Leptin causes vasodilation in humans.

Leptin, a product of the ob gene, plays an important role in the regulation of body fat and has been suggested to cause vasodilation in rats. The purpose of this study was to evaluate whether leptin also has a vasodilating effect in humans. Using a strain-gauge plethysmography, we evaluated forearm blood flow (FBF) during intra-arterial infusion of leptin (1, 10 or 100 ng/kg/min for 5 min) in the absence and presence of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA; 8 micromol/min for 5 min) in ten healthy men (mean age, 23.0+/-1.2 years). Leptin infusion significantly increased the FBF (8.5+/-3.8, 20.3+/-7.0 and 17.7+/-5.4% at 1, 10 and 100 ng/kg/min of leptin, respectively; p<0.05) and the forearm vascular resistance (FVR; -6.9+/-3.1, -14.6+/-4.3 and -13.4+/-3.9% at 1, 10 and 100 ng/kg/min of leptin, respectively; p<0.05). No significant changes in blood pressure or heart rate were detected during infusion of leptin. The intra-arterial infusion of L-NMMA did not alter the FBF response (6.6+/-4.9, 22.1+/-7.5, 13.3+/-3.2% at 1, 10 and 100 ng/kg/min of leptin, respectively) or the FVR response (-4.3+/-4.6, -15.2+/-5.4, -11.1+/-2.5% at 1, 10 and 100 ng/kg/min of leptin, respectively) to leptin. These findings suggest that leptin per se directly causes vasodilation and that leptin-induced vasodilatation is nitric oxide-independent in healthy men.     

Increased coronary effects of stimulation of endothelin-B receptor in experimental hypercholesterolemia

BACKGROUND: Vasoconstriction in response to endothelin-1 has been shown to be primarily related to its effects on the endothelin-A receptor. Experimental hypercholesterolemia is associated with an increase in coronary vasoconstrictor response to endothelin-1 in vivo, although the relative contributions of subtypes of endothelin receptor in this model remain unknown. OBJECTIVE: To test the hypothesis that there is an increase in coronary vasoconstriction in response to stimulation of endothelin-B receptor in hypercholesterolemia, which might be related to attenuation of activity of endothelin-derived relaxing factor. METHODS: We infused 5 ng/kg/min sarafotoxin, a specific endothelin-B receptor agonist, or 50 micrograms/kg/min NG-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of nitric oxide synthase, into the left anterior descending coronary arteries of pigs before and after feeding them a cholesterol-rich diet for 10 weeks. RESULTS: There was a significant increase in serum level of cholesterol. After 10 weeks, infusion of sarafotoxin resulted in an accentuated decrease in coronary blood flow (CBF) compared with baseline (decreases by 60 +/- 7 versus 34 +/- 6%, P < 0.05). There was no significant difference between the effects on diameter of coronary arteries for the two time periods. The effect of L-NMMA on CBF was attenuated after 10 weeks (by 5 +/- 10.1 versus 45.6 +/- 4.7%, P < 0.05). Endothelin-receptor status of epicardial coronary arteries remained unchanged. Sarafotoxin and L-NMMA were co-infused at the above-mentioned doses into normolipidemic animals; the decrease in CBF in response to this co-infusion was comparable to the decrease observed with sarafotoxin alone in hypercholesterolemic animals (decreases of 67 +/- 5 versus 60 +/- 7, NS). CONCLUSIONS: The present results demonstrate that selective stimulation of the endothelin-B receptor increases coronary vasoconstriction in experimental hypercholesterolemia, primarily at the level of the microvasculature. These findings may be related to the attenuation of activity of endothelin-derived relaxing factor in this model, and support the hypothesis that endothelin-B receptor plays a role in the regulation of coronary vascular tone in pathophysiologic states.     

Cytochrome P450 2C9 is involved in flow-dependent vasodilation of peripheral conduit arteries in healthy subjects and in patients with chronic heart failure

