Hisashi Kai

Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia.

BACKGROUNDThis study aimed to determine if cholesterol-lowering therapy improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia.METHODS AND RESULTSNine patients with hypercholesterolemia were studied before and after cholesterol-lowering therapy with pravastatin (an inhibitor of HMG-CoA reductase) for 6 +/- 3 months, which lowered serum cholesterol from 272 +/- 8 to 187 +/- 16 mg/dL (P < .01). Control patients with serum cholesterol of 218 +/- 23 mg/dL also were studied twice in a similar interval (8 +/- 2 months) with no cholesterol-lowering drugs. Acetylcholine (the endothelium-dependent vasodilator) and papaverine and nitrate (endothelium-independent vasodilators) were infused into the study coronary artery. Changes in the diameter of the epicardial coronary artery and coronary blood flow were assessed by quantitative coronary arteriography and an intracoronary Doppler catheter. In patients with hypercholesterolemia, acetylcholine-induced vasoconstriction of the epicard...

Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans.

BackgroundIt has been suggested that endothelium-related vasomotion is important in the control of coronary circulation. Our goal was to determine if endothelium-dependent dilation of the coronary vasculature was altered with aging in 18 patients with atypical chest pain (age, 23-70 years) who had angiographically normal coronary arteries and no coronary risk factors. Methods and ResultsWe infused an endothelium-dependent vasodilator acetylcholine (1, 3, 10, and 30, gg/min) and an endothelium-independent vasodilator papaverine (10 mg) into the left coronary artery. The large coronary diameter was assessed by arteriography, and the increase in coronary blood flow was measured using the intracoronary Doppler catheter technique. Acetylcholine increased coronary blood flow in a dose-dependent manner with no changes in arterial pressure and heart rate. The maximum increase in coronary blood flow evoked by acetylcholine varied widely among patients (increase in coronary blood flow ranged from 200%o to 560%o) and was correlated significantly with aging (r=-.86, p<.001), whereas the peak coronary blood flow response to papaverine was affected slightly by aging (r=-.44, P=.07). The percent increase in blood flow response to acetylcholine to the response to papaverine correlated with aging (r=-.87, p<.001). The slope of the coronary blood flow response to acetylcholine also correlated significantly with aging. The large epicardial coronary artery response to the low doses of acetylcholine (10 pg/min) correlated inversely with aging. ConclusionsThe results of this study suggest that endothelium-dependent dilation of coronary arteries evoked by acetylcholine may be decreased with aging in humans.

Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions.

We examined whether coronary risk factors and atherosclerotic lesions in the study artery were associated with impaired endothelium-dependent dilation of coronary resistance arteries. Acetylcholine (ACH) at graded doses (1, 3, 10 and 30 micrograms/min) and papaverine (10 mg) were selectively infused into the left anterior descending coronary artery of 28 patients, in whom the study artery was angiographically normal (n = 16) or with mild stenosis < or = 40% (n = 12). Coronary blood flow (CBF) was estimated from the product of mean CBF velocity measured by an intracoronary Doppler catheter and the arterial cross-sectional area of the study artery determined by quantitative arteriography. ACH increased CBF in a dose-dependent manner. However, the maximum CBF response to ACH varied widely among patients (from 50% to 660%). By multivariate analysis, the presence of atherosclerotic lesions in the study artery was an independent predictor for impaired CBF response to ACH (P < 0.01). Hypertension (P < 0.001), hypercholesterolemia (r = -0.52, P < 0.005), age > or = 50 yr (P < 0.01) and total number of coronary risk factors (r = -0.62, P < 0.001) were associated with the impaired increase in CBF with ACH by univariate analysis. The percent increase in CBF evoked with papaverine did not correlate with these risk factors. The results suggest that mild atherosclerotic lesions in the study artery and coronary risk factors are accompanied by impaired endothelium-dependent dilation of coronary resistance arteries evoked with ACH. Endothelial dysfunction of coronary resistance arteries may result in altered regulation of myocardial perfusion in patients with mild coronary atherosclerosis and coronary risk factors.

