Pharmacological properties of endothelins and big endothelins in ketamine/xylazine or urethane anesthetized rats.
Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor peptide formed through a specific conversion of its intermediate precursor, big ET-1, by an endothelin-converting enzyme (ECE). The present study evaluates the capacity of the ECE to convert the three big endothelins (big ET-1, big ET-2, and big ET-3), by comparing the pressor responses to these peptides with those induced by their respective metabolites (ET-1, -2, and -3) in the rat in vivo, anesthetized either with a mixture of ketamine/xylazine or with urethane. The mean basal arterial pressure under urethane anesthesia was not significantly different from that of ketamine/xylazine-treated animals (90/15 mg/kg; intramuscularly), although the basal heart rate was significantly higher in the former animals (urethane: 407 +/- 10 beats/min, ketamine/xylazine: 276 +/- 4 beats/min, P < .01; n = 8 to 17). In ketamine/xylazine and hexamethonium-treated rats (5-min infusion, 10 mg/kg intravenously), intravenous injection of ET-1 (1 nmol/kg) and big ET-1 (1 nmol/kg) induced potent vasopressor effects which lasted for more than 20 min. ET-2 (1 nmol/kg) produced similar pressor responses while big ET-2 (1-37) and big ET-2 (1-38) were twofold less potent than ET-2 (P < .05; n = 3 to 4). Big ET-3 induced a pressor effect only at 4 nmol/kg and was found to be at least 10 times less potent than ET-3. In animals anesthetized with urethane (1.5 g/kg intraperitoneally), the pressor responses induced by the endothelins and their intermediate precursors, as well as the pressor responses to angiotensin II and norepinephrine, were reduced by more than 60% (P < .01) when compared to ketamine/xylazine-treated animals. Big ET-3 was found inactive under urethane anesthesia. Ganglion blockade by hexamethonium did not affect the response to ET-1, big ET-1, ET-3, or big ET-3 in rats anesthetized with either ketamine/xylazine or urethane. On the other hand, big ET-2 (1-38), in contrast to ET-2 or big ET-1, did not release prostacyclin from the rat perfused lung, thus indicating that big ET-2 (1-38) is poorly converted in the pulmonary vasculature, and that the phosphoramidon-sensitive ECE responsible for the pressor effects of big ET-2 is localized elsewhere in the systemic circulation. Our results also show that the choice of anesthetics is crucial for the proper monitoring of the pressor responses to endothelins as well as other pressor agents. Nonetheless, even in what we consider as optimal conditions of anesthesia (threshold dose for the pressor response to ET-1 in ketamine/xylazine-treated rats: 0.01 nmol/kg), big ET-3 remains far less active than big ET-1 as a pressor peptide in the rat, suggesting a preferential processing of the latter by the ECE.
Gratton
J P
JP
Department of Pharmacology, Medical School, University of Sherbrooke, Québec, Canada.
Maurice
M C
MC
Rae
G A
GA
D'Orléans-Juste
P
P
D000777:Anesthetics / Q000008:administration & dosage*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000494:pharmacology*; D007649:Ketamine / Q000008:administration & dosage; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases; D011311:Pressoreceptors / Q000187:drug effects*; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014520:Urethane / Q000008:administration & dosage; D014991:Xylazine / Q000008:administration & dosage
D000777:Anesthetics; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D014991:Xylazine; D014520:Urethane; D007649:Ketamine; D001120:Arginine; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes