George T. Griffing

Reversal of diuretic-induced secondary hyperaldosteronism and hypokalemia by enalapril (MK-421): A new angiotensin-converting enzyme inhibitor

The study reported here prospectively evaluated the prevention of diuretic-induced secondary hyperaldosteronism and hypokalemia by a converting enzyme inhibitor, enalapril (MK 421). Eighteen normal subjects were randomized into three groups: (1) a HCTZ group (hydrochlorothiazide (HCTZ) 50 mg/day); (2) a MK-421 group (MK-421 10 mg/day); and (3) a HCTZ + MK-421 group [HCTZ 50 mg/day plus MK-421 10 mg/day]. Following a five-day control and a 28-day treatment period, the HCTZ group demonstrated an attenuated but persistent secondary hyperaldosteronism and hypokalemia, the MK-421 group manifested a gradual decline in aldosterone secretion, and the HCTZ + MK-421 group had a delayed but effective correction of secondary hyperaldosteronism and hypokalemia at 28 days but not before. In conclusion, MK-421 reversed diuretic-induced secondary hyperaldosteronism and hypokalemia after 28 days of hydrochlorothiazide therapy. Therefore, converting enzyme inhibitors, such as enalapril, provide useful adjunctive therapy in diuretic-treated patients, but potassium supplementation may be required before the start of four weeks of combined therapy.

The Therapeutic use of a new Potassium-Sparing Diuretic, Amiloride, and a Converting Enzyme Inhibitor, Mk-421, in Preventing Hypokalemia Associated with Primary and Secondary Hyperaldosteronism

This presentation is a summary of our recent clinical studies on the therapeutic use of a new potassium-sparing diuretic, amiloride, and a converting enzyme inhibitor, MK-421, in preventing hypokalemia associated with primary and secondary hyperaldosteronism. These drugs are quite different in their physiologic action but they both may be effective in preventing the potassium depletion associated with increased aldosterone production. Amiloride, which blocks the sodium channels in distal renal tubular cells, was administered to 10 patients with primary hyperaldosteronism and five patients with Bartters syndrome (secondary hyperaldosteronism). Amiloride, at doses of 10-40 mg/day, increased mean plasma potassium levels in both primary hyperaldosteronism (3.2-4.5 mEq/L) and, to a lesser extent, in Bartters syndrome (2.5-3.6 mEq/L). The blood pressure fell slightly but significantly in primary hyperaldosteronism (171/112 vs 150/97 mm Hg) and remained unchanged in Bartters syndrome (116/80 vs 117/71 mm Hg). The plasma renin activity and plasma aldosterone rose in primary aldosteronism (PRA 0.39-2.21 ng A1/m1/h and PA 28.4-54.3 ng/d1); but in Bartters syndrome, the PRA declined (25.3-11.9 ng A1/m1/h) and the PA rose (19.5-38.0 ng/d1). The discrepancy in the PRA between primary aldosteronism and Bartters syndrome may be due to the effects of potassium repletion on suppressing renin and stimulating aldosterone; while in primary aldosteronism, a mild diuretic effect could explain the rise in PRA. In both of these disorders, despite the rise in plasma potassium levels, amiloride produced a counter-therapeutic rise in PA which could potentiate further potassium losses. Therefore, we undertook a study to evaluate the prevention of diuretic-induced hypokalemia and secondary hyperaldosteronism using a new converting enzyme inhibitor, MK-421. Eighteen normal subjects were randomized into three groups receiving either (1) hydrochlorothiazide alone (50 mg/day), (2) MK-421 alone (10 mg/day), or (3) hydrochlorothiazide (50 mg/day) plus MK-421 (10 mg/day). Although MK-421 did not prevent diuretic-induced hypokalemia or hyperaldosteronism in the first week, after that time hypokalemia was reversed and ASR returned to normal. In these studies, it therefore appears that while potassium-sparing diuretics may remain the medical mainstay in treating primary aldosteronism, new converting enzyme inhibitors such as MK-421 may be more effective in treating secondary hyperaldosteronism, since potassium levels can be normalized without increasing aldosterone secretion.

Temporal enhancement of renin‐aldosterone blockade by enalapril, an angiotensin‐converting enzyme inhibitor

Interruption of the renin‐aldosterone system with angiotensin‐converting enzyme inhibitors (CEI) should result in a low aldosterone secretion, but most investigators have measured aldosterone production only indirectly by plasma aldosterone (PA) levels or urinary metabolites. We evaluated the effects of CEI of the aldosterone secretion rate (ASR) and compared them with PA, urinary tetrahydroaldosterone (THA), plasma renin activity (PRA), and electrolyte balance in six normotensive subjects in a metabolic unit during a control period (5 days) and during administration of 10 mglday enalapril for 28 days. Our results demonstrated that (1) the ASR did not decline until after 1 wk of CEI therapy and this was reflected by a corresponding decline in the urine potassium:sodium ratio, (2) upright PA levels at day 1 declined, but supine PA levels were unchanged, (3) THA excretion remained essentially unchanged and the THA:ASR ratio rose progressively during therapy, (4) PRA rose and was maximal on day 3, but subsequently declined. In conclusion, enalapril‐induced hypoaldosteronism required several days to become demonstrable and this was not accurately assessed by PA or THA — possibly due, in part, to altered aldosterone metabolism. The simultaneous decline in both PRA and ASR could be due to a decrease in renin substrate. Caution is therefore warranted when assessing aldosterone secretion indirectly by either PA levels or urinary metabolites during CEI therapy.

The effects of hydrochlorothiazide on the renin-aldosterone system

Abstract This study prospectively evaluates the determinants and time course of diuretic-induced secondary hyperaldosteronism. Initial metabolic balance studies (days 5–7) and subsequent out-patient studies (days 8–28) were undertaken in 6 healthy subjects receiving hydrochlorothiazide 50 mg/day. Upon initiation of therapy, a discordance was observed between the natriuresis (maximal on day 1), the plasma renin activity (PRA) (maximal on day 3), and aldosterone secretion (maximal on day 7). The PRA increment correlated best with the urinary sodium deficit and the aldosterone increment correlated best with both PRA and urinary sodium deficit together. The secondary hyperaldosteronism persisted throughout the study, as determined by the aldosterone secretion rate, but the tetrahydroaldosterone excretion and the plasma aldosterone became normal within 3 wk of diuretic therapy. Hypokalemia also persisted throughout the study and was probably related to the secondary hyperaldosteronism since the urinary potassium deficit correlated with the aldosterone secretion but not the sodium excretion. In conclusion, (1) the urinary sodium deficit is the major determinant of diuretic-induced secondary hyperaldosteronism, (2) secondary hyperaldosteronism is the most important factor maintaining diuretic-induced hypokalemia, and (3) secondary hyperaldosteronism may be overlooked if only tetrahydroaldosterone excretion or plasma aldosterone levels are measured during diuretic therapy.

Biphasic Plasma Aldosterone Responses to Four Single‐Dose ACTH Regimens

Adenocorticotropic hormone (ACTH) administration increases cortisol synthesis but produces a biphasic aldosterone response. Some investigators believe that the hypercortisolism from prolonged ACTH administration is responsible for this aldosterone response. The present study evaluated the plasma aldosterone response to four acute single‐dose ACTH regimens that produced only a transient increase in plasma cortisol. Fourteen normal adult men received (1) 1–18 ACTH intravenous bolus (IV), (2) 1–18 ACTH intramuscular (IM), (3) 1–39 ACTH (IM), and (4) 1–24 ACTH (IV). The plasma aldosterone increased within one hour and tended to parallel the cortisol increment with all four ACTH regimens. With all of these ACTH regimens, the plasma aldosterone level decreased below placebo with 1–24 ACTH (IV) (24 hours), 1–39 ACTH (IM) (24 hours), and 1–18 ACTH (IV) and (IM) (48 hours) at a time when the cortisol had returned to normal. These results suggest that the delayed ACTH‐induced aldosterone inhibition production are not directly related to cortisol production and do not require prolonged ACTH administration. These observations are consistent with ACTH induction of a nonaldosterone mineralocorticoid, which is independently suppressing aldosterone production.

