The renin-angiotensin system and thirst: a reevaluation.

Systemic injections of renin that stimulate substantial amounts of drinking in nephrectomized rats can produce plasma renin activities that fall well above the physiological range. Furthermore, increases in plasma renin activities that occur in rats with intact kidneys during experimental hypotension appear to be too low to provide the basis for the observed elevations in water intake. These findings question the contribution of the renin-angiotensin system to thirst under normal physiological conditions.

The multiple factors affecting plasma renin activity in essential hypertension.

Seventy-nine patients with essential hypertension were evaluated for peripheral renin activity in response to injection of 60 mg of furosemide and to upright posture. Age and supine diastolic blood pressure were found to be significant determinants of responsiveness, with contributions from sex and race. Patients with impaired responsiveness were predominantly older and female, while the group of hyperresponders was younger, male, and had significantly lower supine diastolic pressures. Aldosterone responses in relation to changes in peripheral renin activity were found to be nearly random with both furosemide and with posture. Thus, patients could be subdivided into renin subgroups, but not into parallel aldosterone subgroups. Data on four patients with primary hyperaldosteronism were discussed for comparison.

Relaxation therapy for hypertension. Comparison of effects with concomitant placebo, diuretic, and beta-blocker.

We compared the effects of relaxation therapy in hypertensive patients taking placebo, a beta-blocker (atenolol, 100 mg/d), or a diuretic (chlorthalidone, 50 mg/d), and we also compared the effects of relaxation therapy with the effects of the latter two drugs alone. Blood pressures were measured not only in the relaxation therapists' office and at a hypertension clinic, but also in the patient's environment by means of 24-hour ambulatory blood pressure recordings. The effect of relaxation therapy, while statistically significant, was modest. There was no generalization of effect to ambulatory blood pressure. Atenolol was significantly more effective than relaxation in reducing both systolic and diastolic pressure. Chlorthalidone was significantly more effective than relaxation in reducing systolic but not diastolic pressure in the hypertension clinic only. The long-term effects of relaxation were independent of concomitant drug use, but within the actual relaxation sessions blood pressure dropped further during chlorthalidone than during placebo or atenolol treatment.

Relationships of quality-of-life measures to long-term lifestyle and drug treatment in the Treatment of Mild Hypertension Study.

OBJECTIVES: To compare 5 antihypertensive drugs and placebo for changes in quality of life (QL). To assess the relationship of lifestyle factors and change in lifestyle factors to QL in participants with stage I diastolic hypertension. METHODS: The Treatment of Mild Hypertension Study (TOMHS) was a randomized, double-blind, placebo-controlled clinical trial with minimum participant follow-up of 4 years. It was conducted at 4 hypertension screening and treatment academic centers in the United States. The cohort consisted of 902 men and women with hypertension, aged 45 to 69 years, with diastolic blood pressures less than 100 mm Hg. Informed consent was obtained from each participant after the nature of the procedures had been fully explained. Sustained nutritional-hygienic intervention was administered to all participants to reduce weight, to reduce dietary sodium and alcohol intake, and to increase physical activity. Participants were randomized to take (1) acebutolol (n = 132); (2) amlodipine maleate (n = 131); (3) chlorthalidone (n = 126); (4) doxazosin mesylate (n = 134); (5) enalapril maleate (n = 135); or placebo (n = 234). Changes in 7 QL indexes were assessed based on a 35-item questionnaire: (1) general health; (2) energy or fatigue; (3) mental health; (4) general functioning; (5) satisfaction with physical abilities; (6) social functioning; and (7) social contacts. RESULTS: At baseline, higher QL was associated with older age, more physical activity, lower obesity level, male gender, non-African American race, and higher educational level. Improvements in QL were observed in all randomized groups, including the placebo group during follow-up; greater improvements were observed in the acebutolol and chlorthalidone groups and were evident throughout follow-up. The amount of weight loss, increase in physical activity, and level of attained blood pressure control during follow-up were related to greater improvements in QL. CONCLUSIONS: In patients with stage I hypertension, antihypertensive treatment with any of 5 agents used in TOMHS does not impair QL. The diuretic chlorthali-done and the cardioselective beta-blocker acebutolol appear to improve QL the most. Success with lifestyle changes affecting weight loss and increase in physical activity relate to greater improvements in QL and show that these interventions, in addition to contributing to blood pressure control, have positive effects on the general well-being of the individual.

