Leslie Baer

Essential Hypertension: Renin and Aldosterone, Heart Attack and Stroke

Abstract In 219 patients with essential hypertension, aldosterone excretion and plasma renin activity were related to daily sodium excretion and compared to a nomogram drawn from 52 normal volunteers studied over the same continuous range of sodium balance. Plasma renin activity was subnormal in 27 per cent, normal in 57 per cent and elevated in 16 per cent. Further study showed eight patterns of renin and aldosterone secretion. Patients with normal or high renin had an 11 and 14 per cent frequency respectively of heart attacks or strokes. However, during a similar period of observation, none of 59 low renin patients had any of these complications. They appear protected despite similar hypertension, similar left ventricular enlargement, and despite higher mean age. Plasma renin activity emerges as a potential risk factor for patients with essential hypertension — useful for identifying etiologies, determining prognosis and applying therapy.

Propranolol inhibition of renin secretion. A specific approach to diagnosis and treatment of renin-dependent hypertensive diseases.

Abstract The antihypertensive effect and mechanism of propranolol were studied in 47 hypertensive patients classified according to high, normal, or low plasma renin activity. The drug was uniformly effective in 13 patients with high renin activity and malignant, renovascular, or essential hypertension, producing a mean fall in diastolic pressure of 30 mm of mercury. In 22 with normal renin, propranolol reduced mean diastolic pressure by 20 mm of mercury, but individual responses were less consistent. In contrast, the drug was uniformly ineffective in the 12 patients with low-renin essential hypertension. In all three groups, the action of propranolol closely correlated with both the control renin levels and the degree of renin suppression produced. Propranolol usually suppressed aldosterone secretion but to a lesser extent than it did renin, perhaps because of a hyperkalemic effect of the drug. These special effects of propranolol in renin-dependent hypertensions point to the possibility of an associated ...

Renin, angiotensin and aldosterone system in pathogenesis and management of hypertensive vascular disease

Abstract The renin angiotensin aldosterone concatenation, via two effector components, angiotensin II and aldosterone, simultaneously regulates (1) body sodium and water content, (2) arterial blood pressure and (3) potassium balance. Renin, secreted in response to stimuli which compromise kidney perfusion, increases plasma angiotensin and this stimulates aldosterone secretion. Vascular tone is regulated by an interaction between angiotensin levels and available (intravascular) sodium ions. The two hormones thus restore sodium balance and arterial pressure, thereby turning off renin release. Potassium homeostasis is maintained by two direct but opposing effects of plasma potassium levels on aldosterone and renin secretion. Derangements of this cybernetic system are involved in the pathogenesis of malignant hypertension, primary and pseudoprimary aldosteronism, renovascular hypertension and oral contraceptive hypertension. Subtler abnormalities in the renal adrenal axis occur in essential hypertension: Three major subgroups exhibit low (27 per cent), normal (57 per cent) or high plasma renin activity (16 per cent). When aldosterone is included, eight different hormonal profiles have been identified. Longitudinal studies indicate that, in contrast to groups with normal and high renin activity, patients with low renin essential hypertension appear to be protected from the development of strokes and heart attacks despite similar hypertension and cardiac enlargement and a higher age. Taken with the observations in malignant hypertension, plasma renin activity emerges as a risk factor predisposing to serious vascular injury. It thus may be a useful guide for determining etiology and prognosis. New therapeutic strategies are also suggested. Patients with low renin activity may not require early treatment whereas it should be diligently applied in those with high renin activity. Moreover, individualized antihypertensive therapy to correct specific derangements in the renin system holds special promise.

Renovascular hypertension: renin measurements to indicate hypersecretion and contralateral suppression, estimate renal plasma flow, and score for surgical curability.

Abstract Twenty-nine hypertensive patients with renal arterial stenosis were evaluated preoperatively with determinations of peripheral renin activity and differential renal vein renin levels. Three indicators were defined and evaluated to identify renovascular hypertension and to predict its curability: (1) an abnormally high peripheral plasma renin activity in relation to sodium excretion indicating increased renin secretion, (2) complete suppression of renin secretion (V−A ~ O) from the contralateral uninvolved kidney, and (3) an abnormally increased renal vein renin content relative to arterial renin from the suspect kidney [(V−A)/A > 0.48] which reflects and can be used to estimate the degree of renal ischemia, provided there is complete suppression of renin secretion from the contralateral uninvolved kidney. Each of the three indices, taken separately, are subject to sufficient technical variability to make them somewhat unreliable. Accordingly, a scoring system has been devised which weighs information contributed by each of the three indicators that appears to provide a high order of predictability of cure of renovascular hypertension. In 19 adult patients, in whom all three indices were measured, this scoring system predicted surgical cure in 13 of 13 (100 per cent), as well as lack of cure in 5 of 5 (100 per cent) and identified a technical error in 1. Altogether this analysis of the data supports the view that abnormal renin secretion is intimately involved in the pathogenesis of curable renovascular hypertension in man.

The influence of potassium administration and of potassium deprivation on plasma renin in normal and hypertensive subjects

The effect of potassium administration and of dietary potassium deprivation on plasma renin activity and aldosterone excretion has been studied in 10 normal subjects and in 12 hypertensive patients maintained on a constant dietary regimen. Potassium administration reduced plasma renin activity in 18 of 28 studies of both normal and hypertensive subjects. Suppression of renin often occurred despite sodium diuresis induced by potassium administration. The renin suppression was related to induced changes in plasma potassium concentration and urinary potassium excretion. The failure of suppression of plasma renin in 10 studies could be accounted for by the smaller amounts of potassium administered to these subjects, together with a possibly overriding influence of an induced sodium diuresis. In six studies potassium deprivation invariably increased plasma renin activity even though a tendency for sodium retention often accompanied this procedure. The data indicate that both the suppression of plasma renin activity induced by potassium administration and the stimulation of renin activity which follows potassium depletion occur independently of associated changes in either aldosterone secretion or in sodium balance. However, the results do suggest that in various situations, the influence of potassium on plasma renin activity may be either amplified or preempted by changes in sodium balance. These interactions between potassium and plasma renin could be mediated by an ill-defined extrarenal pathway. But the findings are more consistent with an intrarenal action of potassium ions to modify renin release. Potassium might modify renin secretion directly by acting on the juxtaglomerular cells or by a change in its tubular reabsorption or secretion. The effects of potassium ions on renin secretion might also be mediated indirectly via an induced change in tubular sodium transport.

Erectile dysfunction is a marker for cardiovascular complications and psychological functioning in men with hypertension.

The aim of this study was to investigate the incidence of cardiovascular complications in hypertensive patients with erectile dysfunction (ED). An anonymous questionnaire was mailed to 467 and received from 104 hypertensive male patients. Despite the low response rate of 22%, the following interesting findings could be observed: 70.6% of the patients who responded suffered from ED. The hypertensive patients with ED had significantly higher prevalence of cardiovascular complications (P<0.05). The correlation between depression and low quality of life as well as between ED and low sexual satisfaction was also statistically significant (P=0.05). ED in hypertensive patients can be considered as a marker for cardiovascular complications in this patient group.

The Role of Renin in the Exaggerated Natriuresis of Hypertension

Hypertensive patients were classified according to their plasma renin response when challenged by the potent diuretics, ethacrynic acid (50 mg IV), or furosemide (40 mg IV), into renin-unresponsive and renin-responsive groups. In the latter plasma renin activity rose by at least 0.5 ng of angiotensin/ml/hr after the diuretic. The response to volume expansion with 2 L of isotonic saline infused over 60 min was then studied. Peak rate of sodium excretion after saline loading was 994±186 &mgr;Eq/min in the renin-unresponsive group and peak urine flow was 11.9 ± 2.1 ml/min. In the renin-responsive hypertensives peak sodium excretion was 448 ± 149 &mgr;Eq/min and peak urine flow was 5.4 ± 1.5 ml/min. Both the sodium excretion and urine flow responses were significantly higher (P < 0.05) in the renin-unresponsive group. The degree of saline-induced diuresis and natriuresis was not related to the preexisting level of aldosterone production. Plasma renin changed little in either group during saline infusion but tended to be higher at all times in the renin-responsive subjects. The enhanced capacity of the renin-unresponsive hypertensive subjects to excrete a salt load suggests either a functionally significant degree of extracellular fluid volume expansion or a direct role for renin in the natriuresis accompanying volume expansion.

The renin axis and vasoconstriction volume analysis for understanding and treating renovascular and renal hypertension.

