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Biomedical subjects

R G Dluhy

Publications and source records attributed to R G Dluhy.

At least 73 records · Page 4Linked to original sources
PubMed1980

Increase in prostaglandins during converting enzyme inhibition.

1. Because changes in the plasma concentration of angiotensin II and bradykinin appear inadequate to account completely for the hypotensive response to captopril, we measured changes in plasma prostaglandins in response to increasing doses of captopril in nine supine normal male subjects studied on both a high (200 mol/l) and low (10 mol/l) sodium intake. 2. On both the high and low sodium diets, captopril induced significant (P < 0.01) increments in the 13,14-dihydro-15-keto metabolite of the vasodilatory prostaglandin E2, which correlated significantly with the fall in blood pressure (P < 0.0001). 3. No significant changes were noted in the plasma levels of 6-keto-prostaglandins F1 alpha or thromboxane B2, the stable products of prostacyclin and thromboxane A2 respectively.

Adult↗
PubMed1980

Captopril-induced changes in prostaglandin production: relationship to vascular responses in normal man.

Captopril is a potent hypotensive agent whose efficacy has hitherto been attributed to its ability to alter either angiotensin II formation or kinin degradation. Our purpose was to examine captopril's acute effect on prostaglandin production, because changes in neither the renin-angiotensin nor the kallikrein-kinin systems appear adequate to account for the fall in arterial pressure. The plasma levels of angiotensin II, kinins, and prostaglandins were determined in response to increasing doses (5, 12.5, and 25 mg) of captopril and these responses were compared with the change in arterial pressure observed in nine supine normal male subjects studied on both a high (200 meq) and low (10 meq) sodium intake.Captopril significantly (P < 0.01) increased the levels of the 13,14-dihydro-15-keto metabolite of prostaglandin E(2) (PGE(2)-M), a potent vasodilator, with similar responses being observed on both a high and a low sodium intake. No significant changes in the plasma levels of 6-keto-prostaglandin F (1)alpha, or thromboxane B(2), the stable products of prostacyclin and thromboxane A(2), respectively, occurred. The depressor response to captopril correlated with the change in PGE(2)-M (r = 0.52, t = 5.44, P < 0.0001). On the other hand, although significant (P < 0.02) decrements in angiotensin II and increments in plasma kinins accompanied the hypotensive response in sodium-restricted subjects, in sodium-loaded subjects where the renin-angiotensin system was suppressed, no change in angiotensin II, and only a modest change in kinins was noted, even though significant (P < 0.01) decrements in diastolic blood pressure occurred (-10+/-2 mm Hg).Thus, changes in depressor prostaglandin production can better account for the hypotensive response to captopril, thereby extending to yet another vasoactive system an influence by this class of drugs and providing a new approach to dissecting the abnormality in the control of vascular tone in patients with hypertension.

Adult↗
PubMed1980

Primacy of the renin-angiotensin system in mediating the aldosterone response to sodium restriction.

The primacy of angiotensin II as the mediator of the adrenal's response to sodium restriction is controversial. We administered the oral converting enzyme inhibitor, captopril (SQ 14225), to test whether reduction of angiotension II generation for 26 h in sodium-restricted subjects would lower plasma aldosterone levels to values observed in subjects on a high sodium intake. Accordingly, plasma angiotensin II and aldosterone levels were measured in nine recumbent normal subjects on high (200 meq) and low (10 meq) sodium intakes and low sodium intake with captopril (12.5--25 mg four times a day for 26 h). Captopril reduced the sodium-restricted angiotensin II levels from 31 +/- 6 to 13 +/- 2 pg/ml, which was indistinguishable from that measured on the high sodium intake (11 +/- 2 pg/ml). Concomitantly, aldosterone levels were reduced from 25 +/- 4 to 7 +/- 1 ng/dl, which was similar to the high sodium value (8 +/- 1 ng/dl). There were no significant changes in serum sodium, cortisol, or potassium at the three sampling times. Thus, the complete suppression of the sodium-restricted levels of both angiotensin II and aldosterone into the high sodium range by captopril provides strong support for the hypothesis that the renin-angiotensin system is the prime mediator of the adrenal's response to sodium restriction.

Adult↗
PubMed1979

The adrenal receptor for angiotensin II is altered in essential hypertension.

