We performed experiments to determine the effects of the combined 5-hydroxytryptamine2 (5-HT2) receptor and Ca2+ channel antagonist LU49938 ((2S)-5-[N-methyl-N-(n-hexyl)]amino-2-isopropyl-2(3.4.5-trimethoxy phenyl)-valeronitril-hydrochloride) on vascular smooth muscle (VSM) and endothelium in isolated porcine coronary arteries. Rings with and without endothelium were suspended in conventional organ chambers for measurement of isometric force. LU49938 inhibited contractions evoked by serotonin, norepinephrine (NE), and prostaglandin F2 alpha (PGF2 alpha) in a concentration-dependent and noncompetitive manner. The lower concentrations of LU49938 (10(-7) and 10(-6) M) did not affect contractions to serotonin in the presence of ketanserin. However, a higher concentration of LU49938 (10(-5) M) significantly decreased the concentration-response curve to the monoamine in the presence of ketanserin. These finding suggest that LU49938 has a dual inhibitory effect on contractions: selective inhibition of 5-HT2 receptor and nonselective inhibition of the contractile process in VSM. The mechanism of this nonselective inhibition of VSM is likely to be related to inhibition of Ca2+ entry because LU49938 inhibited responses to several agonists. The time course and degree of relaxation caused by LU49938 were comparable in rings with and without endothelium in control solution or after incubation with nitro-L-arginine and/or indomethacin. LU49938 did not affect endothelium-dependent relaxations induced by serotonin and bradykinin. These results suggest that LU49938 does not affect endothelium-dependent responses in porcine coronary artery.