Steven G. Chrysant

Comparative Effects of Candesartan Cilexetil and Amlodipine in Patients With Mild Systemic Hypertension

The comparative antihypertensive efficacy and tolerability of the angiotensin II receptor blocker candesartan cilexetil and the calcium channel blocker amlodipine were evaluated in an 8-week, multicenter, double-blind, randomized, parallel-group, forced-titration study in 251 adult patients (45% women, 16% black) with mild hypertension (stage 1). Following a 4- to 5-week placebo run-in period, patients with sitting diastolic blood pressure (BP) of 90 to 99 mm Hg received candesartan cilexetil 16 mg (n = 123) or amlodipine 5 mg (n = 128) once daily. After 4 weeks of double-blind treatment, patients were uptitrated to candesartan cilexetil 32 mg or amlodipine 10 mg once daily. There were no significant differences between the candesartan cilexetil and amlodipine regimens for reducing BP; mean systolic BP/diastolic BP reductions were -15.2/-10.2 mm Hg versus -15.4/-11.3 mm Hg, respectively (p = 0.88/0.25). Overall, 79% of patients on candesartan cilexetil and 87% of those on amlodipine were controlled (diastolic BP <90 mm Hg). A total of 3.3% of patients on candesartan cilexetil discontinued treatment, compared with 9.4% of patients on amlodipine, including 2.4% versus 4.7% for adverse events and 0% versus 1.6% for peripheral edema, respectively. Peripheral edema, the prespecified primary tolerability end point, occurred with significantly greater frequency in patients on amlodipine (22.1%; mild 8.7%, moderate 11.8%, severe 1.6%) versus patients on candesartan cilexetil (8.9%; mild 8.1%, moderate 0.8%) (p = 0.005). Candesartan cilexetil and amlodipine are both highly effective in controlling BP in patients with mild hypertension. Candesartan cilexetil offers a significant tolerability advantage with respect to less risk of developing peripheral edema.

Pathophysiologic significance of 'stress' or relative polycythemia in essential hypertension

Fourteen patients with essential hypertension (blood pressure 167 ± 2106 ± 2 [mean ± standard error of the mean] mm Hg) were studied prospectively to determine the pathophysiologic correlates of their “stress” or relative polycythemia. All patients had a high hematocrit level (53.1 ± 0.4 vol percent), contracted plasma volume (16.2 ± 0.4 ml/cm height) and normal red cell mass and serum erythropoietin levels. Blood and plasma viscosity (0.076 ± 0.005 and 0.017 ± 0.001 poise, respectively) were increased, and plasma renin activity in the supine, resting state averaged 1.8 ± 0.3 ng/ml per hour. All patients were treated with methyldopa to achieve normal arterial pressure and the previous determinations were repeated after 1 and 4 weeks of treatment. Reduction of pressure was associated with expansion of plasma volume (P < 0.001) and significant decreases in hematocrit, blood and plasma viscosity and resting plasma renin activity (P < 0.001). Red cell mass and serum erythropoietin levels remained unchanged. Therefore, the so-called stress polycythemia is a pathophysiologic manifestation of the hypertensive vascular disease in which the abnormal hemodynamic and rheologic alterations can be reversed by antihypertensive therapy. The significance of this reversal may have some bearing upon the high prevalence rates of severe cardiovascular complications associated with so-called stress polycythemia and high renin essential hypertension.

Antihypertensive and metabolic effects of a new converting enzyme inhibitor, enalapril

Thirty‐one men with mild, uncomplicated essential hypertension were studied for 18 wk in a double‐blind, placebo‐controlled, randomized clinical trial. Those whose supine diastolic pressure was 90 to 104 mm Hg after 4 wk of placebo were randomly assigned to three groups. Group I (11 subjects) initially received one 10‐mg enalapril capsule in the morning and one placebo capsule in the evening. Group II (10 subjects) received one 5‐mg enalapril capsule twice daily. Group III (10 subjects) received one placebo capsule twice daily. Drug dosages were doubled and then quadrupled in all groups at wk 8 and 12. Metabolic, ophthalmologic, and audiometrie studies were done on all subjects at wk 2, 4, 8, 12, and 16. Enalapril lowered diastolic pressure in the supine and upright positions in single and divided doses. Its antihypertensive effect was dose dependent, and it was greater in white patients than in black patients. The drug was well tolerated by all subjects and did not cause clinical or metabolic complications. It is concluded that enalapril is effective in lowering the arterial pressure in single and divided daily doses; its effect is dose dependent and is greater on the diastolic arterial pressure than on the systolic pressure; and it is well tolerated.

Effects of Diuretics On Lipid Metabolism in Patients With Essential Hypertension

Available clinical evidence indicates a high prevalence of hyperuricemia in patients with essential hypertension; this becomes accentuated with diuretic therapy. Since there is an association of hyperlipidemia with hyperuricuria and hypertension and since hyperuricemia is a feature of diuretic therapy, we explored whether these relationships might be provoked by prolonged diuretic therapy. Eighteen male patients with uncomplicated essential hypertension of mild severity were treated for 9 months with hydrochlorothiazide and supplemental potassium chloride, 100 mg and 45 mEq/day, respectively. Arterial pressure, renal function, and serum electrolyte, uric acid, blood glucose, and lipid concentrations were measured several times before and during therapy. Arterial pressure remained significantly reduced during therapy (P less than 0.001); this was associated with reduced serum potassium (P less than 0.01) and increased blood glucose and serum uric acid concentrations (P less than 0.005, P less than .025, respectively). Blood urea nitrogen, serum creatinine, sodium, cholesterol and triglyceride levels did not significantly change with treatment. Thus, although diuretics increase serum uric acid and blood glucose, their effect on serum lipid concentration is negligible.

