Edward J. Walaszek

Structure determinations and synthesis of pharmacologically active phospholipids from kidney and intestine

The chemical structures of an acidic phospholipid originally isolated from equine intestine by Vogt and of a phospholipid isolated from rabbit kidney medulla by Walaszek are shown by total synthesis to be similar mixtures of 2-alkyl (and alkenyl)-4-hydroxymethyl-1,3-dioxolane-dihydrogen phosphate esters. In these materials, the alkyl residues derive primarily from oleyl, palmityl and linoleyl aldehydes. The smooth muscle contracting activity observed in the natural substances is shown to reside exclusively in the oleyl aldehyde derivative.

DRUGS THAT MODIFY ACTIONS OF PHARMACOLOGICALLY ACTIVE POLYPEPTIDES

The qualitative effects on smooth muscle of most of the pharmacologically active polypeptides are usually similar and thus their identification and estimation in mixtures is very difficult. As yet we do not possess specific antagonists to these agents which would help in characterizing them in a fashion similar to that of acetylcholine vs. atropine, histamine vs. antihistaminics or serotonin vs. lysergic acid diethylamide (LSD). The possession of a specific antagonist for one of these polypeptides would be of immense value. It is not known whether specific receptors exist for the pharmacologically active polypeptides. Specific antagonists may help resolve this problem and may provide clues which could lead to conclusions as to the mechanisms of action and possible physiological roles of some of these active polypeptides. Furthermore, a specific antagonist for angiotensin may be a useful therapeutic agent for some forms of hypertension and a specific antagonist for bradykinin may be a useful therapeutic agent for some inflammatory conditions. A substance which would modify the action of the neurohumoral polypeptide substance P may be a useful agent in the treatment of some mental disorders. Materials and Methods

Brain Neurohormones and Cortical Epinephrine Pressor Responses as Affected by Schizophrenic Serum

Publisher Summary This chapter focuses on pressor response and the influence of various drugs and serum of schizophrenic patients upon cortical epinephrine pressor response (CEPR). The influence of the cerebral cortex upon the cardiovascular system has been suggested by clinical observations of blood pressure, heart rate, and localized vasomotor disturbances in patients with verified cerebral cortical lesions. Experimental lesions in animals also yield evidence of vasomotor representation at the cortical level. In the transection studies cited in the chapter, a number of centrally acting drugs modified the CEPR. Reserpine and tetrabenazine—tranquilizers that deplete norepinephrine and serotonin from brain depots—markedly augmented the pressor response while chlorpromazine—a tranquilizer with adrenergic blocking activity—blocked the pressor response. Iproniazid and other amine oxidase inhibitors—drugs that elevate the levels of norepinephrine and serotonin in the brain—markedly diminished the CEPR. Parasympathomimetic drugs that pass the blood–brain barrier also diminished the pressor response. The hallucinogens, lysergic acid diethylamide and bufotenine, were able to potentiate the pressor response to cortically applied epinephrine. Pentobarbital, hexobarbital, procaine, and morphine did not modify the pressor response while ethyl ether inhibited the response. The chapter discusses a tentative explanation of the effects of schizophrenic serum on the CEPR from the standpoint of catecholamine levels in the hypothalamus.

In vitro inhibition by synthetic phospholipids of pressor responses to renin

Incubation mixtures containing kidney extracts and standard doses of renin or angiotensin were injected i.v. into awake rats. Pressor responses to injected renin were reduced while those to angiotensin were unaffected. 2 of 5 synthetic phospholipids had the same effects as the kidney extracts; the oleyl and palmityl derivatives were effective while the stearyl, lauryl, and myristyl derivatives were not. By contrast, the prostaglandins E1 and F2α both inhibited responsiveness not only to renin but also to angiotensin and norepinephrine. Neither blockade of vascular angiotensin receptors nor suppression of endogenous converting enzyme explains selective inhibition of response to renin. An enzymatic inhibition of renin also appears unlikely since degree of reduction in response was unaffected by duration of incubation. Our results may be due to the formation of micelles on renin molecules in vitro.

The Use of Computer-Assisted Teaching Systems (CATS) in Pharmacology

The general rule of study is that time is a constant and achievement a variable. Since the study of drugs by physicians must be a lifetime endeavor we will begin by instituting achievement as the constant and time as a variable.

NMR investigation of histamine-phospholipid interaction

Summary Dispersions of histamine and phosphatidyl-L-serine, phosphatidyl-ethanolamine, and phosphatidylcholine were investigated at acidic and alkaline pD values using nmr. A specific interaction between histamine and phosphatidyl-L-serine was observed in the acidic pD range and involved only the imidazole protons of histamine. No interactions between histamine and the other phospholipids were observed.

