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PubMed1998

The contribution of nitric oxide to cardiovascular status and responses to vasodilators in conscious, hypertensive, transgenic ((mRen-2)27) rats.

1. The aim of the study was to measure the regional haemodynamic responses to vasodilators, and the effects of nitric oxide (NO) synthase inhibition, in conscious, hypertensive, transgenic ((mRen-2)27) rats (TG rats) and normotensive, Hannover Sprague-Dawley (SD) rats. 2. The hypotensive response to acetylcholine was greater in TG than in SD rats, but the renal vasodilator responses were not different. 3. The responses to bradykinin were similar in the two strains, except that hindquarters vasodilatation occurred only in SD rats. 4. Salbutamol caused smaller renal and hindquarters vasodilatation in TG rats than in SD rats, and there was mesenteric vasodilatation only in the latter strain. 5. The hypotensive response to sodium nitroprusside was smaller, but the accompanying mesenteric vasodilatation was greater, in SD than in TG rats. 6. The contribution of NO to the vasodilator responses was taken as the difference between the responses in the presence of the NO synthase inhibitor, NG-nitro-L-arginine methylester (L-NAME), compared to those in the presence of a co-infusion of angiotensin II and vasopressin (to match the haemodynamic effects of L-NAME). 7. In TG rats, L-NAME caused a greater absolute pressor effect, but a smaller mesenteric vasoconstriction, than in SD rats. 8. L-NAME affected the vasodilator responses to all the challenges similarly in the two strains. 9. Collectively, the results provide no direct evidence for impaired NO-mediated vasodilator mechanisms in TG rats. It is feasible that the reduced hindquarters response to bradykinin and the reduced renal and hindquarters responses to salbutamol, in TG rats are due to abnormal beta2-adrenoceptor-mediated processes.

Acetylcholine↗
PubMed2002

AT(2) receptor-dependent vasodilation is mediated by activation of vascular kinin generation under flow conditions.

Physiological roles of angiotensin II type 2 receptor (AT(2)) are not well defined. This study was designed to investigate the mechanisms of AT(2)-dependent vascular relaxation by studying vasodilation in pressurized and perfused rat mesenteric arterial segments. Perfusion of angiotensin II in the presence of AT(1) antagonist elicited vascular relaxation, which was completely dependent on AT(2) receptors on endothelium. FR173657 (>1 microM), a bradykinin (BK) B(2)-specific antagonist, significantly suppressed AT(2)-dependent vasodilation (maximum inhibition: 68.5% at 10 microM). Kininogen-deficient Brown Norway Katholiek rats showed a significant reduction in AT(2)-mediated vasodilatory response compared with normal wild-type Brown Norway rats. Indomethacin (>1 microM), aprotinin (10 microM) and soybean trypsin inhibitor (10 microM) also reduced AT(2)-dependent vasodilation. Our results demonstrated that stimulation of AT(2) receptors caused a significant vasodilation through local production of BK in resistant arteries of rat mesentery in a flow-dependent manner. Such vasodilation counterbalances AT(1)-dependent vasoconstriction to regulate the vascular tone.

Angiotensin II↗
PubMed2004

Non-esterified fatty acids impair endothelium-dependent vasodilation in rat mesenteric resistance vessels.

Elevated circulating levels of NEFAs (non-esterified fatty acids) are associated with states of insulin resistance and increased risk of vascular disease. Previous animal and human studies have demonstrated NEFA-induced endothelial dysfunction of large conduit arteries, reversible by the antioxidant ascorbic acid. We therefore investigated the effect of NEFAs on carbachol-induced endothelium-dependent vasodilation of rat resistance arteries in vitro using the technique of wire myography. In addition, we investigated the effect of co-incubation of NEFAs and ascorbic acid. Cumulative concentration-response curves to carbachol (endothelium-dependent vasodilation) and SNAP (S-nitroso-N-acetyl-DL-penicillamine; endothelium-independent vasodilation) were constructed. Those to carbachol were repeated following a 30 min incubation with either oleic acid (10(-4) M) or palmitic acid (10(-4) M), demonstrating significant impairment of endothelium-dependent vasodilation with both [P<0.05, comparison of pD2 values (the negative log concentration of agonist required to effect a 50% response)]. A cumulative concentration-response curve to carbachol was repeated following co-incubation with palmitic acid (10(-4) M) and the antioxidant ascorbic acid (10(-5) M), demonstrating an abolition of the previously observed endothelial dysfunction induced by palmitic acid. There was no impairment of vasodilation to SNAP following NEFA incubation. We conclude that NEFAs directly impair endothelial function in rat resistance arteries via an increase in oxidative stress at the vascular endothelium.

