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Biomedical subjects

G T Griffing

Publications and source records attributed to G T Griffing.

53 records · Page 3Linked to original sources
PubMed1983

19-nor-deoxycorticosterone excretion in primary aldosteronism and low renin hypertension.

Nonaldosterone mineralocorticoids, such as deoxycorticosterone (DOC) and 18-hydroxy-DOC, have been reported to be elevated in some patients with primary aldosteronism (PA). Since DOC is a probable precursor of a more potent mineralocorticoid, 19-nor-deoxycorticosterone (19-nor-DOC), this study evaluated urinary free (UF) 19-nor-DOC excretion in 6 patients with PA and compared the results to those from 11 patients with low renin hypertension (LRH) and 7 normotensive subjects. PA was due to either an aldosterone-producing adenoma (APA; 4 patients) or bilateral adrenal hyperplasia (2 patients) diagnosed by adrenal venous catheterization or surgery. Compared to LRH subjects, patients with PA had a higher mean blood pressure (137 +/- 9 vs. 114 +/- 3 mm Hg), a lower plasma potassium level (3.1 +/- 0.2 vs. 3.9 +/- 0.1 meq/1) and greater renin suppression (0.3 +/- 0.1 vs. 0.6 +/- 0.1 ng angiotensin I/ml . h). UF 19-nor-DOC levels were elevated in PA subjects compared to those in normotensives (3,716 +/- 1,517 vs. 428 +/- 112 ng/day) but not compared to those in LRH patients (1,237 +/- 471). Two patients with APA had distinctly elevated UF 19-nor-DOC levels (11,137 and 7,744 ng/day), but another APA patient had the lowest value (305 ng/day). UF 19-nor-DOC positively correlated with the aldosterone secretion rate in PA (r = 0.75) but not LRH subjects. In conclusion, this study demonstrates that patients with PA may have elevated levels of UF 19-nor-DOC which are proportional to the aldosterone excess and could be a contributing factor to the hypertension, hypokalamia, and excess mineralocorticoid activity of this disease.

Adenoma↗
PubMed1983

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 Bartter's 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 Bartter's 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 Bartter's 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 Bartter's 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 Bartter's 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.

Adult↗
PubMed1982

Primary empty sella syndrome, ACTH hypersecretion, and normal adrenocortical function. Report of two cases.

Although the primary empty sella syndrome (PESS) is associated with normal endocrine function or subtle pituitary insufficiency, pituitary hormone hypersecretion associated with PESS has also been recognized. ACTH hypersecretion and primary empty sella syndrome have previously been reported in patients with either Cushing's disease or Addison's disease. This report describes two unique patients with ACTH hypersecretion, primary empty sella syndrome, and normal cortisol dynamics. The investigators speculate that this association may have resulted from infarction of hyperplastic adenohypophyseal corticotrophes due to production of an ACTH peptide with reduced biologic activity. These two cases emphasize that primary empty sella syndrome may be associated with ACTH hypersecretion and normal adrenocortical function.

Adrenal Cortex↗
PubMed1982

Amiloride in Bartter's syndrome.

Hypokalemia in Bartter's syndrome (BS) is often difficult to correct despite all measures. Amiloride is a new potassium-sparing diuretic that blocks sodium channels in distal renal tubular cells, independent of aldosterone. Four patients with BS were studied, in an outpatient clinic, while on amiloride therapy (10 to 40 mg/day). Before receiving amiloride the patients were treated with combinations of prostaglandin synthetase inhibitors, potassium-sparing diuretics, and potassium supplements. After a baseline observation period, the potassium-sparing diuretics were discontinued and amiloride therapy was instituted. Cumulative mean plasma potassium level rose after amiloride (0.5 mEq/l; P less than 0.05). The mean plasma potassium levels in three of the patients rose and one of these patients eventually became normokalemic. There were very few adverse reactions and none could be attributed to amiloride alone. Amiloride may be a useful and safe drug for the treatment of the hypokalemia of BS.

