mediated responses appear to contribute more to endothelium-dependent dilation in small arteries and arterioles than in large vessels such as aorta or pulmonary arteries (23). In the canine coronary vasculature, we (27) and others (31) have reported that EDHF-mediated, agonist-induced vasodilation is clearly demonstrated in the microcirculation but not in upstream small arteries. It must be pointed out that some of the initial observations of EDHF were made in large epicardial coronary arteries (24, 26), although it is difficult to calculate changes in diameters based on measurements of isometric tension. Nonetheless, over the diameter range of microvessels we studied, the contribution of EDHF to BK-induced dilation became progressively greater as vessels became smaller. In contrast, agonists can induce NO-mediated dilation in all sizes of coronary vessels (7, 16, 27, 31). Thus the roles of NO and EDHF in endothelium-dependent relaxation may also be different because of varying locations for their actions. Importantly, these observations were made after inhibition of NO production. Thus, with significant negative feedback of NO on EDHF, it is difficult to assess the actual roles of NO and EDHF in mediating microvascular responses. We speculate that in the coronary microcirculation, EDHF may be a "second line of defense" in that the dilation occurs only after the NO pathway is compromised. Indeed, many vascular diseases that are associated with decreases in NO production (12) appear to have other compensatory vasodilatory mechanisms. Hypertension results in a compensatory increase in the activity of K channels and, possibly, increased synthesis/release of the putative hyperpolarizing factors (1, 5). Hypercholesteroleremia in rabbits showed an enhanced role of calcium-dependent potassium channels in rabbit coronary arteries (25). These data may show that EDHF-mediated response is spared or even augmented in the presence of impaired endothelial NO production.In conclusion, we found that small doses of the NO donor, SNP, inhibited in vivo EDHF-mediated vasodilation in the coronary microcirculation. This suggests that the contribution of EDHF to BK-induced vasodilation increases after inhibition of NO production, because the normal production of NO may be exerting a tone-negative feedback action on EDHF. We conclude that in the microcirculation of the beating heart, EDHF serves as a back-up vasodilator when NO production is impaired.
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ACKNOWLEDGEMENTS |
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These studies were supported by National Heart, Lung, and Blood Institute Grants HL-32788 and HL-59448 (to W.M. Chilian) and Grants-in-Aid from the American Heart Association, Northland Affiliate (to Y. Nishikawa).
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FOOTNOTES |
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Address for reprint requests and other correspondence: W. M. Chilian, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: chilian{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. §1734 solely to indicate this fact.
Received 27 May 1999; accepted in final form 27 January 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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