Octreotide potentiates PKC-dependent vasoconstrictors in portal-hypertensive and control rats.
OBJECTIVE
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 (alpha1-agonist methoxamine, endothelin [ET-1], phorbol ester [PdBu], and potassium chloride [KCl]).


RESULTS
Octreotide did not affect baseline perfusion pressures (without preconstriction). alpha1-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 alpha1-adrenergic vasoconstriction by octreotide was significantly enhanced by nitric oxide inhibition (N(W)-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 micromol/L), phospholipase A2 (quinacrine, 5 micromol/L), and cyclooxygenase (indomethacin, 20 micromol/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 muscle 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.
Wiest
R
R
Hepatic Hemodynamic Laboratory, Veterans Administration Medical Center, West Haven, Connecticut 06516, USA.
Tsai
M H
MH
Groszmann
R J
RJ
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000503:physiopathology; D006975:Hypertension, Portal / Q000503:physiopathology*; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D015282:Octreotide / Q000494:pharmacology*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D019332:Endothelin-1; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D008729:Methoxamine; D015282:Octreotide