William R. Wilson

Cardiorenal hemodynamic effects of ethacrynic acid

Abstract Ethacrynic acid, studied in normal subjects as well as in patients with hypertension or edema, reduces glomerular filtration rate slightly and has little or no effect on estimated renal plasma flow while decreasing filtration fraction. It causes a prompt increase in the volume of urine, with the excretion of 8 to 19 per cent of sodium filtered 30 minutes after intravenous administration. It also produces a reduction in urine pH, as well as a profuse diuresis of chloride and a lesser diuresis of potassium. With large doses there is a slight increase in the excretion of uric acid, whereas with lower doses there is retention of uric acid. In well-hydrated patients, the clearance of free water is reduced when osmotic clearance is maximal. The systemic hemodynamic effects of the drug are not striking. In our study, cardiac index and right atrial pressure fell after acute administration, whereas heart rate and total systemic resistance increased slightly. Although there was a tendency for blood pressure to fall in patients treated with ethacrynic acid in both the acute and subacute studies, the post-drug values were not significantly different from control values. The renal and systemic hemodynamic effects of the drug are best explained by a reduction in the plasma or circulating blood volume caused by the profuse diuresis of electrolytes and, to a lesser extent, water. The renal effects which we observed could be explained on the basis of a reduction in the reabsorption of sodium in the ascending loop of Henle or by an effect of ethacrynic acid on the proximal and distal tubular sodium reabsorption sites. Ethacrynic acid increased the osmolality of the urine in one patient with diabetes insipidus slightly more than did chlorothiazide in similar studies. Ethacrynic acid is a potent diuretic capable of causing massive loss of electrolytes and water. No adverse effects on hemopoietic, hepatic, or central-nervous-system function were noted in this short-term study.

The acute hemodynamic effects of α-methyldopa in man☆

NEW approaches to the treatment of hypertension have developed rapidly in the past decade. The recent serendipitous discovery by OATES, GILLESPIE, UNDENFRIEND and SJOERDSMA [2] of the anti-hypertensive effect in man of the decarboxylase inhibitor, a-methyl-3,4-dihydroxy-DL-phenylalanine (a-methyldopa) has intensified the interest in the role of aromatic amines in human hypertension. Catecholamines have long been implicated as important factors in the regulation of sympathetic nervous system activity and many of the currently used depressor drugs, such as the RauwoEa alkaloids, guanethidine and bretylium, act by selective interference with these pathways. Initially, the seemingly logical hypothesis was formulated that a-methyldopa inhibited the formation of dopamine from dopa and the resultant depletion of catecholamines in both the central and peripheral sympathetic nervous systems, in turn produced the blood pressure lowering effect. Subsequent studies have demonstrated difficulties in correlating the effect of the drug on catecholamine levels with the antihypertensive response in animals [3]. Alpha-methyldopa is the racemic formof a-methyl-3,4-dihydroxy-DL-phenylalanine. The levorotatory form of the drug has been designated methyldopa (Aldomet); this L-isomer possesses the decarboxylase inhibitory activity and also accounts for the hypotensive effects [3,4]. Chemical studies in patients which showed that the &cornpound is inactive [4] suggested that the depressor mechanism of this new anti-hypertensive was indeed related to its competitive inhibition of dopa decarboxylase. Other studies revealed that the answer was not so simple. When given intravenously to dogs [5] or to man, the depressor action of methyldopa did not appear for l-3 hr, and lasted 12-24 hr. On the other hand, the inhibitory effect on decarboxylation was evident at once, and became less apparent or was dissipated when the delayed blood pressure lowering effect appeared [5]. At present, the exact mechanism of the depressor effect of methyldopa is not known. The purpose of this paper is to report the acute effects of methyldopa on various hemodynamic responses in man.

Effect of propranolol on morphine metabolism

Morphine metabolism was studied in 12 normal subjects. Six were studied before and while receiving propranolol, 20 mg every 6 hr, and 6 were studied before and while receiving propranolol, 40 mg every 6 hr. The study was performed to determine whether propranolol affects morphine metabolism or morphine‐induced respiratory depression. Plasma and urinary levels of free morphine and conjugated morphine when propranolol and morphine were given together were similar to the levels after morphine alone. Respiratory minute volumes, while breathing a 4% CO2 in air mixture, were also unchanged from control. The findings indicate that propranolol does not affect morphine metabolism or morphine‐induced respiratory depression in man.

Correlation of beta blockade with serum practolol levels after oral administration

This study relates practolol levels with the ability to block changes in heart rfite, blood pressure, and systolic time intervals (STI) during two levels of upright exercise and two levels of intravenous isoproterenol infusion. Normal men received placebo or oral practolol (1.5, 3.0, and 12 mg. per kilogram) on separate days in random fashion. Responses to exercise and isoproterenol were determined 2 and 4 hours later and those to exercise only at 7.5 hours. Serum pmctolol was measured in a serial manner after dosage. Practolol did not change oxygen uptake at rest or during exercise. Practolol produced a serum concentration‐dependent reduction in average heart rate and systolic blood pressure responses to exercise. Exercise shortened STI. Following practolol, electromechanical systole and left ventricular ejection time during exercise were markedly prolonged, whereas the duration of the prejection period did not change. Pmctolol produced a serum concentration‐dependent reduction in heart rate, systolic and diastolic blood pressure, and STI changes during isoproterenol infusion. Near maximal beta blockade occurred at serum practolollevels of 2 εg per milliliter. The half‐life of practolol was 6.9 hours. Practolol is a potent beta blocking drug with a relatively long duration of action when given orally. The serum concentration‐dependent reduction of the diastolic response to isoproterenol by practolol suggests blockade of peripheral beta receptors.

