Species-dependent differences in inotropic effects and phosphoinositide hydrolysis induced by endothelin-3 in mammalian ventricular myocardium

1 Species-dependent variations in the positive inotropic effect (PIE) of endothelin-3 (ET-3), and the relationships between the PIE and specific binding sites for [I-125]-ET-3 and the PIE and the acceleration of phosphoinositide hydrolysis by ET-3, were studied in ventricular muscles from the rat, guinea-pig, rabbit, ferret and dog. 2 ET-3 in the presence of (+/-)-bupranolol (0.3 mu M) and prazosin (0.3 mu M) elicited a concentration-dependent PIE in the ventricular muscle from the rat, guinea-pig, rabbit and ferret. The potency of ET-3 and its efficacy in inducing a PIE were highest in the rabbit, intermediate in the rat and guinea-pig and lowest in the ferret. ET-3 did not have any inotropic effect on ventricular muscle from the dog. 3 Specific high-affinity binding of [I-125]-ET-3 was observed with membrane fractions derived from the ventricular muscle of the five species. The maximal specific binding (B-max) of ET-3 was highest in the rat and guinea-pig, intermediate in the rabbit and ferret and lowest in the dog. The values of K-D in the rabbit and dog (33 and 52 pM) were lower than those in the rat, guinea-pig and ferret (141-221 pM). 4 In slices of ventricular muscle from all five species, ET-3 increased the accumulation of [H-3]-inositol monophosphate (IP1) in a concentration-dependent manner. The extent of accumulation of IP1 was highest in the rat, intermediate in the guinea-pig and rabbit and lowest in the ferret and dog. 5 The results demonstrate the wide range of variations in the PIE of ET-3 on mammalian ventricular muscles. The variations in the coupling processes subsequent to the acceleration of the hydrolysis of PI, triggered by the binding of ET-3 to its receptor, might be important in these species-dependent differences in the PIE of ET-3.