Adult↗
PubMed1982

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 mg/day 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.

Adult↗
PubMed1982

Amiloride in primary hyperaldosteronism.

Amiloride is a potassium-sparing diuretic used in spontaneous and diuretic-induced hypokalemia. The effect of amiloride was studied prospectively in 12 patients with primary hyperaldosteronism. Four patients had unilateral adrenal adenomas and eight had bilateral adrenal hyperplasia. All patients were hypertensive and their mean plasma potassium levels were low. Amiloride, 10 to 40 mg daily, was given for 6 mo. Mean plasma potassium levels rose (0.96 mEq/l, P less than 0.001) and remained normal throughout the study without potassium supplementation. Mean blood pressure was lowered by amiloride (22/10 mm Hg, P less than 0.001) but normotension required concomitant antihypertensive therapy in most patients. No significant adverse clinical or laboratory experiences could be directly attributed to amiloride therapy. There was no correlation between the response to therapy and the plasma aldosterone levels, aldosterone secretion rate, or presence of a unilateral adrenal adenoma. Our study demonstrates the efficacy of amiloride in the correction of hypokalemia and amelioration of hypertension in primary hyperaldosteronism.

Adult↗
PubMed1982

Altered fractional tetrahydroaldosterone excretion during pharmacological blockade and activation of the renin-aldosterone system.

Tetrahydroaldosterone (THA) is the principal metabolite and generally a good index of aldosterone secretion. This study undertakes the evaluation of the aldosterone secretion rate (ASR) and excretion of THA during pharmacological blockade and activation of the renin-aldosterone system. THA was measured by a simplified RIA and compared to ASR over a period of 28 days in 18 normotensive volunteers receiving either 1) a diuretic [hydrochlorthiazide (HCTZ), 50 mg/day], 2) an angiotensin-converting enzyme inhibitor (MK-421, 10 mg/day), or 3) combined therapy [HCTZ (50 md/day) plus MK-421 (10 mg/day)] in a metabolic unit on a controlled diet. Results of this study at 28 days indicate that 1) HCTZ, while producing secondary hyperaldosteronism, lowered the fractional THA excretion (defined as THA/ASR) (from 0.51 to 0.33; P less than 0.05); 2) MK-421 produced hypoaldosteronism and a slight increase in the THA/ASR (from 0.43 to 0.53; 0.05 less than P less than 0.01); 3) combined HCTZ and MK-421 resulted in a normalization of both aldosterone secretion and THA/ASR (from 0.51 to 0.50). In conclusion, HCTZ decreases the THA/ASR whereas MK-421 tends to increase it. Combined administration of HCTZ and MK-421 restores the THS/ASR to normal. Therefore, the determination of THA excretion can be an inaccurate index of aldosterone secretion when measured during either pharmacological blockade or activation of the renin-aldosterone system.

Adult↗
PubMed1982

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.

Adrenal Cortex↗
PubMedDate not supplied

The effect of amiloride on the renin-aldosterone system in primary hyperaldosteronism and Bartter's syndrome.

Amiloride is a potassium-sparing diuretic which has been advocated for the treatment of hypokalemic disorders. This agent was prospectively evaluated in hypokalemic patients with either primary hyperaldosteronism (ten patients) or Bartter's syndrome (five patients). Vital signs, electrolytes, and ambulatory hormonal studies were assessed during a control period and treatment period with amiloride therapy at 10 to 40 mg/day over two to 24 weeks. During the treatment period the systolic and diastolic blood pressure fell significantly in primary hyperaldosteronism but remained unchanged in Bartter's syndrome. In summary, amiloride therapy (1) increased plasma potassium in both diseases; (2) increased plasma renin activity (PRA) in primary hyperaldosteronism but decreased PRA in Bartter's syndrome; and (3) increased plasma aldosterone in both diseases. Since potassium is known to suppress renin production and stimulate aldosterone secretion, correction of the hypokalemia in this study probably accounts for the decreased PRA and increased plasma aldosterone observed in Bartter's syndrome. The increase in both PRA and plasma aldosterone in primary hyperaldosteronism, however, may be evidence of either a direct activation of the renin-aldosterone system or, alternatively, may be due to the mild natriuretic effects of amiloride.

