Yasuhiko Harasawa

Role of nitric oxide in reactive hyperemia in human forearm vessels.

BACKGROUND The role of nitric oxide (NO) in reactive hyperemia (RH) is not well known. We investigated whether NO plays a role in RH in human forearm vessels by examining the effects of NG-monomethyl-L-arginine (L-NMMA), a blocker of NO synthesis, on reactive hyperemic flow. METHODS AND RESULTS Forearm blood flow (FBF) was measured by strain-gauge plethysmography with a venous occlusion technique. The left brachial artery was cannulated for drug infusion and direct measurement of arterial pressure. To produce RH, blood flow to the forearm was prevented by inflation of a cuff on the upper arm to suprasystolic pressure for intervals of 3 and 10 minutes. After the release of arterial occlusion (AO), FBF was measured every 15 seconds for 3 minutes. Resting FBF was 4.3 +/- 0.3 mL.min-1.100 mL-1 before 3 minutes of AO and 4.1 +/- 0.6 mL.min-1.100 mL-1 before 10 minutes of AO. FBF increased to 32.3 +/- 1.9 and 38.2 +/- 3.1 mL.min-1.100 mL-1 immediately after 3 and 10 minutes of AO, respectively, and gradually decayed (n = 13). Intra-arterial infusion of L-NMMA (4 mumol/min for 5 minutes) decreased baseline FBF (P < .01) without changes in arterial pressure. L-NMMA did not affect the peak reactive hyperemic FBF after 3 and 10 minutes of AO. L-NMMA significantly decreased total reactive hyperemic flow (flow debt repayment) by 20% to 30% after 3 and 10 minutes of AO. Simultaneous infusion of L-arginine (a precursor of NO) with L-NMMA reversed the effects of L-NMMA. CONCLUSIONS Our results suggest that NO plays a minimal role in vasodilation at peak RH but plays a modest yet significant role in maintaining vasodilation after peak vasodilation. Our results also suggest that reactive hyperemia in human forearms is caused largely by mechanisms other than NO.

Bradykinin-Induced Vasodilation Is Impaired at the Atherosclerotic Site but Is Preserved at the Spastic Site of Human Coronary Arteries In Vivo

BACKGROUND Bradykinin causes endothelium-dependent vasodilation of isolated human coronary arteries in vitro. However, the effect of bradykinin on vasomotion of human coronary arteries in vivo has not been studied. The aim of this study was to examine whether bradykinin-induced vasodilation is altered at the atherosclerotic or spastic site of human coronary arteries in vivo. METHODS AND RESULTS The effect of bradykinin on vasomotion of epicardial coronary arteries was evaluated in 8 patients with normal coronary arteries (control group), 14 patients with organic coronary stenosis (coronary artery disease [CAD] group), and 8 patients with vasospastic angina (VSA group). Changes in the diameter of epicardial coronary artery were assessed by quantitative coronary arteriography. Intracoronary administration of bradykinin at graded doses (60, 200, and 600 ng) dilated epicardial coronary arteries without altering arterial pressure or heart rate in all patients of either group. In the control group, vasomotor responses of the site where acetylcholine caused dilation were compared with the responses of the site where acetylcholine caused constriction. The magnitudes of bradykinin-induced dilation at the site with acetylcholine-induced dilation (mean +/- SD: 6 +/- 6%, 11 +/- 9%, and 15 +/- 9%) were comparable to that (3 +/- 6%, 8 +/- 8%, and 13 +/- 9%) at the site with acetylcholine-induced constriction. In the CAD group, vasomotor responses of the stenotic site (% diameter stenosis, 15% to 50%) and nonstenotic site were examined. The bradykinin-induced dilation at the stenotic site (0 +/- 4%, 3 +/- 8%, and 5 +/- 9%) was significantly less (P < .01) than at the nonstenotic site (3 +/- 4%, 8 +/- 6%, and 16 +/- 11%) and in the control group. Coronary vasodilation with nitrate at the stenotic site (20 +/- 11%) was comparable to that at the nonstenotic site (22 +/- 16%) and in the control group (21 +/- 10%). In the VSA group, vasomotor responses of the site with acetylcholine-induced spasm and the site without spasm were examined. The bradykinin-induced vasodilation at the spastic site (5 +/- 5%, 16 +/- 15%, and 33 +/- 17%) was comparable to that at the nonspastic site (4 +/- 8%, 12 +/- 14%, and 21 +/- 9%). Nitrate-induced dilation was comparable at the spastic site (51 +/- 19%) and the nonspastic site (32 +/- 13%). The ratio of bradykinin-induced vasodilation to nitrate-induced vasodilation at the spastic site was comparable to the control group. CONCLUSIONS These results suggest that bradykinin causes vasodilation of human epicardial coronary arteries in vivo and that bradykinin-induced endothelium-dependent vasodilation is impaired at the stenotic site but is preserved at the angiographically normal site where endothelium-dependent vasodilation by acetylcholine is impaired and at the spastic site.

