ALTERED PROSTACYCLIN SYNTHESIS BY AORTAE FROM HEPATIC PORTAL VEIN-CONSTRICTED RATS - EVIDENCE FOR EFFECTS ON PROTEIN-KINASE-C AND CALCIUM

To investigate the mechanisms causing reduced systemic vascular reactivity to vasoconstrictor agents in portal hypertension, we studied receptor- and signal-transduction-linked PGI(2) (a vasodilator) synthesis (measured as 6-oxo-PGF(1 alpha) by radioimmunoassay) in the aorta (ex vivo) of portal vein-constricted rats. PGI(2) synthesis was stimulated by adrenaline (via heterogeneous alpha-adrenoceptors), phorbol ester dibutyrate (a protein kinase C activator), arachidonic acid (the substrate for PGI(2) synthesis) and the Ca2+ ionophore A23187 (A23187) and thapsigargin (both of which elevate intracellular Ca2+, which in turn elicits the release of arachidonic acid). The release of PGI(2) by the aortae of rats with portal hypertension in comparison to sham-operated controls was: 1) enhanced in response to adrenaline, 2) reduced in response to phorbol ester dibutyrate, A23187 and thapsigargin and 3) unchanged in response to arichidonic acid. These data indicate that in aortae from rats with experimental portal hypertension: i) there are no changes in the enzymes involved in PGI(2) synthesis (cyclooxygenase, PGI(2) synthase) ii) there is a specific increase in adrenoceptor-linked PGI(2) synthesis in aortae which may contribute to arterial vasodilation in this experimental model and 3) the diminished response of PGI(2) synthesis to A23187, phorbol ester dibutyrate and thapsigargin indicates that there is a generalised attenuation of protein kinase C activator activity and of Ca2+. Since Ca2+ is a key component of excitation-contraction coupling and protein kinase C activator has been implicated in mediating this event, attenuation of these systems may also explain, at least in part, the known reduced vasoactivity of aortae from rats with portal hypertension. Whether a similar alteration of these mechanisms occurs in the vasculature of patients with portal hypertension warrants consideration. (C) Journal of Hepatology.