Adult↗
PubMedDate not supplied

Biphasic plasma aldosterone responses to four single-dose ACTH regimens.

Adrenocorticotropic 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.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

19-Nor-corticosteroids in health, in hypertensive states in humans including 17 alpha-hydroxylase deficiency and in the spontaneously hypertensive rat (SHR).

Since Gomez-Sanchez isolated 19-nor-DOC from the urine of rats with adrenal regeneration hypertension, we have demonstrated that 19-nor-DOC is a naturally occurring substance in other hypertensive animal models as well as in man. Certain 19-nor-corticosteroids are potent mineralocorticoids and may have a role in the regulation of systemic arterial blood pressure and could be involved in the pathogenesis of hypertension. We have previously demonstrated that 19-nor-DOC is greatly influenced by ACTH and dexamethasone but less so by high and low sodium diets in normotensive human subjects and, that 19-nor-DOC is greatly increased in some but not all hypertensive patients. Studies by Gomez-Sanchez and by our own group have shown that 19-nor-DOC is not secreted by the adrenal gland directly but rather the adrenal secretes a 19-oic-DOC precursor which is converted peripherally by extra-adrenal tissues. Biosynthesis of 19-oic-DOC has been demonstrated to occur by prior hydroxylation of DOC and progressive oxydation to the acidic form. More recently it has been shown that 19-nor-DOC is excreted in the urine of mammals as a free unconjugated compound but to a greater extent as a 21-monoglucuronide. In the studies described we will report the quantification of urinary excretion of 19-nor-DOC as a free and unconjugated compound and also as a 21-monoglucuronide in patients with hypertension as well as in patients with specific forms secondary hypertension such as that found in 17 alpha hydroxylase deficiency which is a syndrome associated with hypogonadism, hypertension and hypokalemia. In this disorder of cortisol biosynthesis adlosterone production, is not elevated and therefore other known and unknown mineralocorticoid account for the excess in mineralocorticoid activity observed. Our study demonstrated that 19-nor-DOC, the potent hypertensinogenic mineralocorticoid was elevated in both plasma and urine from a young woman with 17-alpha hydroxylase deficiency. This patient was examined for various corticosteroids in basal and ACTH-stimulated, dexamethasone-suppressed and cortisol-treated states. In the basal state, urinary and plasma 17 alpha-hydroxy corticosteroids were decreased but the 17-deoxycorticosteroids were extremely elevated including corticosterone, 18-hydroxy corticosterone, tetrahydro corticosterone, tetrahydro-deoxycorticosterone and 18 hydroxy-tetrahydro-DOC. Both basal urinary free 19-nor-DOC was markedly elevated both by HPLC and radioimmunoassay measurements.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Glands↗
PubMedDate not supplied

Relationship of 19-nor-deoxycorticosterone to other mineralocorticoids in low-renin hypertension.

A number of mineralocorticoids have been proposed as etiologic factors in low-renin hypertension. In this study, urinary free 19-nor-deoxycorticosterone (UF 19-nor-DOC) was compared to other mineralocorticoids--aldosterone, deoxycorticosterone (DOC), and 18-OH-DOC, in 11 low-renin hypertensive patients on a controlled diet in a metabolic unit. Results demonstrated that both UF 19-nor-DOC and tetrahydro-DOC (TH-DOC) excretion were elevated (2086 +/- 926, nl = 339-579 ng/day, and 18 +/- 7, nl = 5-15 mcg/day, respectively), and positively correlated (r = 0.95). Neither 18-OH-DOC nor aldosterone secretion rates were elevated, and neither of these hormones correlated with UF 19-nor-DOC, with exception of the supine plasma aldosterone (SPA) (r = 0.86). In conclusion, both UF 19-nor-DOC and TH-DOC were increased and positively correlated in the present series of hypertensives. This association is possibly indicative of a precursor-product relationship between DOC and 19-nor-DOC. 19-Nor-DOC, furthermore, correlated with supine plasma aldosterone (SPA), which could, in part, reflect their shared adrenocorticotropic hormone (ACTH) dependence.

