Noriyasu Noguchi

Effects of a new angiotensin-converting enzyme inhibitor, alacepril, on changes in neurohormonal factors and arterial baroreflex sensitivity in patients with congestive heart failure

AbstractObjective: Patients with heart failure have abnormal neurohormonal regulation during orthostatic stress, and abnormal arterial baroreflex function. This study investigated the effects of alacepril, a new angiotensin-converting enzyme inhibitor with sulfhydryls, on changes in neurohormonal factors during tilt and on the arterial baroreflex control of heart rate. Methods: Plasma concentrations of noradrenaline, adrenaline, renin activity, angiotensin II, and atrial natriuretic peptide were measured at supine rest and after 30° head-up tilt with measurements of central venous pressure and cardiac dimensions in seven patients with congestive heart failure (65 years, ejection fraction = 34%). Arterial baroreflex control of heart rate was assessed by phenylephrine bolus. The arterial baroreflex test was re-examined 3 h after oral alacepril (37.5 mg). The tilt and arterial baroreflex tests were repeated 12 weeks after alacepril treatment (50 mg␣·␣day−1). Results: Heart rate, blood pressure, and neurohormonal factors did not differ before and after chronic alacepril, except for a trend toward an increase in renin activity (2.0 vs 4.9 ng · ml−1· h−1). Head-up tilt decreased central venous pressure (−2.5 mmHg) with a decrease in cardiac dimensions in the pre-alacepril phase. These changes were accompanied by increases in noradrenaline, adrenaline, and angiotensin II and a decrease in atrial natriuretic peptide. After chronic alacepril, the increase in noradrenaline during head-up tilt tended to be smaller (84 vs 30 pg · ml−1), with similar changes in central venous pressure (−3.4 mmHg) and cardiac dimensions. Both acute (3.6 vs 4.8 ms · mmHg−1) and chronic (3.6 vs 6.7 ms · mmHg−1) alacepril treatment was associated with a trend towards an increase in the arterial baroreflex control of heart rate. Conclusion: These results suggest that treatment with alacepril may cause a reduction of sympathetic activation during orthostatic stress and may enhance arterial baroreflex function in patients with mild to moderate heart failure.

Use‐dependent effects of pirmenol on and conduction in guinea‐pig ventricular myocardium

1 The use‐dependent effects of pirmenol, a new antiarrhythmic drug, on the maximal rate of rise of the action potential, conduction velocity, and their corresponding recovery kinetics were studied in isolated papillary muscles of guinea‐pig. Standard microelectrode techniques were used to monitor the conduction and action potential characteristics of the muscles. 2 Pirmenol decreased and the overshoot of action potentials in a dose‐dependent fashion. Also, doses of pirmenol greater than 1 mm abolished the generation of action potentials. Low concentrations of pirmenol (3 and 10 μm) prolonged the action potential duration, while concentrations greater than 0.1 mm shortened it markedly. 3 The resting block of in the presence of 10 and 30 μm pirmenol was 9.48 ± 3.12 and 20.36 ± 3.61%, and that of conduction velocity 2.87 ± 1.52 and 6.58 ± 2.09%, respectively. 4 The degree of use‐dependent block induced by 10 and 30 μm pirmenol during 0.2, 1, 2 and 3 Hz stimulations was dose‐ and rate‐dependent. 5 In the presence of 30 μm pirmenol, mean values of time constants for the onset of the use‐dependent inhibition of and conduction velocity during a 2 Hz stimulation were 1.32 ± 0.15 and 1.28 ± 0.09 s, respectively. The recovery time constants averaged 15.83 ± 2.14 (for ) and 27.80 ± 8.74 (for conduction velocity) s in the presence of 30 μm pirmenol. 6 These results showed that the characteristics of the use‐dependent inhibition of and conduction velocity induced by pirmenol are similar to those of slow kinetic drugs such as disopyramide rather than of fast ones.

Nicorandil suppressed myocardial purine metabolism during exercise in patients with angina pectoris.