Animals↗
PubMed1999

Adding ischaemic hand exercise during occlusion of the brachial artery increases the flow-mediated vasodilation in ultrasound studies of endothelial function.

A non-invasive method has been introduced to study endothelial function by evaluating flow-mediated, endothelium-dependent vasodilation of the brachial artery. One weakness of this method is that the post-occlusion vasodilation response is very small in subjects above the age of 60 years, which is a problem when quantifying endothelial dysfunction above this age. We have therefore evaluated whether a higher post-occlusion flow stimulus and a larger vasodilation response can be achieved by adding ischaemic hand exercise during the occlusion of the brachial artery. The subject population was men (n = 12), aged 60 years, free from cardiovascular disease. B-mode ultrasound images for the measurement of lumen diameter of the brachial artery were recorded before and after reactive hyperaemia induced by occlusion of the artery. Blood flow velocity was recorded intermittently using a Doppler technique. Hyperaemia was induced in two different ways: first by occlusion only and then by adding ischaemic hand exercise during the occlusion. The results showed that flow velocity was higher and the duration of flow increase was longer after ischaemic hand exercise compared with occlusion only. Two minutes after cuff pressure release, the increase in blood flow velocity was significantly higher after ischaemic hand work compared with occlusion only (P < 0.01). The corresponding maximal lumen diameters after cuff pressure release were 4.63 +/- 0.35 and 4.45 +/- 0.34 respectively (P < 0.01). The flow-mediated vasodilation increased significantly from 2.24 +/- 2.00% after occlusion only to 7.42 +/- 3.32% after occlusion plus ischaemic hand exercise (P < 0.01). In conclusion, this study showed that a maximal endothelial-dependent vasodilation was not achieved after occlusion only in these 60-year-old men. Adding ischaemic hand exercise may therefore be of value when quantifying endothelial dysfunction in this age group.

Blood Flow Velocity↗
PubMed2000

An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice.

In addition to nitric oxide (NO) and prostacyclin (PGI(2)), the endothelium generates the endothelium-derived hyperpolarizing factor (EDHF). We set out to determine whether an EDHF-like response can be detected in wild-type (WT) and endothelial NO synthase knockout mice (eNOS -/-) mice. Vasodilator responses to endothelium-dependent agonists were determined in vivo and in vitro. In vivo, bradykinin induced a pronounced, dose-dependent decrease in mean arterial pressure (MAP) which did not differ between WT and eNOS -/- mice and was unaffected by treatment with N(omega)-nitro-l-arginine methyl ester and diclofenac. In the saline-perfused hindlimb of WT and eNOS -/- mice, marked N(omega)-nitro-l-arginine (l-NA, 300 micromol/liter)- and diclofenac-insensitive vasodilations in response to both bradykinin and acetylcholine (ACh) were observed, which were more pronounced than the agonist-induced vasodilation in the hindlimb of WT in the absence of l-NA. This endothelium-dependent, NO/PGI(2)-independent vasodilatation was sensitive to KCl (40 mM) and to the combination of apamin and charybdotoxin. Gap junction inhibitors (18alpha-glycyrrhetinic acid, octanol, heptanol) and CB-1 cannabinoid-receptor agonists (Delta(9)-tetrahydrocannabinol, HU210) impaired EDHF-mediated vasodilation, whereas inhibition of cytochrome P450 enzymes, soluble guanylyl cyclase, or adenosine receptors had no effect on EDHF-mediated responses. These results demonstrate that in murine resistance vessels the predominant agonist-induced endothelium-dependent vasodilation in vivo and in vitro is not mediated by NO, PGI(2), or a cytochrome P450 metabolite, but by an EDHF-like principle that requires functional gap junctions.

