Inhibition by phosphoramidon of the regional haemodynamic effects of proendothelin-2 and -3 in conscious rats.
1. Regional haemodynamic studies were carried out in conscious, Long Evans rats, chronically-instrumented with pulsed Doppler flow probes and intravascular catheters. 2. In the first experiment, proendothelin-2 and -3 (0.1 and 1.0 nmol kg-1, i.v. boluses) were found to cause dose-dependent pressor, bradycardic, and renal and, particularly, mesenteric vasoconstrictor effects. The hindquarters showed an initial vasodilatation (which was not dose-dependent) followed by a vasoconstriction (which was dose-related). The pressor and renal and mesenteric vasoconstrictor effects of proendothelin-3 were greater than those of proendothelin-2. 3. In the second experiment, it was demonstrated that phosphoramidon (10 mumol kg-1, i.v. bolus) abolished the pressor, bradycardiac, and hindquarters vasoconstrictor effects of proendothelin-2 (1.0 nmol kg-1), and inhibited significantly the renal and mesenteric vasoconstrictor actions of this peptide. Phosphoramidon had similar effects on the responses to proendothelin-3 (1.0 nmol kg-1), although a slight pressor effect of this peptide remained in the presence of phosphoramidon. 4. In the third experiment, it was found that phosphoramidon had no significant effect on the pressor or vasoconstrictor responses to endothelin-2 or -3 (0.1 nmol kg-1). 5. Collectively, the results indicate that the haemodynamic effects of proendothelin-2 and -3 in vivo in conscious rats are probably due to their conversion to endothelin-2 and -3, respectively, by an enzyme(s) that is inhibited by phosphoramidon. There appears to be no obvious difference between proendothelin-2, proendothelin-3 and proendothelin-1 in this respect.
Gardiner
S M
SM
Department of Physiology and Pharmacology, University of Nottingham Medical School, Queen's Medical Centre.
Kemp
P A
PA
Bennett
T
T
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016232:Endothelins / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D012079:Renal Circulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D016232:Endothelins; D006020:Glycopeptides; D011498:Protein Precursors; C078162:proendothelin 2; C078163:proendothelin 3; D015260:Neprilysin; C008890:phosphoramidon