Charles P. Tifft

Antihypertensive Effect of the Oral Angiotensin Converting-Enzyme Inhibitor Sq 14225 in Man

We investigated the antihypertensive effect of the angiotensin converting-enzyme inhibitor SQ 14225 in 12 hypertensive patients for periods of three to 24 weeks. Blood pressure decreased in all patients (from 177 +/- 8/110 +/- 2 to 136 +/- 6/88 +/- 2 mm Hg--mean +/- S.E.); oral doses ranged from 400 to 1000 mg daily. Concomitant effects noted were small increases in plasma potassium concentration and pulse rate. One patient experienced a transient febrile reaction. Plasma renin activity rose during treatment, plasma aldosterone decreased, and angiotensin-converting-enzyme activity was virtually eliminated. There was no significant correlation between pretreatment plasma renin activity and degree of blood-pressure fall with SQ 14225. The exact mechanisms contributing to the blood-pressure-lowering effect of this agent remain unclear. SQ 14225 is a promising new antihypertensive agent, effective in patients refractory to traditional medical therapy.

Mineralocorticoid-Induced Hypertension in Patients with Orthostatic Hypotension

The mechanism of recumbent hypertension induced by fludrocortisone was studied in seven patients with orthostatic hypotension. All showed increases in blood pressure in the recumbent and standing positions, and hypertensive levels were achieved on recumbency in four of them. Hypertensive retinopathy developed in two patients and cardiomegaly in one. Initial blood-pressure elevations were associated with sodium retention and plasma-volume expansion. However, with long-term treatment, plasma volume decreased to control levels despite further blood-pressure increases. Treatment did not affect plasma levels of catecholamines but did enhance pressor responsiveness to infused norepinephrine in some subjects. Hemodynamic studies indicated that hypertension in the recumbent position was related to increases in total peripheral-vascular resistance and not to changes in cardiac output. Clinically, hypertension in the recumbent position is an important risk of fludrocortisone treatment in patients with orthostatic hypotension. This unusual model of chronic mineralocorticoid-induced hypertension is not volume dependent but is related to increased peripheral-vascular resistance.

Renal Revascularization in the Azotemic Hypertensive Patient Resistant to Therapy

We undertook this study to assess the frequency of renovascular hypertension in patients with azotemia and hypertension refractory to drug therapy and to determine the effects of renal revascularization on blood pressure and renal function in these subjects. Thirty-nine of 106 consecutive patients admitted for diagnostic evaluation of severe hypertension proved to have renovascular hypertension. Of 21 hypertensive patients with renal insufficiency, 10 appeared to have renovascular hypertension with either bilateral atherosclerotic renovascular disease or unilateral renal arterial stenosis in a solitary functioning kidney. Medical therapy in the hospital often induced further deterioration of renal function despite enhanced blood-pressure control. However, surgical revascularization or percutaneous transluminal angioplasty produced improvement or stabilization of renal function and control of blood pressure in all patients with azotemia who were treated in this manner, despite longstanding hypertension. The benefits of therapy have persisted for 10 to 42 months of follow-up. These studies indicate that refractory hypertension in association with renal insufficiency is a relatively common clinical presentation for renovascular hypertension and bilateral renal-artery disease. Diagnostic evaluation and consideration of renal revascularization appear warranted in such patients, both for the control of the hypertension and for improvement in renal function.

Postural changes in diastolic blood pressure and the risk of myocardial infarction: the Normative Aging Study.

To assess the relationship of postural changes in blood pressure to risk of myocardial infarction, 1359 men were followed for an average of 8.7 years. The men were participants in the Normative Aging Study, a longitudinal study of aging initiated in 1963 at the Veterans Administration Outpatient Clinic in Boston. It was found that the relationship of sitting blood pressure to the subsequent incidence of myocardial infarction was modified by a variable formed by subtracting supine from standing diastolic blood pressure (delta DBP). The effect of sitting diastolic blood pressure on risk of myocardial infarction was confined primarily to men with a delta DBP of 10 mm Hg or more. The effect of sitting systolic blood pressure on risk of myocardial infarction was apparent in all categories of delta DBP (less than 1, 1 to 9, greater than or equal to 10 mm Hg), but the gradient of risk became stronger with increasing levels of delta DBP. The modifying influence of delta DBP remained even when standard coronary risk factors were included in multivariate analyses. These findings suggest a relationship of vascular responsiveness to risk of subsequent myocardial infarction and may have clinical utility.

Norepinephrine and renin activity in chronic renal failure. Evidence for interacting roles in hemodialysis hypertension.

SUMMARY To assess the interaction between adrenergic activity and blood pressure regulation in patients with chronic renal failure, plasma norepinephrine (NE) and plasma renin activity (PRA) were measured before and after rigorous ultrafiltration. The significance of PRA was further assessed by anglotensin blockade with saralasin. Two patterns of response were defined: nine patients had low levels of PRA before and after hemodialysis. These patients showed a net fall in norepinephrine and no angiotensin dependence at any time. Failure to stimulate either PRA or norepinephrine was also observed during periods of marked hypotension. Seven other patients had higher PRA, which rose during bemodialysis. This was associated with an increase in NE and postdialysis angiotensin dependence. Patients experiencing hypotension in this group showed a sharp rise in NE, suggesting baroceptor-mediated adrenergic stimulation. In all patients sustaining hypotension during therapy, postdialysis PRA was closely correlated with NE. These results Indicate that hemodialysis mobilizes the renin-angiotensln system to maintain hypertension in a greater proportion of dialysis patients than previously supposed and that impaired renin release following hypotension may represent uremic autonomic dysfunction.