Acetylcholine↗
PubMed1997

Coronary vasodilator reserve in primary and secondary left ventricular hypertrophy. A study with positron emission tomography.

OBJECTIVES: Coronary vasodilator reserve is reduced in hypertrophic cardiomyopathy and secondary left ventricular hypertrophy despite angiographically normal coronaries. The aim of the present study was to assess whether quantitative differences exist between these conditions. METHODS: Using positron emission tomography with H2(15)O, myocardial blood flow was measured at baseline and following intravenous dipyridamole (0.56 mg.kg-1) in 12 hypertrophic cardiomyopathy patients (age 34 (11) years, mean (SD), all male), 16 secondary left ventricular hypertrophy patients (age 58 (20) years, P < 0.01 vs hypertrophic cardiomyopathy; 10 female) and 40 normal controls (age 54 (20), 13 female). In view of the known decline of post-dipyridamole myocardial blood flow with age, myocardial blood flow was compared between the patient groups and appropriately matched subsets of the total control group. RESULTS: Baseline myocardial blood flow in the hypertrophic cardiomyopathy patients was 0.82 (0.23) ml.min-1.g-1 vs 0.94 (0.14) ml.min-1.g-1 in its matched control group, P = ns. For the secondary left ventricular hypertrophy patient group, baseline myocardial blood flow was 1.17 (0.40) ml.min-1.g-1 vs 1.06 (0.28) ml.min-1.g-1 for the secondary left ventricular hypertrophy matched control group, P = ns. Following dipyridamole, myocardial blood flow was 1.64 (0.44) ml.min-1.g.-1 in hypertrophic cardiomyopathy patients vs 3.50 (0.95) ml.min-1.g-1 for the hypertrophic cardiomyopathy matched control group, P = 0.0001. For the left ventricular hypertrophy patients, post-dipyridamole myocardial blood flow was 2.27 (0.60) ml.min-1.g-1 vs 2.94 (1.29) ml.min-1.g-1 for the left ventricular hypertrophy controls, P = 0.06. Coronary vasodilator reserve (dipyridamole-myocardial blood flow/baseline-myocardial blood flow) was 2.05 (0.61) for hypertrophic cardiomyopathy patients vs 3.81 (0.98) for the hypertrophic cardiomyopathy controls (P = 0.0001, patients vs controls) and 2.06 (0.62) for left ventricular hypertrophy patients vs 2.90 (1.38) for the left ventricular hypertrophy controls, P < 0.03 patients vs controls. After correction of baseline myocardial blood flow for baseline heart rate x systolic pressure product, coronary vasodilator reserve for the hypertrophic cardiomyopathy patients was 2.06 (1.06) vs 4.34 (1.54) for the hypertrophic cardiomyopathy controls. P = 0.0002 and in the secondary left ventricular hypertrophy patients, the values were 2.13 (0.64) vs 2.89 (1.42) in the secondary left ventricular hypertrophy controls, P < 0.05. CONCLUSION: In both hypertrophic cardiomyopathy and secondary left ventricular hypertrophy, the computed coronary vasodilator reserve is impaired, even after correction for baseline cardiac work. However, the extent of the reduction is greater in the hypertrophic cardiomyopathy patients. In the blunting of vasodilator reserve of secondary left ventricular hypertrophy, the patients' greater hyperaemic response is partly offset by the higher baseline myocardial blood flow.

Adult↗
PubMed2000

Propofol selectively attenuates endothelium-dependent pulmonary vasodilation in chronically instrumented dogs.