To elucidate the effect of Nicorandil on myocardial energy metabolism and myocardial sympathetic activity, we administered Nicorandil orally to eight patients with angina pectoris prior to exercise testing. Arterial and coronary sinus levels of lactate, ammonia, hypoxanthine (HX), adrenaline and noradrenaline were measured during exercise in order to determine the irrespective myocardial extraction ratios (MER). Compared to placebo, Nicorandil increased the time to development of significant ST depression (322 vs 390 s) while decreasing the maximum amplitude of ST depression (0.244 vs 0.216 mV). Heart rate, systolic blood pressure, and the rate pressure product during exercise were not significantly affected. The MER of lactate, measured during exercise, was significantly higher after Nicorandil than placebo (13.6 vs 27.9). Similarly, the MERs of ammonia and HX were significantly higher after Nicorandil (-46.0 vs 7.4% and −47.0 vs 9.9% respectively). Nicorandil, had no apparent effect on myocardial sympathetic activity as the MERs of adrenaline and noradrenaline were essentially unaffected. We conclude that Nicorandil decreased myocardial ischaemia and suppressed myocardial accelerated purine metabolism (a marker of cellular energy metabolism) during exercise in patients with angina pectoris. This effect appears not to be related to myocardial sympathetic activity.

Suppression of sympathetic nervous system activity by nicorandil during exercise

1. Treadmill testing was done and plasma epinephrine and norepinephrine were measured during exercise and recovery in 21 patients with coronary artery disease given nicorandil. 2. Epinephrine levels during exercise did not change significantly with nicorandil, but the percent change in epinephrine with nicorandil tended to be lower during exercise. 3. Norepinephrine levels after exercise were suppressed with nicorandil (with, 424 +/- 15 pg/ml; without, 760 +/- 16, P less than 0.05). 4. Also, the percent change in norepinephrine with nicorandil was significantly decreased during exercise and recovery (with, 259 +/- 11%; without, 555 +/- 19, P less than 0.01). 5. Therefore, nicorandil suppressed the sympathetic nervous system hyper-response to exercise.

An electrophysiological study of 9-amino-1,2,3,4-tetrahydroacridine (THA) on sino-atrial node preparations of rabbits

1. The electrophysiological effect of 9-amino-1,2,3,4-tetrahydroacridine (THA) on the rabbit sino-atrial node was studied using double-microelectrode voltage clamp methods. 2. THA (above 10 microM) caused statistically significant decreases in the maximum rate of rise, the action potential amplitude, the rate of diastolic depolarization, and increases in the spontaneous cycle length, the action potential duration at 50% repolarization. 3. On the current systems, THA obviously depressed the time-dependent outward K+ current. The compound also decreased the slow inward Ca2+ current and the hyperpolarization-activated inward current. 4. These findings indicate that THA exerts an inhibitory action on the automaticity of sino-atrial node via effects on both outward and inward current systems.

Transient increase in the contractile force induced by antiarrhythmic drugs in guinea pig cardiac muscles

Abstract During clinical treatment of arrhythmia in patients with chronic heart failure, cardiac function sometimes worsens due to the use of class I antiarrhythmic drugs. Morganroth and Horowitz 1 reviewed the risk of chronic heart failure induced by antiarrhythmic drugs. The class I drugs are classified as local anesthetics because of their sodium channel-inhibiting property. Suppression of the fast sodium current causes a decrease in intracellular calcium concentration and, therefore, a decrease in contractile force of muscles. 2–4 Dennis and Vaughan Williams 5 discussed the role of a reduction in the slow inward current in the negative inotropic effect of antiarrhythmic drugs. Recently, Honerjaeger et al 6 compared several class I antiarrhythmic drugs and tetrodotoxin. They concluded that class I antiarrhythmic drugs have negative inotropic effects due to the sum of sodium channel block and variable additional inotropic properties. They 6 examined calcium channel inhibition as a major additional mechanism underlying the negative inotropic effects, and suggested that several effects result from the sodium, potassium-adenosine triphosphatase inhibition. Concerning the inotropic properties of class I antiarrhythmic drugs, we now report that eibenzoline and aprindine (but not quinidine or disopyramide) transiently increase force by enhancing the effects of intrinsic adrenergic nerves in ventricular muscle at concentrations comparable to those used clinically.

