Irwin H. Slater

Somatostatin inhibits adrenergic and cholinergic neurotransmission in smooth muscle.

Abstract Somatostatin reduced the response to field stimulation in the guinea pig ileum and reduced the spontaneous contractions in the rabbit jejunum, an effect that was blocked by tetrodotoxin. Somatostatin also inhibited field stimulated alpha adrenergic contractions in the rat vas deferens and rabbit ear artery. However, the responses to direct application of either acetylcholine in the ileum or to norepinephrine in the ear artery or vas deferens were not affected by somatostatin. These results strongly suggest that somatostatin inhibits neuronal release of cholinergic and adrenergic transmitter substances in smooth muscle.

In vitro Relaxation of Arteries and Veins by Prazosin: Alpha-Adrenergic Blockade with No Direct Vasodilation

Controversy exists regarding the mechanism by which prazosin lowers blood pressure without a marked increase in heart rate; a mechanism involving both sympatholytic activity and direct smooth muscle relaxation has been suggested. alpha-Adrenergic receptor blockade by prazosin is well documented and occurred to exogenous norepinephrine and to field stimulation in vitro in rat arteries and veins. A parallel shift of the norepinephrine concentration response curves in the aorta and mesenteric artery contrasted with a nonparallel shift and a marked depression of maximal norepinephrine responses in the inferior vena cava, portal, iliac and femoral veins. Nonspecific direct acting vasodilators will antagonize contractile responses to all agonists. However, prazosin (10(-8) M) specifically antagonized norepinephrine-induced responses. Concentration response curves to potassium chloride or to serotonin were not affected in these rat tissues. In addition, prazosin (up to 10(-6) M) did not significantly relax aortic tissue previously contracted with potassium chloride or serotonin, whereas the vasodilator, nitroglycerin, produced a clear relaxation. Prazosin only reduced the tone of vessels contracted with norepinephrine. These data indicate that prazosin exhibits minimal, if any, direct smooth muscle relaxant properties in concentrations higher than those producing alpha-adrenergic receptor blockade, and relaxes rat veins by a mechanism involving alpha-adrenergic receptor blockade.

Metabolic interactions between nortriptyline and thioridazine in rats

Abstract Plasma drug concentrations in rats were higher when nortriptyline was given in combination with thioridazine than when nortriptyline was given alone, regardless of whether the route of administration was po, ip, or iv. Nortriptyline concentrations in brain were also elevated, and the half-life of nortriptyline in brain was prolonged, after thioridazine administration. Although metabolites of thioridazine reacted in the assay for plasma nortriptyline, the elevated drug contents were found to be due to nortriptyline, not to thioridazine metabolites, by measurement of drug concentrations in brain (in which case thioridazine metabolites did not interfere) and by experiments with radioactive nortriptyline and thioridazine. Concentrations of radioactivity after [ 14 C]nortriptyline administration were elevated in all tissues studies, especially in the liver, by concurrent administration of thioridazine. Hypothermia occurred in rats given large oral doses of thioridazine, but not nortriptyline; greater hypothermic effects were produced by the drug combination. Large ip doses of nortriptyline produced marked hypothermia and gave high plasma drug concentrations comparable to those found when oral nortriptyline was given in combination with thioridazine. The enhanced hypothermia found with the drug combination, therefore, seemed to be due to the combined pharmacologic effects of thioridazine and nortriptyline and probably relates to the enhanced lethality of the drug combination observed by others. The interaction at high doses is not limited to this tricyclic antidepressant-phenothiazine combination, for enhanced hypothermia was also observed when amitryptyline and perphenazine were coadministered. Although the results with large doses in laboratory animals may not have direct relevance to clinical doses of these psychotropic drugs, they do suggest a need for caution when tricyclic antidepressant drugs and phenothiazines are used in combination clinically.

Pharmacological properties of recanescine, a new sedative alkaloid from Rauwolfia canescens Linn.

Summary A new alkaloid isolated from Rauwolfia canescens, recanescine, appears to lack the methoxyl group in the C-ll position of reserpine. Preliminary evidence indicates that this compound retains the characteristic pharmacologic activity of reserpine. Thus, the methoxyl group is not essential for the sedative and hypotensive action of reserpine. Note added in proof Since submission of this manuscript, Stoll and Hofmann have reported the isolation of a new alkaloid, canes-cine, which is probably identical with our recanescine. (Stoll, A., and Hofmann, A., J. Am, Chem. Soc, 1955, v77, 820.)

Plasma concentrations and electrocardiographic alterations after repetitive administration of propoxyphene to dogs.

Abstract Propoxyphene hydrochloride was administered orally to four dogs every 8 hr for 19 days. Initial doses of 20 mg/kg were increased to 60 mg/kg in 5 to 15 mg/kg increments every 3 to 4 days. At the conclusion of the experiments animals were ambulatory although signs of toxicity including anorexia, sedation, tremors, and emesis were noted periodically throughout the study. Slight elevations in alkaline phosphatase and serum glutamate pyruvate transaminase values were also observed. Plasma concentrations of propoxyphene (P) (2.3±0.5 μg/ml) and norpropoxyphene (NP) (18.4±4.7 μg/ml), its major metabolite, were markedly elevated over those observed with a single near-lethal dose administered to naive dogs (P, 0.83 μg/ml; NP, 2.56 μg/ml). Tissue concentrations of P and NP were in excess of plasma concentrations showing marked tissue accumulation of both compounds. Electrocardiograms (ECG) showed an increase in PR interval after the first dose of propoxyphene. Doses from 20 to 45 mg/kg produced no further lengthening of the PR interval. Only when dogs were receiving 60 mg/kg (three times daily) were further changes in this interval observed, along with alterations in the QRS complex and T wave portions of the ECG. The average heart rate of these dogs was not significantly altered during the course of the study. At necropsy, mild superficial focal erosions in the mucosa of the stomach and upper small intestine were noted. No other histological changes were observed. These results demonstrated that in the dog, high plasma and tissue concentrations of P and NP can occur without causing significant toxic or lethal effects.

Daily rhythm of liver tyrosine transaminase and of plasma tyrosine and glucose after removal of the pancreas of rats

Abstract Liver tyrosine transaminase varied over a four-fold range in a daily rhythm in pancreatectomized rats as in intact rats. Highest enzyme activity was reached in pancreatectomized rats about six hours earlier than in intact rats. Plasma tyrosine was higher in pancreatectomized rats, but varied in a rhythm like that in intact animals. Removal of the pancreas led to high plasma glucose concentrations and a pronounced daily rhythm in plasma glucose. Pancreatic hormones do not seem to be essential for the daily rhythm of liver tyrosine transaminase present in rats fed ad libitum .

NEUROENDOCRINE AND BEHAVIORAL STUDIES WITH FLUOXETINE, AN INHIBITOR OF SEROTONIN UPTAKE IN BRAIN

Abstract 1 When fluoxetine was given to inhibit serotonin uptake, functional changes in experimental animals indicated that activity of serotonin on synaptic receptors was increased despite a compensatory reduction in the formation and release of serotonin. 2 In combination with L-5HTP, fluoxetine stimulated corticosterone, prolactin and luteinizing hormone secretion and blocked ovulation in rats. 3 Fluoxetine alone did not change gross behavior, but in combination with other agents caused certain behavioral changes thought to involve serotonin-mediated synapses in experimental animals. Fluoxetine antagonized behavioral and hyperthermic effects of p-chloroamphetamine by blocking its uptake into serotonin neurons. 4 Fluoxetine suppressed REM sleep in rats and cats, and the effect was enhanced by L-5HTP.