Ira Rosenblum

Studies in cardiac necrosis: I. Production of cardiac lesions with sympathomimetic amines

Abstract The results of these experiments indicate that many sympathomimetic amines can cause cardiac lesions. Of the 15 compounds studied in detail, 10 caused cardiac lesions in 50% or more of the test animals. Though a number of the actions and effects of amines can be implicated as causing lesions, no single action or effect can be correlated with lesion production. The histopathology of the cellular response to the amines is typically an inflammatory cell response which is confined to the interstitial spaces. The response to isoproterenol is atypical in this respect because only isoproterenol caused cardiac parenchymal cell necrosis.

Studies in cardiac necrosis: II. Cardiovascular effects of sympathomimetic amines producing cardiac lesions☆☆☆

Abstract The purpose of this study was to determine the mechanisms by which lesion-producing doses of some representative sympathomimetic amines could cause impairment of myocardial function. Impairment of myocardial function was indicated when the aortic outflow was significantly lowered by lesion-producing doses of all the test drugs. The probable mechanisms of impairment differed among the drugs, thus confirming the pluricausal origin of drug-induced myocardial necrosis. Three mechanisms for impairment of function are proposed. Ephedrine, methoxamine, and norephedrine acted through a myogenic mechanism manifested as a reduction in myocardial contractile force. Nordefrin and norepinephrine acted through a physical mechanism by causing an increase in mean aortic pressure which opposed left ventricular pressure. Isoproterenol probably acted by a third mechanism which is believed to be at the level of myocardial utilization of substrate.

Single and double blind studies with oral monosodium glutamate in man.

Abstract Single and double blind studies were done with single oral doses of monosodium glutamate (MSG) in human volunteers. A total of 169 doses were given, including controls. Ninety-eight received 5 g of MSG in single blind studies, 6 received 8 g, and 5 received 12 g in double blind studies. Physical examinations were done on all subjects. Those taking 5 g of MSG filled out a questionnaire 1 hr after ingestion. Based on the questionnaire, as few as 23% or as many as 80% of the subjects in any group registered complaints. There was a low incidence of most complaints except for lightheadedness and tightness in the face. In the double blind studies in which clinical chemistry, blood pressure, and pulse were measured in addition to clinical examination, no significant differences between MSG and sodium chloride were detected. No subject reported or was observed to have experienced the triad of symptoms described as the Chinese Restaurant Syndrome.

Studies in cardiac necrosis: III. Metabolic effects of sympathomimetic amines producing cardiac lesions☆☆☆

Abstract The effects on plasma nonesterified fatty acids (NEFA) and glucose of five sympathomimetic amines were investigated in order to determine the importance of these metabolic effects in the etiology of cardiac lesions as induced by these amines. Of these five, isoproterenol, nordefrin, and norepinephrine caused significant elevations in both plasma total NEFA and glucose. Methoxamine caused a significant reduction in plasma NEFA while elevating plasma glucose, and ephedrine produced no significant changes in the plasma levels of either NEFA or glucose. It is proposed that amines which cause a marked elevation in plasma NEFA also cause an accumulation of lipids in the myocardium. Accumulation of these lipids, which are esters of fatty acids, can lead to the development of cardiac lesions through an ultimate mechanism which is still unknown. Because cardiac lesions can be produced also by amines which have no significant effects on either plasma NEFA or glucose, the etiology of these lesions must have more than a single mechanism.

Cardiovascular responses to cyclohexylamine

Abstract The cardiovascular effects of cyclohexylamine have been studied in cats. In appropriate doses, cyclohexylamine produced a rise in arterial blood pressure, an increase in myocardial contractile force, and tachycardia. Higher doses caused a vasodepressor response, bradycardia, and a reduction in myocardial contractile force. Repeated injections of cyclohexylamine led to tachyphylaxis, but the pressor effect could be partially restored by injection of norepinephrine. The pressor response could be reduced with cocaine or phenoxybenzamine and increased by iproniazid. It was unaffected by ganglion blockade, α-adrenergic receptor blockade, reserpine, bilateral adrenalectomy, nephrectomy, and it persisted in decerebrate and in spinal cats. These observations suggest that cyclohexylamine caused its cardiovascular effects by direct stimulation of α-adrenergic receptors, but it may also release endogenous catecholamines from sites other than the adrenal medulla.