Hemodynamic Effects of Isometric Exercise in Normotensive Hypertensive Subjects Hypertension

Isometric exercise increases arterial pressure and heart rate in normotensive individuals and also in patients with labile and fixed essential hypertension. The hypertensinogenic effect of isometric exercise is mediated through an increase in cardiac output because the peripheral vascular resistance is usually not affected. The cardioaccelerating effects of isometric exercise are mediated through an initial vagal withdrawal and a later stimulation of the sympathetic system. However hypertensive patients with defective sympathetic adjustments are not immune to the hypertensinogenic and cardioaccelerating effects of isometric exercise. Since isometric exercises are performed several times during daily activities, they may result in dangerous elevations in arterial pressure in patients with already increased arterial pressure, and this may eventually lead to cerebrovascular accidents and/or cardiac decompensation. It is therefore recommended that patients with elevated arterial pressure, or persons prone to hypertension, should refrain from such activities.

Systemic and renal hemodynamic effects of trimazosin: a new vasodilator.

Trimazosin was administered for 2 days in doses-ranging from 50 to 200 mg to 16 patients with essential hypertension. The patients were randomized on the third day and received either the active drug in a single dose of 300 mg or a placebo. Systemic hemodynamic studies in both the supine and 50 degrees upright tilt position, including the Valsalva maneuver and a 1 min sustained handgrip test at 30% maximal voluntary contraction, were performed during control and 0, 1, 2, and 3 hr after drug administration. Renal function studies including plasma renin activity (PRA) were performed during control period and 3 hr after drug administration. Trimazosin reduced arterial pressure and peripheral vascular and renal vascular resistances, increased heart rate, cardiac output, and renal blood flow, and had no effect on glomerular filtration rate or PRA. Placebo had no effect on any of the above-mentioned parameters. The increase in renal blood flow was independent of cardiac output. We conclude that trimazosin lowers arterial pressure through a direct arteriolar dilation and reduction in peripheral vascular resistance. Its direct renal effects would make it a useful agent in the treatment of hypertension associated with renal function impairment.

The Effects of Salt and Meclofenamate Administration on the Hypertension of Spontaneously Hypertensive Rats

The effects of prolonged (3 mos) high sodium intake and meclofenamate were studied in 2 groups of male SHR. Group 1 (6 rats) received 1% NaCl in tap water and Group 2 (8 rats) received 1% NaCl in tap water plus 50 microgram of meclofenamate per ml of drinking fluid. Renal metabolic and hemodynamic studies in the unanesthetized unrestrained state, showed that the meclofenamate treated rats had higher arterial pressures (p less than .005), left ventricular weight (p less than .05) and renal vascular resistance (p less than .005); lower glomerular filtration rate (p less than .005) than the control rats. The hematocrit and right ventricular weight were similar in the two groups of rats. This study has demonstrated that the combination of high sodium intake and meclofenamate have a greater damaging effect on the arterial pressure and renal function of SHR than salt alone.

Systemic and renal hemodynamic effects of bupicomide: A new vasodilator*

The systemic and renal hemodyanmic effects of bupicomide were studied in 10 male patients with uncomplicated essential hypertension of moderate severity. Bupicomide significantly reduced systolic, diastolic, and mean arterial pressure and peripheral vascular resistance and this hypotensive effect was associated with a reflexive increase in heart rate, left ventricular ejection rate, and cardiac index; it had no effect upon other reflexive sympathetic adjustments induced by upright tilt and the Valsalva maneuver. Bupicomide also increased renal blood flow and decreased renal vascular resistance, but it had no effect upon the glomerular filtration rate. The hypotensive mechanism of bupicomide therefore is mediated by peripheral arteriolar dilation, through vascular smooth muscle relaxation. The more immediate clinical side effects of bupicomide are related to its strong vasodialting action and include headaches, cutaneous flushing, and tachycardia.

Effects of Amiloride on Arterial Pressure and Renal Function

Amiloride was administered to 13 male patients with mild essential hypertension and normal renal function. It effectively reduced supine and standing arterial pressures. The antihypertensive response was associated with a significant decrease in renal inulin clearance and a rise in plasma creatinine concentration, although both values at the end of seven weeks of therapy remained within normal limits. Serum potassium concentrations rose but did not reach hyperkalemic levels. Amiloride did not increase blood levels of glucose, uric acid, lipids, calcium, or urea nitrogen. We conclude that amiloride is an effective antihypertensive and antikaliuretic agents for patients with mild hypertension and normal renal function.

Renal functional and organic changes induced by salt and prostaglandin inhibition in spontaneously hypertensive rats.

The prolonged (3 months) effects of high sodium intake and sodium meclofenamate were studied in two groups of male spontaneously hypertensive rats. Group 1 (8 rats) received 1% NaCl in tap water ad libitum and served as control. Group 2 (8 rats) received, besides 1% NaCl in tap water, 50 micrograms/ml of sodium meclofenamate per rat daily. Renal metabolic, hemodynamic and histologic studies were done at the end of the study. The renal functional studies were performed in the unanesthetized, unrestrained state. Group 2 rats developed significantly higher arterial pressures, renal vascular resistance and histologic changes (p less than 0.005), larger left ventricular weights (p less than 0.05) and significantly lower effective renal plasma flow, renal blood flow (p less than 0.005) and glomerular filtration rate (p less than 0.05) than group 1 rats. There were no differences between the two groups of rats with respect to heart rate, hematocrit, right ventricular weight, body weight, fluid intake, urine output, sodium and potassium excretion and serum electrolytes. The results suggest that the combination of high sodium intake and prostaglandin synthesis inhibition exert a greater damaging effect on the arterial pressure and renal function of spontaneously hypertensive rats than salt alone.