Circadian rhythm of plasma aldosterone concentration in patients with primary aldosteronism.

Plasma aldosterone, cortisol, and renin activity were measured in nine recumbent patients with hyperaldosteronism, including seven with adenomas, one with idiopathic hyperplasia, and one with glucocorticoid suppressible hyperplasia. All had peak values of plasma aldosterone concentration from 3 a.m. to noon and lowest values at 6 p.m. or midnight. This rhythm was similar to the circadian pattern of plasma cortisol in the same patients. When these data were normalized to eliminate the wide variation in ranges of plasma aldosterone and cortisol between individuals, there was an excellent correlation (r = + 0.87, P < 0.005) between the two hormones. In contrast, plasma aldosterone concentrations did not correlate with plasma renin activity before or after normalization of data. Short term suppression of ACTH by administration of dexamethasone eliminated the circadian variation of plasma aldosterone in both patients with hyperplasia and in four of five patients with adenomas, while it markedly altered the rhythm in the fifth. Similar doses of dexamethasone were administered to four normal subjects and did not flatten the circadian rhythm of plasma aldosterone. These data suggest that patients with primary aldosteronism have a circadian rhythm of plasma aldosterone mediated by changes in ACTH.

Glucagon structure-function relationships using isolated rat hepatocytes.

The ability of glucagon and several of its semi-synthetic analogues to stimulate glucose production in isolated rat hepatocytes was measured and compared for relative potencies. The order of decreasing biological activities of glucagon in this assay was as follows: glucagon greater than [HArg12]-glucagon greater than [des-Asn28, Thr29][homoserinehydrazide27]-glucagon approx. equal to [des-His1]-glucagon greater than [des-Asn28, Thr29][homoserinelactone27]-glucagon greater than [des-Asn28, Thr29]-[n-butylhomoserineamide27]-glucagon greater than glucagon1-21. Qualitatively, these results are similar to those obtained previously in the hepatic plasma membrane adenylate cyclase assay. Minor exceptions were noted for the hydrazide derivative and the partial agonist [des-His1]-glucagon, both of which were slightly more potent relative to glucagon in the glycogenolytic assay than in the adenylate cyclase assay. The assay provides important insight into glucagon structure-function relationships.

Routine chest roentgenograms and electrocardiograms. Usefulness in the hypertensive workup.

We reviewed the records of all patients entering the hypertension Clinic in 1974. One hundred sixteen met the criteria for hypertension and had a routine chest roentgenogram and/or ECG obtained for the evaluation of hypertension, Routine chest films and ECGs led to therapeutic or diagnostic interventions in only two instances, were not useful as baseline examinations, were never used for prognostic purposes, and not once influenced hypertensive management. We conclude that the value of routine chest roentgenograms and ECGs cannot be defended on the basis of their contribution to the workup of hypertension.

Salt restriction in hypertensive patients. Comparison of advice, education, and group management.

The purpose of this study was to identify the best of three methods of treating hypertensive outpatients in order to minimize dietary sodium levels and thereby decrease the need for antihypertensive drugs. Forty-eight outpatients with hypertension were randomly assigned to three treatment programs: (1) advice; (2) an intensive educational program; and (3) small-group management plus feedback. This last program had a problem-solving format in which patients shared ideas and provided mutual support for dietary change. Only these group management patients were told the results of their sodium determinations. In a one-year study, group management plus the feedback to patients of information on the sodium content of their urine was more effective in decreasing dietary sodium intake than advice or an intensive educational effort.

Increasing compliance. Patient-operated hypertension groups.

Compliance was compared in 52 previously noncompliant hypertensive patients randomly assigned for eight weeks to either a nurse-operated hypertension clinic (control) or a patient-operated hypertension group] (experimental). Control patients listened to audiotapes on hypertension and its management and met individually with a nurse who adjusted their drug regimens. Experimental patients were trained to take their own blood pressure (BP) and select their own drugs in a group program emphasizing informed self-help. After the eight-week training period and at two- and six-month follow-up visits, both groups had significantly lower BPs. Compared with control patients, experimental patients had lower diastolic BPs, better pill counts, and better attendance (all P < .05). This study suggests that training noncompliant patients in groups to manage their own hypertension may achieve better results than traditional management programs.

Familial Bartter's syndrome.

Two sisters were found to have Bartter's syndrome. Both had hypokalemia, hyperreninemia, normal BPs, and decreased pressor responses to angiotensin II. During a water diuresis, patient 1 had an abnormally low distal tubular fractional reabsorption of chloride initially, but this normalized after hypokalemia was corrected for one year. Patient 2 had no demonstrable defect in chloride transport. Hypokalemia in Bartter's syndrome may be caused by some hereditary mechanisms other than defective reabsorption of chloride in the distal tubules.

Management of obese patients with diabetes mellitus: comparison of advice education with group management.

