J. J. Morton

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.

CHANGES OF VASOPRESSIN IN HYPERTENSION: CAUSE OR EFFECT?

Plasma concentrations of arginine-vasopressin (antidiuretic hormone) have been measured in 40 patients with benign essential hypertension and 12 patients with malignant-phase hypertension. Values tended to be low in the benign phase and high in the malignant phase. 5 normal subjects were infused with synthetic arginine-vasopressin, producing plasma concentrations up to five times the highest value recorded in malignant-phase hypertension, without any effect on blood-pressure. There is no evidence that vasopressin has a direct role in the pathogenesis of benign essential hypertension or its transition to the malignant phase. On the contrary, abnormal vasopressin concentrations may be caused by hypertension.

Hyponatraemic hypertensive syndrome with renal-artery occlusion corrected by captopril.

Malignant hypertension with severe hyponatraemia, hypokalaemia, depletion of sodium and potassium, and elevated blood levels of renin, angiotensin I, angiotensin II, aldosterone, and arginine vasopressin developed in a woman with renal-artery occlusion. Plasma angiotensin II was disproportionately high in relation to exchangeable sodium. Captopril, by inhibiting conversion of angiotensin I to angiotensin II, further elevated the blood levels of renin and angiotensin I but corrected all other abnormalities. Unilateral nephrectomy was subsequently curative.

Amiloride, spironolactone, and potassium chloride in thiazide‐treated hypertensive patents

Dose‐response curves for amiloride and spironolactone were defined in 15 hypertensive patients treated with bendroflumethiazide (bendrofluazide). The relative potency amiloride : spironolactone in correcting hypokalemia was 2.8:1, an estimate significantly lower than the 5:1 potency currently accepted. The relative potency for reduction of plasma sodium was 3.9:1 (amiloride:spironolactone). A miloride was disproportionately potent in lowering serum bicarbonate, and the data do not suggest that these drugs elevate plasma potassium simply by correcting metabolic alkalosis. Changes in blood pressure were confounded by the presence of carryover effect between treatment phases. Both drugs increased plasma angiotension II and aldosterone, but the rise in aldosterone with spironolactone was smaller than expected from concurrent plasma angiotension II and potassium concentrations. This was consistent with a partial block of aldosterone biosynthesis by spironolactone. The activity of spironolactone did not require the presence of hyperaldosteronism. In a smaller study potassium chloride induced a significant log dose‐response on plasma potassium, but the effect was small in absolute terms. A t least 64 mmole potassium chloride was needed to match the effect of 20 mg amiloride or 56 mg spironolactone.

The effect of sodium deprivation and of angiotensin II infusion on the peripheral plasma concentrations of 18-hydroxycorticosterone, aldosterone and other corticosteroids in man.

Abstract The effect of angiotensin II infusion on plasma cortisol, 11-deoxycorticosterone, corticosterone, 18-hydroxycorticosterone and aldosterone concentrations was compared in 6 normal subjects before and after different degrees of sodium depletion. Cortisol, 11-deoxycorticosterone and corticosterone levels were unaffected by sodium depletion or by angiotensin II infusion in either replete or deplete states. Plasma 18-hydroxycorticosterone and aldosterone concentrations rose in parallel when sodium replete subjects were infused with angiotensin II. Sodium depletion had a proportionately greater stimulating effect on plasma 18-hydroxycorticosterone than on aldosterone, particularly in the more severely depleted subjects. The rise in plasma aldosterone concentration following angiotensin II infusion was greater in sodium deplete than in sodium replete subjects and this difference increased with the severity of sodium depletion. Basal 18-hydroxycorticosterone concentrations were much higher in the sodium deplete state than when the subjects were replete with sodium, but the subsequent effect of angiotensin II infusion, although further increasing 18-hydroxycorticosterone levels, was less consistent. The effect of angiotensin II was not secondary to a rise in ACTH since, in a seventh subject pretreated with dexamethasone, the response was not abolished It is concluded that one effect of angiotensin II must occur at or before 18-hydroxylation in the biosynthetic pathway. The availability of a larger pool of aldosterone precursor as a result of sodium depletion may be an explanation of the phenomenon of sensitization of aldosterone production to angiotensin II infusion in this condition. The possibility of a second effect of angiotensin II on the conversion of 18-hydroxycorticosterone to aldosterone is also discussed.

