Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program. SHEP Cooperative Research Group.

BACKGROUND: Previous studies often of short duration have raised concerns that antihypertensive therapy with diuretics and beta-blockers adversely alters levels of other cardiovascular disease risk factors. METHODS: The Systolic Hypertension in the Elderly Program was a community-based, multicenter, randomized, double-blind, placebo-controlled clinical trial of treatment of isolated systolic hypertension in men and women aged 60 years and older. This retrospective analysis evaluated development of diabetes mellitus in all 4736 participants in the Systolic Hypertension in the Elderly Program, including changes in serum chemistry test results in a subgroup for 3 years. Patients were randomized to receive placebo or treatment with active drugs, with the dose increased in stepwise fashion if blood pressure control goals were not attained: step 1, 12.5 mg of chlorthalidone or 25.0 mg of chlorthalidone; and step 2, the addition of 25 mg of atenolol or 50 mg of atenolol or reserpine or matching placebo. RESULTS: After 3 years, the active treatment group had a 13/4 mm Hg greater reduction in systolic and diastolic blood pressure than the placebo group (both groups, P<.001). New cases of diabetes were reported by 8.6% of the participants in the active treatment group and 7.5% of the participants in the placebo group (P=.25). Small effects of active treatment compared with placebo were observed with fasting levels of glucose (+0.20 mmol/L [+3.6 mg/dL]; P<.01), total cholesterol (+0.09 mmol/L [+3.5 mg/dL]; P<.01), high-density lipoprotein cholesterol (-0.02 mmol/L [-0.77 mg/dL]; P<.01) and creatinine (+2.8 micromol/L [+0.03 mg/dL]; P<.001). Larger effects were seen with fasting levels of triglycerides (+0.9 mmol/L [+17 mg/dL]; P<.001), uric acid (+35 micromol/L [+.06 mg/dL]; P<.001), and potassium (-0.3 mmol/L; P<.001). No evidence was found for a subgroup at higher risk of risk factor changes with active treatment. CONCLUSIONS: Antihypertensive therapy with low-dose chlorthalidone (supplemented if necessary) for isolated systolic hypertension lowers blood pressure and its cardiovascular disease complications and has relatively mild effects on other cardiovascular disease risk factor levels.

Serum lipids and incidence of coronary heart disease. Findings from the Systolic Hypertension in the Elderly Program (SHEP).

BACKGROUND: The association of serum lipids with coronary heart disease has been studied extensively in middle-aged men and, to a lesser extent, in similar women. Less well defined are lipid variables predictive of CHD in individuals of age > or = 60 years. METHODS AND RESULTS: The Systolic Hypertension in the Elderly Program recruited 4736 persons (mean age, 72 years; 14% were black; and 43% were men). Mean systolic and diastolic blood pressures were 170 and 77 mm Hg, respectively. Baseline mean total cholesterol was 6.11 mmol/L (236 mg/dL); HDL cholesterol, 1.39 mmol/L (54 mg/dL); and non-HDL cholesterol, 4.72 mmol/L (182 mg/dL). Triglyceride levels were 1.62 mmol/L (144 mg/dL) for fasting participants and 1.78 mmol/L for the total group. LDL cholesterol, estimated in fasting samples with triglycerides of < 4.52 mmol/L, averaged 3.98 mmol/L (154 mg/dL). Mean follow-up was 4.5 years. In multivariate Cox regression analyses, baseline total, non-HDL, and LDL cholesterol levels and the ratios of total, non-HDL, and LDL to HDL cholesterol were significantly related to CHD incidence. HDL cholesterol and triglycerides were not significant in these analyses. In fasting participants with triglyceride levels of < 4.52 mmol/L, a 1.03 mmol/L (40 mg/dL) higher baseline total, non-HDL, or LDL cholesterol was associated with a 30% to 35% higher CHD event rate. CONCLUSIONS: The results of this study support the concept that serum lipids are CHD risk factors in older Americans.

Coronary heart disease risk factors in men and women aged 60 years and older: findings from the Systolic Hypertension in the Elderly Program.

