Levine Tb

Acute and long-term response to an oral converting-enzyme inhibitor, captopril, in congestive heart failure.

SUMMARYCaptopril (SQ 14,225), an oral angiotensin converting-enzyme inhibitor, was administered to 11 patients with severe congestive heart failure (CHF). Peak effect was observed at 1.5 hours after administration. At peak effect right atrial pressure fell from 3.4 to 0.0 mm Hg, pulmonary capillary wedge pressure (PCW) fell from 22.7 to 12.3 mm Hg, mean arterial pressure (MAP) fell from 79.5 to 62.1 mm Hg, systemic vascular resistance (SVR) fell from 1989 to 1370 dyn-sec-cm-5, pulmonary vascular resistance fell from 843 to 523 dyn-sec-cm-, and cardiac index (CI) rose from 1.96 to 2.43 1/min/m2. These were all statistically significant. Control plasma renin activity (PRA) was elevated (25.9 ng/ml/hr) and correlated with resting PCW (r = 0.65). The acute hemodynamic response was related to PRA: a fall in MAP (r = 0.74), a fall in PCW (r = 0.80), a fall in SVR (r = 0.45) and a rise in CI (r = 0.45). Eight patients were placed on chronic captopril therapy. After 2 or more months, their exercise time was significantly increased, from 6.8 to 11.7 minutes. Their cardiothoracic ratios showed a significant decrease, from 0.55 to 0.52, and most patients reported symptomatic improvement. Chronic response was not predicted by acute hemodynamic response. Captopril is therefore a vasodilator with both arterial and venous effects that are at least partially caused by inhibition of the renin-angiotensin system. It may be useful for the treatment of CHF.

The neurohumoral and hemodynamic response to orthostatic tilt in patients with congestive heart failure.

Thirty-five patients with varying degrees of congestive heart failure were subjected to 60° upright tilt. Eight of the patients with normal resting hemodynamics had elevated resting plasma norepinephrine levels (PNE) (p < 0.001), but their response to upright tilt was similar to that in normal subjects: All had increases in heart rate, plasma norepinephrine (from 263 ± 32 to 483 ± 78 pg/mg, p < 0.02) and plasma renin activity (from 4.8 ± 0.9 to 13.7 ± 7.6 ng/ml/hour, p < 0.05). In 27 patients with high resting pulmonary wedge pressure and low cardiac index, resting PNE was higher (668 ± 71 ng/ml), but PNE, plasma renin activity and heart rate did not increase significantly during tilt despite a fall in pulmonary capillary wedge pressure and cardiac index. In 18 of these patients, PNE rose during tilt, whereas in nine it did not change or fell; the regting hemodynamics and the hemodynamic response to tilt were not significantly different in these two groups. These data suggest that an abnormality of mechanoreceptor or baroreceptor function is common in patients with CHF. This abnormality corresponds in part to the severity of the resting hemodynamic abnormality, but among patients with severe CHF, the reflex neurohumoral abnormality may provide independent information about the severity of the disease.

Hyponatraemia as a marker for high renin heart failure.

The factors that might activate the renin-angiotensin system in treated heart failure were explored. Serum Na+ correlated inversely with plasma renin activity. The degree of congestive heart failure measured by right atrial pressure, pulmonary capillary wedge pressure, cardiac index, and systemic vascular resistance did not correlate with plasma renin activity. Similarly, renal function as measured by blood urea nitrogen, creatinine, and urinary Na+ excretion did not correlate with plasma renin activity. In a prospectively screened group, seven patients with congestive heart failure who were found to be hyponatraemic had plasma renin activities greater than 15 ng/ml per h. Serial determinations in one patient showed plasma renin activity to vary inversely with the serum Na+. It is concluded that serum sodium can be used to identify those patients with congestive heart failure who have a high plasma renin activity. The value of identifying these high renin heart failure patients was seen in their response in four cases to specific therapy with a converting enzyme inhibitor.