Time trends in the use of cholesterol-lowering agents in older adults: the Cardiovascular Health Study.

OBJECTIVES: To describe recent temporal patterns of cholesterol-lowering medication use and the characteristics that may have influenced the initiation of cholesterol-lowering therapy among those aged 65 years or older. SUBJECTS AND METHODS: A cohort of 5201 adults 65 years or older were examined annually between June 1989 and May 1996. We added 687 African American adults to the cohort in 1992-1993. We measured blood lipid levels at baseline and for the original cohort in the third year of follow-up. We assessed the use of cholesterol-lowering drugs at each visit. RESULTS: The prevalence of cholesterol-lowering drug use in 1989-1990 was 4.5% among the men and 5.9% among the women; these figures increased over the next 6 years to 8.1% and 10.0%, respectively, in 1995-1996. There was a 4-fold increase in the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors during the 6 years of follow-up, from 1.9% of all participants in 1989-1990 to 7.5% in 1995-1996. The use of bile acid sequestrants, nicotinic acid, and probucol declined from initial levels of less than 1% each. Among the participants who were untreated in 1989-1990, but eligible for cholesterol-lowering therapy after a trial of dietary therapy according to the 1993 guidelines of the National Cholesterol Education Panel, less than 20% initiated drug therapy in the 6 years of follow-up, even among subjects with a history of coronary heart disease. Among participants untreated at baseline but eligible for either cholesterol-lowering therapy or dietary therapy, initiation of cholesterol-lowering drug therapy was directly associated with total cholesterol levels, hypertension, and a history of coronary heart disease, and was inversely related to age, high-density lipoprotein cholesterol levels, and difficulties with activities of daily living. Other characteristics that form the basis of the 1993 National Cholesterol Education Panel guidelines-diabetes, smoking, family history of premature coronary heart disease, and total number of risk factors-were not associated with the initiation of cholesterol-lowering drug therapy. CONCLUSIONS: Given the clinical trial evidence for benefit, those aged 65 to 75 years and with prior coronary heart disease appeared undertreated with cholesterol-lowering drug therapy.

Comparison of sodium and potassium intake with excretion.

Nine well-motivated adults, knowledgeable about nutrition, kept food records, saved food portions equal to what had been eaten, and collected 24-hour urine samples for 3 consecutive days. Estimates of sodium and potassium intake were calculated from food table analyses of written food records and from flame photometric analyses of food portions. For each subject the mean of the estimates for each of the 3 days was compared with the mean of urine analyses for sodium and potassium for each of the 3 days. For the group of nine subjects, the average estimate of sodium intake from analyses of food records was 11% lower than the average estimate of urinary sodium excretion; the average estimate of sodium intake from analysis of food portions was 2% higher than urinary sodium excretion. For individuals, there were large differences between estimates of intake and measurement of sodium excretion. For the group of nine subjects, the average estimate of potassium intake from analysis of food records was less than 1% lower than the average estimate of potassium urinary excretion; the average estimate of potassium intake from analysis of food portions was 13% higher than potassium urinary excretion. For individuals, as with sodium, there were large differences between estimates of intake and measurement of potassium excretion.

Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Treatment of Mild Hypertension Study (TOMHS)

Problems with sexual function have been a long-standing concern in the treatment of hypertension and may influence the choice of treatment regimens and decisions to discontinue drugs. The Treatment of Mild Hypertension Study (TOMHS) provides an excellent opportunity for examination of sexual function and effects of treatment on sexual function in men and women with stage I diastolic hypertension because of the number of drug classes studied, the double-blind study design, and the long-term follow-up. TOMHS was a double-blind, randomized controlled trial of 902 hypertensive individuals (557 men, 345 women), aged 45 to 69 years, treated with placebo or one of five active drugs (acebutolol, amlodipine maleate, chlorthalidone, doxazosin maleate, or enalapril maleate). All participants received intensive lifestyle counseling regarding weight loss, dietary sodium reduction, alcohol reduction (for current drinkers), and increased physical activity. Sexual function was ascertained by physician interviews at baseline and annually during follow-up. At baseline, 14.4% of men and 4.9% of women reported a problems with sexual function. In men, 12.2% had problems obtaining and/or maintaining an erection; 2.0% of women reported a problem having an orgasm. Erection problems in men at baseline were positively related to age, systolic pressure, and previous antihypertensive drug use. The incidences of erection dysfunction during follow-up in men were 9.5% and 14.7% through 24 and 48 months, respectively, and were related to type of antihypertensive therapy. Participants randomized to chlorthalidone reported a significantly higher incidence of erection problems through 24 months than participants randomized to placebo (17.1% versus 8.1%, P = .025). Incidence rates through 48 months were more similar among treatment groups than at 24 months, with nonsignificant differences between the chlorthalidone and placebo groups. Incidence was lowest in the doxazosin group but was not significantly different from the placebo group. Incidence for acebutolol, amlodipine, and enalapril groups was similar to that in the placebo group. In many cases, erection dysfunction did not require withdrawal of medication. Disappearance of erection problems among men with problems at baseline was common in all groups but greatest in the doxazosin group. Incidence of reported sexual problems in women was low in all treatment groups. In conclusion, long-term incidence of erection problems in treated hypertensive men is relatively low but is higher with chlorthalidone treatment. Effects of erection dysfunction with chlorthalidone appear relatively early and are often tolerable, and new occurrences after 2 years are unlikely. The rate of reported sexual problems in hypertensive women is low and does not appear to differ by type of drug. Similar incidence rates of erection dysfunction in placebo and most active drug groups caution against routine attribution of erection problems to antihypertensive medication.

Alpha and beta adrenergic-induced renin release in man.

Changes in hemodynamic variables and renin release, induced with both alpha and beta adrenergic agonists, were studied in 5 normal men. Saline (0.9% NaCl), methoxamine (1.6 and 5.9 mug/kg/min), and isoproterenol (0.015 and 0.026 mug/kg/min) were infused individually in a random order for 30 min. Methoxamine and isoproterenol caused the predicted directionally opposite cardiovascular changes but caused nearly equal and dose-related increases in plasma renin activity, as measured by radioimmunoassay. Saline infusion had no effect. Propranolol (0.125 mg/kg) caused decreases in systolic pressure and heart rate, and a significant decrease in plasma renin activity. Propranolol prevented the renin-releasing effects of isoproterenol and methoxamine, but only the cardiovascular effects of isoproterenol. It appears that alpha or beta agonists stimulate renin release equally in man and that at least one step in renin is propranolol-sensitive. Such sensitivity may be independent of its beta receptor blocking activity.

Perindopril as monotherapy in hypertension: a multicenter comparison of two dosing regimens. The Perindopril Study Group.

Perindopril erbumine, a new long-acting, non-sulfhydryl-containing angiotensin converting enzyme inhibitor, was evaluated in 289 patients with hypertension in a 16-week, double-blind, placebo-controlled dose-ranging study. After 4 weeks of single-blind placebo treatment, patients with supine diastolic arterial pressures from 95 to 114 mm Hg were randomized to receive placebo, 4 mg perindopril once daily, or 2 mg perindopril twice daily. The daily dose of perindopril was increased by 4 mg every 4 weeks to a maximum of 16 mg per day. Mean decreases in systolic and diastolic arterial pressure were greater with perindopril than with placebo (p < 0.05). The dose-response curve flattened after 8 mg per day, and there was no difference in arterial pressure reduction or in the percentage of responders between once- and twice-daily administration of perindopril. Adverse reactions with perindopril were generally mild and, with the exception of cough, were similar with placebo. The findings of this study indicate that perindopril is effective, well tolerated, and suitable for once-daily administration for the treatment of hypertension.

Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Review of a 25-year experience with 68 cases.

