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Nisoldipine, a calcium channel blocking agent, is known to have antihypertensive, renal tubular and hemodynamic effects. The present studies were designed to examine the effects of this drug on the renal tubular transport of calcium in 12 saline-loaded SHR rats. Calcium-45 was infused into three different nephron segments: early proximal, late proximal and early distal sites with or without nisoldipine. Calcium efflux averaged 93.6 +/- 4.9 and 90.5 +/- 8.7% after early and late proximal administration, respectively, indicating that the proximal tubule and the loop of Henle are highly efficient in transporting calcium out of the tubule. In distal nephron segments, calcium transport was limited to 41.1 +/- 4.8% of the amount delivered to these tubules. Nisoldipine inhibited the efflux of simultaneously infused calcium. This apparent inhibitory effect occurred predominantly in distal nephron segments where the drug reduced calcium efflux from 41.1 +/- 4.8 to 22.5 +/- 2.7%, indicating a 45.3% reduction in net calcium reabsorption. The results are consistent with the interpretation that nisoldipine-induced reduction in the tubular efflux of calcium was secondary to a direct inhibition of voltage-sensitive, L-type calcium channels or to a blunting of the rate of phosphorylation of channel proteins by protein kinase C in the distal tubular epithelial cells.

A number of studies have shown an antihypertensive effect for high-calcium diets, but others have found no effect or, even a prohypertensive effect. Because of these disparate results, studies were conducted in spontaneously hypertensive rats (SHR) fed either a normal calcium diet (1.0% calcium) or a high-calcium diet (4.0% calcium) with or without verapamil HCl (50 mg/kg body weight) from ages 5 to 12 weeks. Systolic blood pressure (SBP) and heart rate (HR) were measured by indirect tail cuff method. During the analysis of the electrolytes and vasoactive hormones monitored in this study, it was found that rats fed high-calcium diet had significantly elevated serum ionized and total calcium and calcium excretion. Systolic blood pressure for the verapamil-normal calcium diet (week 5, 148 +/- 4 mm Hg; week 7, 162 +/- 4 mm Hg) did not differ significantly from that of normal calcium diet (week 5, 152 +/- 2 mm Hg; week 7, 160 +/- 1 mm Hg). The high-calcium diet potentiated the development of hypertension, i.e., SBP was (157 +/- 2 mm Hg) on the 5th week and (174 +/- 4 mm Hg) on the 7th week. Conversely, verapamil high-calcium diet prevented the development of hypertension (week 5, SBP was 139 +/- 4 mm Hg; week 7, SBP was 146 +/- 3 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

The renal action of guanabenz, a centrally acting antihypertensive drug, was evaluated in anesthetized New Zealand genetically hypertensive rats and in normotensive Sprague-Dawley rats using clearance techniques. In high doses (1 mg/kg/hr), the drug lowered systemic blood pressure in the hypertensive rats without reducing glomerular filtration rate. Mean urine flow increased from 2.42 +/- 0.34 to 36.52 +/- 4.52 microliters/min per 100 g b.wt. while fractional water excretion increased from 0.34 +/- 0.05 to 4.36 +/- 0.50%. The renal and hemodynamic actions of the drug were sustained throughout the experiment. In a lower dose (10 micrograms/kg/hr), guanabenz reduced blood pressure in the hypertensive rats to an extent similar to that of the higher dose but had only a moderate effect on kidney function. Renal elimination of water, sodium and potassium increased slightly and glomerular filtration rate remained unchanged. Infusion of the vehicle alone did not cause significant changes in the hemodynamic and renal excretory functions. In the normotensive rats, receiving the high dose of the drug, mean urine osmolarity declined nearly 10-fold from 2466 +/- 136 to 290 +/- 37 mOsl while total solute excretion doubled. Infusion of the vehicle alone did not cause significant changes in the hemodynamic and renal excretory functions. The drug appears to have a primary action on the renal tubular handling of water and sodium. It may inhibit the secretion of antidiuretic hormone or block the antidiuretic hormone-stimulated cAMP-dependent increase in water permeability of the collecting tubules through its alpha 2-adrenoceptor agonistic effect. Natriuresis may have resulted in part from a lowered sympathetic tone to the kidneys.