BACKGROUND: Coronary heart disease (CHD) is the most common cause of death in men and women aged 60 years and older. Although a number of studies support the concept that CHD risk factors that have been defined in younger adults are significantly associated with CHD events in older adults, others do not support this thesis, and further definition of the risk-factor concept in older adults is required. METHODS AND RESULTS: The Systolic Hypertension in the Elderly Program recruited 4736 persons (mean age, 72 years); 14% were black, and 43% were men. Mean systolic and diastolic blood pressures were 170 and 77 mm Hg, respectively. About 13% of participants were current smokers; 10% had a history of diabetes; 5%, a prior myocardial infarction; 5% angina pectoris; 2.3%, intermittent claudication; and 7%, a carotid bruit. Mean total cholesterol value was 6.11 mmol/L. Mean follow-up was 4.5 years. In multivariate Cox regression analyses for CHD, variables that were significant were baseline total cholesterol value, smoking, history of diabetes, presence of carotid bruit, and treatment group in the trial. Active treatment yielded a 27% reduction in CHD risk. For each 1.03 mmol/L increase in total cholesterol value, there was an increase in risk of about 20%. Current smokers had a 73% increase, diabetics a 121% increase, and those with carotid bruit a 113% increase in CHD risk. CONCLUSIONS: The results of this study support the concept that CHD risk factors are important in older men and women with isolated systolic hypertension.

Angiotensin receptors: physiology and pharmacology.

The renin-angiotensin system is critical for regulating extracellular fluid volume and blood pressure. Angiotensin II, the active peptide hormone produced by the renin enzymatic cascade, sustains vascular volume and blood pressure by constricting vessels, stimulating adrenal aldosterone secretion, increasing renal tubular sodium absorption, activating the sympathetic nervous system, and increasing cardiac contractility. These actions are a disability in the pathophysiologic states of hypertension and congestive heart failure (CHF), however, since reactive increases in renal renin and angiotensin II stimulate sympathetic activity and renal sodium retention, leading consequently to circulatory volume over-load. The actions of angiotensin II are mediated by its interactions with specific cell-surface angiotensin II receptors, namely, AT1 and AT2; most cardiovascular actions of angiotensin II come from its interaction with the AT1 receptor. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II-receptor blockers antagonize the actions of the renin-angiotensin axis, neutralizing its effects on hypertension and heart failure. Losartan is the first oral, nonpeptide, selective AT1-receptor blocker to be approved. Clinical trials show it to be effective and well tolerated as therapy for hypertension and CHF. Data obtained thus far suggest ACE inhibitors and AT1-receptor blockers have similar efficacy for treating these conditions, but the receptor blockers appear to produce fewer adverse effects. Whether the sustained increase in angiotensin II concentrations after AT1-receptor antagonism produces deleterious effects is not known. The concern is that these high levels may stimulate unblocked AT2 receptor; the effect of that stimulation may not be important, however.

Baroreceptor sensitivity in prehypertensive young adults.

Decreased baroreceptor reflex sensitivity has been implicated in the pathogenesis of hypertension. The purpose of this study is to determine if alterations of baroreceptor function precede the development of hypertension in humans. Baroreceptor function was evaluated in 13 young adult white men with relatively high blood pressures sustained for 12 to 15 years and 12 age-matched men with sustained relatively low blood pressures. High pressure baroreceptor activity was evaluated by measuring change in pulse interval in response to decreases and increases of arterial pressure, induced by graded infusions of nitroprusside and angiotensin II, respectively. In response to both agents, baroreceptor slopes did not differ in the high and low blood pressure groups. Plasma norepinephrine also increased similarly in both blood pressure groups in response to nitroprusside. To study low-pressure baroreceptor function, responses to graded levels of lower-body negative pressure (LBNP) were measured. Comparing both blood pressure groups, there were similar increases of heart rate, total peripheral resistance, and plasma norepinephrine in response to LBNP. Both blood pressure groups also had similar increases of heart rate and blood pressure in response to isometric (handgrip) exercise. Thus, high-pressure and low-pressure baroreceptor function is not altered in prehypertensive young adults. However, continued follow-up will be required to determine if these individuals with sustained relatively high blood pressures are truly prehypertensive.

Effect of transdermal clonidine on the endocrine responses to insulin-induced hypoglycemia in essential hypertension.

Clonidine hydrochloride via the central nervous system lowers blood pressure, inhibits ACTH and catecholamine release, and stimulates growth hormone secretion. To evaluate the effect of this drug on the release of glucoregulatory hormones during hypoglycemia, we studied the responses to insulin-induced hypoglycemia (0.1 units/kg) in 10 patients with mild essential hypertension before and after treatment for 16 weeks with transdermal clonidine. Clonidine significantly lowered blood pressure, basal plasma norepinephrine levels, and epinephrine and renin activity but did not affect basal growth hormone concentrations. Clonidine significantly reduced the norepinephrine and epinephrine responses to hypoglycemia (norepinephrine AUC from 207 +/- 16 SE to 156 +/- 25 nmol/L/min, epinephrine from 157 +/- 28 to 99 +/- 29 nmol/L/min; both p less than 0.05) and increased the growth hormone response (AUC from 763 +/- 148 ng/min/ml to 1164 +/- 292 ng/min/ml; p less than 0.05) but did not affect the cortisol response or the magnitude or rate of glucose recovery from hypoglycemia. Thus transdermal clonidine has several effects on glucose counterregulatory hormones that do not significantly alter insulin sensitivity or impair recovery from hypoglycemia.