Autonomic stimulating and direct actions of cyclohexylamine in isolated tissues.

Abstract The effects of cyclohexylamine have been studied in isolated tissues. It caused contraction of the smooth muscle of the guinea pig ileum by activation of cholinergic atropine-sensitive receptors but not strychnine-sensitive presynaptic receptors. The contractions of the ileum were not enhanced by physostigmine. It also contracted the rat urinary bladder by activation of hexamethonium-sensitive receptors. Contraction of rat vas deferens could be blocked by either phenoxybenzamine, phentolamine, or atropine, indicating activation of alpha adrenergic receptors as well as cholinergic receptors of that tissue. Contraction of a skeletal muscle, the frog rectus abdominis, could not be blocked by d -tubocurare demonstrating a noncholinergic stimulation by cyclohexylamine. This action on skeletal muscle occurred in a calcium-free medium and after muscle depolarization with excess potassium. Although the contraction could be reversed in part, by addition of acid to the medium, it was not due entirely to a pH effect of cyclohexylamine.

Self administration of dextropropoxyphene by Rhesus monkeys to the point of toxicity

This study has shown that Rhesus monkeys will self-administer dextropropoxyphene without prior stabilization on other self-administered drugs. Throughout this program, animals maintained an inverse relationship between unit dosage of drug per injection and the rate of responding while the total daily intake of drug was directly related to the dosage unit. At no time did a monkey voluntarily discontinue self-administration of dextropropoxyphene nor was there any evidence of physical dependence when saline was substituted for the drug. The pattern of self-administration indicates that dextropropoxyphene may posses properties which limit the daily intake of drug over a wide dose range.

The anticonvulsant activity of triethylcholine in cats

Abstract Convulsant thresholds to pentylenetetrazol were elevated by triethylcholine and phenobarbital in both spinal and midbrain transected cats. The maximal electroshock seizure thresholds in rabbits were not, however, affected by triethylcholine though they were elevated by phenobarbital. The selective anticonvulsant effect of triethylcholine against pentylenetetrazol may be related to its ability to inhibit acetylcholine synthesis.

Reduction in cardiovascular and metabolic responses to phenylephrine in acutely pancreatectomized dogs

Abstract The cardiovascular and metabolic responses to l -phenylephrine were studied, comparatively, in groups of normal and acutely pancreatectomized dogs. Pancreatectomy in dogs had the effect of reducing the rise in systolic pressure, myocardial contractile force, and plasma glucose, as well as causing the reduction in heart rate which was produced by an infusion of phenylephrine, 10.0 μg per kilogram per minute. The responses to infusion of isoproterenol, however, were not generally altered by pancreatectomy. Of the changes in response to phenylephrine due to pancreatectomy, the addition of 2 units of insulin per kilogram to the infusion was able to restore partially the pressor response. It may be speculated that these results indicate a role for insulin in facilitating the response to sympathomimetic amines, which act to some extent on intracellular stores of endogenous catecholamines.

Light deprivation as a means of lowering electroshock thresholds in rabbits

Abstract Maximal electroshock seizure thresholds were determined in thirty-two rabbits exposed alternately to either continuous full illumination or continuous darkness. In most rabbits, continuous darkness caused a lowering of the individual electroshock thresholds. The seizure pattern was also changed during continuous darkness with an increase in the clonic phase and the postictal phase of the maximal seizure. The threshold-lowering effect of light deprivation may be related to decreased high energy phosphate metabolism during continuous darkness.