Mechanisms of action of centrally acting antihypertensive drugs.

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Publication Type dissertation
School or College College of Pharmacy
Department Pharmacology & Toxicology
Author Madsen, Parley William.
Title Mechanisms of action of centrally acting antihypertensive drugs.
Date 1982-06
Description The dose-response effects of clonidine on transmission through somatospinal reflex, viscerospinal reflex, intraspinal, and spinal-bulbospinal reflex pathways were determined in spinal or chloralose-anesthetized cats to assess principal sites of drug action. Clonidine rapidly produced parallel, dose-dependent depression of transmission through each pathway which was antagonized by tolazoline or yohimbine. The order of descending sensitivity was found to be spinal-bulbospinal, intraspinal, and spinal reflex pathway. Analysis of the relative depression of transmission at spinal and at brainstem levels indicates that the spinal site is more sensitive to clonidine that it is generally considered to be. The effect of the serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP) was also assessed on the intraspinal pathway and somatospinal reflex. In contrast to clonidine, 5-HTP was more effective in depressing the spinal reflex than the intraspinal pathway, and both pathways could be depressed completely. Clonidine and 5-HTP appear to depress the excitability of sympathetic neurons by activating alpha(,2)- and 5-HT receptors, respectively. The intraspinal pathway was rapidly and markedly enhanced for 1-2 hours by two methylxanthines. Clonidine depressed intraspinal transmission and prevented enhancement by the xanthines; alpha(,2)-receptor antagonists blocked the effect of clonidine and not only restored but also markedly prolonged the enhancement by the xanthines. The results suggest that the excitability of sympathetic preganglionic neurons may be regulated by cyclic AMP through activation of different subtypes of adrenergic receptors that are either positively or negatively coupled to adenylate cyclase. Methyldopa (MD) produced a moderate enhancement of transmission through three central sympathetic pathways three hours after an i.v. infusion of 150 mg/kg. However, a subsequent dose of 5 mg/kg dose of reserpine, which alone causes no depression, produces prompt, marked depression of transmission through each pathway which is antagonized by yohimbine, suggesting that reserpine releases an active metabolite of MD to depress sympathetic preganglionic neurons by activing alpha(,2)-receptors. Depletion of epinephrine by blockade of phenylethanolamine-N-methyltransferase prevents this depression that occurs with the transmitter release. Propranolol modestly enhances transmission through the pathways tested.
Type Text
Publisher University of Utah
Subject Pharmacokinetics; Clonidine; Methyldopa
Subject MESH Antihypertensive Agents; Propranolol
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Mechanisms of action of centrally acting antihypertensive drugs." Spencer S. Eccles Health Sciences Library. Print version of "Mechanisms of action of centrally acting antihypertensive drugs." available at J. Willard Marriott Library Special Collection. RM 31.5 1982 M33.
Rights Management © Parley William Madsen III.
Format Medium application/pdf
Identifier us-etd2,190
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
ARK ark:/87278/s6417bpv
Setname ir_etd
Date Created 2012-04-23
Date Modified 2012-04-23
ID 193391
Reference URL