Effects of calcium on renin and aldosterone.

A series of experiments was undertaken to assess the effects of calcium administration, in vivo, on renin and aldosterone secretion. In the anesthetized dog, renin secretion was decreased by renal arterial infusions of calcium chloride and calcium gluconate; aldosterone excretion was not affected. In the sodium chloride-deprived rat, dietary calcium chloride loading decreased plasma renin activity, whereas calcium gluconate did not. Both calcium salts increased aldosterone production. In the non-filtering, denervated, papaverine-treated dog kidney, renin release was stimulated by renal arterial infusion of verapamil. In the rat, chronic oral verapamil administration decreased plasma aldosterone but had no effect on renin. In humans, chronic oral verapamil decreased aldosterone responsiveness to infusion of angiotensin II. Thus, in vivo renin release is inhibited by hypercalcemia and stimulated by blocking calcium transport; conversely, aldosterone production is stimulated by a high calcium intake and inhibited by blocking calcium transport. These effects of calcium on renin and aldosterone may have implications for understanding the putative relation between calcium and hypertension.

Dissociation between plasma renin and plasma aldosterone induced by dietary glycine hydrochloride.

We evaluated the effects of selective dietary chloride loading (without sodium) on plasma renin activity (PRA) and plasma aldosterone in the sodium-deprived Sprague-Dawley rat. Three groups of animals were fed one of the following diets for 13 days: 1) low NaCl; 2) high NaCl; or 3) low sodium, high chloride, provided as glycine hydrochloride. Compared with NaCl-deprived animals, PRA and plasma aldosterone were lower (P less than 0.01) in animals fed low sodium high chloride, whereas aldosterone in animals fed glycine hydrochloride was higher (P less than 0.01) than that of NaCl-deprived animals. In contrast, plasma concentrations of corticosterone and 18-hydroxycorticosterone were not increased by selective chloride loading. Glycine chloride-fed animals were acidotic and had elevated plasma concentrations of potassium and ionized calcium. Thus stimulation of aldosterone by selective chloride loading is not related to PRA or ACTH but may be due to a direct effect of acidosis or an indirect effect of acidosis on potassium and/or calcium. Additionally, selective chloride loading appears to stimulate the conversion of 18-hydroxycorticosterone to aldosterone.

Adverse effect of phenytoin on mineralocorticoid replacement with fludrocortisone in adrenal insufficiency.

Two patients with longstanding adrenal insufficiency developed severe mineralocorticoid deficiency during concomitant phenytoin treatment. A 64-year-old man with primary adrenal insufficiency of 41 years duration was treated with phenytoin for an acute seizure disorder. He subsequently developed mineralocorticoid insufficiency despite taking his customary dosages of cortisone acetate and fludrocortisone. This responded to volume repletion and increased fludrocortisone requirement from 0.05 mg to 0.4 mg daily, which decreased to the former amount following discontinuation of phenytoin. A 42-year-old woman with primary adrenal insufficiency of 3 years duration and a lifelong seizure disorder treated with phenytoin incurred multiple, life-threatening episodes of mineralocorticoid insufficiency. Her fludrocortisone requirement was ultimately established as 2.0 mg daily with a normal hydrocortisone requirement and clearance rate. Fludrocortisone thus appears to be another synthetic steroid whose metabolism is sensitive to drugs that increase hepatic 6-beta-hydroxylation, such as phenytoin. Treatment with these inducing drugs may markedly alter mineralocorticoid requirements in patients with primary adrenal insufficiency.

Renin secretion and loop of Henle chloride reabsorption in the adrenalectomized rat.