BACKGROUND: Flow-mediated dilation (FMD) of human conduit arteries is, in part, related to shear stress-induced release of endothelium-derived nitric oxide (NO). However, NO synthase inhibitors do not completely abolish this FMD-response. Recently, a cytochrome P450 (CYP) epoxygenase of the 2C family was linked to NO- and prostacyclin-independent relaxation of conduit arteries. We therefore evaluated the contribution of CYP 2C9 to FMD in humans. METHODS AND RESULTS: FMD of the radial artery was determined in 12 healthy volunteers by high-resolution ultrasound and analyzed before and after intra-arterial infusion of sulfaphenazole, a specific CYP 2C9 inhibitor, L-NMMA (NO synthase inhibitor) and co-infusion of both. Endothelium-independent vasodilation was characterized after intra-arterial infusion of SNP. FMD was reduced after sulfaphenazole (11.5+/-0.87% vs. 7.4+/-0.95%, p<0.01), after L-NMMA (6.0+/-0.71%; p<0.01), and after co-infusion 3.9+/-0.73% (p<0.05 vs. L-NMMA; p<0.01 vs. sulfaphenazole). Sulfaphenazole had no effect on endothelium-independent vasodilation. In patients with chronic heart failure, the portion of FMD blocked by sulfaphenazole was not affected. CYP 2C was detected by immunohistochemistry in radial artery samples obtained from patients undergoing coronary bypass surgery. CONCLUSIONS: FMD in human conductance arteries is reduced after inhibition of CYP 2C9, supporting the concept that CYP 2C metabolites contribute to endothelium-mediated vasodilation of peripheral conduit arteries in vivo. In patients with heart failure, the CYP-dependent FMD appears to be preserved.     

Important role of endogenous hydrogen peroxide in pacing-induced metabolic coronary vasodilation in dogs in vivo.

OBJECTIVES: We examined whether endogenous hydrogen peroxide (H2O2) is involved in pacing-induced metabolic vasodilation in vivo. BACKGROUND: We have previously demonstrated that endothelium-derived H2O2 is an endothelium-derived hyperpolarizing factor in canine coronary microcirculation in vivo. However, the role of endogenous H2O2 in metabolic coronary vasodilation in vivo remains to be examined. METHODS: Canine subepicardial small coronary arteries (> or =100 microm) and arterioles (<100 microm) were continuously observed by a microscope under cyclooxygenase blockade (ibuprofen, 12.5 mg/kg intravenous [IV]) (n = 60). Experiments were performed during paired right ventricular pacing under the following 7 conditions: control, nitric oxide (NO) synthase inhibitor (N(G)-monomethyl-L-arginine [L-NMMA], 2 micromol/min for 20 min intracoronary [IC]), catalase (a decomposer of H2O2, 40,000 U/kg IV and 240,000 U/kg/min for 10 min IC), 8-sulfophenyltheophylline (SPT) (an adenosine receptor blocker, 25 mug/kg/min for 5 min IC), L-NMMA+catalase, L-NMMA+tetraethylammonium (TEA) (K(Ca)-channel blocker, 10 microg/kg/min for 10 min IC), and L-NMMA+catalase+8-SPT. RESULTS: Cardiac tachypacing (60 to 120 beats/min) caused coronary vasodilation in both-sized arteries under control conditions in response to the increase in myocardial oxygen consumption. The metabolic coronary vasodilation was decreased after L-NMMA in subepicardial small arteries with an increased fluorescent H2O2 production compared with catalase group, whereas catalase decreased the vasodilation of arterioles with an increased fluorescent NO production compared with the L-NMMA group, and 8-SPT also decreased the vasodilation of arterioles. Furthermore, the metabolic coronary vasodilation was markedly attenuated after L-NMMA+catalase, L-NMMA+TEA, and L-NMMA+catalase+8-SPT in both-sized arteries. CONCLUSIONS: These results indicate that endogenous H2O2 plays an important role in pacing-induced metabolic coronary vasodilation in vivo.     

Magnesium causes nitric oxide independent coronary artery vasodilation in humans

OBJECTIVE—To determine how magnesium affects human coronary arteries and whether endothelium derived nitric oxide (EDNO) is involved in the coronary arterial response to magnesium.
DESIGN—Quantitative coronary angiography and Doppler flow velocity measurements were used to determine the effects of the nitric oxide synthase inhibitor N^G-monomethyl-L-arginine (L-NMMA) on magnesium induced dilation of the epicardial and resistance coronary arteries.
SETTING—Hiroshima University Hospital a tertiary cardiology centre.
PATIENTS—17 patients with angiographically normal coronary arteries.
INTERVENTIONS—Magnesium sulfate (MgSO₄) (0.02 mmol/min and 0.2 mmol/min) was infused for two minutes into the left coronary ostium before and after intracoronary infusion of L-NMMA.
MAIN OUTCOME MEASURES—Diameter of the proximal and distal segments of the epicardial coronary arteries and coronary blood flow.
RESULTS—At a dose of 0.02 mmol/min, MgSO₄ did not affect the coronary arteries. At a dose of 0.2 mmol/min, MgSO₄ caused coronary artery dilation (mean (SEM) proximal diameter 3.00 (0.09) to 3.11 (0.09) mm; distal 1.64 (0.06) to 1.77 (0.07) mm) and increased coronary blood flow (79.3 (7.5) to 101.4 (9.9) ml/min, p < 0.001 v baseline for all). MgSO₄ increased the changes in these parameters after the infusion of L-NMMA (p < 0.001 v baseline).
CONCLUSIONS—Magnesium dilates both the epicardial and resistance coronary arteries in humans. Furthermore, the coronary arterial response to magnesium is dose dependent and independent of EDNO.