BACKGROUND: The objective was to investigate the effects of propofol anesthesia on the pulmonary vascular response to endothelium-dependent and -independent vasodilators, compared with the responses measured in the conscious state. METHODS: Twenty-six conditioned, male, mongrel dogs were instrumented long-term to measure the left pulmonary vascular pressure-flow relation. Pressure-flow plots were measured on separate days in conscious and propofol-anesthetized (5.0 mg/kg plus 0.5 mg. kg-1. min-1 intravenously) dogs at baseline, after preconstriction with the thromboxane mimetic U46619, and during the cumulative intravenous administration of endothelium-dependent (acetylcholine and bradykinin) and -independent (proline-nitric oxide) vasodilators. RESULTS: Propofol had no effect on the baseline pressure-flow relation compared with the conscious state. A lower (P < 0.05) dose of U46619 was necessary to achieve the same degree of preconstriction during propofol anesthesia. The pulmonary vasodilator responses to bradykinin and proline-nitric oxide were similar in the conscious and propofol-anesthetized states. In contrast, the pulmonary vasodilator response to acetylcholine was markedly attenuated (P < 0.01) during propofol anesthesia. The intralipid vehicle for propofol had no effect on the acetylcholine dose-response relation. CONCLUSION: These results suggest that propofol causes a specific defect in the signal transduction pathway for acetylcholine-induced pulmonary vasodilation. This defect involves the endothelial and not the vascular smooth muscle component of the response.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Beta-blocking agents with vasodilating action.

beta-Adrenoceptor-blocking drugs in current use can be separated into two main groups: those nonselective and those selective for beta 1-receptors. Members of each group reduce cardiac output and lead to an increase in peripheral resistance with a concomitant reduction in blood flow. beta-Blocking drugs not only may occupy the receptor preventing stimulation but also may have intrinsic sympathomimetic activity. Those with marked partial agonist activity at the beta 2-receptor giving some beta 2-mediated vasodilation can be regarded as the first multiple-action beta-blocking drugs. Subsequently, drugs have been developed that in addition to blocking the beta-receptor have an important peripheral vasodilator activity. Labetalol was the first drug of this group to be developed; prizidolol followed but has been withdrawn because of toxicity. Several other agents have been described, including bucindolol, carvedilol, celiprolol, dilevalol (one of the isomers of labetalol), and medroxolol. Three mechanisms have been reported to be responsible for peripheral vasodilation: alpha-receptor blockade, beta 2-agonism, and a dilator action independent of either the alpha- or beta-receptors. Evidence for these various mechanisms is more readily obtainable from animal experiments, but some confirmatory evidence has been obtained in humans. Inhibition of alpha-stimulation had been found with labetalol, medroxalol, and carvedilol and suggested with celiprolol. beta 2-Mediated vasodilation has been demonstrated by, for example, celiprolol and dilevalol; evidence of a vasodilation independent of alpha-blockade or beta 2-stimulation has been reported with celiprolol and carvedilol.

Adrenergic alpha-Antagonists↗
PubMed1998

Differential effects of N-acetylcysteine on nitroglycerin- and nicorandil-induced vasodilation in human coronary circulation.

We investigated the role of the availability of sulfhydryl groups during vasodilation of the human coronary circulation induced by nitroglycerin and nicorandil. In patients with normal coronary arteries (n = 29) or with coronary artery disease (CAD; n = 26), coronary blood flow (CBF) and epicardial coronary artery diameter after intracoronary administration of 50 microg nitroglycerin or 0.5 mg nicorandil were measured, before and after the intravenous infusion of saline or 100 mg/kg of N-acetylcysteine (NAC). In normal subjects, saline infusion did not alter the nitroglycerin- and nicorandil-induced vasodilation in large epicardial coronary artery. In contrast, NAC potentiated both nitroglycerin- and nicorandil-induced vasodilation. In patients with CAD, nitroglycerin and nicorandil induced less dilation than in normal subjects. NAC augmented the nitroglycerin- and nicorandil-induced vasodilation in the small epicardial coronary artery, but not in the large epicardial segments. In both groups, NAC potentiated the increase in CBF in response to nitroglycerin. However, NAC had no effects on the CBF response to nicorandil. Sulfhydryl availability is at least one determinant of the in vivo responsiveness to nitroglycerin of conductance and resistance vessels in normal human coronary circulation. In patients with CAD, external augmentation of sulfhydryl availability did not affect the depressed response to nitroglycerin in the large epicardial coronary artery. Although nicorandil acts as an NO donor, similar to nitroglycerin, in dilating the epicardial coronary artery, other effects, such as the opening of K(ATP) channel, play a more important role in the nicorandil-induced vasodilation of resistance vessels.

