Andreas P. Niarchos

Hemodynamic effects of captopril in pulmonary hypertension of collagen vascular disease

Captopril 12.5 to 50 mg as a single dose was given to six patients with pulmonary hypertension secondary to collagen vascular disease. Total pulmonary resistance was decreased in four patients from 19% to 39%, but mean pulmonary artery pressure (63 +/- 15 mm Hg) was not decreased, probably because of the concurrent increase in cardiac output from 21% to 52% (2p less than 0.05). The systemic arterial pressure was slightly decreased due to the decrease in total systemic resistance. Control plasma renin activity ranged from 0.15 to 16 ng/ml/hr and was increased during captopril from 19% to 356%. These results, although preliminary, suggest that captopril may be beneficial in certain patients with pulmonary hypertension secondary to collagen vascular disease.

Hemodynamic characteristics of hypertension after coronary bypass surgery and effects of the converting enzyme inhibitor

In 13 patients with hypertension after coronary bypass surgery, the underlying hemodynamic mechanism was an increased systemic vascular resistance. To elucidate the role of the renin-angiotensin system in left ventricular function, plasma renin activity and hemodynamic measurements were performed during the peak of the hypertensive episode and 15 to 30 minutes after the administration of the converting enzyme inhibitor SQ20881 (1 mg/kg body weight). Eight of the 13 patients responded to the inhibitor; in these patients control plasma renin activity was 8.78 ± 2.3 ng/ml per hour, and mean arterial pressure decreased markedly from 123 ± 6 to 101 ± 5 mm Hg (P < 0.005), due to a decrease in systemic vascular resistance from 22 ± 2 to 14 ± 1 units (P < 0.005). The decrease in systemic vascular resistance induced by the inhibitor correlated with the control plasma renin activity (r = 0.825, P < 0.05). In the responders, administration of the inhibitor also increased cardiac output from 5.26 ± 0.36 to 7.39 ± 0.61 liters/min (P < 0.005) because of an increase in stroke volume from 61 ± 3 to 78 ± 5 ml/beat (P < 0.005), although left ventricular filling pressure decreased from 8.5 ± 1 to 6.0 ± 1 mm Hg (P < 0.005). In the remaining five patients (nonresponders to the inhibitor), control plasma renin activity was 1.8 ± 0.3 ng/ml per hour (P < 0.05 compared with the responders), but the control hemodynamic data did not differ from those of the responders. In the nonresponders the small decrease in mean arterial pressure (from 128 ± 5 to 123 ± 4 mm Hg, P < 0.025) was due to a decrease in stroke volume and cardiac output, but systemic vascular resistance did not change. As in the responders, administration of the inhibitor decreased left ventricular filling pressure in this group from 8 ± 1 to 6 ± 0.8 mm Hg (P < 0.025). These results indicate that the renin-angiotensin system is often involved in postcoronary artery bypass hypertension. In patients with increased renin, blockade of angiotensin II improved left ventricular function by reducing afterload rather than preload, thus indicating that angiotensin II acts on the heart and veins.

Effects of diuretic therapy in low-, normal- and high-benin isolated systolic systemic hypertension☆

In 30 patients with isolated systolic systemic hypertension, diuretic therapy decreased body weight from 71.33 +/- 2.67 to 70.37 +/- 2.65 kg (p less than 0.0005) and the systolic blood pressure from 174 +/- 3 to 156 +/- 3 mm Hg (p less than 0.0005). Diastolic blood pressure and heart rate did not change significantly. Plasma renin activity increased from 2.25 +/- 0.33 to 4.27 +/- 0.43 ng/ml/hour (p less than 0.0005) and urinary aldosterone from 9 +/- 1 to 16 +/- 2 micrograms/24 hours (p less than 0.005). The antihypertensive effect of diuretics was significantly related only to the pretreatment plasma renin activity (r = -0.50, n = 30, p less than 0.05), and therefore the greatest decrease in systolic blood pressure occurred in the low-renin group, whereas the smallest occurred in the high-renin group (-22 +/- 2 vs -3 +/- 9 mm Hg, p less than 0.005). The diastolic blood pressure was significantly decreased only in the low-renin group (-7 +/- 2 mm Hg, p less than 0.005). There were no significant changes in blood pressure in 11 untreated control patients. These results indicate that diuretics are effective antihypertensive agents in most patients with low- and normal-renin isolated systolic systemic hypertension.

Angiotensin I converting enzyme activity in hypertension. Relationship to blood pressure, renin-sodium profiles, and antihypertensive therapy

The activity of the angiotensin I converting enzyme was measured in 55 patients with untreated essential hypertension, 11 patients with untreated renovascular hypertension, five patients with untreated primary aldosteronism, and 23 normotensive subjects. Converting enzyme activity was significantly higher (p less than 0.025 or less) in essential hypertension (28 +/- 1 units/ml) and renovascular hypertension (28.5 +/- 3 units/ml) when compared with the activity in the normotensive subjects (21 +/- 1.5 units/ml). Seventeen (31 percent) of the patients with essential hypertension and three (27 percent) patients with renovascular hypertension had an elevated converting enzyme activity above the mean +2 standard deviations value of the normotensive subjects (32.8 units/ml), ranging from 33 to 55.8 units/ml. Converting enzyme activity was similar in black and white patients and in male and female patients, but it tended to decrease with increasing age in both the hypertensive and the normotensive subjects. In the untreated patients with essential hypertension (n = 55), converting enzyme activity was inversely related to mean arterial pressure and age (r = -0.34, p less than 0.01) and positively related to plasma renin activity (r = 0.31, p less than 0.05). Converting enzyme activity was always decreased during captopril therapy, and it was not affected by beta blockers, but it was increased by diuretics. These findings indicate that converting enzyme activity is elevated in patients with essential and renovascular hypertension.