Keywords: coronary artery; coronary blood flow; magnesium sulfate; nitric oxide     

Insulin-stimulated myocardial glucose uptake and the relation to perfusion and the nitric oxide system

In skeletal muscle, insulin increases glucose uptake through endothelium-derived nitric oxide (EDNO)-dependent vasodilation. Insulin also enhances myocardial glucose uptake, but it is unknown whether vasodilation participates in the underlying mechanism. We studied whether insulin-stimulated myocardial glucose uptake (MGU) is associated with perfusion changes and whether MGU is EDNO dependent. Myocardial perfusion (MBF) and MGU were measured three times with positron emission tomography in 8 healthy volunteers (56 +/- 6 years): (1). During a hyperinsulinemic euglycemic clamp (clamp), (2). during clamp and blockage of the nitric oxide synthesis by L-NMMA and (3). during clamp and nitric oxide stimulation with nitroglycerin. We measured MBF at rest before and during clamp utilizing (13)N-ammonia and (18)F-fluoro-deoxy-glucose as perfusion and glucose tracers, respectively. Hemodynamics were affected neither by insulin nor by L-NMMA. Nitroglycerin reduced rate-pressure product. Insulin did not affect MBF. L-NMMA reduced MBF (0.60 +/- 0.15 vs. 0.66 +/- 0.14 ml/g/min; p < 0.05), while MGU was unchanged. Nitroglycerin did not alter MBF, while MGU was reduced (0.44 +/- 0.11 vs. 0.52 +/- 0.13 micromol/g/min; p = 0.05). Insulin-stimulated MGU does not rely on a simultaneous increment of MBF. Myocardial glucose uptake can be stimulated even when MBF decreases, suggesting that autoregulation of MGU is preserved despite uncoupling of vascular autoregulation.     

Effect of activation of the H1 receptor on coronary hemodynamics in man

We evaluated the effects of selective activation of H1 receptors on coronary hemodynamics in 16 patients divided into two groups: group A, 11 patients with atypical angina or valvular heart disease and normal coronary arteries, and group B, five patients with spontaneous angina, four of whom had significant (greater than 70% stenosis) coronary artery disease and one with normal coronaries. Selective H1 receptor stimulation was achieved by infusing 0.5 microgram/kg/min of histamine intravenously for 5 min after pretreatment with cimetidine (25 mg/kg). Heart rate was maintained constant (100 beats/min) by coronary sinus pacing and coronary blood flow (CBF) was measured by thermodilution. In group A, during histamine infusion mean aortic pressure fell from 99 +/- 5 to 77 +/- 4 mm Hg (mean +/- SEM, p less than .001), coronary vascular resistance (CVR) decreased from 1.07 +/- 0.17 to 0.82 +/- 0.14 mm Hg/ml/min (p less than .02), and CBF and myocardial oxygen consumption remained unchanged. None of the patients in this subgroup developed angina during histamine infusion. In group B, while no significant average changes in mean arterial pressure, CVR, or CBF were observed, two of the five patients (40%) developed angina during histamine infusion, accompanied by ST-T elevation, a decrease in CBF, and an increase in CVR. In one of these two patients circumflex coronary arterial spasm was angiographically demonstrated during histamine-induced angina. Our results suggest that stimulation of the H1 receptor induces a reduction of CVR, probably resulting from vasodilation of small coronary resistance vessels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers synergistically increase coronary blood flow in canine ischemic myocardium: role of bradykinin

OBJECTIVES: We examined whether the combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) synergistically mediates coronary vasodilation and improves myocardial metabolic and contractile dysfunction in ischemic hearts. BACKGROUND: Either an ACE inhibitor or ARB mediates coronary vasodilation in ischemic hearts. METHODS: In dogs with myocardial ischemia, we infused an ACE inhibitor (temocaprilat, 10 microg/kg/min) or ARB (RNH-6270, 10 microg/kg/min) into the coronary artery. RESULTS: Perfusion pressure of the left anterior descending coronary artery was reduced from 104 +/- 8 to 42 +/- 2 mm Hg, so that coronary blood flow (CBF) decreased to one-third of the baseline value. Ten minutes after starting the infusion of temocaprilat, the cardiac bradykinin level increased (from 32 +/- 6 to 98 +/- 5 pg/ml). Coronary blood flow (29 +/- 2 to 44 +/- 3 ml/100 g/min) and the cardiac level of nitric oxide (NO) (7.8 +/- 1.9 to 17.5 +/- 3.2 microm) also increased, with these changes being attenuated by either N(omega)-nitro-L-arginine methyl ester or HOE140. RNH-6270 alone caused a modest increase in CBF (34 +/- 3 ml/100 g/min), with no increase in the cardiac NO or bradykinin levels. Both temocaprilat and RNH-6270 caused a further increase in both CBF (51 +/- 4 ml/100 g/min) and cardiac NO levels, without increasing the bradykinin level, and these changes were inhibited by HOE140. In the nonischemic heart, RNH-6270 augmented bradykinin-induced increases in CBF. CONCLUSIONS: The combination of an ACE inhibitor and ARB mediates greater increases in CBF and more potent cardioprotective effects through bradykinin-dependent mechanisms than either drug alone.     