Renin release is increased in the adrenalectomized rat and is not inhibited by sodium chloride administration. The purpose of this study was to determine whether increased renin release is related to impaired absorptive chloride transport in the loop of Henle. Chloride transport in the loop was measured before and after acute saline infusion in three groups of rats: 1) saline-drinking adrenalectomized rats (Adx); 2) saline-drinking dexamethasone-treated adrenalectomized rats (Dex); and 3) water-drinking sham-operated controls. Unrelated to differences of arterial pressure, glomerular filtration rate, or net sodium chloride balance, chloride reabsorption in the loop of Henle of Adx [836 +/- 172 peq/min (SE)] was less (P less than 0.01) than in controls (1,646 +/- 353) and Dex (1,377 +/- 318) before saline infusion. After saline infusion, chloride delivery to the loop increased (P less than 0.05) in all three groups. However, loop chloride reabsorption increased (P less than 0.01) only in controls and Dex but not in Adx. Before saline infusion, plasma renin concentration (PRC) of Adx (350 +/- 108 U/ml) was greater (P less than 0.01) than that in controls (56 +/- 6) or Dex (108 +/- 36); sodium chloride infusion failed to inhibit PRC in Adx, whereas PRC was suppressed (P less than 0.01) by saline in Dex and controls. Thus stimulation of renin release in adrenalectomized animals was associated with decreased absorptive chloride transport in the loop of Henle. Dexamethasone normalized loop function and renin responsiveness to sodium chloride.

Adrenal steroid responses to ACTH in glucocorticoid-suppressible aldosteronism.

To investigate adrenal responses to adrenocorticotrophin (ACTH), we infused graded doses of ACTH (1.25 to 20.0 mIU/30 minutes) in normal subjects, patients with low-renin essential hypertension (LREH), primary aldosteronism (PA), and glucocorticoid-suppressible hyperaldosteronism (GSH). Plasma aldosterone, cortisol, corticosterone, and 18-hydroxycorticosterone were measured. The results revealed a greater increase in the plasma aldosterone and 18-hydroxycorticosterone levels evoked by ACTH in the GSH group than in any other group, which suggested enhanced responsiveness of the aldosterone-producing cells to ACTH and a probable adrenal abnormality.

Salt-sensitive hypertension: contribution of chloride.

The effect of the anion associated with sodium loading on the development of hypertension in the Dahl salt-sensitive rat was determined. For 5 weeks rats were fed a diet containing normal or high concentrations of sodium chloride or high concentrations of sodium provided as a mixture of sodium bicarbonate, phosphate, and amino acids. After 1 week on these diets and until the end of the study the rats receiving high concentrations of sodium chloride had higher systolic blood pressures than the rats in the other two groups. There were no statistically significant group differences in plasma volume, arterial pH, or plasma concentrations of Na+, K+, Cl-, Ca2+, or creatinine, or in renomedullary prostaglandin E2 production. Compared to the animals receiving normal concentrations of sodium chloride, those receiving high concentrations of sodium chloride or amino acids showed decreased plasma renin activity and plasma aldosterone concentrations. Thus, the anion ingested with sodium alters the development and severity of hypertension in the Dahl salt-sensitive rat.

Effects of digoxin on responsiveness to the pressor actions of angiotensin and norepinephrine in man.

Abnormalities in sodium metabolism, including the presence of endogenous circulating digitalis-like sodium transport inhibitors, have been implicated in the genesis of essential hypertension. Digitalis has also been reported to affect adrenal steroid output in vitro. We studied the effects of 4 days of treatment with the digitalis glycoside digoxin upon blood pressure, the renin-aldosterone axis, and pressor and steroidogenic responses to graded norepinephrine, angiotensin, and ACTH infusions in six normal men after pretreatment with dexamethasone. Digoxin produced no significant changes in blood pressure, urinary electrolyte or aldosterone excretions, PRA or aldosterone concentrations, or the incremental responses of aldosterone or cortisol to angiotensin or ACTH. However, digoxin significantly augmented pressor responsiveness to both norepinephrine and angiotensin without significantly affecting the steady state baroreceptor-heart rate reflex. These findings support the hypothesis that digitalis-like factors may have important effects upon arterial blood pressure control in man.

Prazosin as initial antihypertensive therapy: correlates of sympathetic function.

Abnormal sympathetic function has been proposed as a factor in the development of essential hypertension. If this is the case, prazosin hydrochloride, which works by a selective, peripheral, antisympathetic effect--postsynaptic alpha blockade--may have an advantage over other antihypertensive agents. In this study, blood pressure response and measures of sympathetic and baroreflex function were followed in 13 hypertensive patients. Prazosin alone significantly reduced standing and sitting diastolic blood pressures without affecting pulse rates, plasma catecholamines or baroreflex slopes in all patients. The addition of a thiazide diuretic in persons who did not achieve goal blood pressure on prazosin alone was generally successful in reducing blood pressure to desired levels, and increased both plasma renin activity and aldosterone concentrations. No significant relation was apparent between specific characteristics of sympathetic function and response to prazosin as initial therapy, although patients responding tended to have initially higher plasma norepinephrine concentrations.

Hypothyroidism: diversity of presentation.