Twenty-four hypertensive women over 40 years of age were given calcium carbonate 1 g/d for 12 weeks after a 4-week period of observation. Blood pressures were measured every 2 weeks. Plasma ionized calcium (Ca++), sodium (Na), and potassium (K) were measured twice in the control period and twice in the Ca-supplementation period. Urine measurements included Ca, Magnesium (Mg), Na, K, prostaglandin E2, and osmolality. Blood pressures were averaged to get group means, and these were compared using the paired t-test. For the group, seated systolic blood pressure fell from 141.5 +/- 13.2 to 136.3 +/- 11.4 mm Hg (p less than 0.025) at the end of 12 weeks of supplementation, and diastolic blood pressure fell from 84.5 +/- 7.5 to 81.1 +/- 7.1 mm Hg (p less than 0.025). There was no correlation between serum Ca++ and blood pressure. The urinary Na excretion was markedly elevated during the Ca supplementation period: 25.8 +/- 14.2 vs. 18.4 +/- 7.9 mmol/4 hr (p less than 0.005). These results suggest an indirect (natriuretic) effect as the means by which Ca supplementation lowers blood pressure.

Renal prostaglandin synthesis in 36 obese hypertensive patients was estimated from measurements of 24-hour urinary prostaglandin E2 (PGE2) excretion rates. PGE2 was measured by radioimmunoassay using Dray antiserum prior to and 1 week after starting a fast supplemented by 320 cal derived from 30 g of carbohydrate, 45 g protein, and 2 g essential fatty acids. Sodium intake was 120 mEq daily or less. Comparisons were made to a control population of age-matched, nonobese, normotensive, healthy volunteers on a normal diet. Mean weight fell from 260 +/- 8 to 247 +/- 8lb, p less than 0.001. Urinary PGE2 in the obese patients prior to the fast was 104 +/- 27 ng/day, significantly lower than the 404 +/- 124 ng/day found in the control population, p less than 0.005. After the 1st week of the fast urinary PGE2 rose to 213 +/- 55, p less than 0,02. This value was not different from that in the control group. Blood pressure fell (p less than 0.001) in these patients from 143/94 +/- 3/2 to 134/87 +/- 3/2 mm Hg after the 1st week of the fast. Deficient renal prostaglandin synthesis in obese hypertensive patients was corrected by fasting. Such changes in the prostaglandin system may mediate or occur in response to changes in the sodium-volume balance of these patients. These changes in renal prostaglandin synthesis may partly contribute to the blood pressure reduction of these patients.

The safety and efficacy of sustained-release diltiazem 120 to 180 mg, 2 times a day, were compared with hydrochlorothiazide 25 to 50 mg, 2 times a day, and the combination of diltiazem and hydrochlorothiazide in 56 patients with mild to moderate hypertension (supine diastolic blood pressure between 95 and 114 mm Hg) using a placebo-controlled, parallel-design protocol. Data from an additional 21 patients were evaluated for safety only. The data reported herein represent the preliminary experience from a larger 200-patient multicenter study. All patients received placebo for 4 weeks, followed by either hydrochlorothiazide or diltiazem titrated to achieve a diastolic blood pressure reduction of greater than or equal to 10 mm Hg to reach a goal supine diastolic blood pressure of less than 90 mm Hg. Patients not achieving the treatment goal received hydrochlorothiazide plus diltiazem. At week 14, on maintenance monotherapy, diltiazem and hydrochlorothiazide produced comparable reductions in blood pressure from placebo baseline (160.3 +/- 24.3/101.7 +/- 5.5 to 145.2 +/- 24.1/89.8 +/- 7.4 mm Hg with diltiazem, 156.0 +/- 15.6/103.7 +/- 4.7 to 134.1 +/- 12.5/89.2 +/- 9.5 mm Hg with hydrochlorothiazide, p less than 0.001 for both). Diltiazem and hydrochlorothiazide achieved goal blood pressure in 42% and 45% of patients, respectively. The effects in responders were sustained for 6 months. In patients who did not achieve the treatment goal, 63% responded to diltiazem plus hydrochlorothiazide.No clinically significant postural hypotension was observed on any regimen. Heart rate was slightly lower with diltiazem than with hydrochlorothiazide. Adverse effects were minimal with diltiazem, hydrochlorothiazide and diltiazem plus hydrochlorothiazide but more hypokalemia occurred with hydrochlorothiazide.(ABSTRACT TRUNCATED AT 250 WORDS)

