PHORBOL ESTER POTENTIATION OF CANINE PULMONARY VASOREACTIVITY TO HISTAMINE

The effect of phorbol myristate acetate (PMA) on canine pulmonary vasoreactivity to histamine was determined in the isolated blood-perfused dog lung. Pulmonary vascular resistances and compliances were measured by using vascular occlusion techniques. Histamine (10(-5) M) significantly increased postcapillary resistance by venoconstriction and significantly attenuated total vascular compliance by decreasing large-vessel compliance and middle-compartment compliance. Pretreatment with the phorbol ester PMA (10(-7) M) significantly potentiated the vasoactive response to histamine and elicited an edemagenic effect in the isolated dog lung through modulation of the histaminergic vasoconstrictor effect on precapillary resistance, postcapillary resistance, and pulmonary vascular compliance. Pretreatment with the protein kinase C inhibitors staurosporine (10(-7) M) and calphostin C (10(-6) M) and the dihydropyridine Ca2+ channel blocker nifedipine (10(-5) M) significantly attenuated the effect of PMA on histaminergic-mediated vasoconstriction. The results of this study indicate that phorbol esters may exert their effect on canine pulmonary vasoreactivity predominantly through activation of protein kinase C and influx of Ca2+ through voltage-dependent Ca2+ channels.