Analysis of responses to endothelins 1, 2, and 3 and sarafotoxin 6b in airways of the cat.
Airway responses to endothelin (ET) 1, ET-2, ET-3, and sarafotoxin 6b (S6b) were investigated in paralyzed, anesthetized, mechanically ventilated cats. Intravenous injections of ET-1 (0.1-1 nmol/kg) increased transpulmonary pressure (Ptp) and lung resistance (RL) and decreased dynamic compliance (Cdyn) in a dose-related manner. Airway responses to ET-1 were decreased significantly by sodium meclofenamate, a cyclooxygenase inhibitor, and by SKF 96148, a thromboxane receptor blocking agent. In terms of relative bronchoconstrictor activity, the thromboxane mimic, U-46619, was threefold more potent than ET-1 on a molar basis in increasing Ptp. ET-1 and ET-3 had similar bronchoconstrictor activity, and these peptides were less potent than ET-2 and S6b. Bronchoconstrictor responses to ET-2, ET-3, and S6b were also decreased significantly by meclofenamate and by thromboxane receptor blocking agents. The ET-1 precursor ET-1-(1-38) (big ET-1) caused a significant slowly developing increase in Ptp, RL, and aortic pressure (PAO) and a decrease in Cdyn, whereas a monocyclic ET-1 analogue and ET-1-(16-21) hexapeptide fragment had little or no activity in the airways. The present data indicate that ET-1, ET-2, ET-3, and S6b have significant bronchoconstrictor activity in the cat and that responses are dependent in part on the release of arachidonic acid and the formation of thromboxane A2. These data also suggest that big ET-1 is converted into a mature peptide in the cat and that ET-1-(16-21) hexapeptide fragment and a monocyclic ET-1 analogue have little if any bronchoconstrictor activity in the anesthetized cat.
Dyson
M C
MC
Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112.
Kadowitz
P J
PJ
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1; D016232:Endothelins / Q000494:pharmacology*; D005260:Female; D008297:Male; D011498:Protein Precursors / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000378:metabolism; D017482:Receptors, Thromboxane; D012137:Respiratory System / Q000187:drug effects*; D013928:Thromboxane A2 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014757:Viper Venoms / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D013928:Thromboxane A2