Acetylcysteine↗
PubMed2006

Impaired endothelium-dependent vasodilation in normotensive and normoglycemic obese adult humans.

Acetylcholine (ACh)-mediated endothelium-dependent vasodilation has been shown to be impaired in obese adults. However, the mechanisms responsible for this impairment are not clear. We determined whether the blunted forearm vasodilator response to acetylcholine with obesity is due, at least in part, to reduced muscarinic receptor responsiveness. Twenty-eight sedentary middle-aged adults were studied: 14 normal weight (BMI, 23.6 +/- 0.5 kg/m) and 14 obese (32.2 +/- 0.9 kg/m). Forearm blood flow (FBF) was determined in response to intraarterial infusion of acetylcholine (8-128 microg/min) and sodium nitroprusside (SNP: 2.0-8.0 microg/min). Regardless of the dose, forearm blood flow responses to acetylcholine were 25% (P < 0.01) lower in the obese (from 4.2 +/- 0.3 to 12.0 +/- 0.8 mL/100 mL tissue/min) compared with normal weight (4.4 +/- 0.3 to 16.9 +/- 1.0 mL/100 mL tissue/min) adults. Of note, forearm blood flow responses to acetylcholine plateaued at doses higher than 32 microg/min in both groups, no further increase in forearm blood flow was observed at either 64 or 128 microg/min. EC50 for acetylcholine-stimulated vasodilation was not different between the obese (7.8 +/- 0.8 microg/min) and normal weight (7.8 +/- 0.6 microg/min) adults. There were no group differences in the vasodilator response to sodium nitroprusside. These results indicate that the obesity-related impairment in acetylcholine-mediated vasodilation in the human forearm is not due to reduced muscarinic receptor responsiveness or sensitivity.

Acetylcholine↗
PubMed2003

Comparative profile of vasodilation by CVT-3146, a novel A2A receptor agonist, and adenosine in conscious dogs.

The purpose of this study was to determine the magnitude of vasodilation by CVT-3146 in different vascular beds and to compare it with that by adenosine in conscious dogs. Intravenous bolus injections of CVT-3146 (0.1-2.5 microg/kg) or adenosine (10-250 microg/kg) caused a dose-dependent increase in the coronary blood flow (CBF) and a dose-dependent decrease in the late diastolic coronary resistance. Although the maximal increase in CBF response to the two drugs was not significantly different, the ED50 of CVT-3146 and adenosine were 0.45 +/- 0.07 microg/kg and 47 +/- 7.77 microg/kg, respectively. The highest dose of CVT-3146 caused a much longer coronary vasodilation than the highest dose of adenosine. There were no significant differences in increases in cardiac output induced by higher doses of CVT-3146 or adenosine. Most importantly, CVT-3146 resulted in a smaller decrease in total peripheral resistance (TPR) compared to that seen with adenosine. In addition, CVT-3146 yielded a smaller increase in the lower body flow (LBF) than adenosine. Adenosine also caused dose-dependent renal vasoconstriction, whereas CVT-3146 did not affect the renal blood flow. The administration of CVT-3146 or adenosine caused a dose-dependent vasodilation in the mesentery, which was not significantly different from each other. In summary, CVT-3146 is a 100-fold more potent coronary vasodilator than adenosine. CVT-3146 causes smaller decreases in TPR and smaller increases in LBF than those induced by adenosine, indicating that it is more selective for coronary than peripheral vasodilation. Furthermore, CVT-3146 did not cause renal vasoconstriction. These features make CVT-3146 a better candidate for pharmacologic stress testing.

