Tetrandrine is an alkaloid from a Chinese herb which has been used to treat hypertension in humans. The mechanism(s) of its antihypertensive action is not clear. The goal of this study was to examine the direct effects of a derivative of tetrandrine, 7-O-ethyl tetrandrine (TD), on vascular smooth muscle. In particular, the goals were to study (1) the involvement of the endothelium in the responses of isolated aortic rings to TD, and (2) the effects of TD at intracellular sites involved in muscle contraction in skinned aortic strips treated with saponin. TD (1-100 mumol/l) decreased noradrenaline (NA) and K(+)-evoked contraction of isolated aortic rings with or without endothelium in a concentration-dependent manner although to a lesser degree with the K(+)-evoked contraction. In NA-contracted rings, the IC50 for TD was approximately 28-30 mumol/l, at which a 20% decrease in K(+)-force development of aortic rings was observed. The slope of the concentration-relaxation curve was steeper in aortic rings with endothelium than without endothelium (1.09 vs. 0.88) in NA-contracted rings. TD increased tone in acetylcholine (ACh)-relaxed rings but did not change the force in aortic rings relaxed by sodium nitroprusside (NaNP) or ATP. In TD pretreated rings, TD blocked ACh-induced relaxation, but not NaNP or ATP-induced relaxation. In skinned aortic strips, TD decreased Ca2+ uptake by the SR (IC50 approximately 77.4 mumol/l, slope = 0.88), did not affect Ca2+ release from the SR, and decreased Ca2+-activation of the contractile proteins at 300 mumol/l TD.