A 10 mg bolus of the angiotensin blocker saralasin was injected 113 times in 68 subjects with essential or renovascular hypertension. Ninety percent of injections caused a transient increase in blood pressure, which correlated with plasma renin activity (PRA) (r = -0.54); Mean increase at 2 minutes was 21/13.4 mm Hg (P less than 0.001) and was independent of pre-injection control blood pressure, with a rapid decrease to or below control values thereafter. Thirty-seven subjects were studied on successive days before and after furosemide-induced sodium depletion (152 +/- 26 mEq [SE] sodium loss). In the low renin group, sodium depletion did not change PRA or the magnitude of the pressor response to saralasin, but significantly decreased control MAP by 13 mm Hg (P less than 0.01). In normal and high renin patients, MAP was unchanged after diuresis, but PRA increased significantly and the pressor response was attenuated. The net effect of sodium depletion was to reduce the pressor response to saralasin in all renin subgroups by 9 to 12 mm Hg. Saralasin bolus injection, unlike infusion, saturates available vascular receptors only briefly, eliminating prolonged pressor responses.

Saralasin was used as a functional test of the renin-angiotensin axis in 4 renal transplant patients with hypertension. Blood pressure was recorded by an automatic recording device and plasma renin activity was measured by radioimmunoassay of angiotensin I. A positive saralasin test suggested renin-mediated hypertension despite normal peripheral renin levels in a 40-year-old man whose original kidney disease was nephrosclerosis. Since the blood pressure was refractory to intravenous sodium nitroprusside saralasin was used for 14 hours to control blood pressure before and after arteriography in the patient. Removal of the native kidneys markedly ameliorated the hypertension. A 35-year-old woman with transplant hypertension was responsive to angiotensin blockade only during a period of abrupt worsening of blood pressure associated with an acute rejection episode. Finally, 2 patients with advanced chronic rejection responded to saralasin administration. These studies confirm that 1) angiotensin blockade is a useful tool in the diagnosis of renin-dependent hypertension even when plasma renin levels are not elevated, 2) saralasin can be used to control renin-dependent forms of hypertension that are refractory to intravenous sodium nitroprusside therapy and 3) transplant hypertension associated with acute and chronic rejection appears to be renin-dependent.

Antihypertensive medications have a variable effect on renal hemodynamics and may contribute to renal insufficiency in some patients. Since clonidine has actually been found to improve renal hemodynamics in patients with essential hypertension, we studied the effects of clonidine therapy in patients with renal transplant hypertension. Baseline measurements of BP and renal hemodynamics were made in six patients after two weeks of therapy with furosemide. Clonidine was then added and titrated until BP was controlled. Repeated measurements of renal hemodynamics were made four and 16 weeks after clonidine therapy was begun. Glomerular filtration and effective renal plasma flow as assessed by inulin and aminohippurate sodium clearances were preserved during prolonged clonidine therapy.

Previous studies have shown reduced levels and total urinary excretion of prostaglandin E2 in a heterogeneous population of patients with hypertension. The following study was undertaken to extend these observations to focus on the influence of age and blood pressure on renal prostaglandin E2 excretion in males. Four groups of human subjects were studied on an ad libitum diet of at least 2 g salt per day: group 1 consisted of normal young men; group 2 consisted of young men with essential hypertension; group 3 consisted of older nonhypertensive men; group 4 consisted of older hypertensive men. Reduced urinary prostaglandin E2 excretion was seen in the elderly hypertensive group but not the young hypertensives. Thus, when all hypertensives were compared to control the reduced prostaglandin E2 excretion was accounted for primarily by the elderly hypertensives. The reduction of prostaglandin E2 excretion could not be accounted for by normal ageing alone. Whether cause or effect, alterations of renal prostaglandin physiology accompanied hypertension in elderly men. No clear alteration of prostaglandin E2 physiology was noted in young male hypertensives.