Coronary dilation with standard dose dipyridamole and dipyridamole combined with handgrip

Intravenous dipyridamole is widely used to produce coronary vasodilation during cardiac imaging procedures. However, the routinely used dose of dipyridamole (0.56 mg/kg IV over 4 min) does not always result in maximal coronary dilation. The addition of isometric handgrip during dipyridamole coronary dilation has been reported to substantially increase coronary blood flow over dipyridamole alone. We compared the coronary vasodilation resulting from infusion of the standard dose of dipyridamole with that resulting from a maximally dilating dose of intracoronary papaverine in 12 patients with angiographically normal coronary arteries. We also assessed the effect on coronary blood flow velocity of the addition of isometric handgrip during dipyridamole coronary dilation. Changes in coronary blood flow velocity were measured with a 3F coronary Doppler catheter. The coronary flow reserve (peak/resting coronary flow velocity ratio) after dipyridamole (3.7 +/- 1.2 [mean +/- SD] was less than that seen after papaverine (4.4 +/- 0.5, p less than 0.05), and the coronary vascular resistance index during dipyridamole coronary vasodilation (0.28 +/- 0.09) was greater than during papaverine (0.22 +/- 0.03, p less than 0.05). The dipyridamole coronary flow reserve was less than 3.0 in four subjects and was 2.0 or less in two subjects. The addition of isometric handgrip to dipyridamole coronary vasodilation produced an 8% increase in mean heart rate and a 17% increase in mean arterial pressure, but coronary flow reserve was unchanged (3.8 +/- 1.1 before handgrip vs. 4.0 +/- 1.1 with handgrip). Quantitative angiography in six patients revealed no change in coronary caliber with the addition of handgrip.(ABSTRACT TRUNCATED AT 250 WORDS)     

AT1-receptor antagonism improves endothelial function in coronary artery disease by a bradykinin/B2-receptor-dependent mechanism

Impaired flow-dependent, endothelium-mediated vasodilation is an early finding in patients with coronary artery disease (CAD). Experimental and some clinical studies observed that angiotensin type-1 receptor antagonists (AT1A) enhance endothelium-dependent relaxation in CAD. The present study was designed to determine whether AT1A improves flow-dependent dilation (FDD) in patients with CAD and, if so, whether bradykinin and NO are involved. High-resolution ultrasound was used to measure radial artery diameter at rest and during reactive hyperemia, causing endothelium-mediated vasodilation. Twenty patients with CAD were randomly assigned to receive intrabrachial infusion of candesartan (800 microg/min) with and without icatibant, a bradykinin B2-receptor antagonist (90 microg/min; group A) or N-monomethyl-l-arginine (L-NMMA), an NO-synthase inhibitor (7 micromol/min; group B). The AT1A candesartan improved FDD by >40%, an effect that was inhibited by icatibant (group A: control, 7.3+/-0.9; candesartan, 10.3+/-1.1; candesartan+icatibant, 5.0+/-0.5%). Similarly, L-NMMA blunted the beneficial effect of candesartan (group B: control, 6.3+/-0.6; candesartan, 8.9+/-0.6; candesartan+L-NMMA: 4.7+/-0.5%; each P<0.01). The angiotensin type-1 receptor antagonist candesartan improves flow-dependent, endothelium-mediated vasodilation in patients with CAD. This effect is inhibited by either icatibant and or L-NMMA, suggesting that both bradykinin and NO contribute to the vascular effects of AT1-receptor antagonists in this patient population.     

The contribution of nitric oxide and vasodilatory prostanoids to bradykinin-mediated vasodilation in Type 1 diabetes.