19-Nor-Corticosteroids in Experimental and Human Hypertension

Recent reports demonstrate that the 19-nor-corticosteroids (19-nor-DOC) are naturally-occurring substances in hypertensive animal models as well as man. Since some 19-nor-corticosteroids are potent mineralocorticoids, they may have a role in regulating systemic arterial pressure and be involved in the pathogenesis of hypertension. This paper reports the probable biosynthetic pathway, factors regulating the secretion or production, and measurement of 19-nor-DOC in man and the spontaneously hypertensive rat (SHR). These studies demonstrate (1) 19-nor-DOC is greatly influenced by ACTH and dexamethasone but less so by high and low salt diets in normotensive subjects; (2) 19-nor-DOC is greatly increased in some but not all hypertensive patients; (3) 19-nor-DOC is increased in prehypertensive SHR compared to WKY rats. The likelihood of metacorticoid hypertension and possible role of other 19-nor-corticosteroids, including 19-nor-progesterone, are discussed. It can be concluded that 19-nor-corticosteroids are synthesized by extra-adrenal tissues in biologically active quantities. They are increased and possibly pathogenetic in certain states of human and experimental hypertension.

An Adrenal Cyst Associated with 19-Nor-Deoxycorticosterone Excess and Low Renin Hypertension

Adrenal cysts are rare, but they have been disproportionately associated with hypertension. This report describes a hypertensive patient with increased levels of 19-nor-deoxycorticosterone (19-nor-DOC), a potent mineralocorticoid. The patient was a thirty year old man with hypokalemia, moderately severe hypertension, suppressed PRA, and low aldosterone secretion. Following surgical removal of a 10 cm adrenal cyst, the hypertension improved, the hypokalemia resolved, and the PRA and the aldosterone secretion normalized. Urinary 19-nor-DOC pre-op was elevated 4.6 microgram per day (normal less than 1.0 microgram/day and subsequently became normal at 0.7 microgram per day following surgery. The adrenal cyst was a fibrous walled structure containing mucinous straw-colored fluid. Pericystic adrenocortical tissue demonstrated increased 19-OH-DOC production (a 19-nor-DOC precursor) which may have been responsible for the 19-nor-DOC excess. We hypothesize that compressive adrenal damage from the cyst may produce a form of adrenal regeneration hypertension which is known to be associated with 19-nor-DOC excess.

Hormone-Secreting Tumors

Tumors may produce many classes of substances including hormones, enzymes, and biogenic amines. These substances are usually indistinguishable from their native counterparts and are normally synthesized and secreted in response to physiological stimuli. This discussion will focus on hormone-secreting tumors and their clinical presentations. For practical purposes, every hormone known to be physiologically secreted has been associated with ectopic tumor secretion. Peptide hormones are the most frequently produced ectopic hormones. Ectopic secretion of corticosteroids and thyroid hormones are extremely rare, probably because they require more sophisticated, compartmentalized enzymatic synthesis.

Adrenocortical Factors in Hypertension

T he adrenal cortex has long been implicated in the pathogenesis of hypertension. It has been noted that hypertension cannot be produced or sustained in the absence of adrenocortical tissue or dietary salt. Bilateral adrenalectomy without hormonal replacement or sodium chloride supplement is followed by a marked natriuresis with a sodium deficit and a decrease in vascular smooth muscle adrenergic sensitivity. This results in a progressive fall in blood pressure, culminating in circulatory collapse and death. Adrenal hyperactivity has been clearly associated with hypertension in three disorders: (1) Gushing’s syndrome, (2) primary aldosteronism, and (3) adrenocortical enzymatic defects (congenital adrenal hyperplasia). These three diseases combined, however, account for less than 1% of the cases of hypertension. In the remaining group of hypertensives, an adrenocortical etiology for this disease remains to be established.

Effect of peripheral sex steroid metabolism on pituitary gonadotropin reserve of women with hypothalamic amenorrhea

Women with hypothalamic amenorrhea without evidence of pituitary tumor were studied to ascertain (1) whether affected patients have altered pituitary sensitivities and reserves to a constant gonadotropin-releasing hormone (GnRH) infusion and (2) whether altered sex steroid metabolism contributed to altered pituitary synthesis or secretion of gonadotropin. Women with hypothalamic amenorrhea displayed abnormal gonadotropin reserves without altered pituitary sensitivity to GnRH. Those altered reserves may have reflected, abnormally low estradiol levels, which directly or indirectly affected, pituitary gonadotropin synthesis. However, sex steroid metabolism or normally cycling and amenorrheic women were not significantly different. The ovaries of both groups of patients were equally reactive to stimulation with endogenous gonadotropin, as reflected by circulating estradiol levels attained at the end of the GnRH infusion.