To determine the mechanism underlying altered adrenal responsiveness in patients with essential hypertension, the renin-angiotensin-aldosterone axis was assessed in normotensive and hypertensive subjects using three pharmacological probes: SQ 20881, a converting enzyme inhibitor; saralasin, a competitive angiotensin antagonist with prominent agonist properties; and angiotensin itself. All subjects were studied while supine and in balance on a 10 meq Na/100 meq K intake. The decrement in plasma aldosterone with SQ 20881 in 26 hypertensive subjects (15+/-3 ng/dl) was normal (13+/-4 ng/dl), suggesting that the altered adrenal responsiveness in hypertensives is not because of a change in a postreceptor event or in the relative contribution of angiotensin to the control of aldosterone secretion. Saralasin at a dose (0.1 mug/kg per min) that reduced aldosterone levels in all normals produced a normal aldosterone decrement (14+/-3 ng/dl) in 19 patients with renovascular hypertension (12+/-4 ng/dl). The same dose, however, had no net effect on plasma aldosterone levels in 70 patients with normal or high renin essential hypertension (-1+/-1 ng/dl) despite identical metabolic balance and control renin and angiotensin levels. The altered response could be explained by an agonist effect, aldosterone rising in 45 of the essential hypertensives. There were no significant differences between normal and abnormal responders in pre- and postcortisol, -potassium, -renin and -angiotensin concentrations. Angiotensin was infused (0.1-3 ng/kg per min) in 15 patients with normal renin essential hypertension, previously studied with saralasin. A probit transformation defined the dose required to induce a 50% increase in aldosterone (ED50). In the patients in whom aldosterone rose with saralasin, the dose required to induce a 50% increase was significantly greater (P < 0.001) than in those in whom aldosterone fell normally (1.02+/-0.06 [SD] vs. 0.38+/-0.07 ng/kg per min). Vascular responses were similar in the various groups. We conclude that altered adrenal responsiveness to angiotensin in some essential hypertensive patients is secondary to a change in the interaction of angiotensin with its adrenal receptor.

Adrenal Glands↗
PubMed1979

Abnormal adrenal responsiveness and angiotensin II dependency in high renin essential hypertension.

Adrenal responsiveness to angiotensin II (AII) and the diastolic blood pressure responses to saralasin were studied in 19 patients with high renin essential hypertension (HREH) on a 10-meq Na(+)/100 meq K(+) diet. The increment in plasma renin activity (PRA) between supine and upright positions was used as an estimate of the acute stimulation of the adrenal gland by endogenous AII; the normal increment in plasma aldosterone divided by the increment in PRA was >3.8. 7 of 19 had abnormal upright posture responses with significantly greater mean PRA increments (24+/-6 ng/ml per h) and significantly smaller plasma aldosterone increments 47 +/- 16 ng/dl) (P < 0.036) compared to the increments observed in HREH patients with normal adrenal responsiveness (PRA = 15 +/- 1 ng/ml per h; plasma aldosterone = 87 +/- 17 ng/dl). When AII was infused at doses of 0.1-3 ng/kg per min, only patients with normal posture responses had normal plasma aldosterone increments; plasma aldosterone levels failed to significantly increase even at the highest infusion rate in the patients with the abnormal upright posture responses. The AII competitive inhibitor, saralasin (0.3-30 mug/kg per min) was then infused to study the occurrence of angiotensinogenic hypertension in both HREH subgroups. The mean decline in diastolic blood pressure to saralasin in the subnormal adrenal responsive patients (-15 +/- 3 mm Hg) was significantly greater than in the normal adrenal responsive group (-3 +/- 2 mm Hg) (P < 0.02).It is concluded that patients with HREH are not a homogeneous population; approximately one-third have AII-dependent hypertension. In these patients, the mechanism responsible for the elevated renin and blood pressure could be a compensatory increase secondary to decreased adrenal responsiveness to AII. In the remainder, the high PRA levels have little, if any, causal role in the pathogenesis of the hypertension but could reflect a marker of other pathophysiologic processes.

Adrenal Cortex↗
PubMed1978

Failure of renin suppression by angiotensin II in hypertension.