AIMS: To investigate the effect of bradykinin on endothelial tone in normoalbuminuric Type 1 diabetic patients and specifically whether any changes are mediated through nitric oxide or prostaglandins. METHODS: Forearm blood flow was measured using venous occlusion plethysmography at baseline and after brachial artery infusions of incremental doses of bradykinin (50, 100 and 200 ng/min) in 15 patients with Type 1 diabetes and 13 non-diabetic controls. Forearm blood flow at baseline and following bradykinin was then re-examined after local infusion of L-NMMA, a nitric oxide synthase inhibitor, and L-NMMA with indomethacin, a cyclo-oxygenase inhibitor. RESULTS: Baseline blood flow in the diabetic and control groups were similar (4.46 +/- 1.11 vs. 3.41 +/- 1.23 ml/min/100 ml, respectively; P = 0.07). After infusion of L-NMMA and L-NMMA with indomethacin, there was a similar reduction in blood flow responses to bradykinin in both groups. There was no significant difference between the diabetic patients and control subjects in the percentage reduction in forearm blood flow following L-NMMA (16.55 vs. 18.12%, respectively, P = 0.94) and L-NMMA with indomethacin (47.1 vs. 37.3%, respectively, P = 0.14). CONCLUSIONS: This study demonstrates that bradykinin-stimulated vasodilation is mediated by both nitric oxide and prostaglandin release from the endothelium in patients with Type 1 diabetes and normoalbuminuria, and in healthy control subjects. We have also shown that the relative contributions of nitric oxide and prostaglandin to bradykinin-mediated vasodilation are similar in these diabetic patients compared with non-diabetic subjects.     

Potential role of leptin and insulin resistance assessed by the glucose clamp technique in coronary artery disease

OBJECTIVES: Leptin may correlate with insulin resistance and be an important factor in patients with coronary artery disease. Therefore, we examined whether plasma leptin levels and insulin resistance are linked with coronary artery disease. METHODS: Plasma leptin levels and insulin resistance, assessed by the hyperinsulinemic euglycemic clamp technique, were measured in control subjects (n = 12, mean age 62 +/- 10 years), and in patients with obstructive coronary artery disease (n = 15, mean age 64 +/- 8 years) or vasospastic angina (n = 12, mean age 62 +/- 12 years). RESULTS: Plasma leptin levels were significantly higher (p < 0.017) in patients with obstructive coronary artery disease (8.4 +/- 2.7 ng/ml) and vasospastic angina (7.9 +/- 2.1 ng/ml) than in patients without obstructive coronary artery disease (4.7 +/- 1.4 ng/ml). Mean glucose infusion rate was significantly (p < 0.017) lower in patients with obstructive coronary artery disease (4.39 +/- 1.78 mg/kg/min) and vasospastic angina (3.57 +/- 1.72 mg/kg/min) than in patients without obstructive coronary artery disease (8.74 +/- 1.05 mg/kg/min). The plasma levels of leptin were negatively correlated with mean glucose infusion rate (r = -0.67, p < 0.01). The other coronary risk factors were similar in these three groups. CONCLUSIONS: Plasma leptin levels are correlated with insulin resistance and may be associated with coronary artery disease.     

Endothelin-dependent effects limit flow-induced dilation of conductance coronary vessels after blockade of nitric oxide formation in conscious dogs

OBJECTIVE: To determine whether endothelin (ET)-dependent effects limit shear stress-induced dilation of large epicardial coronary arteries after blockade of nitric oxide (NO) formation. METHODS: In conscious dogs instrumented for measuring coronary blood flow (CBF) and external diameter (CD) of the circumflex coronary artery, flow-dependent CD dilation was elicited by intracoronary (i.c.) adenosine (500 ng kg-1 min-1). RESULTS: I.c. adenosine increased CBF by 28 +/- 4 from 38 +/- 5 ml min-1 and CD by 0.25 +/- 0.03 from 3.53 +/- 0.07 mm without other hemodynamic effects. After N omega-nitro-L-arginine methyl ester (L-NAME), baseline CD fell (P < 0.01) to 3.35 +/- 0.08 mm but CBF was not significantly altered (36 +/- 5 ml min-1). CBF increases caused by adenosine were smaller (17 +/- 2 ml min-1, P < 0.05) and CD responses were nearly abolished (0.02 +/- 0.01 mm, P < 0.01). I.c. Ro 61-1790, an ETA receptor blocker, given after L-NAME did not significantly influence baseline CBF (36 +/- 5 ml min-1) but increased (P < 0.01) CD to 3.45 +/- 0.09 mm. CBF responses to adenosine were not significantly altered by Ro 61-1790 but CD responses (0.10 +/- 0.01 mm) were partially restored (P < 0.01). In contrast, blockade of ETB receptors with Ro 46-8443 after L-NAME had no further effects on CD and CBF responses to adenosine. CONCLUSION: ETA receptor-mediated effects limit flow-dependent dilation of large epicardial coronary arteries in conscious dogs. Suppression of the L-arginine/NO-dependent pathway with L-NAME reveals significant ET-dependent effects.     