Adenosine↗
PubMed1978

The effects of vasodilators in the perfused hind limbs of spontaneously hypertensive and normotensive rats.

The vascular effects of isoproterenol and nitroprusside were evaluated in the perfused hind limbs of age-matched normotensive Wistar (NW) and spontaneously hypertensive (SH) rats. The vasodilating effects of these two compounds were assessed in the presence of concentrations of noradrenaline sufficient to raise the basal perfusion pressure to 85--110 mmHg. The sensitivity of the hind limb vessels of SH rats to the vasodilating action of isoproterenol (2.4 x 10-6--1.0 x 10-4 M) was slightly greater than that of the hind limb vessels of NW rats. On the other hand, the sensitivity to the vasodilating effect of nitroprusside (1.7 x 10-7--3.3 x 10-5 M) was similar in the hind limb vessels of both groups of rats. Propranolol (7.6 x 10-6 M) inhibited to a similar extent the isoproterenol-induced dilation of NW or SH hind limb vessels, but did not modify the vasodilating effect of nitroprusside in these preparations, thus suggesting that the vasodilating action of isoproterenol was due to the stimulation of vascular beta-adrenergic receptors. These results do not support the hypothesis suggesting the existence of a deficient vascular relaxation in hypertensive rats.

Animals↗
PubMed2000

K-Cl cotransport in vascular smooth muscle and erythrocytes: possible implication in vasodilation.

K-Cl cotransport, the electroneutral-coupled movement of K and Cl ions, plays an important role in regulatory volume decrease. We recently reported that nitrite, a nitric oxide derivative possessing potent vasodilation properties, stimulates K-Cl cotransport in low-K sheep red blood cells (LK SRBCs). We hypothesized that activation of vascular smooth muscle (VSM) K-Cl cotransport by vasodilators decreases VSM tension. Here we tested this hypothesis by comparing the effects of commonly used vasodilators, hydralazine (HYZ), sodium nitroprusside, isosorbide mononitrate, and pentaerythritol, on K-Cl cotransport in LK SRBCs and in primary cultures of rat VSM cells (VSMCs) and of HYZ-induced K-Cl cotransport activation on relaxation of isolated porcine coronary rings. K-Cl cotransport was measured as the Cl-dependent K efflux or Rb influx in the presence and absence of inhibitors for other K/Rb transport pathways. All vasodilators activated K-Cl cotransport in LK SRBCs and HYZ in VSMCs, and this activation was inhibited by calyculin and genistein, two inhibitors of K-Cl cotransport. KT-5823, a specific inhibitor of protein kinase G, abolished the sodium nitroprusside-stimulated K-Cl cotransport in LK SRBCs, suggesting involvement of the cGMP pathway in K-Cl cotransport activation. Hydralazine, in a dose-dependent manner, and sodium nitroprusside relaxed (independently of the endothelium) precontracted arteries when only K-Cl cotransport was operating and other pathways for K/Rb transport, including the Ca-activated K channel, were inhibited. Our findings suggest that K-Cl cotransport may be involved in vasodilation.

Alkaloids↗
PubMed2003

Regulation of nitric oxide-dependent vasodilation in coronary arteries of estrogen receptor-alpha-deficient mice.

