Endogenous synthesis of endothelin-1 may mediate a delayed pressor response after injection of endothelin-1 in rats.
We previously described delayed pressor response (DPR) 3 h after endothelin (ET)-1 injection in normotensive rats. In the current study, we examined effects of the ETA receptor antagonist BQ123 (0.01 mumol/kg/min intravenously, i.v.), phosphoramidon (100 mumol/kg i.v.), the neutral endopeptidase inhibitor SQ28603 (112 mumol/kg + 0.04 mumol/kg/min i.v.), the angiotensin-converting enzyme inhibitor enalaprilat (10 mumol/kg i.v.), and the thromboxane receptor antagonist, SQ29548 (0.5 mumol/kg + 0.5 mumol/kg/h i.v.) on DPR. Vehicle and ET-1 (1.0 nmol/kg i.v.) were administered on day 1; vehicle or drug and ET-1 were administered on day 2. BQ123 inhibited DPR 36% (vehicle 44 +/- 5, BQ123 28 +/- 3 mm Hg); phosphoramidon inhibited DPR 56% (vehicle 45 +/- 4, and phosphoramidon 20 +/- 5 mm Hg). DPR was unchanged after SQ28603 (vehicle 39 +/- 2 and SQ28603 44 +/- 2 mm Hg), enalaprilat (vehicle 39 +/- 2 and enalaprilat 38 +/- 7 mm Hg), or SQ29548 (vehicle 46 +/- 6 and SQ29548 43 +/- 3 mm Hg). The results suggest that DPR 3 h after ET-1 injection in rats is mediated in part through ETA receptors. DPR does not appear to involve thromboxane or synthesis of angiotensin II (AII), but may be related to synthesis of ET-1.
Bird
J E
JE
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
Waldron
T L
TL
D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015773:Enalaprilat / Q000008:administration & dosage / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000008:administration & dosage / Q000096:biosynthesis / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated; D006020:Glycopeptides / Q000008:administration & dosage / Q000494:pharmacology; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors
D019086:Bridged Bicyclo Compounds, Heterocyclic; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D005231:Fatty Acids, Unsaturated; D006020:Glycopeptides; D006834:Hydrazines; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D017482:Receptors, Thromboxane; C065359:SQ 28603; C045749:SQ 29548; D015773:Enalaprilat; D000409:Alanine; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C008890:phosphoramidon