Reproducible uniform coronary vasomotor tone with nitrocompounds: prerequisite of quantitative coronary angiographic trials

In quantitative analysis of repeated coronary angiograms, a variable vasomotor tone of the epicardial coronary arteries may influence the accuracy of the results. Therefore, we evaluated the extent and reproducibility of coronary artery dilation with nitrocompounds. In 32 patients with coronary artery disease, the vasodilatory response of angiographically normal coronary segments to different nitrocompounds was analyzed with the computer-assisted contour detection system CAAS. Twenty patients received 5 mg or 10 mg of isosorbide dinitrate sublingually. After 10 to 15 min, a maximal diameter increase was measured with an average of 16 +/- 11% (5 mg: P less than 0.01) and 28 +/- 13% (10 mg: P less than 0.001) from control. Another 12 patients received 0.025 mg per kg body weight of SIN-1, the active metabolite of molsidomine, as an intravenous infusion over 5 min. A comparable maximal dilation (29 +/- 5%; P less than 0.001) occurred after 10 to 15 min and could not be enhanced further with 0.8 mg nitroglycerin administered sublingually (28 +/- 7%; n.s.). One hour after square root of Sin-1, coronary dilation was still 24 +/- 8% (P less than 0.001 compared with control), and 0.8 mg of nitroglycerin sublingually reestablished the previous maximal dilation of 28 +/- 8%. We conclude that high doses of nitrocompounds induce a reproducible maximal coronary dilation that eliminates a substantial source of error in quantitative analysis of repeated coronary angiograms. At present, sublingual administrations of either 10 mg isosorbide dinitrate once or 0.8 mg nitroglycerin repeatedly seem to represent the easiest practicable modes to achieve maximal coronary vasodilation for an adequate period.     

Interaction between cholinergic and nitrergic vasodilation: a novel mechanism of blood pressure control

OBJECTIVE: Cholinergic vasodilation has been thought to play little if any role in the regulation of blood pressure in humans. Autonomic denervation potentiates the vasoconstriction evoked by nitric oxide synthase inhibition in humans, but the mechanism is unclear. We hypothesized that this may be related to loss of neuronal, non-nitric-oxide-dependent vasodilation. METHODS: To test this hypothesis, we examined effects of cholinergic blockade on blood pressure, heart rate and peripheral vascular responses to systemic infusion of the nitric-oxide-dependent vasoconstrictor L-NMMA (0.5 mg/kg/min over 15 min) in eight normal subjects. RESULTS: The L-NMMA-induced increase in mean (+/-S.E.) arterial pressure was roughly three times larger (P=0.002) in the presence than in the absence of cholinergic blockade (38+/-6 vs. 13+/-2 mmHg). Similarly, the increase in systemic and calf vascular resistance was more than twofold larger during L-NMMA-atropine. This potentiation was specific for nitric-oxide-dependent vasoconstriction, because atropine did not alter the responses to phenylephrine infusion. Cholinergic blockade also altered (P=0.004) the heart rate response to nitric oxide synthase inhibition; during L-NMMA alone heart rate decreased by 10+/-2 beats/min, whereas during L-NMMA-atropine infusion it increased by 14+/-4 beats/min. CONCLUSION: Cholinergic mechanisms play an important hitherto unrecognized role in offsetting the hypertension and cardiac sympathetic activation caused by nitric oxide synthase inhibition in humans. Decreased parasympathetic activity and impaired nitric oxide synthesis characterize several cardiovascular disease states, as well as normal aging. The conjunction of these two defects could trigger sudden death and contribute to the hypertension of the elderly.     

The effect of rapid decreases of blood pressure by different mechanisms on coronary flow and flow reserve in normal coronary arteries