The role of plasma osmolality, angiotensin II and dopamine in vasopressin release in man

A sensitive and specific radioimmunoassay for arginine vasopressin was used to compare the relative importance of changes in plasma osmolality, angiotensin II and dopamine in the regulation of vasopressin secretion in man. One hour after water loading plasma vasopressin fell from 0·40 to 0·06 pmol/1, while 8 h and 24 h fluid restriction resulted in a rise of vasopressin from 0·29 to 0·54 and 1·37 pmol/1 respectively. In contrast neither dietary sodium deprivation, when plasma angiotensin II increased 5‐fold, nor dopamine infusion, at a rate which increased circulating dopamine levels up to 244‐fold, had any effect on basal plasma vasopressin values. These results confirm that, under physiological conditions, osmoregulation is the major mechanism controlling vasopressin release and suggests that circulating angiotensin II and dopamine have no significant part to play.

The effect of angiotensin II infusion on plasma corticosteroid concentrations in normal man

Abstract Angiotensin II infusion at graded rates into sodium replete, normal male subjects caused marked increases in the plasma concentrations of 18-hydroxycorticosterone and aldosterone. The magnitude of the increase was similar for each compound and plasma concentrations correlated closely with concurrent plasma angiotensin II concentration. No clear evidence of changes in the plasma concentrations of the other aldosterone precursors, DOC and corticosterone, was obtained and levels of cortisol, 11-deoxycortisol and 18-hydroxy-DOC were unaffected by angiotensin II infusion.

Amiloride in the treatment of primary hyperaldosteronism and essential hypertension.

Amiloride (40 mg/day) was given to nineteen patients with primary hyperaldosteronism. There were significant falls in systolic and diastolic blood pressure, in total exchangeable sodium, and in serum sodium and bicarbonate; while total exchangeable potassium, total body potassium, serum potassium, chloride and urea, and plasma renin, angiotensin II and aldosterone all increased significantly. Amiloride was effective in reducing blood pressure in patients with and without adrenocortical adenoma. No carry‐over effect was seen on withdrawing amiloride. Similar changes were associated with amiloride treatment in five patients with essential hypertension; hyperkalaemia was not observed. Only negligible side‐effects were encountered in the entire series of twenty‐four patients.

The interaction of ACTH and angiotensin II in the control of corticosteroid plasma concentration in man

Abstract Angiotensin II infusion into normal human subjects increases the plasma concentration of aldosterone and 18-hydroxycorticosterone but leaves those of other corticosteroids unaffected. This contrasts with the response of adrenocortical cells in vitro . However, if a low, constant rate infusion of ACTH is maintained throughout increasing rates of angiotensin II infusion, the concentrations of cortisol, corticosterone and 18-hydroxy-11-deoxycorticosterone also correlate positively and significantly with the prevailing angiotensin II concentration. Plasma 11-deoxycorticosterone levels also rise. A possible explanation of this finding is that the presence of ACTH is necessary for a full corticosteroid response to angiotensin II and that infused angiotensin II inhibits ACTH secretion.

THE RENIN–ANGIOTENSIN SYSTEM AND TOTAL BODY SODIUM AND POTASSIUM IN HYPERTENSIVE WOMEN TAKING OESTROGEN–PROGESTAGEN ORAL CONTRACEPTIVES

Measurements of total body sodium and potassium, and of components of the renin–angiotensin–aldosterone system, were made in a group of women who developed hypertension while taking oestrogen–progestagen oral contraceptives. The results were compared with similar measurements made in age‐matched women with essential hypertension. Total body sodium and potassium were normal in both groups. Plasma renin‐substrate was significantly elevated in the women taking oral contraceptives, while concentrations of active renin were similar and normal in both groups. Thus plasma angiotensin II was significantly elevated in the pill users; overall the product of renin and renin substrate concentrations correlated significantly with angiotensin II. The rise in plasma angiotensin II in conjunction with normal total body sodium could therefore contribute to the increase in blood pressure induced by oestrogen–progestagen oral contraceptives.