Effects of endothelin-1 in isolated perfused rat heart.
We examined the effects of the vasoconstrictor peptide endothelin-1 in the isolated heart and defined interactions of endothelin-1 with other hormone systems. Isolated isovolumic rat hearts were perfused with Krebs-Henseleit buffer at constant pressure. First, the effect of a single bolus of endothelin-1 (4-400 pmol) was followed for 90 min. The effect of high dosages (40 and 400 pmol) of endothelin-1 on coronary flow was biphasic, with an early vasodilator and a late vasoconstrictor component that was irreversible. Second, cumulative dose-response curves were obtained for endothelin-1 boluses of 0.04-400 pmol. Coronary flow declined with increasing dosages and was almost abolished at 400 pmol. Neither alpha- nor beta-blocking agents (phentolamine and propranolol) nor the Ca2(+)-channel blocker nifedipine altered the effects of endothelin-1, but prostaglandin synthesis inhibition by indomethacin significantly augmented vasoconstriction by endothelin-1. Angiotensin-converting enzyme (ACE) inhibition by captopril antagonized endothelin-1-dependent vasoconstriction to a small extent at 400 pmol. Coronary constriction due to endothelin-1 could not be reversed by nitroglycerin. We conclude that in isolated rat heart endothelin-1 causes marked and long-lasting coronary constriction. The effect is not influenced by sympathetic and Ca2(+)-channel blockade, is enhanced by prostaglandin synthesis inhibition, and is reduced by ACE inhibition.
Medizinische Universitätsklinik, Würzburg, F.R.G.
S
S
Neubauer
G
G
Ertl
U
U
Haas
F
F
Pulzer
K
K
Kochsiek
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D016232:Endothelins; D006321:Heart / Q000187:drug effects*; D006334:Heart Function Tests; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D016232:Endothelins; D010455:Peptides; D011448:Prostaglandin Antagonists; D014662:Vasoconstrictor Agents; D005996:Nitroglycerin