Hypertension refractory to standard dialystic maneuvers developed in a 25-year old female who had been on long-term hemodialysis. Lowering the target dry weight and adding antihypertensives did not ameliorate the hypertension. Hypercalcemia, due to vitamin D administration, was discovered and, following its correction, there was subsequent normalization of the blood pressure. This report discusses some of the mechanisms whereby calcium can interface with blood pressure regulatory mechanisms in individuals with end stage renal disease.

Amiloride hydrochloride has now been recognized as a safe and effective potassium-sparing diuretic alternative to triamterene with a similar mechanism of pharmacologic activity. Studies were undertaken to assess the difference between therapy with the triamterene-hydrochlorothiazide combination (Dyazide) and an amiloride hydrochloride-hydrochlorothiazide combination (Moduretic) on renal prostaglandin production, since an increase in renal prostaglandin synthesis has been shown to mediate or enhance the pharmacologic action of certain diuretic drugs. Eight subjects treated for four weeks with triamterene-hydrochlorothiazide were compared with nine patients similarly treated with amiloride-hydrochlorothiazide. A 24-hour urine sample for prostaglandin E2 (PGE2) assay was collected under control conditions and after six weeks of therapy with either diuretic in all patients. The PGE2 excretion increased in the amiloride-hydrochlorothiazide-treated group; in the other group PGE2 excretion actually declined. It is concluded from these studies that therapy with amiloride-hydrochlorothiazide enhanced renal PGE2 production, whereas that with triamterene-hydrochlorothiazide actually decreased renal PGE2 production. This difference is an important renal consequence of the use of either drug and should be considered in the choice between these diuretic combinations.

The results of a multicenter trial conducted in order to determine the therapeutic efficacy of the gastrointestinal therapeutic system (GITS) formulation of nifedipine in comparison with hydrochlorothiazide and placebo in the management of mild to moderate essential hypertension are presented. During a one-week wash-out phase, antihypertensive therapy was discontinued in all patients. After a three-week single-blind placebo period, eligible patients were randomly assigned in a double-blind fashion to one of three treatment groups for a one-week titration period and a nine-week efficacy period. Patients received either nifedipine GITS, 30 or 60 mg daily; hydrochlorothiazide, 25 or 50 mg daily; or placebo. Sitting and standing blood pressures decreased by an average 11.6/10.4 and 10.8/10.8 mm Hg, respectively, with nifedipine GITS therapy, and 14.8/10.8 and 14.3/8.2 mm Hg, respectively, with hydrochlorothiazide therapy. Compared with placebo, these changes were highly significant for both sitting (p less than or equal to 0.005) and standing (p less than or equal to 0.02) measurements. Heart rate remained essentially unchanged in all three groups. It was therefore concluded that monotherapy with nifedipine GITS, at doses of 30 or 60 mg given once daily, effectively reduces blood pressure in patients with hypertension to a degree comparable with that seen in hydrochlorothiazide therapy.

The effects of beta-blocker therapy with either nadolol or propranolol were compared during therapy with hydrochlorothiazide (HCTZ) 50 mg b.i.d. on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), effective renal blood flow (ERBF), blood pressure, and heart rate in 22 patients with essential hypertension and mild to moderate renal insufficiency. The clearances of inulin and para-aminohippurate (PAH) were used to estimate renal hemodynamic measurements. These parameters were determined after 2 weeks of HCTZ plus placebo and at 1, 3, and 6 months after the addition of beta-blocker to HCTZ. Significant reductions in blood pressure and heart rate were seen, but no significant reduction of renal hemodynamics were seen with either beta-blocker-HCTZ combination. Since 50% of the patients in each drug group were either Black or White, hemodynamic data were also analyzed by race. One month after beta-blocker addition there was a slight reduction of GFR in both Whites (47 +/- 6 vs. 40 +/- 5 ml/min, p greater than .05) and Blacks (44 +/- 5 vs. 40 +/- 6 ml/min, p less than .05). By month 6, GFR in Whites rose to 57 +/- 9 ml/min, whereas in Blacks it fell significantly to 36 +/- 6 ml/min (p less than .01). Similarly, at month 1, ERBF declined by 12% and 13% in Whites and Blacks, respectively. However, at month 6, ERBF rose by 28% in Whites and remained 11% lower in Blacks, p less than .05. In summary, in the group as a whole neither beta-blocker significantly altered renal hemodynamics when added to HCTZ therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Systolic and mean blood pressures were shown to increase from means of 159 +/- 7 and 111 +/- 7 mm Hg to 174 +/- 8 and 122 +/- 6 mm Hg, respectively (p less than 0.05 in each case), after a 2-hour intravenous infusion of CaCl2 during which serum magnesium levels were found to decrease from 1.8 +/- 0.06 to 1.4 +/- 0.05 mg/dl (p less than 0.0005). A significant increase in blood pressure was not seen when MgSO4 was given intravenously concomitantly with the CaCl2 so that serum magnesium levels did not decline. We conclude that hypercalcemic hypertension is due in part to altered serum magnesium and is prevented if serum magnesium is sustained.