EFFECTS OF AMINE OXIDASE INHIBITORS ON CEREBRAL CORTICAL RESPONSES TO EPINEPHRINE

Recent developments have shown that the adrenal hormone epinephrine has the property of acting directly on neuronal aggregates of the central nervous ~ystem.l-~ Clinical observations have been reported that epinephrine can initiate emotional changes such as anxiety and mental Combined physiological and clinical data thus support the working hypothesis that the reactivity of cerebral structures to epinephrine may constitute a major factor in normal cerebral functions and, possibly, in cerebral disorders. An experimental approach based on a recently developed technique strengthens this hypothesis. This technique consists of an evaluation of systemic blood-pressure changes that follow the topical application of epinephrine to the frontoparietal area of the exposed cerebral cortex of the anesthetized rabbit? The experiments were performed with adult rabbits anesthetized with urethane. The cerebral hemispheres were exposed, the dura opened, and mean systemic arterial blood pressure was measured via a cannula in the left femoral artery. Next, a very small piece of filter paper (3 to 5 mm. square), moistened with a freshly prepared 5 per cent solution of epinephrine bitartrate in Ringer’s solution, was placed on the frontoparietal zone of the cortex. After a very short contact (15 to 30 sec.) the systemic blood pressure rose 30 to 60 mm. Hg, maintained a maximum for 0.5 to 2 min., and then decreased to its initial value. The size and duration of the cortically induced pressor effects depend upon the area treated. They were maximal after local administration of epinephrine on the median frontoparietal cortex, smaller and more transient on the frontal area, and generally negligible on the temporal and occipital regions. This cortically induced pressor effect could also be elicited in rats, guinea pigs, and cats. There was no effect on the systemic blood pressure upon the application to the cerebral cortex of Ringer’s solution, 5-hydroxytryptamine, or histamine. Electric stimuli produced a small and transient hypotension. Applications of norepinephrine produced a pressor response that was much smaller than the pressor response due to epinephrine. One of the characteristics of this phenomenon is the fact that the bloodpressure response increases gradually after repeated applications of epinephrine (at 10-min. intervals) on the same area. The hypertension engendered by cortical application of epinephrine is due to a mechanism that is essentially different from that produced by intravenous injections of the same hormone. Both effects could be differentiated through an intravenous administration of a Subsequent applications were made a t 10-min. intervals.

THE CARDIOVASCULAR EFFECTS OF SUBSTANCE P IN THE CHICKEN

In 1931, Euler and Gaddum‘ reported the presence of an unidentified depressor substance in extracts of various tissues, particularly those of the brain and intestine. This depressor agent was referred to as “substance P” and it was suggested that the fall in arterial pressure produced by substance P in the atropinized rabbit is due to peripheral vasodilatation.‘. 2. Subsequent investigations have shown that intraarterial injections of substance P cause a pronounced dilatation of the vessels in the perfused, chronically-denervated rabbit The depressor activity of substance P has also been demonstrated in other mammals and its hypotensive effect has been found to be unaffected by atropine, antihistaminics or ganglionic-blocking agents.6 In cats and rabbits, intracisternal or intraventricular injections of substance P have been observed to produce prominent respiratory manifestations with very slight and variable hemodynamic effects.’ In healthy human subjects, it has been reported that intravenous infusions of substance P produce facial flushing, increased blood flow in the muscles and skin, hypotension and tachycardia.*, 9. lo These various observations indicate that in mammals, the predominant factor responsible for the depressor response to substance P is a peripheral vasodilatation. The present experiments were conducted to investigate the cardiovascular effects of substance P in the chicken.

Polypeptide Receptor Mechanisms: Influence of pH

This study was undertaken to ascertain the influence of pH on the effects of various pharmacologically active peptides. We believed that such a study would shed light upon polypeptide receptor mechanisms and hoped it would provide evidence regarding peptide-receptor interactions. In addition, information would be found that may indicate whether the peptide bearing an anionic or cationic charge would be more apt to combine with cationic or anionic receptors respectively. It is well known that conformational changes in proteins can be induced by changes in pH (Bernal, 1962). It may be that the conformation of the peptide and/or receptor would be optimal at certain pH values.

Antagonism of some toxic effects of ethoheptazine by nalorphine

Summary The toxic effects of ethoheptazine in rats were antagonized by the prior administration of nalorphine. The effect of ethoheptazine in rats and mice was similar; however, there is a species difference in the required dosage of ethoheptazine to produce these toxic effects. A similar antagonism of the effects of ethoheptazine by nalorphine was not demonstrated in mice. This is similar to results obtained with dextropropoxyphene in that nalorphine antagonism can be demonstrated in rats but not mice.