Information defining the renin-angiotension-aldosterone axis as a control system concurrently regulating salt balance and blood pressure has been applied to reexamine the role of renin in experimental and clinical forms of renovascular and renal hypertension, and thence to develop criteria for differentiating these entities. Experimentally, there are two models of renovascular hypertension; one is characterized by excess renin with reduced sodium (vasoconstrictor form) and the other by excess sodium with reduced renin (volume form). But with sodium depletion, the volume form converts to a vasoconstrictor form illustrating how the two factors coordinate to maintain blood pressure. In man, renovascular and renal hypertensions appear to be sustained by the same two mechanisms. Studies in man show that, in the absence of unilateral disease, the supine renal venous renin level in each kidney is consistently 24 percent higher than the peripheral level. Because of this constant relationship, the peripheral renin level is a measure of the renal secretion rate. Our studies indicate the curable unilateral renovascular hypertension is, in fact, renin-dependent vasoconstrictor hypertension. Three criteria, derived from four renin measurements, identify this situation: (1) Hypersecretion of renin is reflected by a high peripheral level when indexed against sodium excretion. (2) Lateralization of renin secretion with contralateral suppression rules out occult bilateral disease. It is indicated by V-A equal 0 from the uninvolved kidney. (3) (V-A)/A greater than 48 per cent from the ipsilateral kidney supports unilateralization. With data derived from patients with essential hypertension as a reference, the degree to which (V-A)/A is greater than 0.48 can be used to estimate the degree of renal ischemia, using Ficks principle. Corroborative evidence to support these three criteria can be developed from the blood pressure response to angiotensin blocking drugs or to antirenin therapy with propranolol. Clinical analysis validates these criteria to identify curable hypertension from unilateral renovascular or parenchymal disease. In patients with either occult or overt bilateral renal disease, the volume factor often predominates and is expressed by some suppression of plasma renin levels. Continued

Cigarette smoking in hypertensive patients. Blood pressure and endocrine responses

The blood pressure and endocrine responses to cigarette smoking were studied in 19 hypertensive patients to determine whether smoking activates the renin-aldosterone axis. Blood pressure rose from 140 +/- 7/99 +/- 3 (mean +/- SEM) to 151 +/- 5/108 +/- 2 mm Hg (p less than 0.01) within 10 minutes after smoking, and pulse rate also increased significantly (69 +/- 2 to 96 +/- 4 beats per minute). Plasma renin activity did not change but rose 15 minutes after ambulation. In contrast, plasma aldosterone and plasma cortisol levels increased significantly after smoking and peaked at 20 minutes: 13.9 +/- 0.9 to 20.2 +/- 2.0 ng/dl (p less than 0.01) and 10.2 +/- 1.0 to 22.0 +/- 2.2 micrograms/dl (p less than 0.01), respectively. These responses were closely correlated (r = 0.6467, p less than 0.01), suggesting a pituitary-adrenal mechanism is activated during smoking. Plasma ACTH levels rose from 58 +/- 6 to 87 +/- 10 pg/ml in 10 minutes (p less than 0.001) and to 90 +/- 14 pg/ml at 20 minutes (p less than 0.01). Total plasma catecholamine levels also rose from 468 +/- 60 to 624 +/- 73 pg/ml 10 minutes after smoking (p less than 0.01) and to 724 +/- 69 pg/ml (p less than 0.01) 15 minutes after ambulation. In hypertensive smokers, cigarette smoking is associated with an increase in blood pressure, pulse rate, and plasma ACTH, cortisol, aldosterone, and plasma catecholamine levels. The long-term significance of these acute hormonal changes in regard to blood pressure homeostasis and vascular disease in cigarette smokers remains to be determined. Smoking should be avoided prior to blood pressure and endocrine determinations.

Detection of Renovascular Hypertension with Angiotensin II Blockade

Angiotensin II blockade with sarcosine 1-alanine 8-angiotensin II (saralasin, P-113) was done in 40 studies of 20 hypertensive patients. Eleven of 12 patients with a depressor response to angiotensin II blockade had significant renovascular or renal disease, and nine of 10 had renal vein renin measurements that lateralized to the abnormal kidney. In contrast, none of the patients without a depressor response had renovascular abnormalities. Plasma renin activity was usually high in responders to saralasin (18 ng/ml-h) when compared with nonresponders (0.5 ng/ml-h). In these studies a correlation between the fall in blood pressure and the rise in plasma renin activity during angiotensin II blockade was observed while renin was unchanged in the absence of depressor responses. In two renovascular renin-dependent hypertensive patients, treatment with diuretics induced severe hyperreninemia and a rise in blood pressure that was reversed by sodium loading.