Mechanism of ergonovine-induced contraction in the mesenteric artery from deoxycorticosterone acetate-salt hypertensive rat

S. W. Watts, R Clinton Webb

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Contractile responsiveness of the rat mesenteric artery to the ergot alkaloid ergonovine is enhanced in deoxycorticosterone acetate (DOCA) hypertension. This study determines if this abnormality is mediated through serotonergic or alpha adrenergic receptors and investigates the cellular mechanism of the contraction. Mesenteric arteries were dissected from DOCA hypertensive and normotensive rats for use in isolated tissue experiments. Contractions to 5-hydroxytryptamine, phenylephrine, norepinephrine, dopamine and histamine were of a similar maximum in the hypertensive and sham artery with phenylephrine, dopamine and serotonin more potent in hypertension. Ergonovine contracted hypertensive arteries (maximum = 245 ± 27 mg) but only minimally in sham arteries (maximum = 83 ± 19 mg). Endothelium removal did not enhance contraction to ergonovine. The alpha-1 antagonist prazosin (10- 6 M) and the serotonergic antagonist 1-naphthylpiperazine (10-6 M) shifted the ergonovine concentration response of the hypertensive artery rightward. The alpha-2 receptor antagonist idazoxan (10-6 M) and dopamine antagonist haloperidol did not affect contraction to ergonovine. Contraction to ergonovine was not altered by indomethacin or 2-nitro-4-carboxyphenyl-N,N- diphenylcarbamate and was minimally affected by genistein, indicating that ergonovine does not activate pathways which involve cyclooxygenase, phospholipase C or tyrosine kinases, respectively. The protein kinase C inhibitor chelerythrine (10-5 M), nifedipine (10-6 M) and calcium-free medium blocked ergonovine-induced contraction. These studies support that 1) DOCA hypertension induces a dramatic change in arterial responsiveness to ergonovine; 2) a portion of this response is dependent on stimulation of alpha-1 adrenergic and serotonergic receptors; and 3) arterial contraction to ergonovine is dependent on enhanced protein kinase C activation which is dependent on extracellular calcium.

Original languageEnglish (US)
Pages (from-to)617-625
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume269
Issue number2
StatePublished - Jan 1 1994
Externally publishedYes

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Ergonovine
Desoxycorticosterone
Mesenteric Arteries
Acetates
Salts
Arteries
Phenylephrine
Hypertension
Protein Kinase C
Dopamine
Serotonin
Adrenergic alpha-1 Receptors
Ergot Alkaloids
Calcium
Receptors, Adrenergic, alpha
Dopamine Antagonists
Protein C Inhibitor
Genistein
Prazosin
Type C Phospholipases

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Mechanism of ergonovine-induced contraction in the mesenteric artery from deoxycorticosterone acetate-salt hypertensive rat",
abstract = "Contractile responsiveness of the rat mesenteric artery to the ergot alkaloid ergonovine is enhanced in deoxycorticosterone acetate (DOCA) hypertension. This study determines if this abnormality is mediated through serotonergic or alpha adrenergic receptors and investigates the cellular mechanism of the contraction. Mesenteric arteries were dissected from DOCA hypertensive and normotensive rats for use in isolated tissue experiments. Contractions to 5-hydroxytryptamine, phenylephrine, norepinephrine, dopamine and histamine were of a similar maximum in the hypertensive and sham artery with phenylephrine, dopamine and serotonin more potent in hypertension. Ergonovine contracted hypertensive arteries (maximum = 245 ± 27 mg) but only minimally in sham arteries (maximum = 83 ± 19 mg). Endothelium removal did not enhance contraction to ergonovine. The alpha-1 antagonist prazosin (10- 6 M) and the serotonergic antagonist 1-naphthylpiperazine (10-6 M) shifted the ergonovine concentration response of the hypertensive artery rightward. The alpha-2 receptor antagonist idazoxan (10-6 M) and dopamine antagonist haloperidol did not affect contraction to ergonovine. Contraction to ergonovine was not altered by indomethacin or 2-nitro-4-carboxyphenyl-N,N- diphenylcarbamate and was minimally affected by genistein, indicating that ergonovine does not activate pathways which involve cyclooxygenase, phospholipase C or tyrosine kinases, respectively. The protein kinase C inhibitor chelerythrine (10-5 M), nifedipine (10-6 M) and calcium-free medium blocked ergonovine-induced contraction. These studies support that 1) DOCA hypertension induces a dramatic change in arterial responsiveness to ergonovine; 2) a portion of this response is dependent on stimulation of alpha-1 adrenergic and serotonergic receptors; and 3) arterial contraction to ergonovine is dependent on enhanced protein kinase C activation which is dependent on extracellular calcium.",
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