Vasoconstriction-volume analysis for understanding and treating hypertension: the use of renin and aldosterone profiles

This bipolar analysis assumes that chronic hypertension is maintained by (1) arterial overfilling (volume hypertension), (2) arteriolar constriction without increased volume (vasoconstrictor hypertension) or (3) an inappropriate interaction of the two. In this formulation, the basis for all hypertension is an excess of volume relative to arteriolar capacity. The kidneys play a key role by sustaining sodium and volume retention in excess of vascular capacity despite increased renal perfusion pressure. This renal behavior can result from vasoconstriction, aldosterone stimulation or intrinsic renal disease.Since the renin-angiotensin-aldosterone system regulates both volume and arterial vasoconstriction, hypertensive disorders ought to exhibit a primary or a reactive disturbance in this system. Thus, measurements of these hormones considered in the physiologic setting would expose defects and suggest treatments.Two hypertensions are caused by specific derangements of the renin system: Primary aldosteronism exemplifies volume hypertension. Malignant hypertension is vasoconstrictor hypertension, supported by secondary aldosteronism-induced volume excess.Moreover, in all other hypertensive disorders hormonal profiling can characterize relative participation of the volume and vasoconstrictor components. Whatever the primary disturbance, low renin hypertensions are largely volume sustained, high renin hypertensions largely vasoconstrictor, and normal renin hypertensions express inappropriate volume-vasoconstrictor interaction.This construction has etiologic, prognostic and therapeutic implications. Low renin hypertensions, with presumably more open arterial bed and better tissue perfusion, appear less prone to cardiovascular complications. Moreover, the renin-sodium index enables predictable, more specific pharmacologic treatment. Volume hypertensions (low renin and some normal renin) respond to diuretics alone. Conversely, vasoconstrictor hypertensions (high renin and some normal renin) respond to antirenin-aldosterone therapy alone using drugs like propranolol.     

Modern system for treating high blood pressure based on renin profiling and vasoconstriction-volume analysis: a primary role for beta blocking drugs such as propranolol.

A new system is proposed for treating the spectrum of patients with high blood pressure. It is based on studies of the renin axis using renin profiling, pharmacologic probes and our bipolar vasoconstriction-volume hypothesis. The new system does not require renin profiling, pharmacologic testing or a vasoconstriction-volume analysis for widespread application. But these procedures, whenever available, will make treatment more efficient and more certain, and at the same time provide better base line definition. In the new system, all patients, except the elderly and those with congestive heart failure, bradycardia or a history of asthma, are treated first with propranolol alone, a procedure which will diminish or normalize blood pressure in many patients with high and noraml renin levels. For nonresponders, diuretic therapy is then superimposed. Subsequently, a propranolol subtraction trial picks out the low-renin patients who will usually respond to a diuretic alone. This program is likely to be fully effective in possible up to 85 per cent of patients. For the residual smaller fraction, drugs such as hydralazine, methyl DOPA, clonidine, reserpine or guanethidine are then added in traditional trial and error fashion. The proposed system has the theoretic attraction for long-term commitment, implicit in antihypertensive therapy, of achieving blood pressure control in large fractions with one drug instead of two or with two drugs instead of three or more. Moreover, the large groups who respond to therapy with propranolol alone (most high-renin and normal-renin patients) or to diuretics alone (most low-renin patients) gain the advantage of simple, more specific, long-term (i.e., antirenin or antivolume) therapy. The use of propranolol alone has practical and theoretic advantages over diuretics. Control may be achieved with even fewer side effects and without hypokalemia and chronic dehydration with its possibly adverse consequences (hyperuricemia, azotemia, hyperlipidemia, hyperreninemia, increased blood viscosity). Also, propranolol provides more direct control of the increased peripheral resistance and of neurogenically-induced swings in blood pressure. At the same time, the new system efficiently exploits the long-term use of diuretic therapy alone in low-renin patients in whom volume excess seems a causal factor. And it tends to avoid the use of diuretics in high-renin patients and of beta-blockers in low-renin patients in whom these drug types may be contraindicated.     

Comparison of antihypertensive and hormonal effects of captopril and propranolol at rest and during exercise

Captopril and propranolol were given alone and in combination to 13 hypertensive men and the effects studied at rest (seated, supine and standing) and during exercise. The two drugs were equipotent at rest, and individual patients showed similar blood pressure responses to the two drugs. Both produced slight reduction of urinary aldosterone; when given in combination, both blood pressure and aldosterone were further reduced. During exercise the increase in blood pressure was unaffected by captopril but reduced by propranolol, and there was no correlation between individual responses to the two drugs. It is concluded that the similar effects of the two drugs on resting blood pressure are consistent with their effects on the renin-angiotensin system.     

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

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.