Species-dependent differences in inotropic effects and phosphoinositide hydrolysis induced by endothelin-3 in...

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 [125I]-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 microM) and prazosin (0.3 microM) 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 [125I]-ET-3 was observed with membrane fractions derived from the ventricular muscle of the five species. The maximal specific binding (Bmax) 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 KD 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 [3H]-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.