Angiotensin II was infused at rates varying from 0.1 to 10 ng/kg per minute into 49 subjects with hypertension and 26 normotensive subjects and changes in blood pressure, plasma angiotensin II, and plasma renin activity (PRA) were determined after 20 and 30 minutes at each dose. Similar dose-related increases in angiotensin II and blood pressure occurred with a threshold of 1 ng/kg per minute in the normotensive and hypertensive subjects. Whereas angiotensin II induced a significant, dose-related decrement in renin activity in the normotensive subjects, with a threshold of 1.0 ng/kg per minute, no significant change in renin activity occurred in either the normal-renin or high-renin hypertensive subjects. In a separate study, nine normotensive and six hypertensive sodium-restricted subjects were given a converting enzyme inhibitor, SQ 20881, 30 microgram/kg. Despite a significantly greater fall in blood pressure (P less than 0.006) and angiotensin II concentration (P less than 0.045) in the hypertensive subjects, they did not have a greater rise in plasma renin activity. We conclude that angiotensin II reduces renin release in normal man at infusion rates that yield plasma angiotensin II levels within the physiological range but has a strikingly reduced influence on renin release in hypertension. In high-renin hypertension due to renal artery stenosis or nephrosclerosis, renin release is presumed to be relatively autonomous because of a dominant, intrarenal mechanism. The mechanism in normal-renin essential hypertension is not clear, but the abnormality could well be related to the pathogenesis of the hypertension.

Adult↗
PubMed1978

Corticosteroids: clinical pharmacology and therapeutic use.

The widespread use of corticosteroids in clinical practice emphasises the need for a thorough understanding of their metabolic effects. In general, the actions of corticosteroids on carbohydrate, protein, and lipid metabolism result in increased hepatic capacity for gluconeogenesis and enhanced catabolic actions upon muscle, skin, lymphoid, adipose and connective tissues. Because of the morbidity associated with steroid therapy, the clinician must carefully consider in each case the gains that can reasonably be expected from corticosteroid therapy versus the inevitable undesirable side effects of prolonged therapy. Thus, it is important to remember that the enhanced anti-inflammatory activity of the various synthetic analogues of cortisol is not dissociated from the expected catabolic actions of glucocorticoid hormones. Replacement therapy with physiological doses of cortisol in primary or secondary adrenal insufficiency is intended to simulate the normal daily secretion of cortisol. Short term, high dose suppressive glucocorticoid therapy is indicated in the treatment of medical emergencies such as necrotising vasculitis, status asthmaticus and anaphylactic shock. With improvement of the underlying disorder, the steroid dosage can be rapidly tapered and then discontinued over a 2 to 3 day period. Long term, high dose suppressive therapy is often commonly used to treat certain diseases (see sections 4.7.2 and 4.7.3). In this setting, suppression of the hypothalamic-pituitary-adrenal axis may persist for as long as 9 to 12 months following steroid withdrawal if steroid doses are administered in the supraphysiological range for longer than 2 weeks. In general, higher doses, longer duration of usage, and frequent daily administration are all correlated with the severity of pituitary ACTH suppression. When steroid therapy is to be withdrawn, gradual tapering of the dosage is necessary; the steroid dosage should also be given as a single morning dose if possible. Rapid or total withdrawal of the steroid therapy may be associated with exacerbation of the underlying disease or with a steroid withdrawal syndrome. An additional important point to remember in any withdrawal programme is that the steroid dosage should be appropriately increased for an exacerbation of the underlying disease or for intercurrent major stress. Alternate day therapy is recommended as a steroid maintenance programme for patients requiring high dose glucocorticoid therapy over a prolonged period of time. Thus, it is usually employed to maintain a therapeutic benefit which had previously been extablished by daily steroid treatment. Complications resulting from corticosteroid therapy include: (1) proximal muscle weakness; (2) osteopenia; (3) unmasking of latent diabetes mellitus; (4) sodium retention and/or elevation of mean arterial blood pressure; (5) adverse psychiatric reactions; (6) development of glaucoma; and (7) reactivation of latent infections (such as tuberculosis).

Adrenocorticotropic Hormone↗
PubMed1978

Adrenal function testing.

Glucocorticoid stimulation and suppression tests are essential to the definitive diagnosis of diseases of the hypothalamic-pituitary-adrenal axis, because they document abnormal physiologic control of hormonal secretion. Similarly, diseases of the renin-angiotensin-aldosterone axis are diagnosed by mineralocorticoid stimulation and suppression testing. [Ed. Note: See Moore TJ, Williams GH: Adrenal causes of hypertension, in this issue.] Unlike tests of glucocorticoid function, testing of the renin-angiotension-aldosterone system is more complicated, because knowledge of posture and dietary sodium are necessary to interpret the results. However, measurement of the tropic hormone renin and plasma levels of aldosterone can be accurately made, allowing precise definition of this system. Errors are most commonly encountered when dynamic tests of cortisol output are performed in patients taking medications that may interfere with the assays or with the metabolism of the administered compounds, such as dexamethasone or metyrapone. Abnormal, spurious values may also be obtained in some individuals who do not have adrenocortical hyperfunction if they are very obese or if testing is performed in a setting of clinical stress. Careful attention to these pitfalls will avoid errors and allow the clinician to arrive at the correct diagnosis.

