Biomedical subjects
Publications and source records attributed to J W Constantine.
A vehicle containing ethanol and Emulphor EL620 lowers blood pressure and increases heart rate in morphine-chloralose anesthetized dogs. These effects are associated with histamine release caused by Emulphor EL620.
The time course of plasma concentrations of sublingually administered pirbuterol was investigated in anesthetized dogs; there was a dose-related increase in plasma drug concentrations which reached maximum values 1 hr or more after administration. In a second study plasma drug levels were correlated with antagonism of histamine-induced changes in pulmonary compliance and resistance which also reached maximum values 1 hr or more after drug administration, although marked antagonism was apparent at 15 to 30 min; blood pressure was unaltered at any dose level and heart rate was influenced only at the highest dose level. A convenient method for study of the bioavailability of sublingual formulations is described, and the potential usefulness of a sublingual dosage form of pirbuterol is discussed.
In vagotomized, spinal-sectioned dogs, prazosin and phentolamine enhanced positive chronotropic responses to cardiac accelerator nerve stimulation. In additional dogs the inhibition by clonidine of heart rate response to continuous accelerator nerve stimulation (presynaptic effect), and the vasopressor effect of clonidine (post-synaptic effect), were antagonized by prazosin, phentolamine and yohimbine; cumulative doses for 50% antagonism of the cardiac chronotropic effect were 103, 50 and 13 microgram/kg i.v., respectively, and those for 50% antagonism of the vasopressor effect were 39, 38 and 3 microgram/kg i.v., respectively. On isolated rabbit pulmonary artery, prazosin antagonized electrically evoked contractions but had no effect on 3H output, whereas yohimbine enhanced both. The results indicate that prazosin, like phentolamine and yohimbine, blocks presynaptic alpha-adrenergic receptors on the cardiac accelerator nerve of the dog but, unlike yohimbine, prazosin does not block these receptors on noradrenergic nerves of rabbit pulmonary artery. It is concluded that the relative activity of a compound at pre- and postsynaptic alpha-receptors is not the same for all organs. The results are discussed relative to the fact that prazosin causes hypotension without significant reflex tachycardia in dog and man.
Pirbuterol, 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-tert-butylaminoethyl)pyridine, is a new beta2 adrenergic agonist bronchodilator. Comparison of the relative potencies of pirbuterol, salbutamol and isoproterenol as relaxants of isolated guinea-pig tracheal muscle and as positive chronotropic agents in isolated guinea-pig atria indicate that the relative selectivity of pirbuterol for pulmonary as opposed to cardiac tissue is 9 times greater than that for salbutamol and some 1500 times greater than that for isoproterenol. Pirbuterol is effective by the oral, intravenous and inhalation routes of administration. In conscious guinea pigs, pirbuterol antagonizes both histamine- and acetylcholine-induced bronchoconstriction and "microshock" anaphylaxis; combinations of pirbuterol and theophylline cause additive effects against histamine-induced bronchoconstriction. In conscious dogs, the cardiovascular effects of pirbuterol are clearly distinguished from those of salbutamol, in that salbutamol causes a more pronounced tachycardia. In anesthetized dogs the cardiovascular effects of pirbuterol and salbutamol are comparable; they are less potent than isoproterenol and have less pronounced although longer lasting effects.
N-methanesulfonyl 16-phenoxy-omega-tetranor PGE2 is a prostaglandin analog which is markedly more tissue selective than PGE2. This compound is 10-30 times more potent than PGE2 in animal models which are considered relevant to antifertility effects in humans. In pharmacological tests which are believed to be predictive for side effects in humans, the compound has potency either equal to or less than that of PGE2.
Results of animal studies indicate that the hypotensive effect of prazosin is due to vasodilatation which is dependent on two discernible components of drug action: (1) direct relaxation of vascular smooth muscle and (2) interference with peripheral sympathetic function at a site distal to the alpha-adrenergic receptor.
Certain members of a series of 1-aminotetraline derivatives reversed the epinephrine pressor response in dogs; this effect occurred with the R- but not the S-isomers. Studies with rabbit aortic strips indicated competitive blockade of the alpha adrenergic receptor by the active agents. Receptor protection experiments supported the interpretation that this disruption of receptor function was due to occupancy blockade. This led to a hypothesis defining the steric properties of the alpha receptor and the active conformation of epinephrine at this receptor. However, two hydroxy substituted 1-aminotetralines ans two trihydroxytetrahydrosioquinoline derivatives, which were investigated to support this hypothesis, failed to show the predicted alpha adrenergic agonist activity. It is concluded that the interaction of certain 1-aminotetralines with a stereospecific binding site at the alpha receptor mimics occupancy blockade. However, this binding site is probably not entirely identical with the epinephrine binding site at the alpha receptor. Furthermore, the cyclic tetrahydroisoquinoline derivatives do not represent the active conformation of epinephrine at the receptor.
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