The purpose of our study was to compare the effect on diabetes control of group management with the advice-educational technique traditionally used in managing obese outpatients with poorly controlled non-insulin-dependent diabetes mellitus (NIDDM). Forty-one patients were randomly assigned to these two treatment programs, and 32 patients completed the 6-mo study. Initially, patients were seen for 1-h sessions at 1- and 2-wk intervals and later at 1-mo intervals. Patients were asked to do home blood glucose monitoring, decrease caloric intake, increase exercise, and if they were taking insulin, to adjust the dose to attain approximate euglycemia and to stabilize food and exercise patterns. The combined groups reduced mean +/- SD glycohemoglobin from 10.9 +/- 3.1 to 9.4 +/- 2.4% (P less than .05). Internal Health Locus of Control Scale was negatively and significantly correlated with initial and subsequent glycohemoglobin values (the more internal, the lower the glycohemoglobin). At the end of the study the patients in the group management program had significantly lower blood glucose levels than those given advice and education, but no significant differences in glycohemoglobin values or percentage overweight were observed. One patient had a normal initial glycohemoglobin, and only 4 patients had values in the normal range of 4-6.8% at the end of the study. Better management programs need to be developed for treating obese outpatients with NIDDM.

Suppression of cortisol by a progestational steroid, melengestrol.

Melengestrol, a steroid with progestational activity but with a structure that does not resemble that of cortisol, suppresses plasma cortisol in humans with a potency 1/40th that of dexamethasone. The 6alpha-methyl and 17alpha-acetoxy substituents and the 6,7 double bond of melengestrol acetate are known to slow the metabolism of similar steroids. Insertion of a 6alpha-methyl group markedly increases the glucocorticoid activity of 17alpha-OH-progesterone. The glucocorticoid activity of melengestrol is presumably attributable to the large dose administered in our study, its slow metabolism and limitations of the specificity of glucocorticoid tissue receptors.

Persistent lymphocytopenia as a diagnostic feature of bronchogenic carcinoma.

Patients with abnormalities due to bronchogenic carcinoma, noted on chest films, have decreased peripheral blood lymphocytes and increased total white cells compared to patients with benign lesions. Precision studies of 40 patients revealed that a low percentage of lymphocytes averaged over a three-week period distinguished bronchogenic carcinoma patients from patients with benign lesions with 95 percent overall accuracy. Lesions as small as 1.0 cm were correctly predicted to be malignant. Mean 8 AM plasma cortisol levels were elevated in patients with bronchogenic carcinoma and there was a negative correlation of 8 AM plasma cortisol levels with precentage of lymphocytes. Increased levels of endogenous cortisol may account for lymphocytopenia in bronchogenic carcinoma patients.

Effect of inhaled salmeterol on sulfur dioxide-induced bronchoconstriction in asthmatic subjects.

UNLABELLED: This study tested the capability of a single 42-microgram dose of inhaled salmeterol xinafoate, a long-acting beta 2-agonist, to protect against bronchoconstrictive effects of exposure to 0.75 ppm sulfur dioxide (SO2) during exercise, for up to 24 h. Ten SO2-responsive adult volunteers with stable asthma were studied under 4 conditions of drug pretreatment/exposure, administered in random order, double-blind: salmeterol/SO2, placebo/SO2, salmeterol/clean air, and placebo/clean air. Each subject underwent 10-min exposure/exercise challenges in a chamber 1, 12, 18, and 24 h after pretreatment. Exercise ventilation rates averaged 29 L/min. Response was measured as the decrement in FEV1 between preexposure and postexposure (lowest value within 30 min). After salmeterol, mean decrement post-SO2 was 7% at 1 h and 12% at 12 h. At 18 and 24 h after salmeterol, and at all times after placebo, mean decrements were 25 to 30%. After 18 and 24 h, salmeterol still improved base-line FEV1 relative to placebo, although improvement was not statistically significant at 24 h. Acute symptom increases accompanied FEV1 decrements. CONCLUSION: In our asthmatic subjects, pretreatment with salmeterol imparted clinically and statistically significant (p < 0.01) protection against bronchoconstriction induced by SO2/exercise for at least 12 h, and maintained an improvement in lung function for as much as 18 h.

Clinical studies of a new, low-dose formulation of metolazone for the treatment of hypertension.

Two multicenter, double-blind, randomized studies were performed to determine the antihypertensive efficacy and effects on laboratory values of a new, shorter-acting formulation of metolazone in patients with mild to moderate hypertension. After baseline placebo-control periods, 105 patients were randomly assigned to receive single daily doses of either placebo or 0.5, 1.0, or 2.0 mg of the new formulation of metolazone for six weeks in one study, and 164 patients were randomized to receive 0.5, 1.0, or 2.0 mg of the new formulation of metolazone or 2.5 mg of the older, long-acting metolazone in the other. Mean blood pressure reductions in all three metolazone groups were statistically and clinically significant. Blood pressures of 51% to 58% of patients in the 0.5-mg metolazone group were controlled (diastolic blood pressure less than 90 or a fall of greater than or equal to 10 mmHg from baseline). Reductions in mean serum potassium levels were dose-related. We conclude that 0.5 mg of metolazone is safe and effective therapy for hypertension; it will significantly reduce systolic and diastolic blood pressure and minimizes changes in laboratory test values.

