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Biomedical subjects

R A Hahn

Publications and source records attributed to R A Hahn.

At least 55 records · Page 3Linked to original sources
PubMed1984

Systemic hemodynamic and regional blood flow effects of LY141865, a selective dopamine receptor agonist.

Intravenous infusion of LY141865 (20 micrograms/kg) lowered systemic vascular resistance in anesthetized dogs resulting in a fall in mean arterial blood pressure. These effects require an intact nervous system and involve dopamine receptors as they were abolished by hexamethonium or sulpiride pretreatment. LY141865 does not appear to interact with adrenergic receptors because it did not increase diastolic blood pressure or cardiac rate of normal or hexamethonium-treated dogs, and yohimbine pretreatment did not antagonize its systemic vasodilator and hypotensive actions. Hemodynamic analysis demonstrated that infusion of LY141865 (20 and 100 micrograms/kg i.v.) resulted in persistent arterial hypotension due solely to reduced systemic vascular resistance; aortic blood flow index was maintained. LY141865 produced slight bradycardia and sustained increments in stroke volume index at the highest tested dose. Left ventricular filling pressure was unchanged by LY141865. Regional blood flows to heart, stomach, colon, small intestine, kidneys and marrow-laden bone were not changed during hemodynamic alterations produced by LY141865, although evidence of arteriovenous shunting of blood was observed in skin and skeletal muscle. Comparable systemic vasodilation and arterial hypotension induced by infusion of nitroglycerin reduced gastric and colonic blood flows, but did not produce detectable shunting. The composite data are interpreted to be a reflection of the ability of LY141865 to interact with DA2 dopamine receptors and thereby inhibit neurogenic release of norepinephrine. The present results and known oral efficacy of LY141865 lend further support for the development and use of dopamine receptor agonists for the treatment of cardiovascular disease.

Animals↗
PubMed1984

Primate cardiovascular responses mediated by dopamine receptors: effects of N,N-di-n-propyldopamine and LY171555.

Administration of N,N-di-n-propyldopamine (DPDA) (1-100 micrograms/kg i.v.) and LY171555 (1-100 micrograms/kg i.v.) produced dose-related arterial hypotension accompanied by bradycardia in anesthetized rhesus monkey. The cardiovascular effects of DPDA were of brief duration, whereas hypotension and bradycardia induced by LY171555 were sustained. Pretreatment of monkeys with sulpiride (0.5 mg/kg i.v.) abolished the blood pressure and cardiac rate-lowering effects of DPDA and LY171555. During the time course of cardiovascular alterations produced by LY171555 (100 micrograms/kg i.v.), increments in cardiac rate due to electrical stimulation of the right stellate ganglion were inhibited. This effect also was abolished by sulpiride treatment. The antagonism of neural tachycardia by LY171555 was selective, as the drug had no concomitant inhibitory action on cardiac rate or diastolic blood pressure responses to exogenous norepinephrine. Hemodynamic analysis demonstrated that DPDA (20-200 micrograms/kg i.v.) and LY171555 (1-10 micrograms/kg i.v.) each lowered arterial blood pressure, without reflex tachycardia, by dilating the systemic vasculature; cardiac output and stroke volume were maintained. Furthermore, left ventricular minute work and stroke work were reduced by each drug in association with systemic hypotension. The data suggest that DPDA and LY171555 produce cardiovascular responses by inhibiting neurogenic release of norepinephrine through an interaction with D-2 dopamine receptors. The present primate data also support the potential clinical utility of dopamine receptor agonists in treating cardiovascular disease.

Animals↗
PubMed1983

Resolution and absolute configuration of an ergoline-related dopamine agonist, trans-4,4a,5,6,7,8,8a,9-Octahydro-5-propyl-1H(or 2H)-pyrazolo[3,4-g]quinoline.

The title compound (+/-)-5 (R = Pro) (LY141865) has been resolved into a (-) isomer and a (+) isomer as the D- and L-tartrate salts, respectively. Biological studies have shown that dopamine agonist activity is a property of only the (-) isomer. Crystallographic analysis has proven that the absolute configuration of the active (-) isomer is the same as that of the natural ergolines.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

"Treat the patient, not the lab:" internal medicine and the concept of 'person'.

In different medical systems, notions of person, as patient and as healer, vary widely. An analysis of the talk of a practitioner of internal medicine in the U.S.A. reveals an understanding of patients as syndromes. The work of medicine is 'physiological integrity', distinct from personal and interpersonal integrity. It is suggested that the world view of this practitioner is consistent with the institutions of medicine in which he practices, and with historical movements in U.S. society and Western civilization more broadly.

Anthropology, Cultural↗
PubMed1982

Dopaminergic activity of substituted 6-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines.

6-Chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines were synthesized and evaluated as agonists of central and peripheral dopamine receptors. These benzazepines were prepared by cyclization of certain amino alcohols followed by demethylation of the 7,8-dimethoxy groups of the precursors to the 7,8-catecholic moiety. Preliminary evidence of dopaminergic activity was determined in anesthetized dogs by measuring the effects on renal blood flow and calculating the accompanying changes in renal vascular resistance. The most potent compounds contained an hydroxyl group on the 1-phenyl group or were substituted at the 3' position with a chloro, methyl, or trifluoromethyl group. Evidence for central dopaminergic activity was obtained by measuring rotational effects in rats lesioned in the substantia nigra and also in an in vitro assay which measured stimulation of rat striatal adenylate cyclase. The compounds with the best central dopaminergic activity were generally the benzazepines which were the most lipophilic, were substituted on the 3' position of th 1-phenyl group, and contained either a 3-N-methyl or 3-N-allyl group.

