Endothelin-1-induced alterations in phenylephrine-induced contractile responses are largely additive in...

Endothelin-1 (ET-1) is an important modulator of vasomotor tone that is thought to participate in the etiology of cardiovascular disease by virtue of its ability to amplify the contractile responses of vascular smooth muscle cells to the effects of other vasoactive agents. Despite this fact, few studies have quantitated the expected contribution of ET-1 to the enhanced contractile responses elicited in the presence of another spasmogen. As a first step in this direction, ET-1 and phenylephrine (PE) were used to evaluate the effects of co-activation of the ETA/B or alpha-1 adrenergic receptors, respectively, on contractile responses in isolated rings of rabbit aorta, mesenteric and femoral artery, or strips of corporal tissue. Cumulative steady-state concentration-response curves (CRCs) were constructed to PE alone before the construction of a CRC to ET-1 alone, or a mixture of PE and ET-1 using a previously described drug concentration paradigm. Computer fits of the logistic equation to CRC data revealed that in all vascular tissues examined, the partial substitution of PE with ET-1 was associated with a significant vessel-dependent approximately 3- to 30-fold leftward shift in the CRC (P < .01, Student's t test for paired samples), as judged by a significant increase in the pEC50 (negative logarithm of the concentration of drug that elicits one-half of the calculated maximal effect), in the absence of any detectable effect on the calculated maximal contractile response (Emax) or the slope factor (rho). A theoretical CRC constructed using the Pöch and Holzmann method for equiactive substitution demonstrated that the responses to mixtures of PE and ET-1 were often the result of simple additivity of agonist effects in these preparations, and thus, were "expected" based on detailed knowledge of the individual effects of these two agonists. Regardless of the precision of the Poch and Holzmann CRC in predicting the effects of this drug mixture in these vascular tissues, comparison of the "expected" contractile response with the "observed" response represents an important first step toward establishing a more uniform nomenclature for describing the physiological/pathophysiological effects of mixtures of drugs on diverse vasculature.