BACKGROUND: Changes in mean blood pressure (MBP) alter coronary blood flow (CBF). We evaluated the acute effects of three hypotensive medications on CBF parameters in angiographically normal coronary arteries. METHODS: We performed CBF measurements using the Doppler wire at rest and during hyperemia produced by intracoronary adenosine (18 microg) as follows: 1) in the normal left circumflex coronary artery in 20 patients with coronary artery disease (measurements were performed without drugs, and after intravenous infusion of nitroprusside [0.5 to 2 microg/kg/min] and nitroglycerin [10 to 90 microg/min]; drugs were titrated to decrease MBP 20% to 25% below the control values, and heart rate was held constant using right atrial pacing); and 2) in the normal left anterior descending coronary artery in 19 patients without coronary artery disease (measurements were performed before and after intravenous clonidine infusion [150 microg in 5 min]; time-averaged peak velocity [APV], CBF, and coronary flow reserve [CFR] were measured). RESULTS: Similar decreases in MBP were obtained in the two patient groups. Lumen diameter at the site of Doppler measurements increased after all medications (P <.005), whereas CBF did not change significantly. The CFR decreased after nitroprusside (1.79 +/- 0.48 v 2.54 +/- 0.45, P=.000), did not change significantly after nitroglycerin (2.74 +/- 0.43 v 2.54 +/- 0.45, P =.097), and increased after clonidine (3.12 +/- 0.70 v 2.76 +/- 0.75, P =.006). CONCLUSIONS: In normal coronary arteries the infusion of three hypotensive medications to produce the same decreases in MBP is associated with different effects on CFR (increase with clonidine, decrease with nitroprusside, and no change with nitroglycerin).     

Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/reperfusion injury in canine coronary microcirculation in vivo

OBJECTIVES: We examined whether hydroxyfasudil, a specific Rho-kinase inhibitor, exerts cardioprotective effect on coronary ischemia/reperfusion (I/R) injury and, if so, whether nitric oxide (NO) is involved. BACKGROUND: Recent studies have demonstrated that Rho-kinase is substantially involved in the pathogenesis of cardiovascular diseases; however, it remains to be examined whether it is also involved in ischemia/reperfusion (I/R) injury. METHODS: Canine subepicardial small arteries (SA, >or=100 microm) and arterioles (A, <100 microm) were observed by a charge-coupled device intravital microscope during I/R. Coronary vascular responses to endothelium-dependent (acetylcholine, intracoronary [IC]) and -independent (papaverine, IC) vasodilators were examined after I/R under the following four conditions: control (n = 7), NO synthase inhibitor alone (N(G)-monomethl-L-arginine [L-NMMA], IC, n = 4), hydroxyfasudil alone (IC, n = 7), and hydroxyfasudil plus L-NMMA (n = 7). RESULTS: Hydroxyfasudil significantly attenuated serotonin (IC)-induced vasoconstriction of SA (-7 +/- 1% vs. 2 +/- 1%, p < 0.01). Coronary I/R significantly impaired coronary vasodilation to acetylcholine after I/R (SA, p < 0.05; and A, p < 0.01 vs. before I/R) and L-NMMA further reduced the vasodilation, whereas hydroxyfasudil completely preserved the responses. The vasoconstriction by L-NMMA after I/R was significantly improved by hydroxyfasudil in both-sized arteries (both p < 0.01). Expression of endothelial nitric oxide synthase (eNOS) protein in the ischemic endocardium of left anterior descending coronary artery area (as determined by Western blotting) significantly decreased (79 +/- 4%) compared with the nonischemic endocardium of LCX area (100 +/- 7%), which was improved by hydroxyfasudil (105 +/- 6%, p < 0.01). Hydroxyfasudil significantly reduced myocardial infarct size, and hydroxyfasudil with L-NMMA also reduced the infarct size compared with L-NMMA alone. CONCLUSIONS: Hydroxyfasudil exerts cardioprotective effects on coronary I/R injury in vivo, in which NO-mediated mechanism may be involved through preservation of eNOS expression.     

Effects of intravenous dobutamine on coronary vasomotion in humans

OBJECTIVES: We sought to investigate the vascular mechanisms of dobutamine-induced myocardial ischemia. BACKGROUND: Dobutamine stress is often used as a surrogate for exercise. The effects of dobutamine on the epicardial arteries are incompletely understood and possibly different from those of physical exercise. METHODS: Intravenous (IV) dobutamine (40 microg/kg per min) was administered in 19 patients with normal, 23 patients with mildly atherosclerotic, and 12 patients with stenotic coronary arteries. In another two groups of patients with stenotic arteries, IV dobutamine was preceded by 1) an intracoronary (IC) bolus of the alpha-adrenergic blocker phentolamine (12 microg/kg, n = 12); and 2) an IC infusion of the nitric oxide substrate L-arginine (150 micromol/l per min for 20 min, n = 11). Intravenous saline instead of dobutamine was infused into eight patients with normal arteries. After dobutamine (or saline), an IC bolus of isosorbide dinitrate (ISDN, 0.2 mg) was given. Coronary vasomotion was evaluated by quantitative coronary angiography on angiograms obtained after each dose of dobutamine, saline, phentolamine, L-arginine, and ISDN. RESULTS: Dobutamine increased the rate-pressure product and heart rate similarly in all patients except those who received saline. Dobutamine induced vasodilation in normal (change in luminal diameter [DeltaLD] vs. baseline: 19 +/- 2%) and in mildly atherosclerotic arteries (DeltaLD: 8 +/- 2%, p < 0.05 vs. normal). In stenotic arteries, dobutamine did not induce significant vasomotion (DeltaLD: -3 +/- 3%); the latter was improved by L-arginine (DeltaLD: 10 +/- 3%, p < 0.05 vs. stenotic arteries) and fully restored by phentolamine (DeltaLD: 19 +/- 3%, p < 0.05 vs. stenotic arteries). CONCLUSIONS: Endothelial dysfunction and enhanced alpha-adrenergic tone contribute to the loss of dobutamine-induced vasodilation in coronary atherosclerosis. In contrast to physical exercise, dobutamine does not induce "paradoxical vasoconstriction" of atherosclerotic coronary arteries.     