Impaired Endothelium-Dependent Vasodilation of Large Epicardial and Resistance Coronary Arteries in Patients With Essential Hypertension Different Responses to Acetylcholine and Substance P

Hypertensive patients have impaired endothelium-dependent coronary vasodilation evoked with acetylcholine. The aim of this study was to examine whether the impaired endothelium-dependent dilation of coronary arteries is related to a specific abnormality of the muscarinic receptor that mediates the effects of acetylcholine. Responses of the large epicardial and resistance coronary arteries were assessed in seven hypertensive patients (mean arterial pressure, 106 +/- 14 mm Hg) and seven control subjects (83 +/- 6 mm Hg, P < .01) during cardiac catheterization. To assess coronary endothelial function, we infused acetylcholine and substance P (endothelium-dependent agents that act on different receptors) and papaverine and nitrate (direct vascular smooth muscle dilators) into the left anterior descending coronary artery and determined coronary artery diameter by arteriography and coronary blood flow with an intracoronary Doppler catheter technique. In control subjects, 3 micrograms/min acetylcholine increased (P < .05) and 30 micrograms/min acetylcholine decreased (P < .05) arterial diameter, and in hypertensive patients, 1, 3, 10, and 30 micrograms/min acetylcholine decreased arterial diameter in a dose-dependent manner. Substance P at 3, 10, and 30 ng/min caused comparable increases in diameter in both groups. Increases in coronary blood flow with both acetylcholine and substance P were significantly (P < .01) blunted in hypertensive patients compared with control subjects. No significant differences were noted between the groups in the responses of large epicardial coronary artery diameter and coronary blood flow to papaverine and nitrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of l-arginine on acetylcholine-induced endothelium-dependent vasodilation differs between the coronary and forearm vasculatures in humans☆

OBJECTIVESnThe goal of this study was to determine whether the effect of L-arginine on endothelium-dependent vasodilation evoked with acetylcholine differs between the coronary and forearm vasculatures in humans.nnnBACKGROUNDnAdministration of L-arginine, a substrate in the production of endothelium-derived nitric oxide, may stimulate the release of nitric oxide.nnnMETHODSnSeven patients with normal coronary angiograms and seven with mild coronary artery disease and hypertension underwent coronary arteriography and an intracoronary Doppler catheter technique, and the diameter of the large epicardial coronary artery and coronary blood flow were measured. Forearm blood flow was measured by use of a strain gauge plethysmograph.nnnRESULTSnBefore L-arginine administration, acetylcholine (1 to 30 micrograms/min) increased coronary blood flow with modest vasoconstriction of a large coronary artery. Acetylcholine (4 to 24 micrograms/min) also increased forearm blood flow. The acetylcholine-induced increases in coronary and forearm blood flow were significantly less in patients with coronary artery disease than in control patients. Intracoronary infusion of L-arginine at 50 mg/min did not alter responses of the large coronary artery diameter or coronary blood flow to acetylcholine in either group. In contrast, L-arginine at 10 mg/min significantly (p < 0.01) augmented the forearm blood flow response to acetylcholine (4 to 24 micrograms/min) to a similar extent in the two groups.nnnCONCLUSIONSnThe effect of L-arginine on acetylcholine-induced vasodilation differs between the coronary and forearm vasculatures in humans. It is suggested that impaired acetylcholine-induced coronary and forearm vasodilation in patients with coronary artery disease and hypertension may not be related to a limited availability of L-arginine.

Endothelin-induced CA-independent contraction of the porcine coronary artery

Front surface fluorometry and porcine coronary arterial strips loaded with fura-2 were used to investigate the effect of endothelin on cytosolic Ca concentrations, [Ca]i, and on contractile force, the objective being to elucidate the mechanism of action. Both in the presence and absence of extracellular Ca, endothelin induced rapid and dose-dependent increases in [Ca]i and in contraction. When caffeine-sensitive and histamine-sensitive intracellular Ca stores were depleted, in Ca-free medium, a transient contraction but no increase in [Ca]i followed the subsequent application of endothelin. This Ca-independent component was largely inhibited by the relative protein kinase C inhibitor, H-7, but not inhibited by W-7, calmodulin antagonist. This component is probably linked to activation of protein kinase C.

Endothelin-sensitive intracellular Ca2+ store overlaps with caffeine-sensitive one in rat aortic smooth muscle cells in primary culture

We made use of quin2 microfluorometry to determine the effects of endothelin (ET) on cytosolic free Ca2+ concentrations [Ca2+]i) in rat aortic smooth muscle cells in primary culture. In Ca2+-containing medium, ET induced a rapid and sustained elevation of [Ca2+]i. In the latter component, in particular, the elevation of [Ca2+]i was inhibited by diltiazem. In Ca2+-free medium, ET induced a rapid and transient [Ca2+]i elevation, which was not inhibited by diltiazem. When the caffeine-sensitive intracellular Ca2+ store was practically depleted by repeated treatment with caffeine in Ca2+-free media, ET did not elevate [Ca2+]i. Thus, it was suggested that ET induces [Ca2+]i elevation not only by extracellular Ca2+-dependent, mechanisms but also by releasing Ca2+ from the intracellular store, and that the ET-sensitive Ca2+ store may overlap with the caffeine-sensitive one, in cultured vascular smooth muscle cells.

