Inhibition by phosphoramidon of the regional haemodynamic effects of proendothelin−2 and −3 in conscious rats

Authors


Department of Physiology and Pharmacology, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH

Abstract

  • 1Regional haemodynamic studies were carried out in conscious, Long Evans rats, chronically-instrumented with pulsed Doppler flow probes and intravascular catheters.
  • 2In 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.
  • 3In the second experiment, it was demonstrated that phosphoramidon (10 μmol kg−1, i.v. bolus) abolished the pressor, bradycardic, 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.
  • 4In 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).
  • 5Collectively, 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.

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