Loss of the coronary microvascular response to acetylcholine in cardiac transplant patients.

BACKGROUND. The coronary arteries of transplanted hearts frequently develop accelerated diffuse arteriosclerosis. The effects of this disease on resistance vessel function are unknown. METHODS AND RESULTS. To investigate the integrity of endothelium-dependent small-vessel vasodilation in transplanted hearts, coronary blood flow (CBF) responses to the endothelium-dependent dilator acetylcholine (10(-8) to 10(-6) M) and the essentially endothelium-independent dilator adenosine (10(-6) to 10(-4) M) were assessed in 40 studies of 29 transplant patients 1-3 years after transplantation and in seven nontransplanted controls. CBF was measured at constant arterial pressure with a Doppler catheter in the left anterior descending coronary artery. Controls, year 1 transplant patients, and year 2 transplant patients had similar increases in CBF in response to acetylcholine (232 +/- 40%, 200 +/- 41%, and 201 +/- 54%, respectively; p = NS), whereas year 3 transplant patients had increased CBF of only 100 +/- 39% (p less than 0.05 versus controls). An index of the proportion of CBF reserve attributable to endothelium-dependent dilation was obtained by normalizing each patient's peak acetylcholine flow response by the peak adenosine flow response. In patients receiving both acetylcholine and adenosine, endothelium-dependent flow responses declined over time [57 +/- 9% in controls, 56 +/- 10% for year 1, 47 +/- 12% for year 2, and 29 +/- 9% for year 3 (p less than 0.05 versus controls)]. An increased mean cyclosporine level (range, 99-261 ng/ml) (r = 0.67, p = 0.004) and increased transplant recipient age (range, 20-63 years) (r = 0.51, p = 0.004) predicted a preserved endothelium-dependent microvascular response. CONCLUSIONS. Thus, microvascular endothelium-dependent dilation deteriorates over time in the transplanted heart, which may reflect underlying graft arteriosclerosis and contribute to ischemic damage of the myocardium.     

Abnormal endothelium-dependent coronary vasomotion in hypertensive patients.

Coronary vasomotion is abnormal in hypertensive patients, as evidenced by reduced coronary vasodilator reserve, but endothelium-dependent coronary vasomotion in hypertensive patients has not been studied. To assess the integrity of endothelium-dependent vasodilation, the response of coronary arteries to acetylcholine (an endothelium-dependent vasodilator) and nitroglycerin (an endothelium-independent vasodilator) was studied in 14 patients undergoing cardiac catheterization. Eight patients with essential hypertension were compared with six normotensive patients. None had obstructive disease detectable by coronary arteriography. Coronary artery diameter was measured with digital-subtracted arteriography and coronary blood flow velocity with a Doppler flow velocity catheter. At baseline, coronary artery diameter was similar in the hypertensive and the normotensive control patients (2.4 +/- 0.3 vs. 2.8 +/- 0.7 mm). During intracoronary acetylcholine infusion (30 micrograms/min), coronary artery diameter decreased to 1.3 +/- 0.7 mm in the hypertensive patients (p less than 0.005), but was unchanged (2.7 +/- 0.8 mm) in the normotensive patients. With intracoronary nitroglycerin (200 micrograms), coronary artery diameter increased significantly in both groups. Calculated coronary blood flow decreased during acetylcholine infusion by 59 +/- 31% in the hypertensive patients but increased by 3 +/- 3% in the normotensive group (p less than 0.005). There was a significant negative correlation between the percent change in estimated coronary blood flow during acetylcholine infusion and mean arterial pressure measured at baseline (r = 0.67, p less than 0.02). Therefore, these hypertensive patients exhibited marked coronary vasoconstriction in response to intracoronary acetylcholine but normal vasodilation in response to nitroglycerin, suggesting abnormal endothelium-dependent vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)