Effects of neonatal hypoxia in the rat on inotropic stimulation of the adult heart

doi:10.1016/j.cardiores.2004.12.003

Cardiovascular Research 2005 65(4):861-868; doi:10.1016/j.cardiores.2004.12.003

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Effects of neonatal hypoxia in the rat on inotropic stimulation of the adult heart

Charles V. Rohlicek^a^,*, Stephanie Viau^a, Phan Trieu^b and Terence E. Hébert^b

^aDivision of Cardiology–Department of Pediatrics, McGill University, Canada
^bMontreal Heart Institute Research Center, Canada

^* Corresponding author. Division of Cardiology, Montréal Children's Hospital, McGill University Health Centre, 2300 Tupper Street, Montreal, Québec, Canada H3H 1P3. Tel.: +1 514 412 4423; fax: +1 514 412 4391. Email address: charles.rohlicek{at}mcgill.ca

Objective: To determine whether transient hypoxia in neonatalrats has long-lasting effects on inotropic stimulation of theadult 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 (FiO₂=0.12,days 1–10) while the others had not. The peak responseof left ventricular pressure (LVP) and the maximum rate of pressureincrease (+dP/dtmax) were measured in isolated and perfusedhearts during application of dobutamine, isoproterenol, milrinoneand betaxolol. Left ventricular myocyte membranes were analyzedfor β receptor density, adenylyl cyclase activity and content.

Results: LVP and +dP/dtmax responses to stimulation with dobutamineand isoproterenol were significantly impaired in adult heartsof neonatally hypoxic rats. The inotropic effect of dobutaminewas abolished by blockade with the β₁-selective antagonistbetaxolol. The inotropic effects of the phosphodiesterase inhibitormilrinone were also significantly decreased in neonatally hypoxicadult hearts. There was no difference in left ventricular myocytemembrane β receptor density of adult hearts whether theywere hypoxic neonatally or not. However, left ventricular adenylylcyclase activity on isoproterenol or forskolin stimulation andadenylyl cyclase levels (type V/VI) were significantly reducedin neonatally hypoxic adult hearts.

Conclusions: Neonatal hypoxia in the rat has long-lasting effectson the left ventricular response to inotropic stimulation atmaturity likely at least in part due to diminished left ventricularadenylyl cyclase levels.

KEYWORDS Hypoxia/anoxia; Receptors; Contractile function; Inotropic agents; Signal transduction

Time for primary review 36 days

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