Basal release of nitric oxide is decreased in the coronary circulation in patients with heart failure.

It is unknown whether basal release of endothelium-derived nitric oxide in the coronary artery is altered in heart failure in humans. The aim of the present study was to evaluate the effect of inhibition of nitric oxide synthesis on basal tone of the conduit and resistance coronary arteries in awake patients. Coronary blood flow velocity (Doppler guide wire) and coronary arterial diameter (quantitative coronary angiography) were measured in 14 patients with heart failure caused by nonischemic left ventricular dysfunction (7 idiopathic dilated cardiomyopathy and 7 valvular insufficiency) and 7 patients with normal ventricular function (controls). Intracoronary N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis, at graded doses decreased coronary blood flow in both groups. However, the magnitude of flow reduction was smaller in patients with heart failure than in control patients (P<.0001). The magnitude of coronary blood flow reduction in response to L-NMMA inversely correlated to indexes of left ventricular contractile function (P<.01) but was not affected by the cause of heart failure. Constriction of the large epicardial coronary artery with L-NMMA also tended to be attenuated in patients with heart failure. In summary, vasoconstricting response to L-NMMA was blunted in the coronary resistance artery in heart failure in vivo. These findings suggest that basal release of nitric oxide in the coronary circulation is decreased in patients with heart failure.

Role of Endogenous Nitric Oxide in the Brain Stem on the Rapid AdaptatKion of Baroreflex

It has been shown that nitric oxide in the brain stem plays an important role in the control of sympathetic nerve activity. We examined the role of endogenous nitric oxide in the brain stem in the rapid central adaptation of baroreflex control of sympathetic nerve activity in anesthetized rabbits. Bilateral carotid sinuses were isolated, and a stepwise increase in pressure of 25 or 50 mm Hg for 50 to 60 seconds was applied to the carotid sinuses while the arterial pressure and renal sympathetic nerve activity were recorded. The renal sympathetic nerve activity was inhibited by the stepwise increase in carotid sinus pressure, but thereafter it gradually returned toward the baseline level despite the fact that carotid sinus pressure was kept constant. This procedure was performed after intracisternal injection of N(omega)-nitro-L-arginine methyl ester (L-NAME, 8 micromol), N(omega)-nitro-D-arginine methyl ester (D-NAME, 8 micromol), L-arginine (40 micromol), or the vehicle solution. The magnitude of the immediate and maximal inhibition of renal sympathetic nerve activity caused by a stepwise increase in carotid sinus pressure was similar between the vehicle and L-NAME treatment, but the rate of recovery of the renal sympathetic nerve activity after immediate inhibition was faster after L-NAME than after vehicle. L-Arginine reversed the effects of L-NAME. However, D-NAME or L-arginine alone had no such effects on the rate of recovery of the nerve activity. These results thus suggest that endogenous nitric oxide in the brain stem attenuates rapid adaptation of the arterial baroreflex control of the sympathetic nerve activity in rabbits.

Short-term estrogen administration ameliorates dobutamine-induced myocardial ischemia in postmenopausal women with coronary artery disease.

