Yasunori Ohbayashi

Coronary effects of nicorandil in comparison with nitroglycerin in chronic conscious dogs

SummaryThe effects of nicorandil (0.2 mg/kg, IV) and nitroglycerin (15 μg/kg, IV) on large and small coronary arteries were compared in conscious dogs instrumented with ultrasonic crystals and electromagnetic flow meters in the circumflex coronary artery. Nicorandil dilated the large coronary arteries to the same extent, but with a longer duration of action than nitroglycerin. The small coronary arteries dilated for a very short period of time with nitroglycerin, but dilated markedly with nicorandil. The dilatory action of nicorandil on large coronary arteries persisted after the action on the small coronary artery fell to the control value, indicating that the dilatory action on the large coronary arteries is due to the direct relaxing effect on smooth muscle and is not the result of the flow-dependent effect. The measurement of the plasma concentration of nicorandil after incremental infusions of the agent showed that the dilation of the small coronary artery took place at only a very high level (above 200 ng/ml). On the other hand, the large coronary arteries responded to nicorandil at a much lower concentration (about 100 ng/ml, the clinically effective plasma concentration of nicorandil) than the small coronary resistance arteries. In conclusion, whereas nicorandil possesses a dilatory action on both large and small coronary arteries, din a clinical setting, with a daily dosage of 15–30 mg, part of the beneficial effects of nicorandil may be the result of a dilation of the large coronary arteries and may be due to the fact that a coronary steal phenomenon does not occur after nicorandil administration.

Plasma arteriovenous cGMP difference as a useful indicator of nitrate tolerance in patients with heart failure.

BackgroundThe present study was performed to evaluate the effects of nitroglycerin (GTN) on plasma arteriovenous cGMP production and to compare its hemodynamic effects in patients with congestive heart failure (CHF). We also estimated the potential clinical value of plasma arteriovenous cGMP production as an indicator of nitrate tolerance. Methods and ResultsPlasma arterial and venous cGMP levels, atrial natriuretic peptide level, and hemodynamic parameters were measured before and after GTN infusion in 14 patients with CHF. Although the plasma levels of arterial cGMP and atrial natriuretic peptide decreased immediately after GTN, the plasma level of venous cGMP did not change. GTN infusion caused a dose-dependent increase in plasma arteriovenous cGMP production, and there was a positive correlation between the decrease of pulmonary capillary wedge pressure and the increase of plasma arteriovenous cGMP production immediately after GTN. Hemodynamic tolerance was observed after both 12 and 24 hours, when plasma arteriovenous GMP production was also attenuated. ConclusionsThese findings indicate that the plasma arteriovenous cGMP difference is a clinical indicator of vasodilatory action of GTN and a useful indicator of nitrate tolerance in patients with CHF.

Comparison of antianginal activity of nicorandil, propranolol and diltiazem with reference to the antianginal mechanism

Nicorandil was compared with placebo, propranolol and low and high doses of diltiazem therapy in 12 patients with chronic stable angina pectoris to elucidate its antianginal mechanism. A computer-assisted treadmill exercise test was performed after administration of either placebo, 30 mg of nicorandil, 40 mg of propranolol, or low-dose 60 and high-dose 120 mg of diltiazem. Exercise duration and time to the onset of ischemia were significantly increased after each drug administration and there was no significant difference in the percent increase in exercise duration between nicorandil (44 +/- 7%), propranolol (47 +/- 11%) and high-dose diltiazem (39 +/- 5%) compared with placebo. Nicorandil increased exercise duration in patients with 1-vessel disease more effectively (7.5 +/- 0.7 minutes, p less than 0.05) than either propranolol or low-dose diltiazem (6.7 +/- 0.7, 6.1 +/- 0.9 minutes, respectively). The decrease in blood pressure obtained with nicorandil was approximately the same as that with diltiazem. Nicorandil increased exercise duration associated with higher peak double product compared with low-dose diltiazem. In contrast, high-dose diltiazem increased exercise duration at the same double product as low-dose diltiazem. Propranolol increased exercise duration at a lower level of peak double product. Because our previous study demonstrated that low-dose diltiazem yielded a plasma concentration high enough to reduce coronary tone, it appears unlikely that nicorandil will reduce coronary tone further and subsequently increased coronary reserve. Therefore, left ventricular preload reduction may be the mechanism responsible for higher values of double product obtained with nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of an angiotensin II type 1 receptor blocker, valsartan, on neurohumoral factors in patients with hypertension: comparison with a long-acting calcium channel antagonist, amlodipine.

Summary: This study compared the effects of amlodipine and valsartan on the sympathetic nervous system, the renin‐angiotensin‐ aldosterone system, and brain natriuretic peptide, which are considered important parameters of the long‐term prognosis. Seventythree elderly patients, who had received antihypertensive treatment for more than 6 months with amlodipine, participated in this study. They were randomized to the V group (n = 36) and switched to valsartan from amlodipine, or to the A group (n = 37), which continued treatment with amlodipine. The dose of valsartan was set as that which controlled the blood pressure to the same extent as before switching. Blood samples were measured before and after 6 months of therapy. Data were analyzed by two‐way analysis of variance with the Newman‐Keuls test. In the V group, norepinephrine (from 597.0 ± 52.9 to 475 ± 43.8 pg/ml, p < 0.05) and aldosterone (from 74.5 ± 7.0 to 53.9 ± 5.3 pg/ml, p < 0.001) were decreased significantly after 6 months, although norepinephrine and aldosterone levels were unchanged in the A group. However, brain natriuretic peptide did not show a difference between the two groups. These findings suggested that valsartan is probably superior to amlodipine with respect to less activation of the sympathetic nervous system and preventing upregulation of the renin‐angiotensin‐aldosterone system.

Left ventricular effects of nicorandil in comparison with nitroglycerin in chronic conscious dogs

SummaryNicorandil is a new coronary vasodilator possessing beneficial properties. However, its detailed cardiovascular effects, especially on left ventricular (LV) preload, have not yet been fully elucidated. The purpose of this study was to assess the effects of nicorandil on LV hemodynamics in conscious dogs and to examine the mechanisms of its anti-ischemic action. Nine mongrel dogs were instrumented for instantaneous and continuous measurements of LV diameters, and aortic and LV pressures. The effects of nicorandil (0.2 mg/kg, intravenously) were compared with those of nitroglycerin (15 μg/kg, intravenously) in conscious dogs. Mean aortic pressure decreased similarly with both nicorandil and nitroglycerin (−20.1±3.1% vs. 21.6±2.8%, ns). Heart rate was elevated with both drugs. Both nicorandil and nitroglycerin significantly decreased LV systolic pressure to the same extent (−11.3±0.5% vs.−10.5±11.6^, ns). LV max dp/dt was not significantly changed by either drug. Although both nicorandil and nitroglylerin significantly increased fractional shortening, nicorandil had a greater effect on fractional shortening than nitroglycerin (20.0±3.0% vs. 10.2±2.3%, p<0.05). In this study, nicorandil, administered intravenously, had a salutary effect on cardiac function. LV enddiastolic diameter decreased with nicorandil and nitroglycerin (−6.5±1.5% vs.−12.6±2.6%, p<0.01), respectively. In conclusion, nicorandil decreased LV end-diastolic diameter in conscious dogs, indicating a decrease in venous return and preload of the heart. In addition, nicorandil decreased LV afterload to the same extent as nitroglycerin. The decrease in preload and afterload on the heart is thought to be one of the mechanisms of the antiischemic action of nicorandil.