This paper reports the experiences of our group with 68 patients with progressive systemic sclerosis (PSS) admitted to hospitals of the University of Pittsburgh Health Center between 1955 and 1981 with scleroderma renal crisis (SRC). The onset of SRC was characterized by four features, namely, onset or aggravation, usually abrupt, of arterial hypertension; appearance of Grade III or IV retinopathy; elevations of peripheral renin activity to at least twice the upper limit of normal; and rapid deterioration of renal function within a period of less than one month. Over 90% of our patients in whom these criteria could be determined had at least three of them present with the onset of SRC. Management of these patients during the first 15 years of this period was uniformly ineffective. Before 1971, no patients lived longer than a year; usual survival ranged from 1 to 3 months. With the advent of renal dialysis and the more effective treatment of severe hypertension, along with the utilization of bilateral nephrectomy in selected anuric patients, some improvement in longevity was achieved. However, only in the past few years have we accumulated a group of 11 patients who have survived for longer than one year. The clinical characteristics of the onset and progression of SRC suggest the sudden imposition of severe stress such as cold or an autoimmune insult affecting vulnerable arteries and arterioles. The renal damage becomes self-perpetuating with extremely high renin activity causing further rise in blood pressure and additional renal and systemic vascular damage. Progress in the last few years seems to have been achieved primarily by the advent of pharmacologic agents that specifically block the effect of angiotensin II by inhibiting the angiotensin I converting enzyme. When diagnosis is prompt and the condition is treated as an emergency with these compounds, we and others have found that normal renal function can be restored in a number of patients. The result is a considerably brighter outlook for patients with this previously rapidly fatal complication of progressive systemic sclerosis.

Postural hypotension: adrenergic responsivity and levodopa therapy.

Four subjects with orthostatic hypotension were given intravenous infusions of methoxamine and isoproterenol. Methoxamine caused an elevation in systolic blood pressure. Isoproterenol resulted in a fall in blood pressure in three of the subjects. The heart rate decreased with methoxamine, but increased with isoproterenol. The responsivity in orthostatic hypotension was compatible with denervation supersensitivity. These effects were compared with the responsivity to methoxamine and isoproterenol of five labile hypertensives. Two patients with severe orthostatic hypotension were treated with regimens including levodopa. Levodopa alone would further aggravate postural hypotension. But in one subject given levodopa, ephedrine, and fludrocortisone and in the other managed on levodopa, tranylcypromine, and fludrocortisone, symptomatic orthostatic hypotension was successfully eliminated. These results support the usefulness of levodopa, in combination with adrenergic agents, as a therapeutic measure for advanced forms of orthostatic hypotension.

The evolution of current hypertension therapy.

There has been a continuous evolution in hypertensive therapy during the last 30 years. Now, physicians have access to more than 40 agents for treating this widespread condition. Large-scale clinical trials have established that lowering blood pressure in patients with mild to moderate diastolic hypertension results in a decreased incidence of stroke and, to a lesser extent, a reduction in incidence of coronary heart disease [MacMahon SW, Cutler JA, Furberg CD, et al: Prog Cardiovasc Dis 1986; 29 (suppl 1): 99-118]. Even so, the decrease in overall mortality rate is not consistent. Although hypertension occurs with increasing frequency in those over 60 years of age, patients in this age group represent less than 12 percent of the subjects in large trials. Currently, stepped-care is the recommended approach for managing hypertension in patients of all ages. However, the availability of a variety of agents for initial therapy, all with approximately equal efficacy but differing side-effect profiles, calls such an approach into question.

Renal arterial stenosis and hypertension. II. Current criteria for surgery.

Criteria developed from a previously reported study in 1969 concerning outcome of renal arterial surgery were applied over the next 5 years (1967 through 1971) to a group of 33 patients from a total of 121 with renal arterial stenosis. After demonstration of ischemia of the involved kidney, surgery was performed only when the degree of atherosclerotic disease and complications were minimal. With this selective process the incidence rate of significant postoperative improvement was raised from 26 to 75 percent and was maintained at 60 percent through the end of 1973, the mortality rate decreasing from 35 to less than 10 percent. The data indicate that medical therapy is the initial treatment of choice in patients over 50 to 55 years of age who have atherosclerotic disease but that the outcome of surgery can be satisfactory in properly selected younger patients.

Comparison of the antihypertensive effects of betaxolol to atenolol.