The effects of antihypertensive drugs on glucose metabolism are an important consideration in the selection of pharmacologic therapy for diabetic patients. Diuretics can elevate blood glucose levels, aggravate glucose intolerance, and predispose diabetic patients to hyperosmolar non-ketotic coma. Beta-blocking drugs often exacerbate and prolong insulin-induced hypoglycemia in diabetics. Beta-blockers may also cause hyperglycemia. Central agonists, alpha-blockers, and vasodilators apparently have neutral effects on carbohydrate metabolism in normal subjects or in hypertensive diabetics. Calcium channel blockers may disturb carbohydrate metabolism in diabetic patients. Angiotensin-converting enzyme inhibitors have little effect on glucose metabolism. Because diabetic patients are prone to fluid, electrolyte, hormone, and lipid disturbances, it is important to consider the effects of antihypertensive drugs on these aspects of metabolism when selecting pharmacologic therapy. The effects of various antihypertensive drugs on sodium, calcium, magnesium, and acid/base balance are reviewed. The effects of these drugs on serum uric acid and potassium, as well as on hormone and lipid levels, are also considered.

The safety and efficacy of sustained-release diltiazem, 120 to 180 mg twice daily, was compared with those of hydrochlorothiazide, 25 to 50 mg twice daily, in 207 patients with mild-to-moderate hypertension (supine diastolic blood pressure [BP] 95 to 114 mm Hg) using a baseline, placebo, parallel-design study protocol. All patients received placebo for 2 to 4 weeks, followed by either study drug during the double-blind phase, titrated over 8 weeks to achieve a goal of supine diastolic BP reduction of at least 10 mm Hg and/or a diastolic BP of less than 90 mm Hg. Patients not achieving the treatment goal with either drug alone received the other drug in combination. Both drugs produced significant decreases in supine and upright BP throughout the 26-week study. The magnitude of decrease in mean supine diastolic BP was similar for both drugs as monotherapy at week 14 (-11.4 and -12.1 mm Hg, respectively). Hydrochlorothiazide produced significantly greater reductions at week 14 in mean supine systolic BP than sustained-release diltiazem (-19.5 and -12.7 mm Hg, respectively). The difference in mean supine diastolic BP reduction with the 2 drugs diminished when hydrochlorothiazide (50 mg/day) was compared with sustained-release diltiazem. The BP effects were sustained for 6 months with both drugs. The 2 drugs appeared to lower BP more in patients older than 60 years and more in black than in white patients. The combination of the 2 drugs decreased supine diastolic BP to goal levels in about 56% of the patients not achieving goal with either drug alone. Adverse effects were minimal with either drug alone and in combination, except for hypokalemia, which increased with thiazide alone and in combination.

We evaluated the safety and efficacy of transdermal clonidine (TC) in 23 patients with essential hypertension over a two-year period. Fourteen patients achieved control of blood pressure using TC alone. Six patients achieved control with a combination of TC and the diuretic chlorthalidone (CH). Three patients had control with CH alone or did not achieve control with either TC alone or TC plus CH and were dropped from the study. Of the 20 patients remaining in the study, six patients remained on TC or TC plus CH for the two-year study. Ten of the 20 patients quit the study because of skin reactions and four because of other side effects. No clinically significant changes were noted in serum or urinary laboratory parameters. Finally, TC was effective as long-term monotherapy for essential hypertension in only four of our patients. The major limitation is skin-related side effects.