Hemodynamic effects of massive peripheral edema

The possibility that noncardiac massive peripheral edema reduces venous distensibility was investigated in eight patients in the supine and 80-degree head-up tilt position before and after diuretic therapy. After clearance of the edema with diuretic therapy, total blood volume (TBV) was not significantly decreased; therefore, in the supine position the significant (2p less than 0.001) decrease of right atrial pressure, stroke volume, cardiac output, and cardiopulmonary blood volume (CBV) by the diuretics was due to an improvement in venous compliance which resulted in peripheral redistribution of CBV since the ratio CBV/TBV was decreased during diuretic therapy (2p less than 0.001). Furthermore, before diuretic therapy, tilt significantly decreased right atrial pressure, stroke volume, cardiac output, CBV, and the ratio CBV/TBV; but after diuretic therapy, the decrease of the same variables during tilt was significantly (2p less than 0.001) greater. These results indicate that marked peripheral edema considerably decreases venous compliance which can be improved with diuretic therapy.

Role of renin and aldosterone suppression in the antihypertensive mechanism of clonidine

Abstract The hypothesis that clonidine decreases blood pressure by suppression of the renin-angiotensin II-aldosterone system was investigated in 20 hypertensive patients during a constant sodium and potassium intake. A significant decrease in mean arterial pressure (MAP), from 123 ± 3 to 102 ± 3 mm Hg (P In order to evaluate further the role of renin suppression as an antihypertensive mechanism during clonidine treatment, the renin (angiotensin II) dependency of hypertension was tested prior to the administration of clonidine by giving an infusion of the angiotensin II competitive antagonist, saralasln to eight patients. In four of the eight patients blood pressure was decreased by both clonidine and saralasin, whereas in three patients clonidine decreased MAP, but saralasin elicited a pressor response. Finally one nonresponder to clonidine exhibited a depressor response to saralasin. Thus, clonidine decreased blood pressure in patients with nonrenin-dependent hypertension. Over-all results indicate that although the decrease in blood pressure is related to renin suppression during treatment with clonidine, another antihypertensive mechanism (or mechanisms) still exists in hypertension without renin dependency.

Hemodynamic effects of the converting enzyme inhibitor teprotide in normal‐ and high‐renin hypertension

The hemodynamic effects of the converting enzyme inhibitor teprotide (SQ 20881) were investigated in five patients with normal plasma renin activity who were normotensive during the study (group I), in five patients with hypertension and normal plasma renin activity (group II), and in five patients with hypertension and high plasma renin activity (group III). No significant hemodynamic changes were observed during teprotide administration in group I. In group II there was a decrease in mean arterial pressure by 10 ± 2% (p < 0.005) that was associated with a decrease by 16 ± 7% (p < 0.05) in stroke volume and cardiac output, possibly due to venodilatation and without a concurrent change in total peripheral resistance. In group III the larger decrease of 19 ± 4% (p < 0.005) in mean arterial pressure was due to a decrease by 30 ± 3% (p < 0.005) in peripheral resistance. In this group stroke volume and cardiac output increased by 13 ± 2% (p < 0.025). There were no compensatory changes in heart rate despite the decrease in mean arterial pressure and vasodilatation. These results indicate that teprotide decreases arterial pressure by a dual hemodynamic mechanism. Cardiac output is increased by teprotide in patients with high‐renin hypertension who exhibit the greatest decrements in peripheral resistance.

Hemodynamic effects of diuretics in patients with marked peripheral edema and mild hypertension

Hypertension develops in about 10% to 50% of patients with nephrosis or cirrhosis and peripheral edema, but the hemodynamic mechanism of the hypertension and its reversal by diuretic therapy has not been elucidated. In eight patients with marked edema and mild hypertension, diuretics (furosemide and spironolactone) decreased mean arterial pressure because of concurrent decrease in cardiac output and total peripheral resistance. Neither total blood volume nor plasma volume were decreased by the diuretics and the decrease in body weight was therefore attributed to the decrease in interstitial fluid volume. This, in turn, resulted in increased venous capacitance (as can be judged from the diuretic‐induced decrease in the ratio of cardiopulmonary blood volume/total blood volume).

Effect of Converting Enzyme Inhibition with Teprotide on Hemodynamics and Cardiovascular Reflexes in Normotensive Subjects

Several recent studies, some of which are presented elsewhere in this volume, have provided evidence that the renin-angiotensin-aldosterone system participates in the pathogenesis of elevated arterial pressure in renovascular and essential human hypertension and in some experimental animal models of hypertension. This pathogenetic role of the renin-angiotensin system is now being investigated more precisely because of the availability of the pharmacologic tools that block the renin-angioten-sin system in several sites. These agents include saralasin and the similar angiotensin II competitive antagonists, the converting enzyme inhibitors teprotide and captopril, which block the conversion of angiotensin I to angiotensin II, and more recently the antirenin antibodies and the renin-inhibiting peptides that antagonize renin per se. It is beyond the scope of this chapter to discuss the specificity of these antagonists, since some may have additional pharmacologic effects; nevertheless, it is generally agreed that the cardiovascular effects of saralasin, converting enzyme inhibitors, and the antirenin agents are mainly attributable to their property to interfere with the renin-angio-tensin system.