Objective: To determine whether transient hypoxia in neonatal rats has long-lasting effects on inotropic stimulation of the adult heart.
Methods: The hearts of adult male Sprague-Dawley rats (89+/-1 (S.E.M.) days, 432+/-5 g) were studied. Half the animals had been subjected to neonatal hypoxia (FiO(2)=0.12, days 1-10) while the others had not. The peak response of left ventricular pressure (LVP) and the maximum rate of pressure increase (+dP/dtmax) were measured in isolated and perfused hearts during application of dobutamine, isoproterenol, milrinone and betaxolol. Left ventricular myocyte membranes were analyzed for beta receptor density, adenylyl cyclase activity and content.
Results: LVP and +dP/dtmax responses to stimulation with dobutamine and isoproterenol were significantly impaired in adult hearts of neonatally hypoxic rats. The inotropic effect of dobutamine was abolished by blockade with the beta(1)-selective antagonist betaxolol. The inotropic effects of the phosphodiesterase inhibitor milrinone were also significantly decreased in neonatally hypoxic adult hearts. There was no difference in left ventricular myocyte membrane beta receptor density of adult hearts whether they were hypoxic neonatally or not. However, left ventricular adenylyl cyclase activity on isoproterenol or forskolin stimulation and adenylyl cyclase levels (type V/VI) were significantly reduced in neonatally hypoxic adult hearts.
Conclusions: Neonatal hypoxia in the rat has long-lasting effects on the left ventricular response to inotropic stimulation at maturity likely at least in part due to diminished left ventricular adenylyl cyclase levels.