8-Bromoguanosine 3′:5′-cyclic monophosphate decreases intracellular free calcium concentrations in cultured vascular smooth muscle cells from rat aorta

The effects of 8‐bromoguanosine 3′:5′‐cyclic monophosphate (8‐Br cGMP) on intracellular free calcium concentrations ([Ca2+]i) in cultured rat aortic vascular smooth muscle cells (VSMCs) loaded with fura‐2 were recorded microfluorometrically. Irrespective of whether VSMCs were at rest (in 5 mM K+ PSS), under Ca2+ depletion (in Ca2+‐free medium for 10 min) and K+ depolarization (in high K+ PSS), [Ca2+]i was actively reduced and reached a new and lower steady‐state level with the application of 8‐Br cGMP. This may be the first and direct evidence that cGMP, a putative mediator of various vasodilators, actively reduces [Ca2+]i in VSMCs.

Right-to-left shunt across atrial septal defect related to tricuspid regurgitation: Assessment by transesophageal Doppler echocardiography

The purpose of this study was to assess the factors involved in the development of the right-to-left (R-L) shunt in patients with atrial septal defect (ASD), especially the role of tricuspid regurgitation (TR). Thirty-one consecutive patients with ASD underwent transesophageal Doppler echocardiography to determine the size of ASD, the shunt flow, and the TR flow, and they were compared with hemodynamics examined by cardiac catheterization. Sixteen patients with the R-L shunt were older (53 +/- 11 vs 34 +/- 9 years; p < 0.001) and had higher pulmonary arterial pressure (36 +/- 17 vs 25 +/- 5 mmHg; p < 0.05) and a greater Qp/Qs (3.6 +/- 1.2 vs 2.4 +/- 0.9 L/min; p < 0.01) as compared with 15 patients with the pure left-to-right shunt. In six of 21 patients with TR, the regurgitant flow oriented toward ASD and blew into the left atrium through the defect. Besides the deviation of TR flow, the prevalences of the maximum diameter of ASD > 2.5 cm and the maximal TR flow area > 4 cm2 were significantly higher in the six patients as compared with patients with TR not related to the R-L shunt (p < 0.05 and p < 0.05), despite the pulmonary arterial pressure being similar in the two groups. Reversal of pressure gradient between the left and right atrium was not observed during the cardiac cycle in all patients. In conclusion, TR is a determinant of the R-L shunt in patients with ASD even in the absence of the reversal of pressure gradient between the left and right atrium.

Aortic valve prolapse with aortic regurgitation assessed by Doppler color-flow echocardiography

The incidence of and the Doppler color-flow echocardiographic characteristics of aortic valve prolapse with nonrheumatic aortic regurgitation were examined. Aortic valve prolapse was observed in 21 of 243 patients (15 men and 6 women) with aortic regurgitation as detected by Doppler color-flow echocardiography (rheumatic, 112; nonrheumatic, 131) in 1247 consecutive patients. Patients with aortic valve prolapse included three patients with essential hypertension and one with annuloaortic ectasia. The remaining 17 patients (7% of those with aortic regurgitation) had no other associated cardiovascular disease (idiopathic aortic valve prolapse). Prolapse of the mitral or the tricuspid valve or both was associated with aortic valve prolapse in seven patients. Aortic regurgitation jet was markedly deviated from the axis of left ventricular outflow tract toward the anterior mitral leaflet or the interventricular septum in 17 of 21 (81%) patients with aortic valve prolapse, whereas 28 of 110 (25%) patients with nonrheumatic aortic regurgitation without prolapse and 17 of 112 (15%) patients with rheumatic aortic regurgitation without prolapse showed the deviation of regurgitant jet (p < 0.001). In conclusion, idiopathic aortic valve prolapse is one of the significant causes of aortic regurgitation, and a marked deviation of regurgitant jet is a characteristic Doppler color-flow echocardiographic finding of aortic regurgitation that results from aortic valve prolapse.