Estrogen has been shown to increase endothelium-dependent vasodilation and expression of endothelial nitric oxide (NO) synthase (eNOS); however, the role of estrogen receptors in mediating estrogen effects on endothelial function remains to be elucidated. The purpose of this study was to test the hypothesis that estrogen modulates NO-dependent vasodilation of coronary arteries through its action on estrogen receptor-alpha (ER-alpha) to increase protein levels of eNOS and Cu/Zn superoxide dismutase (SOD-1). Vasodilation to acetylcholine (ACh) and sodium nitroprusside was assessed in isolated coronary arteries from intact and ovariectomized female wild-type (WT) and ER-alpha knockout (ERalphaKO) mice. Protein levels for eNOS and SOD-1 were also evaluated. Vasodilation to ACh was not significantly altered in ERalphaKO mice compared with WT mice. Ovariectomy reduced responsiveness to ACh in ERalphaKO mice but not WT mice. Responses to sodium nitroprusside were not altered by disruption of ER-alpha or by ovariectomy. Supplementation with estrogen restored ACh-induced vasodilation in ovariectomized ERalphaKO mice. eNOS protein was reduced in ERalphaKO mice compared with WT mice. Ovariectomy caused a further reduction in eNOS protein in ERalphaKO mice, but this reduction was reversed by estrogen treatment. SOD-1 protein levels were increased by disruption of ER-alpha. Ovariectomy reduced SOD-1 protein in ERalphaKO mice, but this reduction was partially reversed by estrogen replacement. These results suggest that estrogen modulation of eNOS protein content is mediated in part through ER-alpha. NO-dependent responses are preserved in ERalphaKO mice, possibly through increased SOD-1 expression and enhanced bioavailability of NO.

Acetylcholine↗
PubMed1996

Nitric oxide regulates endothelium-dependent vasodilator responses in rabbit hindquarters vascular bed in vivo.

The objective of this study was to determine whether nitric oxide (NO) could function as a negative feedback modulator of endothelium-dependent vasodilation in vivo. To this end, the influence of exogenous NO on vasodilator responses in the rabbit hindquarters vascular bed was determined. Previous in vitro studies have demonstrated that NO inhibits both neuronal NO synthase from rat cerebellum as well as NO synthase derived from bovine aortic endothelial cells. The present study was conducted in the rabbit hindquarters vascular bed under conditions of constant blood flow so that changes in pressure directly reflected changes in vascular resistance. Under these in vivo conditions, the NO donor agent S-nitroso-N-acetylpenicillamine (SNAP) reversibly attenuated responses to the endothelium-dependent vasodilators, acetylcholine and bradykinin. In contrast, SNAP did not influence the endothelium-independent vasodilator response to SNAP itself or to 8-bromoguanosine 3',5'-cyclic monophosphate. These observations indicate clearly that NO interferes with endothelium-dependent vasodilator action and support the view that endogenous NO may actually play a physiological role in regulating vascular tone.

Acetylcholine↗
PubMed2000

Impaired endothelium-mediated vasodilation is not the principal cause of vasoconstriction in heart failure.

The extent to which abnormal endothelium-dependent vasodilator mechanisms contribute to abnormal resting vasoconstriction and blunted reflex vasodilation seen in heart failure is unknown. The purpose of this study was to test the hypothesis that the resting and reflex abnormalities in vascular tone that characterize heart failure are mediated by abnormal endothelium-mediated mechanisms. Thirteen advanced heart-failure patients (New York Heart Association III-IV) and 13 age-matched normal controls were studied. Saline, acetylcholine (20 microg/min), or L-arginine (10 mg/min) was infused into the brachial artery, and forearm blood flow was measured by venous plethysmography at rest and during mental stress. At rest, acetylcholine decreased forearm vascular resistance in normal subjects, but this response was blunted in heart failure. During mental stress with intra-arterial acetylcholine or L-arginine, the decrease in forearm vascular resistance was not greater than during saline control in heart failure [saline control vs. acetylcholine (7 +/- 3 vs. 6 +/- 3, P = NS) or vs. L-arginine (9 +/- 2 units, P = NS)]. The increase in forearm blood flow was not greater than during saline control in heart failure [saline control vs. acetylcholine (1. 2 +/- 0.3 vs. 1.3 +/- 0.3, P = NS), or vs. L-arginine (1.2 +/- 0.2 ml x min(-1) x 100 ml(-1), P = NS)]. Furthermore, during mental stress with nitroprusside, the decrease in forearm vascular resistance was not greater than during saline control [saline control vs. nitroprusside (7 +/- 3 vs. 5 +/- 4 ml x min(-1) x 100 g(-1), P = NS)], and the increase in forearm blood flow was not greater than during saline control [saline control vs. nitroprusside (1.2 +/- 0.3 vs. 1.3 +/- 0.5 ml x min(-1) x 100 g(-1), P = NS)]. Because the endothelial-independent agent nitroprusside was unable to restore resting and reflex vasodilation to normal in heart failure, we conclude that impaired endothelium-mediated vasodilation with acetylholine-nitric oxide cannot be the principal cause of the attenuated resting- or reflex-mediated vasodilation in heart failure.