A randomized double-blind multicenter study compared a new oral beta 1-adrenergic antagonist, betaxolol 10 to 40 mg (n = 71), with atenolol 25 to 100 mg (n = 75). Each drug was administered once daily for 24 weeks in patients with mild to moderate hypertension. Blood pressure (BP) measurements were taken 24 hours after dosing. Each drug produced significant (p less than 0.01) reductions in mean supine diastolic BP. The mean decrease in supine diastolic BP with betaxolol was significantly greater at weeks 4, 6, 10 and 12 (p less than 0.05). Throughout the remainder of the trial (weeks 14 to 24), no significant differences in BP reduction were noted between treatment groups. Normotension (supine diastolic BP less than or equal to 90 mm Hg) was achieved in 72% of those given betaxolol compared with 52% of those given atenolol (p less than 0.05). The most common side effects noted were bradycardia, fatigue and headache. The incidence of these and of central nervous system side effects was similar between the betaxolol and atenolol groups. Both agents were well tolerated. At recommended doses, betaxolol once daily may be more effective than atenolol once daily in patients with mild to moderate hypertension.

Background and design of the new U.S. trial on diet and drug treatment of "mild" hypertension (TOMHS).

A multicenter, randomized, controlled, double-blind U.S. trial is comparing the combined effects of diet treatment and 1 of 5 active drug regimens with diet treatment alone, for the long-term management of middle-aged adults with "mild" hypertension. Factors stimulating this trial are data documenting the high prevalence of mild hypertension in the adult population; mild hypertension's responsibility for a high proportion of morbidity and mortality attributable to hypertension overall; data from long-term hypertension intervention trials showing reduced morbidity and mortality of people with mild hypertension with use of either diuretics or beta blockers as step-1 therapy, and other trials that failed to demonstrate beneficial impact on morbidity and mortality, possibly due to residual questions concerning aspects of benefit to risk ratios with these medications; recent data from trials showing long-term control of mild hypertension and other risk factors by nutritional means; lack of data from long-term trials on benefit to risk ratios with newer drugs such as selective alpha 1 inhibitors, angiotensin converting enzyme inhibitors and calcium channel blockers; paucity of data from trials on long-term combined effects of diet and drug therapy, and of diet alone, for people with mild hypertension. During the next few years, phase 1 of the trial will study 6 groups of drugs. The step-1 drugs are angiotensin converting enzyme inhibitor (enalapril), alpha 1 inhibitor (doxazosin), beta blocker (acebutolol), calcium channel blocker (amlodipine), diuretic (chlorthalidone) and placebo. All participants are to receive vigorous sustained nutritional counseling to reduce obesity, moderate sodium intake and avoid heavy use of alcohol. Key endpoints for phase 1 of the study are the need for additional medication to control mild hypertension, side effects (i.e., clinical and biochemical) and consequent need to discontinue drug and quality of life. Phase-1 data are to be used to complete the phase-2 design, with the ultimate aim to assess effects on morbidity and mortality.

A historical perspective of elevated systolic vs diastolic blood pressure from an epidemiological and clinical trial viewpoint.

The decision to use diastolic blood pressure as the basis for therapeutic intervention for hypertension was based primarily on clinical trials experience. The majority of observational studies shows as great or greater risk for elevated systolic blood pressure readings. Even many of the clinical trials in which a posteriori analyses have been performed confirm a greater effect of systolic rather than diastolic blood pressure as a predictor of coronary heart disease mortality. The current practice of using diastolic blood pressure readings as the sole treatment criterion should be reexamined in light of the observational studies and clinical trials reviewed here.

Are race differences in the prevalence of hypertension explained by body mass and fat distribution? A survey in a biracial population.

Body mass and body fat distribution are important considerations in the study of hypertension. However, few studies have investigated the relationships with regards to race differences in elevated arterial pressure. A population-based sample of black and white adults was assessed by interview and physical measurement. The prevalence of hypertension (defined as 140/90 mmHg and/or medically treated) was disproportionately higher among blacks than whites. In addition, blacks had a higher prevalence of the more severe hypertension (160/95 mmHg) and hypertension with higher prevalence at earlier ages than whites. Black females had a significantly higher distribution of body mass index (BMI) than white females, while no difference was found in the distributions of males. White males had a higher distribution of waist to hip ratio (WHR) than black males, while black females had the higher values compared to white females. The prevalence of hypertension increased with BMI and WHR. Blacks maintained higher rates of hypertension after controlling for BMI and WHR, however, the margin of difference diminished when BMI and WHR was considered together. The black-white difference in hypertension was not completely explained by BMI and WHR. In addition, the strength of the association of hypertension and body size was different for blacks and whites which suggests possible differences in the mechanisms regulating blood pressure.