Acute hemodynamic effects of nitrendipine in chronic congestive heart failure

Summary The acute hemodynamic response to a single oral dose of nitrendipine (10–20 mg) was evaluated in eight subjects with severe chronic congestive heart failure during right heart catheterization. A hemodynamic effect began within 1 h. At peak effect (1–2 h after drug administration), mean arterial pressure fell from 84.0 ± 9.2 to 76.0 ± 9.2 mm Hg (mean ± SD), right arterial pressure from 10.6 ± 5.9 to 8.0 ± 7.1 mm Hg, mean pulmonary arterial pressure from 35.5 ± 9.2 to 30.1 ± 9.4 mm Hg, pulmonary wedge pressure from 23.6 ± 6.7 to 17.7 ± 6.3 mm Hg, and cardiac index rose from 1.91 ± 0.38 to 2.45 ± 0.34 L/min/m2. Heart rate did not change (85 ± 18 to 82 ± 18 beats/min) despite the significant fall in arterial pressure. Systemic and pulmonary vascular resistances fell significantly. Whereas forearm blood flow increased from 1.44 ±0.52 to 2.06 ± 0.41 ml/min/100g (p < 0.05), hepatic and renal blood flows were unchanged. This study demonstrates the acute effectiveness of nitrendipine in reducing ventricular preload and impedance in heart failure and in increasing cardiac output that appears to be preferentially directed to the skeletal bed. The left-upward shift of the Frank-Starling curve suggests the absence of any clinically important negative inotropic effect of nitrendipine. Nitrendipine therefore may be a useful agent for vasodilator therapy of heart failure.

Acute hemodynamic and hormonal effects of central versus peripheral sympathetic inhibition in patients with congestive heart failure.

Summary: Indoramin, an α1 antagonist, and guanabenz, an α2 agonist, were given to 10 patients with severe congestive heart failure to compare the hemodynamic and hormonal effects of a reduction in sympathetic tone obtained through inhibition of postsynaptic α1 receptors versus the decrease in sympathetic activity achieved by stimulating central or presynaptic peripheral α2 adrenoceptors. Both drugs produced similar reduction in systemic arterial pressure. However, only indoramin significantly decreased systemic and pulmonary vascular resistances from 1529 ± 526 to 1071 ± 356 and from 721 ± 422 to 412 ± 257 dynes ± 5 ± cm-5, respectively, and increased stroke index from 26.6 ± 9.5 to 33.3 ± 9.5 ml/m2 (all p < 0.01). Heart rate fell significantly only after guanabenz. Plasma norepinephrine, unchanged after indoramin, fell in each patient after guanabenz: the mean value decreased from 746 ± 332 to 461 ± 255 pg/ml (p < 0.01). Plasma renin activity increased only after indoramin. The data demonstrate: (a) a decrease in sympathetic activity due to blockade of α1 adrenoreceptors produces marked peripheral and pulmonary vasodilation; (b) noradrenergic transmitter release in heart failure is regulated by α2 receptors; (c) an α2-mediated decrease in sympathetic activity and in plasma norepinephrine has a bradycardic effect but does not produce a vasodilator effect. Although the acute hemodynamic effects of indoramin were more prominent than those of guanabenz, the more favorable neurohumoral effects of guanabenz suggest the possibility of long-term benefit in the treatment of heart failure.

Evidence for a direct renal stimulating effect of prostaglandin E2 on renin release in patients with congestive heart failure.

The reduced responsiveness of the renin-angiotensin system to hemodynamic changes in patients with congestive heart failure (CHF) could be due to a defect of the juxtaglomerular apparatus. To test this hypothesis, the responses to viprostol, an analog of prostaglandin E2 (PGE2) that is known to stimulate both the macula densa and the juxtaglomerular cells, and to nitroprusside were compared in patients with CHF. An average fall in mean arterial pressure (MAP) of 6 mm Hg with viprostol was associated with a fivefold increase in plasma renin activity (PRA) from 11.4 +/- 6.4 to 47.9 +/- 31.0 ng/ml/hr; in contrast PRA did not change with nitroprusside, despite a significant decrease in preload and an average decrease in MAP of 16 mm Hg. These data demonstrate that the renin-angiotensin system could be activated by PGE2 in patients with CHF, this activation is not related to the global hemodynamic changes induced by PGE2, and the previously reported unresponsiveness of the renin-angiotensin system in patients with CHF cannot be attributed to a defective response of the juxtaglomerular apparatus.