OBJECTIVES This study was designed to examine whether short-term estrogen administration ameliorates dobutamine-induced myocardial ischemia in postmenopausal women with coronary artery disease (CAD). BACKGROUND Estrogen replacement therapy in postmenopausal women is associated with a marked reduction in the risk of CAD. Estrogen has been reported to have both short- and long-term effects on the cardiovascular system. However, it remains to be examined whether short-term estrogen administration ameliorates myocardial ischemia caused by increased myocardial oxygen demand in postmenopausal women with CAD. METHODS Eight postmenopausal women with proved CAD underwent dobutamine stress echocardiography (DSE). DSE was performed three times in a placebo-controlled, double-blind manner: 1) 30 min after intravenous administration of saline solution (placebo) and after 2) a low dose (1.25 mg) and 3) a high dose (10 mg) of conjugated estrogen. The effects of estrogen were compared at the maximal comparable stage of DSE, which was the maximal DSE level that the same patient achieved in all three examinations. RESULTS Estrogen dose-dependently ameliorated the dobutamine-induced worsening of symptoms (prolonging time to onset of symptoms by 52% [low dose] and 72% [high dose]), electrocardiographic findings (decreasing the magnitude of summed ST segment changes by 36% [low dose] and 76% [high dose]) and left ventricular wall motion (reducing the wall motion score index by 50% [low dose] and 77% [high dose], all p < 0.01 by analysis of variance). There was no significant difference in blood pressure, heart rate or rate-pressure product among the three examinations at the maximal comparable stage of DSE. CONCLUSIONS Estrogen has short-term anti-ischemic effects on the myocardial ischemia induced by increased myocardial oxygen demand in postmenopausal women with CAD.

A rare case of large ventricular septal defect with minimal pulmonary vascular obstructive changes in a 41-year-old woman.

SummaryWe describe a case of large ventricular septal defect (VSD) with minimal obstructive changes in the small pulmonary arteries of a 41-year-old woman. Before cardiac catheterization, some laboratory findings led us to consider that surgical closure of the defect would not be possible. However, because hemodynamic examinations showed only mildly elevated pulmonary vascular resistance, we patch-closed the VSD successfully. The histology of lung specimens showed only minimal obstructive changes in the small pulmonary arteries. Considering the size of the VSD and the age at which we hemodynamically evaluated the patient, the mildness of the pulmonary vascular obstructive changes appeared to be atypical in the natural course of a VSD of this size.

Isoproterenol infusion provokes vasovagal response without upright tilt in a patient exhibiting syncopal episodes

SummaryWe report a case of a patient with vasovagal syncope, in whom isoproterenol infusion provoked vasovagal response without upright tilting. We subjected the patient, who had had two previous syncopal and several presyncopal episodes, to upright tilting with isoproterenol infusion. Before a control tilt was performed for 10min (80°), the patient was placed in the supine position for 5 min. The control tilt did not provoke a vasovagal response. With isoproterenol being infused at a dose of 1 µg/min, the sequence of positioning in the supine position for 5min and upright tilting for 10min was repeated. This dose of isoproterenol infusion did not provoke any vasovagal response in the patient, either in the supine or in the upright position. When the dose of isoproterenol infusion was then increased to 2 µg/min, the heart rate increased to 121/min, but then suddenly dropped to 74/min; systemic arterial pressure simultaneously fell from 148/80 to 108/80 mmHg. The patient complained of palpitation and anxiety, and showed profound cold sweating. The drop in the heart rate and the fall in blood pressure occurred when the patient was in the supine position, indicating that, unlike upright tilting with isoproterenol infusion, venous return was not decreased at the beginning of vasovagal response in this setting. This observation suggests that isoproterenol infusion, even without upright tilting, may provoke the vasovagal response in some patients.

Evaluation of Dynamic Mechanical Properties of Coronary Arterial System Using Multi-Channel Random Noise Technique

We evaluated, in ten isolated, cross-circulated canine hearts, the dynamic mechanical properties of the coronary arterial system using a multichannel random noise technique. We perturbed coronary arterial pressure with a high speed servo-pump and altered ventricular pressure by random pacing. We then determined admittance spectra where both coronary arterial pressure and left ventricular pressure are the inputs and coronary arterial flow is the output. The coronary arterial admittance from coronary arterial pressure to the flow indicated that the dynamic mechanical properties of the coronary arterial system approximated a windkessel model like the other arterial systems. The coronary admittance from left ventricular pressure to coronary arterial flow indicated that, in the low frequency range, the characteristics of attenuation of coronary arterial flow by ventricular contraction were consistent with the vascular waterfall mechanism. We conclude that the instantaneous coronary arterial flow could be described as a function of coronary arterial pressure and left ventricular pressure in our tested condition.