Animals↗
PubMed1982

Absolute stereochemistry and dopaminergic activity of enantiomers of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine.

Resolution of the unique dopamine receptor agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (1) was achieved by a stereospecific multistep conversion of the readily separated enantiomers of its O,O,N-trimethylated precursor 2. The absolute stereochemistry of the antipodes of 2-MeI was determined by single-crystal X-ray diffractometric analysis, thus permitting assignment of the configuration of stereospecifically related 1, as well as that of the synthetic intermediates. High-performance liquid chromatography of diastereoisomeric derivatives was utilized to determine the enantiomeric excess of the R (greater than 97%) and S (greater than 89%) isomers of 1. Examination of the isomers in several in vitro and in vivo tests for both central and peripheral dopaminergic activity revealed that activity resided almost exclusively in the R isomer. The results suggest that the properly oriented 1-phenyl substituent of 1 is important for dopamine-like activity; it may contribute to receptor binding by interaction with a chirally defined accessory site. Configurational and conformational requirements for receptor binding of 1 are considered in relationship to previously described dopaminergic agents. These studies, in accord with previous suggestions, indicate that (R)-1 interacts with dopamine receptors in a conformation in which the catecholic hydroxyls and basic nitrogen are at least nearly maximally separated.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1982

Characterization of the peripheral and central effects of SK&F 82526, a novel dopamine receptor agonist.

SK&F 82526 (6-chloro-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-(1H)-3-benzazepine) was evaluated for its peripheral cardiovascular activity, effect on renal and central dopamine receptors and mechanism of action. Comparisons were made with dopamine. In anesthetized dogs, SK&F 82526 i.v., produced dose-related dilation of the renal vasculature, apparently through stimulation of postsynaptic dopamine receptors. Unlike dopamine, the increased renal perfusion was not accompanied by increases in arterial blood pressure or heart rate, but rather a decrease in arterial blood pressure at higher doses. The relative lack of efficacy of SK&F 82526 on alpha and beta adrenergic receptors was confirmed in pithed rats and isolated electrically paced papillary muscles of guinea pigs. In conscious dogs, oral administration of SK&F 82526 produced dose-dependent and sustained decreases in renal vascular resistance. The renal hemodynamic activity of SK&F 82526 in anesthetized dogs was not attenuated by phenoxybenzamine, propranolol, atropine, mepyramine plus metiamide, meclofenamic acid or reserpine but was inhibited by metoclopramide and bulbocapnine in a manner suggesting competitive antagonism. In the central nervous system studies, SK&F 82526 stimulated dopamine-sensitive adenylate cyclase of rat caudate (which was inhibited in a concentration-dependent manner by haloperidol and bulbocapnine), induced contralateral rotation in caudate-lesioned rats after intracaudal injection, but did not alter serum prolactin levels after systemic administration. Peripheral administration, however, did not result in significant activation of central dopamine receptors, indicating that SK&F 82526 does not readily cross the blood-brain barrier. These findings demonstrate that SK&F 82526 is a potent, selective, orally active renal vasodilator which acts, at least in part, through stimulation of renal vascular dopamine receptors and is without significant effect on central dopamine receptors after systemic administration.

Adenylyl Cyclases↗
PubMed1980

Antagonism of the renal vasodilator activity of dopamine by metoclopramide.

The interaction of metoclopramide with renal dopamine receptors has been characterized in anesthetized dogs surgically prepared with arterial blood pressure catheters and renal artery blood flowprobes. In normal dogs, i.v. dopamine (3 microgram/kg) produced consistent and selective decrements in renal vascular resistance (RVR) and increments in renal blood flow over a 220 min test period; mean arterial blood pressure and cardiac rate were minimally affected. Pretreatment with metoclopramide, 1 and 10 mg/kg i.v., resulted in dose-related inhibition (maximum inhibition 44% and 94%, respectively) of the renal vasodilator activity of dopamine without altering baseline parameters. The duration of antagonism produced by 1 mg/kg of metoclopramide was approximately 30 min, while 10 mg/kg resulted in significant attenuation for the entire test period. Decreases in RVR produced by prostaglandin A1 (0.03 and 0.3 microgram/kg, i.v.) and bradykinin (3 and 15 microgram/kg, i.v.) that were comparable to those of dopamine were unaltered by metoclopramide. Furthermore, metoclopramide did not affect the diastolic blood pressure responses to noradrenaline (0.2-3 microgram/kg, i.v.) or isoproterenol (0.03-0.3 microgram/kg, i.v.), nor did it alter dopamine-induced vasoconstriction of the iliac vasculature. In phenoxybenzamine (3 mg/kg, i.v.) treated dogs, dopamine (0.3-30 microgram/kg, i.v.) produced dose-related reductions in RVR. Administration of metoclopramide (10 mg/kg, i.v.) resulted in a 10-fold parallel displacement, to the right, of the RVR dose-response curve to dopamine. These findings demonstrate that metoclopramide is an effective antagonist of renal dopamine receptors following systemic administration in the dog. The results are not consistent with the classification of metoclopramide as a selective antagonist of D-2 receptors.

Animals↗