Effect of the angiotensin II antagonist saralasin on plasma aldosterone concentration and on blood pressure before and during sodium depletion in normal subjects.

The effect of the angiotensin II antagonist saralasin on plasma aldosterone, plasma angiotensin II and blood pressure was studied in six normal supine subjects both before and during sodium depletion. Before sodium depletion, infusion of saralasin produced no consistent changes; during sodium depletion, infusion of the angiotensin antagonist caused a fall in plasma aldosterone and an increase in plasma angiotensin II in each subject. It is concluded that angiotensin II plays a major part in stimulating aldosterone secretion during sodium depletion in man.

Minoxidil for severe hypertension after failure of other hypotensive drugs.

Forty-four patients with severe hypertension who were resistant to treatment with more conventional hypotensive drugs or could not tolerate the side effects were treated with minoxidil, a potent peripheral vasodilator. A beta-blocking drug and a diuretic were used routinely to control, respectively, the tachycardia and fluid retention caused by minoxidil. During treatment the outpatient supine blood pressure fell from a mean of 221/134 mm Hg to 162/98 mm Hg. Eleven patients required additional or alternative hypotensive agents before blood pressure was adequately controlled. Side effects were minor, although the invariable hirsuties caused by minoxidil was unacceptable to three women. The possibility of cardiotoxic effects, raised by early studies in dogs, has not been excluded, and therefore this drug should be used only in patients with severe hypertension. In such patients minoxidil appears to be most effective.

Effects of intravenous labetalol on blood pressure, angiotensin II and aldosterone in hypertension: comparison with propranolol.

1. Labetalol, a compound with both alpha- and beta-adrenoreceptor-blocking actions, was given intravenously (1-5-2-0 mg/kg) in twenty recumbent hypertensive patients. 2. There was a rapid reduction in systolic and diastolic pressures in all, maintained up to 24 h in some subjects. 3. Severe hypotension was not seen in recumbent subjects, but postural hypotension was common. 4. Labetalol caused significant lowering of heart rate. 5. Labetalol induced significant and related lowering of plasma angiotensin II and aldosterone concentrations, most obviously when these were initially high. 6. In a cross-over comparison in five patients against 10 mg of propranolol intravenously, labetalol was more effective in lowering blood pressure, but less effective in lowering pulse rate or plasma angiotensin II.

The effects of saralasin, an angiotensin II antagonist, on blood pressure and the renin-angiotensin-aldosterone system in normal and hypertensive subjects.

Blood pressure reduction with saralasin infusion was seen only in hypertensive patients with abnormally elevated basal plasma renin and angiotensin II levels, and after sodium depletion the reduction in blood pressure was more marked. In normal subjects, and in hypertensives with plasma renin and angiotensin II levels within the normal range, there was no marked fall in blood pressure across saralasin infusion regardless of the sodium status of the individual. Plasma aldosterone concentration fell during saralasin infusion in those subjects with high baseline renin and angiotensin II levels. This fall occurred in the sodium replete and deplete states. In the normal subjects, and those hypertensives with normal plasma renin levels, there was no fall in aldosterone in the sodium replete state. However, after sodium depletion the expected rise in aldosterone was abolished during saralasin infusion, the plasma aldosterone falling to within the normal sodium replete range, rising again after the saralasin infusion was stopped. This study supports the concept of a direct role for renin and angiotensin II in the maintenance of hypertension in those subjects with elevated basal plasma renin. Plasma aldosterone would appear to be controlled, at least in part, by the prevailing plasma angiotensin II level in those subjects with elevated basal levels of angiotensin II; that is in high renin hypertensives, and in normal subjects and normal renin hypertensives who are sodium deplete.

Treatment of phaeochromocytoma and of clonidine withdrawal hypertension with labetalol.

1 Labetalol has been used as medical treatment in five patients with phaeochromocytoma. 2 In four of the five patients, blood pressure was satisfactorily controlled, and symptoms and signs were relieved. 3 Labetalol also provided satisfactory cover across surgery for the removal of tumours in two cases. 4 In one instance, it was not possible to give sufficient labetalol orally to suppress the attacks of phaeochromocytoma. This patient was not effectively controlled at operation with a combination of propranolol and phenoxybenzamine. 5 Intravenous labetalol rapidly lowered blood pressure and relieved symptoms in a patient experienced hypertensive crisis after clonidine withdrawal. 6 Labetalol is a useful addition to the medical treatment of phaeochromocytoma.

Effect of blood pressure angiotensin II and aldosterone concentrations during treatment of severe hypertension with intravenous labetalol: comparison with propranolol.