Hypercalcemic conditions are commonly associated with hypertension and with abnormal magnesium homeostasis. The mechanism by which the hypertension of hypercalcemia is mediated is not clear, and the role that magnesium may play in its generation has not been examined. We review here the available clinical and experimental data and propose a role for abnormal magnesium metabolism in the mediation and generation of the hypertension of hypercalcemia.

In eight hypertensive patients treated with transdermal clonidine for one year, there was plasma dilution, as shown by a reduction in serum sodium, hemoglobin, and serum protein levels. Free water clearance did not change significantly. Plasma dilution was likely sustained by increased water intake due to "dry mouth", as frequently seen with central acting drugs such as clonidine.

The number of studies in the literature on diagnostic and therapeutic uses of angiotensin antagonists has been increasing geometrically. Nearly 1,000 publishsd items deal with saralasin alone, although neither saralasin nor captopril is yet approved for general use or widely available. Reports to date represent only a fraction of the eventual situations in which these agents are likely to help the researcher and clinician. Food and Drug Administration approval of both agents is pending, and both are expected to be available soon. Consequently, the practitioner will want to become familiar with their usefulness, especially to screen for secondary forms of hypertension and to treat moderate to severe primary or secondary hypertension.

Effects of once-daily doses of 50 mg triamterene with 25 mg hydrochlorothiazide and 5 mg amiloride with 50 mg hydrochlorothiazide were compared in a randomized, multicenter study of 84 adult subjects with mild to moderate hypertension (diastolic blood pressure 90 to 114 mm Hg). After a 3-wk placebo lead-in period, the subjects entered a 6-wk treatment period. The two drug regimens were compared with respect to antihypertensive effects and effects on serum potassium and magnesium levels during the final week of drug therapy, with the use of the last week of placebo therapy as a covariate. Both drug regimens substantially reduced mean supine systolic and diastolic blood pressures to well within normal limits; there was no significant difference the two groups. Twenty-four of the 41 subjects receiving triamterene-hydrochlorothiazide (59%) and 29 of the 43 patients receiving amiloride-hydrochlorothiazide (67%) had diastolic blood pressure less than 90 mm Hg at week 9. Five subjects receiving amiloride-hydrochlorothiazide (12%) and two subjects receiving triamterene-hydrochlorothiazide (5%) had hypokalemia (serum potassium level less than 3.5 mEq/l) at week 9. The average decrease in serum potassium levels during amiloride-hydrochlorothiazide therapy (-0.33 +/- 0.08 mEq/l) was greater than that after triamterene-hydrochlorothiazide (- 0.08 +/- 0.07 mEq/l). Serum magnesium levels were not changed by either regimen. Weight loss was greater in the amiloride-hydrochlorothiazide group than in the triamterene-hydrochlorothiazide group.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with primary hyperparathyroidism are frequently hypertensive. Studies were performed to determine whether the hypertension in this disorder could be corrected by saralasin infusion. Five patients with primary hyperparathyroidism and one patient with secondary hyperparathyroidism were salt depleted before saralasin testing by the administration of 1 mg/kg furosemide at 1700 h on the evening before testing. Blood pressure was measured every 2 min by an automatic recording device. Saralasin was given as a continuous iv infusion of 1, 3, 6, and 10 micrograms/kg . min for 30 min. Blood for measurement of PRA was drawn 4 min before, immediately before, and 4, 8, 12, 16, 22, 30, 60, and 90 min after the infusion was begun. Saralasin did not reduce blood pressure in these patients. The mean postsaralasin blood pressure (12--20 min after the start of the infusion) was 155/102 mm Hg compared to the control blood pressure of 156/101 mm Hg (blood pressure at -4 and 0 min). The inability of saralasin to effect a vasodepressor response was unexpected, since the mean PRA before saralasin infusion was elevated at 1895 ng/dl . 3 h (normal range, 409--818 ng/dl . 3 hr; 95% confidence limits). These studies suggest that the hypertension associated with hyperparathyroidism is not renin dependent.