18-Hydroxydesoxycorticosterone↗
PubMedDate not supplied

Converting-enzyme inhibitor administration lowers urinary free 19-nor-deoxycorticosterone levels.

19-Nor-deoxycorticosterone (19-nor-DOC) is a human mineralocorticoid. The regulation of its secretion is poorly understood, as renin angiotensin II (ANG II) stimulation has minimal effects on 19-nor-DOC. This study sought to determine if ANG II inhibition would decrease 19-nor-DOC production. Six normal subjects on fixed electrolyte intake were admitted to a metabolic unit. After a 5-day control period to establish electrolyte balance, enalapril, p.o., 10 mg/day, was administered for 28 days. This treatment resulted in ANG II inhibition, which was reflected by a rise in plasma renin activity, a blunting of the postural plasma aldosterone increment, and a decrease in aldosterone secretion rate (ASR). Levels of urinary free (UF) 19-nor-DOC progressively decreased from 294 +/- 108 ng/day on Day 0 to 164 +/- 70 on Day 3, 141 +/- 62 on Day 7, 101 +/- 38 on Day 14, 68 +/- 18 on Day 21, and 106 +/- 31 on Day 28. The decrease in 19-nor-DOC levels was synchronous with the fall in ASR (R = 0.94, n = 5, p less than 0.005), but it was of greater magnitude (71% decrease in 19-nor-DOC levels versus 41% decrease in ASR). In addition, the decrease in 19-nor-DOC levels correlated with a fall in urinary potassium and an increase in both urinary sodium and chloride (R = 0.68, -0.79, -0.87 respectively; n = 6, p less than 0.05). The fall in ASR, on the other hand, was not significantly correlated with the changes in these urinary electrolyte levels (R = 0.65, 0.64, 0.57 respectively; n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Unconjugated and conjugated urinary 19-nor-deoxycorticosterone glucosiduronate. Elevated levels in essential hypertension.

The mineralocorticoid 19-nor-deoxycorticosterone (19-nor-DOC) is present in the urine of rats and humans in unconjugated and conjugated forms. This study sought to compare levels of unconjugated and conjugated 19-nor-DOC glucosiduronate in essential hypertensive subjects. The essential hypertensive and normal subjects were admitted to a metabolic unit, and plasma and urine were collected at fixed intervals on a fixed-electrolyte intake (Na+, 128 mEq/day, K+, 80 mEq/day). The 19-nor-DOC was purified by chromatography and measured by radioimmunoassay. Unconjugated urinary 19-nor-DOC was elevated in essential hypertensive subjects (195 +/- 21 [SE] ng/day; n = 21) compared with levels in normal subjects (118 +/- 30 [SE] ng/day; n = 13, p less than 0.05). Two essential hypertensive subjects had very high levels (673, 729 ng/day), while levels in seven essential hypertensive subjects were below 118 ng/day. Conjugated 19-nor-DOC glucosiduronate also was elevated in essential hypertensive subjects (950 +/- 88 [SE] ng/day; n = 8) compared with levels in normal subjects (680 +/- 90 [SE] ng/day; n = 5). Seven of eight essential hypertensive subjects had levels greater than 680 ng/day. The unconjugated and conjugated urinary 19-nor-DOC glucosiduronate levels were positively correlated in both of these groups (rho = 0.82, p less than 0.01). Other test results including plasma renin activity, plasma aldosterone levels, aldosterone secretion rates, and plasma and urine electrolyte levels were not different between groups. These results indicate that essential hypertensive subjects have increased 19-nor-DOC excretion, which is reflected by increases in both unconjugated and conjugated glucosiduronate forms.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Hyperplasia, Congenital↗