Hideyuki Kitamura

Catecholamines, Renin-Angiotensin-Aldosterone System, and Atrial Natriuretic Peptide at Rest and During Submaximal Exercise in Patients With Congestive Heart Failure

The aim of this study was to determine the responses of plasma catecholamines, renin-angiotensin-aldosterone (RAA) activity, and plasma atrial natriuretic peptide (ANP) to exercise in patients with congestive heart failure (CHF). Cardiac and neurohormonal responses were assessed during submaximal treadmill exercise testing in 23 patients with CHF (New York Heart Association classes I-III) and 13 control subjects (without CHF). Plasma norepinephrine, epinephrine, renin activity (PRA), angiotensin II (ATII), aldosterone, and ANP were measured at rest and immediately after exercise. Exercise duration was shorter in patients with CHF (control, 10.4 +/- 0.9 minute; CHF, 6.2 +/- 0.7 minute; P < 0.01). Heart rate and blood pressure responses were similar except for the smaller peak heart rate (control, 145 +/- 5 beats per minute; CHF, 129 +/- 4 beats per minute; P < 0.05) and higher systolic blood pressure at recovery stage (control, 122 +/- 4 mm Hg; CHF, 142 +/- 4 mm Hg; P < 0.01) in patients with CHF. At rest, plasma norepinephrine levels were insignificantly higher in patients with CHF (control, 110 +/- 10 pg/mL; CHF, 170 +/- 26 pg/mL; P = 0.09), and ANP levels (control, 40 +/- 5 pg/mL; CHF, 94 +/- 17 pg/mL; P < 0.05) and PRA levels (control, 0.77 +/- 0.11 ng/mL/hr; CHF, 4.33 +/- 1.25 ng/mL/hr; P < 0.05) were significantly higher. There were no differences in peak norepinephrine, epinephrine, or ANP between the two groups. Angiotensin II and aldosterone levels were similar between the two groups, although, in patients with CHF, there was a trend toward higher levels of ATII while at rest (control, 12.4 +/- 1.4 pg/mL; CHF, 20.3 +/- 3.3 pg/mL; P = 0.08) and at peak (control, 20.5 +/- 1.8 pg/mL; CHF, 41.0 +/- 9.4 pg/mL; P = 0.10). Peak values of PRA, ATII, and aldosterone positively correlated with respective resting values of PRA (r = 0.88 ng/mL/hr, P < 0.01), ATII (r = 0.63 pg/mL, P < 0.01), and aldosterone (r = 0.99, P < 0.01). Peak norepinephrine and peak ANP also positively correlated with respective resting values of norepinephrine (r = 0.58 pg/mL, P < 0.05) and ANP (r = 0.94, P < 0.01). Analysis of these results showed that patients with CHF had significantly higher levels of PRA and ANP at rest, and a trend toward augmentation in RAA system activity during exercise with less exercise workload. Basal level of neurohormones seemed to be an important determinant for the degree of exercise-induced neurohormonal activation in patients with CHF.

Response of sympathetic nervous system activity to exercise in patients with congestive heart failure.

Abstract. To investigate the serial sympathetic nervous system response to exercise, plasma norepinephrine (NE) and epinephrine (E) concentrations were measured at rest, during each stage of treadmill exercise, and immediately and 5 minutes after exercise in 68 congestive heart failure (CHF) patients (NYHA functional class I 24, II 25, III 19) and 30 normal subjects. Circulatory responses of NYHA class II patients increased at early stages of exercise. Systolic blood pressure and double product at peak exercise were significantly lower in NYHA class III patients. Plasma NE response of NYHA class I patients was similar to that of normal subjects. However, plasma NE at rest, and during and after exercise were significantly higher in NYHA classes II and III patients than in normal subjects and NYHA class I patients (peak NE (pg ml‐1); Normals: 547±37, I: 535±53, II: 867±87, III: 1033±157). There was no significant difference in plasma E levels among the four groups. NE response to exercise was augmented according to the severity of heart failure, which suggested compensatory activation of sympathetic nervous system activity. Circulatory responses were reduced in NYHA class III patients despite the exaggerated compensatory activation of the sympathetic nervous system. Blunted circulatory responses to increased NE concentration in NYHA class III patients might relate to a decreased cardiac responsiveness to sympathetic activity in severe CHF patients.

Sympathetic nervous system response to dynamic exercise in complete AV block patients treated with AV synchronous pacing with fixed AV delay or with auto-AV delay.

