In vitro activity: Phenylephrine causes a rapid translocation of PKC-epsilon (EC50 = 0.9 mM) but the proportion lost from the soluble fraction is less than with ET-1. Phenylephrine at pCa 7 causes a dose-dependent increase in contractile force of the hyperpermeable cells, which is reversible on addition of phentolamine. Phenylephrine also protects cardiomyocytes against subsequent 24 h treatment with hypoxia and serum deprivation. Phenylephrine prevents the down-regulation of Bcl-2 and Bcl-X mRNA/protein and induces hypertrophic growth. Phenylephrine-mediated protection is abrogated by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin and is mimicked by the caspase-9 peptidic inhibitor LEHD-fmk. Phenylephrine stimulates phosphoinositide (PI) hydrolysis, cell growth, and expression of several genes [e.g., atrial natriuretic factor (ANF)] often associated with cardiac hypertrophy. Phenylephrine markedly potentiates HGF-induced hepatocyte DNA synthesis and proliferation. Phenylephrine (10 mM) reversibly increases I(Ca,L) (51.3%; n = 40) and shifted peak I(Ca,L) activation voltage by -10 mV. Phenylephrine also increases local, subsarcolemmal SR Ca2+ release via IP3-dependent signaling. Phenylephrin-induced NOi release requires stimulation of both PI-3K/Akt and IP3-dependent Ca2+ signaling. Phenylephrine-induced NOi release is inhibited by each of 1 mM prazocin, 10 mM L-NIO, 10 mM W-7, 10 mM LY294002, 2 mM H-89, 10 mM ryanodine, 5 mM thapsigargin, 2 mM 2-APB or 10 mM xestospongin C.