Octreotide potentiates PKC-dependent vasoconstrictors in portal-hypertensive and control rats

Abstract

Background & Aims: The effect of octreotide on vascular tone in the superior mesenteric artery (SMA) was studied in portal-hypertensive (portal vein-ligated) and sham-operated rats. Methods: In vitro-perfused SMA vascular beds were tested for the cumulative dose-response to octreotide at baseline conditions and after preconstriction with different vasoconstrictors (α1-agonist methoxamine, endothelin [ET-1], phorbol ester [PdBu], and potassium chloride [KCl]). Results: Octreotide did not affect baseline perfusion pressures (without preconstriction). α1-Adrenergic-, ET-1-, and PdBu-, but not KCl-, induced vasoconstriction was significantly potentiated by octreotide. This effect was dose-dependent and not different in portal vein-ligated and sham rats. Amplification of α1-adrenergic vasoconstriction by octreotide was significantly enhanced by nitric oxide inhibition (NW-nitro-L-arginine, 10-4 mol/L) as well as by removal of the endothelium, and was completely suppressed by inhibition of protein kinase C (calphostin C, 1 μmol/L), phospholipase A2 (quinacrine, 5 μmol/L), and cyclooxygenase (indomethacin, 20 μmol/L). Conclusions: Not directly, but in the presence of vasoconstrictors involving activation of protein kinase C, octreotide exerts a local vasoconstrictive effect on vascular smooth muscie of SMA. This potentiation is equipotent in portal vein-ligated and sham rats, immediate in onset, and mediated via phospholipase A2 and cyclooxygenase-derived prostanoids. This indicates that in preprandial conditions octreotide enhances the vasoconstrictive effect of dependent vasoconstrictors.