Guanadrel sulfate compared with methyldopa for mild and moderate hypertension.

In a two-year study of 547 hypertensive patients receiving diuretics, the addition of guanadrel sulfate or methyldopa reduced elevated blood pressure to a similar degree and provided good control in 70% of the patients. Guanadrel-treated patients experienced less frequent and less severe drowsiness than methyldopa-treated patients. The frequency of morning orthostatic faintness was low and similar in both treatment groups. Guanadrel produced no tissue toxicity. Guanadrel sulfate, a postganglionic sympathetic inhibitor, is nearly free of central nervous system side effects and is recommended over methyldopa for step 2 therapy when diuretics alone fail to control mild or moderate hypertension.

Blood pressure changes following chronic administration to rats of 3beta,16beta-dihydroxy-5-androsten-17-one, 3beta,17beta-dihydroxy-5-androsten-16-one and 21-hydroxy-4-pregnene-3,20-dione-21-acetate.

The urinary excretion of 3beta,16beta-dihydroxy-5-androsten-17-one (16beta-OH-DHEA) is increased in patients with low renin essential hypertension. This steroid and its isomer 3beta,17beta-dihydroxy-5-androsten-16-one (16-oxo-A) have also been reported to have mineralocorticoid activity in adrenalectomized rats. These findings have led to the postulate that excessive secretion of 16beta-OH-DHEA may be responsible for the production of low renin essential hypertension. In this study unilaterally nephrectomized salt loaded rats injected once a week with 30 mg of 11-desoxycorticosterone acetate per/kg of body weight for 2 month periods developed hypertension. Rats given similar amounts of 16beta-OH-DHEA or 16-oxo-A and rats given no steroids did not develop hypertension. We conclude that it is unlikely that 16beta-OH-DHEA and 16-oxo-A are direct causative factors in the production of low renin essential hypertension.

The effects of self-monitoring by patients on the control of hypertension.

The effects of self-monitoring of blood pressure on the control of hypertension were examined in this study. Failure of patients to comply with treatment is presumably attributable in part to the fact that hypertension usually is asymptomatic until complications develop. Self-monitoring might make visible an otherwise asymptomatic condition, and thereby increase motivation. One hundred hypertensive patients beginning outpatient treatment were randomly assigned to experimental and control groups. Subjects were given a sphygmomanometer and instructed in its use. Both groups were given similar antihypertensive medications. After six months of treatment, mean systolic pressure was significantly lower (11.4 mm Hg, p smaller than 0.05) in the experimental than in the control subjects. However, the mean baseline systolic pressure in the control group was 3.9 mm Hg less than that of the experimental group. If this value is substracted from the difference between the last mean systolic pressures in the two groups, the 7.5 mm Hg difference is seen as a very modest effect of self-monitoring. Diastolic blood pressure was insignificantly lower for experimental subjects. Compared to the potent effectiveness of drugs in reducing blood pressure, self-monitoring was of little value.

Increased atrial natriuretic factor secretion after endothelin injection in dogs.

Hemodynamic and hormonal responses to bolus intravenous injections of synthetic porcine endothelin (pET) were examined in anesthetized dogs. There were no significant changes in mean blood pressure (MBP), right atrial pressure (RAP), or plasma atrial natriuretic factor (ANF) concentration in response to 40 pmol/kg of the peptide. However, responses to 400 pmol/kg of the peptide were significant: MBP rose from 114 +/- 6 mmHg (mean +/- SE) to 139 +/- 7 mmHg (p less than 0.01), RAP rose from 5.4 +/- 0.9 mmHg to 7.8 +/- 1.1 mmHg (p less than 0.01), and ANF increased from 45 +/- 10 pg/ml to 277 +/- 33 pg/ml (p less than 0.01). Peak value of RAP was observed 2.6 +/- 0.4 min, while peak of ANF was 11.4 +/- 0.9 min after peptide injection. There was a strongly positive correlation (r = 0.93, p less than 0.01) between the increase in RAP and the increase in ANF in dogs given 400 pmol/kg of pET. These results indicate that exogenously administered pET to anesthetized dogs alters hemodynamics and induces ANP release, and are compatible with a postulate that the ANF release is caused by elevated RAP.

Osteoporosis, osteomalacia, rickets, and Paget's disease.

Although the common form of osteoporosis associated with aging can be treated, it is best to avoid the problem by not letting the disease develop. Osteomalacia is caused by inadequate or delayed mineralization of bone and is treated by correcting the abnormal intake, loss, or metabolism of vitamin D, phosphate, and calcium. Paget's disease is characterized by osteoclastic resorption of bone with new bone laid down in a disorganized fashion.