Hypothyroidism has a number of signs and symptoms known to most all clinicians. However, the disorder has many other presentations that are less frequently recognized. These other manifestations, though not seen often, are also not uncommon. Hypothyroidism is an easily treated, frequent disease, and can be misdiagnosed for years before becoming apparent. Although its symptoms are usually readily reversible with treatment, lack of recognition of its rarer signs and symptoms can lead to unnecessary morbidity. Awareness of the diversity of presentation of this disease may lead to early, effective treatment.

Effect of adrenalectomy on renin release in the rat.

The purpose of this study was to evaluate the mechanism of increased renin secretion in the adrenalectomized (Adx) rat. Plasma renin concentration (PRC) responses to acute infusion of 0.9% NaCl (5% of body weight) were compared in three groups of rats: Adx, Adx rats treated with dexamethasone (Adx + Dex), and sham controls. During the 7 days after adrenalectomy and before acute infusion. Adx animals drank 0.9% NaCl; sham animals drank water. Despite a more positive sodium balance over the 7 days, preinfusion PRC was higher in Adx than in the other two groups (P less than 0.01) and did not decrease with NaCl infusion [31.2 +/- 9.6 (+/-SE) U/30 min to 30.4 +/- 9.5]. PRC was suppressed by NaCl infusion in Adx + Dex (10.2 +/- 2.4 to 4.1 +/- 1.2) and sham controls (9.7 +/- 0.9 to 2.6 +/- 0.5). In separate groups of animals, PRC decreased (P less than 0.01) in response to volume expansion with 25% albumin (1% of body weight) in both Adx (42.6 +/- 8.9 to 23.1 +/- 6.1) and sham controls (10.2 +/- 1.2 to 2.1 +/- 0.7). These results are consistent with the hypothesis that altered responsiveness to NaCl, in the absence of volume contraction, contributes to increased renin release in adrenal insufficiency. Glucocorticoid replacement restored renin responsiveness to NaCl.

Clonidine in patients with diabetes and mild hypertension.

Clonidine has been reported to adversely affect glucose tolerance in experimental animals and normal man. We assessed its short- and long-term effects in 10 patients with both mild hypertension and diabetes mellitus. Patients were studied before and 10 wk after treatment with 0.1 mg clonidine twice daily, which induced reductions in blood pressure (from 148 +/- 5/93 +/- 2 mm Hg sitting, to 125 +/- 4/80 +/- 2) and control of hypertension in all patients. Clonidine increased the glycemic response to intravenous glucose (incremental glucose AUC from 161 +/- 13 to 184 +/- 14) but did not significantly change long-term diabetic control as assessed by weekly fasting serum glucose, glycosylated hemoglobin, and 24-hr urinary glucose excretions before and after treatment. We conclude that low-dose clonidine controlled blood pressure and impaired the response to an acute glucose challenge in midly hypertensive, type II diabetic patients but did not adversely affect diabetic control over 10 wk.

Effects of verapamil on renin and aldosterone in the dog and rat.

The purpose of this study was to evaluate the effects of calcium channel blockade on renin secretion and plasma aldosterone. Verapamil infusion (0.004 mg X kg-1 X min-1) into the renal artery of uninephrectomized dogs with an intact kidney resulted in significant increases (P less than 0.05) in renal blood flow, creatinine clearance, and the excreted fractions of Na+ and Cl-; renin secretion decreased (P less than 0.05) and plasma aldosterone did not change. Conversely, renal arterial infusion of verapamil in dogs with nonfiltering, denervated, papaverine-treated kidneys resulted in no change in renal blood flow and a significant increase (P less than 0.05) in renin secretion. In the rat, compared with untreated control animals, dietary verapamil (12.5 mg X kg-1 X day-1) did not effect plasma renin activity but significantly suppressed plasma aldosterone (P less than 0.001) in animals on NaCl-restricted [14.7 +/- 5.4 vs. 41.6 +/- 7.8 ng/dl (SE)] and NaCl-free [103.7 +/- 7.5 vs. 156.7 +/- 18.7 ng/dl (SE)] diets. In addition, verapamil suppressed (P less than 0.0003) plasma corticosterone [16.1 +/- 5.4 vs. 52.8 +/- 7.1 microgram/dl (SE)]. Thus, acute but not chronic verapamil administration stimulates renin release in the nonfiltering kidney, and chronic verapamil inhibits adrenal mineralocorticoid and glucocorticoid secretion. The disparate effects of verapamil on renin secretion from intact and nonfiltering kidneys may be due to actions of the Ca2+ channel blocker on renal hemodynamic and/or renal tubular mechanisms in the intact kidney that mask a direct effect of verapamil on renin-secreting cells.