Octreotide potentiates PKC-dependent vasoconstrictors in portal-hypertensive and control rats  Reiner Wiest, Ming–Hung Tsai, Roberto J. Groszmann  Gastroenterology  Volume 120, Issue 4, Pages 975-983 (March 2001) DOI: 10.1053/gast.2001.22529 Copyright © 2001 American Gastroenterological Association Terms and Conditions

Fig. 1 Representative tracings for the effect of octreotide in the absence and presence of vasoconstrictors in PVL rats. Arrows indicate time points of bolus application of octreotide, given in increasing doses (−8 to −3.5 [log10] mol/L or 0.001, 0.01, 0.1, 0.5, 1, 5, 10, and 50 μg). (A) At baseline conditions (without vasoconstrictor), octreotide did not induce any effect on perfusion pressure. (B) After preconstriction of mesenteric preparations with KCl, octreotide showed no effect. (C) However, after preconstriction with the α1-adrenergic agonist MT, (D) ET-1, and (E) the PKC-activator PdBU, octreotide did facilitate the preexisting vasoconstriction and increased perfusion pressure dose-dependently. Gastroenterology 2001 120, 975-983DOI: (10.1053/gast.2001.22529) Copyright © 2001 American Gastroenterological Association Terms and Conditions

Fig. 2 Vasoconstrictive effect of octreotide: dependency on NO and endothelium. For PVL (■) and sham (●) animals, cumulative dose-response curves for octreotide in the presence of MT were obtained (A) in untreated mesenteric preparations, (B) after inhibition of NO formation, and (C) after removal of the endothelium. Note the higher dose-response curves in mesenteric vasculature after NO blockade or after removal of the endothelium than in intact normal preparations. ANOVA, P < 0.05. Gastroenterology 2001 120, 975-983DOI: (10.1053/gast.2001.22529) Copyright © 2001 American Gastroenterological Association Terms and Conditions

Fig. 3 Vasoconstrictive effect of octreotide depends on the type of vasoconstrictor present. Cumulative dose-response curves for octreotide in de-endothelialized mesenteric vasculature after preconstriction with (A) ET-1 (2 nmol/L), (B) PdBU (20 μmol/L). ●, PVL; ○, sham. Gastroenterology 2001 120, 975-983DOI: (10.1053/gast.2001.22529) Copyright © 2001 American Gastroenterological Association Terms and Conditions

Fig. 4 Role of PKC, PLA2, and COX in the vasoconstrictive effect of octreotide. Cumulative dose-response curves for octreotide in de-endothelialized mesenteric vasculature in the presence and absence of (A) calphostin C (specific PKC inhibitor), (B) quinacrine (nonselective PLA2 inhibitor), and (C) indomethacin (COX inhibitor). Note that the blocking agents completely suppressed the amplification of α1-adrenergic vascular smooth muscle contraction induced by octreotide under normal conditions. Gastroenterology 2001 120, 975-983DOI: (10.1053/gast.2001.22529) Copyright © 2001 American Gastroenterological Association Terms and Conditions

Fig. 5 Proposed mechanism for the potentiation of local vasoconstriction in mesenteric vascular smooth muscle by octreotide. After binding of the α1-adrenergic agonist (MT) or ET-1 on their respective receptors, the activity of phospholipase C (PLC) is first stimulated. The formed 1,4,5-inositol triphosphate (IP3) opens Ca2+ channels on intracellular Ca2+ stores, increasing intracellular Ca2+ concentration, which is necessary for translocation and binding of PLA2 to membranes. Simultaneous formation of diacylglycerol (DAG) activates PKC, which by phosphorylation of a putative inhibitor (Inh.) allows PLA2 to be stimulated by octreotide. The released arachidonic acid enters the COX pathway, resulting in production of vasoconstrictive prostanoids and potentiation of vasoconstriction. AA, arachidonic acid; SSTR2, somatostatin receptor subtype 2. Modified and reprinted with permission.82 Gastroenterology 2001 120, 975-983DOI: (10.1053/gast.2001.22529) Copyright © 2001 American Gastroenterological Association Terms and Conditions