IGAWA, O., ET AL.: Sympathetic Nervous System Response to Dynamic Exercise in Complete AV Block Patients Treated with AV Synchronous Pacing with Fixed AV Delay or with Auto‐AV Delay. To investigate the sympathetic nervous system (SNS) responses and circulatory responses to exercise in eight patients (five male and three female) with complete atrioventricular block (CAVB) treated with atrio‐ventricular (AV) synchronous pacing, a symptom‐limited, multistaged treadmill stress test was performed, and plasma norepinephrine (NE) and circulatory parameters were measured at rest, at peak exercise, and in the recovery period. The eight patients were tested using the fixed AV interval (150 or 156 msec). Their exercise tolerance was generally poor. In all measured points, plasma NE levels were significantly higher in the eight study patients than those in the 12 normal subjects (eight male and four female). Systolic blood pressure (SBP) of CAVB patients elevated significantly after exercise compared to that at peak exercise. Heart rate (HR) responses of CAVB patients were characterized by their poor increase at peak exercise. These results suggest that some latent cardiac dysfunction continues in the CAVB patients however satisfactorily the AV synchronous pacing might perform. AV synchronous pacing with three different kinds of auto‐atrioventricular delay (auto‐AVD) was applied to three of the eight patients. In each AVD mode, a treadmill stress test was performed repeatedly according to the same protocol. Plasma NE concentrations under the condition with fixed AVD at peak exercise increased compared to those under the other two conditions with auto‐AVD. These findings suggest that AV synchronous pacing with auto‐AVD WQS better than that with fixed AVD during exercise. Plasma NE response to exercise seems to be a useful indicator for evaluating the condition of patients treated with DDD pacemakers and their adaptation for cardiac function.

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.

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.

Excess purine degradation in muscle of chronic hemodialysis patients.

Excess Purine Degradation in Muscle of Chronic Hemodialysis Patients H. Hiromoto Kosaka I. Ichiro Hisatome K. Kazuhíde Oginö Y. Yasushi Tanaka S. Shuichi Osaki H. Hideyuki Kitamura H. Hiroki Omodani T. Tatsuhiko Matsumoto H. Hiroyuki Miyakoda H. Hiroshi Kotake H. Hiroto Mashiba K. Kouji Ono A. Akimichi Inoue First Deparment of Internal Medicine, Tottori University, Yonago; Department of Urology, Saiseikai Sakaiminato General Hospital, Sakaiminato, Japan

Chronotropic effect of nizofenone fumarate in rabbit sino-atrial node in vitro

1 The effects of nizofenone fumarate were studied on the membrane potentials and currents of rabbit sino‐atrial node preparations by means of the double‐microelectrode voltage clamp method. 2 In spontaneously firing pacemaker cells, nizofenone (above 1 μm) decreased the heart rate. Above 3 μm, nizofenone reduced the maximum upstroke velocity, the amplitude of the action potential and the slope of the phase 4 depolarization, and prolonged the action potential duration at 50% repolarization. 3 Under voltage clamp conditions, nizofenone decreased the slow inward current and the time‐dependent potassium outward current in a dose‐dependent manner. 4 These findings suggest that nizofenone exerts an inhibitory action on the automaticity of sinoatrial node preparations via effects on both inward and outward currents.

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.

Syncope and recurrent long sinus arrest in vasospastic angina

Dear Sir, Recently, pharmacological autonomic nerve blockade has been applied as a tool to evaluate the intrinsic sinus node function in patients with the sick sinus syndrome [1]. Although ischemic heart disease has been recognized as an underlying disease of sinus dysfunction, it may involve transient and reversible ischemic disease, such as vasospastic angina. In such patients, pharmacological autonomic nerve blockade using atropine and propranolol may fail to show the intrinsic sinus node function, because propranolol may induce coronary vasospasm, sometimes in patients with vasospastic angina [2-5]. We report a case of a 52-year-old man who showed anginal attacks, syncopes, and recurrent long sinus arrests (3-5 sec, Fig. 1) during Holter monitoring. The electrophysiologic study without drugs revealed a normal sinus node recovery time (1350 msec) and sinoatrial conduction time (104 msec). Coronary arteriography revealed an intact coronary artery system, and the provocation test for coronary spasm using ergonovine maleate was positive. Antianginal therapy using nitrates and a calcium antagonist (diltiazem, 30 mg four times daily), which often aggravates the symptoms in patients with sinus node dysfunction, prevented not only anginal attacks, but also sinus arrests, as confirmed in multiple records of Holder monitoring. This case suggests that transient and reversible ischemia is a cause of symptoms similar to those of sick sinus syndrome and that pharmacological autonomic nerve blockade using atropine and propranolol is not always a perfect tool to evaluate the intrinsic sinus node function in patients with certain types of ischemic heart disease.