Propofol is an hypnotic drug used in anesthesia which was noted to induce marked vasodilation in vivo and in vitro, and to elicit intraoperative penile erections. The goal of this study was to assess the putative mechanistic basis for this later observation by confirming its action in vivo in a rat model of penile erection, as well as by studying its effects in vitro on cultured human corporal smooth muscle cells and isolated corporal tissue strips. In vivo experiments were conducted on Fisher 344 rats anesthetized with sodium pentobarbital or propofol. Intracavernosal pressure was recorded during current stimulation of cavernous nerves. A significant increase in the intracavernous pressure response was recorded at all levels neurostimulation, ranging from 1-10 mA. In vitro experiments were conducted utilizing digital imaging microscopy to assess the effects of propofol (3-12 micrograms/mL) on ET-1-induced (50 nM) intracellular Ca2+ transients [Ca2+]i in Fura-2-loaded cultured human corporal smooth muscle cells (passage 3-4) as well as to evaluate the effects of propofol on phenylephrine (PE)-induced contractile responses on isolated corporal tissue strips. With respect to the former, resting cytosolic calcium levels were not altered during preincubation with propofol alone at clinically effective concentrations (12 micrograms/mL). However, propofol produced a concentration-dependent decrease in the peak amplitude of the transient ET-1-induced (50 nM) [Ca2+]i response (P < 0.001). Preincubation of the cells with calcium free/EGTA (1 mM) buffer produced a reduction in the peak amplitude of the ET-1-induced [Ca2+]i transient (55.5 +/- 6% (n = 10 cells, P < 0.01)) which was indistinguishable from that produced by 8 micrograms/mL of propofol (53.4 +/- 5.6% (n = 12 cells, P < 0.01)). However, propofol had no effect on the histamine-induced [Ca2+]i response. Lastly, preincubation of isolated human corporal tissue strips with propofol (100-200 microM; 30 min) caused a significant diminution in the peak amplitude of the PE-induced contractile response. Taken together, these data indicate that the mechanistic basis for intraoperative penile erections observed with propofol may be related, at least in part, to altered transmembrane calcium flux through voltage-dependent calcium channels, and thus, decreased corporal smooth muscle tone.