Effects of Enalapril on the Exercise Capacity and Neurohumoral Factors during Exercise in Patients with Chronic Heart Failure

The effects of enalapril on exercise capacity and neurohumoral factors during exercise were evaluated in 10 patients with heart failure. Echocardiograms and exercise testing with expired gas analysis were performed before and after enalapril. Blood samples were obtained before and after exercise. Both ejection fraction and percent fractional shortening increased with enalapril (p < 0.05). The anaerobic threshold and peak VO2 did not change with enalapril. Epinephrine and norepinephrine levels at peak exercise decreased with enalapril (p < 0.1). Plasma renin both at rest and at peak exercise increased with enalapril (p < 0.1). Angiotensin II was lower after enalapril both at rest and at peak exercise (p < 0.1 and p < 0.05, respectively). Aldosterone was lower after enalapril both at rest and at peak exercise (p < 0.05). Atrial natriuretic peptide (ANP) was lower after enalapril both at rest and at peak exercise. There was no significant correlations between peak VO2 and changes in neurohumoral factors before and after enalapril during exercise. In conclusion, neurohumoral changes with enalapril occurred during exercise even if exercise capacity did not improve. Moreover, the improvement of cardiac function at rest and neurohumoral factors with enalapril did not lead to a change of exercise capacity.

Effects of Aprindine on Conduction Velocity and Vmax in Guinea-Pig Papillary Muscles

One of the effects of antiarrhythmic drugs is the reduction of conduction velocity. Cable theory predicts that there is a nonlinear relationship between conduction velocity and upstroke velocity (V̇max) of action potential. By using conventional microelectrode techniques, aprindine‐induced reduction of V̇max of action potential and conduction velocity in guinea‐pig papillary muscles were measured. Aprindine‐produced, use‐dependent, and concentration‐dependent changes in conduction velocity and the decline of square of conduction velocity was well fit by a single exponential. Time constants for square of conduction velocity were comparable to simultaneously measured time constants for effects of V̇max. At a concentration of 1 to 10 μM aprindine, onset changes between V̇max and conduction velocity had a log‐linear relationship in a predicted fashion. Whereas, in the recovery process from aprindine‐induced depression, slow recovery time course of conduction velocity was observed. In conclusion, in the presence of aprindine, only onset block of conduction velocity can be analyzed quantitatively in the relationship to observation on V̇max in vitro. These results suggested that in the presence of aprindine, the recovery of internal conductance may be slower than that of V̇max.

Effect of urapidil on the action potentials in the guinea-pig ventricular myocardium

SummaryThe electrophysiological effects of urapidil, a new α1-adrenoceptor antagonist, were assessed in the reserpinized guinea-pig ventricular myocardium. Urapidil suppressed the maximal rate of rise (αmax) of steady-state action potentials elicited by the fast responses at high concentrations independently of blockade of myocardial α-adrenoceptors, but not the αmax of Ca2+-dependent slow action potentials of partially depolarized muscles in concentrations tested (up to 1.1 mM). Urapidil at high concentrations prolonged the action potential durations of the fast and slow responses in a manner similar to the quinidine-like antiarrhythmic drugs. These results suggest that the inhibitory effect of urapidil on the slow inward Ca2+ current and the Na+ current is in practice negligible.

Acute hemodynamic effects of bunazosin in congestive heart failure--differing responses according to degree of cardiac dysfunction.

1. Hemodynamic responses to Bunazosin (BZN) in congestive heart failure (CHF) were evaluated for 6 hours (hr) in 30 patients (A, normal cardiac function; B, mild cardiac dysfunction; C, severe cardiac dysfunction). 2. For 6 hr after BZN, the increments of cardiac index (delta CI) and stroke volume index (delta SVI) with BZN were higher in groups A and B than in group C. 3. A significant positive correlation was observed between ejection fraction and maximum delta CI and SVI, and between % fractional shortening and maximum delta CI and SVI. 4. These data showed that BZN improved the hemodynamics of CHF patients and that patients in groups A and B responded well to this vasodilator, however, patients in group C did not.