1 The actions of labetalol 1.0-2.0 mg/kg intravenously on blood pressure, heart rate, plasma angiotensin II and aldosterone concentrations have been studied in 20 recumbent hypertensive patients. 2 In all subjects there was a reduction in systolic and diastolic blood pressures within 5 min of completion of injection. 3 Severe hypotension was not seen but three patients who had a marked fall in blood pressure experienced side-effects. Postural hypotension was common at the end of the study. 4 Labetalol caused significant reduction in heart rate. 5 Labetalol induced significant lowering of plasma angiotensin II and in plasma aldosterone concentrations, which were most obvious when these were increased initially; overall there was a close correlation between concurrent measurements of angiotensin II and aldosterone concentrations. 6 In five patients a comparison was made against propranolol 10 mg intravenously. Labetalol was more effective in lowering blood pressure but less effective in reducing pulse rate of plasma angiotensin II concentration.

Labetalol (AH5158), a competitive alpha- and beta-receptor blocking drug, in the management of hypertension.

The effects of intravenous labetalol, a drug with both alpha- and beta-adrenergic receptor blocking actions, have been studied in 20 severely hypertensive patients. There was a prompt and sustained fall in arterial pressure; severe hypotension did not occur in recumbent patients but postural hypotension was common. Pulse rate was consistently reduced, but bradycardia was not a problem. Significant and correlated falls in plasma angiotensin II and aldosterone were seen. In a direct comparison with intravenous propranolol, labetalol was less effective in lowering plasma angiotensin II, but more effective in reducing blood pressure. Oral labetalol provided good control of blood pressure and other features in two patients with phaeochromocytoma. Intravenous labetalol was similarly effective in controlling a hypertensive crisis following clonidine withdrawal.

Mechanism of renal hypertension.

Renal hypertension of the two-kidney type is divided into three stages. In the first, hypertension results from the vasoconstrictor effect of angiotensin II. This persists to some extent in the second phase but there is in addition a slow-developing pressor effect, also resulting from angiotensin II and probably attributable to sodium. In the first two phases removal of the abnormal kidney corrects the hypertension. This fails in the third phase because changes in the opposite kidney maintain hypertension. Renin and angiotensin are probably not involved at this stage.

The effects of the angiotensin II antagonist saralasin on blood pressure and plasma aldosterone in man in relation to the prevailing plasma angiotensin II concentration.

The effect of saralasin in lowering blood pressure and plasma aldosterone concentration in normal subjects, both sodium-replete and sodium-deplete, and in patients with various forms of hypertension, is closely related to the basal plasma angiotensin II concentration. These findings confirm and extend earlier studies of angiotensin II/arterial pressure and angiotensin II/aldosterone dose-response curves. They also emphasize the importance of the renin-angiotensin system in the control of aldosterone in sodium depletion and in renal hypertension.

A case of hypopituitarism with diabetes insipidus and loss of thirst. Role of antidiuretic hormone and angiotensin II in the control of urine flow and osmolality.

A 20-yr-old male was found to have diabetes insipidus is association with panhypopituitarism but without any focal neurological lesion being identified. He was initially treated with steroid supplements, the features of diabetes insipidus being controlled with a thiazide diuretic. Eighteen months later the patient lost thirst sensation and stopped treatment, subsequently being re-admitted with severe dehydration, oliguria and focal neurological signs. Further investigation, including brain biopsy, confirmed the presence of an atypical pinealoma which was considered inoperable. Measurements of plasma antidiuretic hormone (ADH) and angiotensin II (AII) concentrations during the severe dehydration showed very high levels of AII, but inappropriately low plasma ADH levels for the severity of dehydration. We consider that the evidence obtained from this case supports the view that the oliguria with hypertonic urine present during severe dehydration was due to a direct renal action of the very high AII levels, possibly supplemented by the residual ADH secretion.

Glucose tolerance and insulin sensitivity in malnourished children

In malnourished, compared with recovered children, fasting blood glucose concentrations were low and there was impared peripheral glycolysis as shown by a failure of blood lactate to raise after glucose was injected intravenously. Homogenates of muscle biopsies from malnourished and recovered children produced equal amounts of lactate when incubated anaerobically with various substrates, but when compared with homogenates of biopsies from normal children the pattern suggested an impairment of glycolysis. The rate of glucose disappearance after intravenous glucose was slow in the malnourished child and there was possibly diminished sensitivity to exogenous insulin. Isocaloric diets relatively high or low in fat were fed to children who had recovered from malnutrition. Glucose tolerance, insulin sensitivity, fasting plasma insulin and insulin response to intravenous glucose were all the same in children on either diet. (AU)