Converting Enzyme Inhibition in Hypertensive Emergencies

The diagnostic and therapeutic value of the angiotensin converting enzyme inhibitor teprotide (SQ 20881) was assessed in 18 patients with hypertensive emergencies. Mean blood pressure fell 31 +/- 18 mm Hg in the 10 subjects who responded to 1 mg/kg body weight administered intravenously, whereas it fell 5 +/- 3 mm Hg in the eight nonresponders. In patients who had received no previous drug treatment, log baseline plasma renin activity and change in mean blood pressure after SQ 20881 correlated significantly (r = 0.651, P less than 0.05). After acute therapy with SQ 20881, the patients who had a satisfactory response to the drug were treated with propranolol and a relatively normal sodium intake (88 meq/day). Nonresponders were treated with diuretics and sodium restriction (10 meq/day), and intermediate responders were given combination therapy. Mean blood pressure responded favorably within 24 h to the chosen regimen for each group from 152 +/- 47 to 102 +/- 31 mm Hg. SQ 20881 allows prompt evaluation of the role of renin in hypertensive emergencies and permits early choice of appropriate therapy based on the prevailing mechanism.

Alpha and beta adrenergic receptor activity in circulating blood cells of patients with idiopathic orthostatic hypotension and pheochromocytoma.

Alpha and beta adrenergic receptor binding has been studied in circulating blood cells of 22 normal subjects, 6 patients with chronic orthostatic hypotension, and 1 with pheochromocytoma. Binding of the radioligand /3H/ dihydroergocryptine to platelet membranes was used to assess alpha 2 receptors and /3H/ dihydroalprenolol binding to polymorphonuclear leukocyte membranes was utilized to examine beta receptors. The findings were correlated with the results of tests of adrenergic function.The alpha 2 and beta receptor levels of most normal subjects varied within relatively narrow limits over several months. In patients with idiopathic orthostatic hypotension, marked increases in the number of both types of receptor sites were present. The changes were associated with significant reduction in plasma norepinephrine and exaggerated responses of blood pressure to infused norepinephrine. Chronic treatment of 4 of the patients with the alpha agonist, ergotamine bitartrate, produced significant increases in blood...

Role of reactive hyperreninemia in blood pressure changes induced by sodium depletion in patients with refractory hypertension.

SUMMARY Sixteen patients with refractory hypertension were submitted to rigorous sodium depletion while cardloTascular bomeostasis was monitored with measurements of hormonal and bemodynamlc parameters and repeat saralasin tests. This regimen resulted in a negative sodium balance by an average of 300 mEq. The loss of sodium closely correlated to the decrease of body weight (r « 0.70, p < 0.005). Blood pressure (BP) decreased from 176/116 ± 8/3 to 155/109 ± 6/3 mm Hg. There was a significant correlation between percent increments in plasma renin activity (PRA) and the rise in plasma norepinephrine (r = 0.68, p < 0.05) and a dose negative correlation between percent increase in PRA and the ratio of fall in mean Mood pressure (MAP), per unit of weight loss (r = −0.73, p < 0.005). Thns, patients with the least percent increase In PRA demonstrated the greatest fall in BP per unit of weight loss, indicating that relative rather than absolute elevation of renin may be tne factor limiting antihypertenslve efficacy of sodium depletion. Sodium depletion induced increase in peripheral resistance and decrease in cardiac output, both mostly attributable to relative hyperreninemia. Indeed, the adverse hemodynamic changes were reversed by angiotensin inhibition, during which BP normalized. It is concluded that vigorous sodium depletion complemented by angiotensin blockade or suppression with sympatholytic agents improves management of otherwise refractory hypertension.

Hypertension and AGE: Clinical and Biochemical Correlates

Plasma renin activity, aldosterone and norepinephrine levels were determined in 247 ambulatory hypertensive patients divided into young, middle aged, and old groups. PRA and the increase of PRA after furosemide were higher in the younger; NE was higher in the old group. Some relationships may be inherent in aging and not necessarily confined to hypertensives. This may explain discrepancies between reports by investigators who studied homogenous groups classified in different ways.

Effects of a novel renin inhibitor in patients with essential hypertension

The effects of A-64662, a new specific renin inhibitor, on plasma renin activity (PRA) and blood pressure (BP) were studied for the first time in patients with essential hypertension. A single intravenous bolus of vehicle, 0.001, 0.003, 0.01, 0.03, and 0.1 mg/kg was given to the first four patients, maintained on a constant 100 mEq Na diet. PRA was promptly reduced from 3.4 ± 2.9 (mean ± SEM) to 0.2 ± 0.06 ng/ml/h, a 94% inhibition with the smallest dose, and to undetectable levels (<0.1 ng/ml/h) with the larger ones. However, BP did not change within this dose range. The subsequent seven patients received larger doses ranging from 0.2 to 1.0 mg/kg. In three cases, there was reduction in BP on the second dosing day, at doses of 0.4, 0.7, and 1 mg/kg. All responses were late (at 110 min after the injection), transient, and unrelated to baseline PRA. These results strongly suggest that there is a dissociation between the effectiveness of A-64662 in inhibiting PRA and its blood pressure lowering effect in hypertensive patients.