Disseminated Nodular Pulmonary Ossification in Patients with Mitral Stenosis

What seem to be rare complications of common diseases may merely be uncommon because no one accumulates a large number. The unusual combination of disseminated nodular bone formation in the lungs and chronic mitral stenosis is more common in young men. The clinical findings in 4 cases are described and the pathogenesis is discussed.

Effects of Hypothyroidism and Hyperthyroidism on Dipyrone Metabolism in Man

A LTERATIONS in thyroid function may affect drug metabolism. A number of different drug metabolizing enzyme systems have been studied in animals and varying effects of thyroid hormone have been found.17 The purpose of the study was to investigate the effects of hypothyroidism and hyperthyroidism on dipyrone metabolism in man. Dipyrone is an aminopyrine derivative which undergoes oxidative N-demethylation to 4-aminoantipyrine in the liver. In studying dipyrone metabolism, both the disappearance of dipyrone from the plasma and the urinary excretion of 4-aminoantipyrine may be determined. This provides an indirect assessment of the effects of altered thyroid function on the hepatic microsomal enzyme, aminopyrine N-demethylase.

Hypotensive effects of clonidine and chlorthalidone: Controlled clinical trial of drugs administered singly and in combination☆

Abstract Thirty patients participated in a carefully controlled double-blind trial of the new hypotensive agent, clonidine. Following four weeks of placebo therapy, patients were randomly allocated to one of three treatment groups: clonidine alone, clonidine and chlorthalidone, or chlorthalidone alone. The dose of clonidine was increased from 300 to 1,200 mcg. per day as tolerated over a four-month period. While clonidine alone only lowered significantly systolic and diastolic blood pressures taken in the standing position, the combination consistently reduced these pressures taken in both the supine and standing positions. Systolic blood pressures taken in the supine and standing positions were lowered significantly more in patients taking the combination than in those taking either drug alone. Heart rate taken with the patient standing was reduced only with clonidine alone. Serious toxicity was not observed. One infant accidentally ingested clonidine but recovered quickly.

Effect of Guanethidine and Adrenal Demedullation on Hyperglycemic Responses to Diazoxide in Rats.

Summary A single intraperitoneal injection of diazoxide, 200 mg/kg, produced a significant elevation of blood sugar and a significant decrease in liver glycogen 3 hours after administration to normal and to de-medullated rats. Guanethidine, 20 mg/kg subcutaneously, had no appreciable effect on blood sugar or liver glycogen of either group. When given together, diazoxide and guanethi-dine also produced a marked elevation in blood sugar and a significant reduction in hepatic glycogen in normal rats. The hyper-glycemic effect of diazoxide was suppressed in the demedullated rats receiving guanethi-dine, although its depleting effect on hepatic glycogen was not attenuated. Generous supplies of diazoxide were made available through the courtesy of Dr. J. Black, Schering Corp., Bloomfield, N. J. The guanethidine supplies were provided by Dr. William Wagner, Ciba Pharmaceutical Co., Summit, N. J.

Effects of triiodothyronine-induced hypermetabolism on factor VIII and fibrinogen in man

Triiodothyronine (liothyronine sodium) (400-500 mug/day for 14 days) was given to six normal subjects. Factor VIII (antihemophilic globulin) activity increased from 109 to 167% (P < 0.05); fibrinogen increased from 344 to 581 mg/100 ml (P < 0.01). To test whether the increases in factor VIII activity and fibrinogen were mediated by beta adrenergic receptors, propranolol (20 mg every 6 hr) was given orally to four other normal subjects in addition to triiodothyronine for 14 days. Factor VIII increased from 100 to 161%; fibrinogen increased from 374 to 564% (P < 0.01). Factor VIII activity did not change in a severe classical hemophiliac made hypermetabolic with triiodothyronine, but it increased from 39 to 82% in a patient with von Willebrands disease. Triiodothyronine-induced hypermetabolism increased the incorporation of selenomethionine-(75)Se into plasma fibrinogen. These results suggest that the increases in clotting factor activity during triiodothyronine-induced hypermetabolism reflect an effect of increased protein synthesis rather than enhanced stimulation of beta adrenergic receptors.

Prostaglandin B2-Induced Cutaneous Vasoconstriction of the Canine Hind Paw

The cutaneous vascular effects of prostaglandin B2 (PGB2) were studied in dogs during constant-flow perfusion of the hind paw. The effects of PGB2 (50–800 ng/kg min−1, ia) on systemic pressure, hind-paw perfusion pressure, and responses to local heating at 45°C (30 seconds) and cooling at 4°C (90 seconds) were measured in 44 dogs. PGB2 increased perfusion pressure by 50 ± 19 mm Hg to 218 ± 21 mm Hg without any effect on systemic arterial blood pressure. The pressor response to cooling increased from 34 mm Hg to 53 mm Hg (50 ng/kg min−1PGB2), but the dilator response to heating was reduced significantly during infusions of PGB2 (50 and 100 ng/kg). Acute denervation and reserpine treatment (0.5 mg/kg dog−1 for 2 days) reduced the constrictor responses to PGB2. The abilities of PGB2 to produce intense vasoconstriction, which is blocked by acute denervation and reserpine, to enhance responses to cooling, and to antagonize responses to heating make this preparation a useful model for the study of Raynauds phenomenon and suggest that a prostaglandin, perhaps PGB2ss, may participate in cutaneous vasospastic disorders.