Comparison of ambulatory and clinic blood pressure and heart rate in older persons with isolated systolic hypertension.

We compared the blood pressure (BP) measurements obtained with a random-zero sphygmomanometer and an ambulatory BP monitor in older persons with isolated systolic hypertension at one site of the multicenter, randomized, double-blind clinical trial, the Systolic Hypertension in the Elderly Program (SHEP) randomized clinical trial. The subjects were community-dwelling elderly participants with isolated systolic hypertension enrolled in the SHEP study and already receiving stable doses of double-blind medication (n = 35 for active treatment group; n = 32 for placebo group). We measured seated (clinic) BP obtained with a random-zero sphygmomamanometer, pulse rate, and BP and heart rate measurements obtained with an ambulatory BP monitor (average 24 h, daytime, and nighttime BP and heart rate). Across treatment groups clinic and ambulatory systolic BPs were not significantly different, but the placebo group had higher ambulatory, but not clinic, diastolic BPs. Within each treatment group (active treatment and placebo) there were no significant differences between clinic and average 24 h, daytime, or nighttime ambulatory systolic BPs. There were also no significant differences between clinic diastolic BP and average 24 h, daytime, or nighttime ambulatory diastolic BPs in the active treatment group, but in the placebo group average 24 h diastolic BP obtained by the ambulatory monitor was 4.6 mm Hg higher than clinic diastolic BP (P = .001). The average 24 h heart rate was 6 to 7 beats/min higher as measured by the ambulatory monitor compared to clinic pulse (P < .01). In the placebo group of this study, average 24 h ambulatory diastolic BPs were consistently higher than clinic diastolic BPs.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationships of the renin-angiotensin-aldosterone system and sodium balance to blood pressure regulation in chronic renal failure of polycystic kidney disease.

In 5 patients with polycystic kidney disease and creatinine clearances ranging from 4 to 40 ml/min, relationships between changes in blood pressure, sodium balance, body fluid compartments, plasma renin activity (PRA), urinary aldosterone excretion, and plasma aldosterone concentrations were studied during periods of low, medium, and high sodium intake. Total body water (TBW), total exchangeable body sodium (TEBS), and extracellular volume (ECV) were measured by isotope dilution techniques, plasma volume with Evan's blue dye, and PRA and aldosterone by radioimmunoassay. Low sodium intake reduced kidney function, blood pressure, and serum sodium, while PRA reached its highest levels. Subsequent increases in sodium intake improved kidney function and increased blood pressure. Plasma volume increased slightly and ECV markedly, while PRA dropped to 15 percent of the value noted after the low sodium intake. TBW and TEBS showed inconsistent changes. Aldosterone changes correlated closely with PRA. Blood pressure showed a negative correlation with PRA, but a positive one with body weight and cumulative sodium balance, and with plasma and extracellular volumes.it is suggested that whereas renin and aldosterone are involved in the maintenance of circulatory homeostasis during sodium loss, sodium retention causes an increase in blood pressure by concomitant changes in body fluids.

The excretion of rosaramicin in breast milk.

The excretion of rosaramicin, a macrolide antibiotic, was studied in the breast milk of ten lactating women. Breast milk and serum samples were collected for 48 hours after a single 250-mg oral dose of rosaramicin. Mean serum half-life, apparent volume of distribution, and oral clearance were 4.4 hours, 3.41 L/kg, and 6.34 mL/min/kg, respectively. Mean milk/serum ratio was 0.12 and the total amount of drug recovered over the first ten hours was 6.25 micrograms, approximately 0.0025% of the dose. A positive correlation between breast milk volume and breast milk clearance was found, suggesting that the amount of drug received by a nursing infant will depend on the volume of milk produced by the mother. Drug-induced toxicity from the parent drug is unlikely to occur in nursing infants since the amount of rosaramicin that a nursing infant could ingest is small.