Acetylcholine↗
PubMed2000

Vasodilator mechanisms in the coronary circulation of endothelial nitric oxide synthase-deficient mice.

Previous studies have demonstrated that responses to endothelium-dependent vasodilators are absent in the aortas from mice deficient in expression of endothelial nitric oxide synthase (eNOS -/- mice), whereas responses in the cerebral microcirculation are preserved. We tested the hypothesis that in the absence of eNOS, other vasodilator pathways compensate to preserve endothelium-dependent relaxation in the coronary circulation. Diameters of isolated, pressurized coronary arteries from eNOS -/-, eNOS heterozygous (+/-), and wild-type mice (eNOS +/+ and C57BL/6J) were measured by video microscopy. ACh (an endothelium-dependent agonist) produced vasodilation in wild-type mice. This response was normal in eNOS +/- mice and was largely preserved in eNOS -/- mice. Responses to nitroprusside were also similar in arteries from eNOS +/+, eNOS +/-, and eNOS -/- mice. Dilation to ACh was inhibited by N(G)-nitro-L-arginine, an inhibitor of NOS in control and eNOS -/- mice. In contrast, trifluoromethylphenylimidazole, an inhibitor of neuronal NOS (nNOS), decreased ACh-induced dilation in arteries from eNOS-deficient mice but had no effect on responses in wild-type mice. Indomethacin, an inhibitor of cyclooxygenase, decreased vasodilation to ACh in eNOS-deficient, but not wild-type, mice. Thus, in the absence of eNOS, dilation of coronary arteries to ACh is preserved by other vasodilator mechanisms.

Acetylcholine↗
PubMed2000

Mechanism of adenosine-induced vasodilation in rat diaphragm microcirculation.

The mechanism of adenosine-induced vasodilation in rat diaphragm microcirculation was investigated using laser Doppler flowmetry. Adenosine (10(-5), 3.2 x 10(-5), and 10(-4) M), the nonselective adenosine agonist 5'-N-ethylcarboxamido-adenosine (NECA) (10(-8)-10(-7) M), the specific A(2A) agonist 2-p-(2-carboxyethyl)phenyl-amino-5'-N-ethyl carboxamidoadenosine (CGS-21680) (10(-8)-10(-7) M), and the adenosine agonist with higher A(1)-receptor affinity, R-N(6)-phenylisopropyladenosine (R-PIA) (10(-7), 3.2 x 10(-7), and 10(-6) M) elicited a similar degree of incremental increase of microcirculatory flow in a dose-dependent manner. The ATP-dependent potassium (K(ATP)) channel blocker glibenclamide (3.2 x 10(-6) M) significantly attenuated the vasodilation effects of these agonists. Adenosine-induced vasodilation could be significantly attenuated by the nonselective adenosine antagonist 8-(p-sulfophenyl)-theophylline (3 x 10(-5) M) or the selective A(2A) antagonist 4-(2-[7-amino-2-(2-furyl)[1,2, 4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl) phenol (ZM-241385, 10(-6) M), but not by the selective A(1) antagonist 8-cyclopentyl-1, 3-dipropylxanthine (5 x 10(-8) M). Adenylate cyclase inhibitor N-(cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride (MDL-12330A, 10(-5)M) effectively suppressed the vasodilator response of adenosine and forskolin. These results suggest that adenosine-induced vasodilation in rat diaphragm microcirculation is mediated through the stimulation of A(2A) receptors, which are coupled to adenylate cyclase activation and opening of the K(ATP) channel.

Adenosine↗