17-Hydroxycorticosteroids↗
PubMed1977

Partial 11- and 21-hydroylase deficiencies in hirsute women.

Thirty-one women with idiopathic hirsutism were evaluated for partial 11- and 21-hydroxylase adrenocortical enzyme deficencies. Twenty-four hour urine collections for 17-ketosteroids, 17-hydroxycorticoids, tetrahydro compound S (THS), and -pregnanetriol were obtained basally and following a continuous 24 hours infusion of alpha 1-24 ACTH (cosyntropin). The results were compared to those in eight normal, nonhirsute women studied under identical conditions. Normal control subjects and 18 of 31 hirsute female patients (Group I) showed similar small increments in the excretion of THS and pregnanetriol following the infusion of cosyntropin. Thirteen hirsute women (Group II) showed cosyntropin-stimulated increments in either THS and/or pregnanetriol that were significantly greater than the mean response of the control group. The cosyntropin-stimulated increments in 17-ketosteroid excertion and basal sebum production rates were also significantly greater in Group II. The results are consistent with partial II - and/or 21-adrenocortical hydroxylase deficiencies in some hirsute women whose condition would have previously been designated as "idiopathic." Thus, prolonged ACTH stimulation testing may identify patients who might benefit from glucocorticoid suppression therapy.

17-Hydroxycorticosteroids↗
PubMed1977

Effect of simultaneous potassium and saline loading on plasma aldosterone levels.

To assess the relative importance of the renin-antiotensin system and potassium in the acute regulation of aldosterone secretion in the salt depleted state, normal subjects were infused with an asotonic saline solution containing potassium chloride (KCl) and the responses compared to the infusions of isotonic saline (500 ml/h) and KCl alone (20 mEq K+/h). Subjects were studied recumbent in balance on a 10 mEq sodium/100 mEq potassium diet. The rates of infusing saline and potassium were selected to produce comparable but opposite effects on the levels of plasma aldosterone. As plasma renin activity (PRA) declined and plama potassium increased during the combined saline-KCl infusions, plasma aldosterone levels appeared to be the arithmetic sum of the changes in these parameters. In fact, the calculated changes in aldosterone levels per unit change in PRA or potassium from each infusion alone, correlated well with the observed levels, further supporting an additive relationship. These data support the concept that in the salt depleted state the renin-angiotensin system and potassium are equally important in the acute regulation of plasma levels of aldosterone.

Aldosterone↗
PubMed1977

Relationship between aldosterone and bradykinin.

To assess relationships between plasma bradykinin and the individual elements of the renin-angiotensin-aldosterone system 11 normal subjects and five subjects with adrenal insufficiency were studied on an intake of 200 mEq sodium/100 mEq potassium. In adrenal insufficiency subjects, plasma bradykinin did not change when angiotensin II levels were increased by an infusion rate of 3 ng/kg per min for 30 minutes; plasma aldosterone remained undetectabel. In normal subjects, angiotensin II at 3 ng/kg per min or potassium at 20 mEq/hour infused intravenously for 2 hours both significantly increased plasma aldosterone levels, yet neither stimulus altered plasma bradykinin. Thus, acute elevations in angiotensin II and plasma aldosterone were not associated with changes in the levels of plasma bradykinin. In five additional normal subjects on an intake of 10 mEq sodium/100 mEq potassium, a threshold dose of converting enzyme inhibitor (SQ 20881) at 30 microng/kg was given intravenously. Five minutes after administration of the drug, blood pressure and plasma angiotensin II levels had significantly declined and plasma bradykinin levels had significantly increased (P is less than 0.02). Within 10-20 minutes, however, all had returned to control accompanied by a sustained increase in plasma renin activity, and a decrement in plasma aldosterone. Plasma renin activity, which had increased by more than 2-fold after the administration of the converting enzyme inhibitor, remained elevated until the completion of the study at 320 minutes. Eighty minutes after beginning the infusion, plasma aldosterone levels returned to control. Thus, the results suggest that plasma bradykinin correlates more closely with acute changes in plasma renin activity (and angiotensin I) than plasma aldosterone or angiotensin II, suggesting a role for converting enzyme in the regulation of both plasma renin activity and plasma bradykinin. Furthermore, the declines in blood pressure observed with converting enzyme inhibition may be attributable to both changes in plasma angiotensin II and plasma bradykinin concentrations. However, it is emphasized that these short-term studies may not reflect the role of bradykinin in the long-term control of blood pressure.

Adrenal Insufficiency↗