Developmental changes in modulation of contractility of rabbit hearts.
We recently described postnatal developmental differences of beta-adrenergic- and G-protein-mediated modulation of L-type calcium currents (ICa) in newborn and adult rabbit heart. To extend the results obtained by ICa experiments, we studied developmental changes in modulation of contractility induced by isoproterenol (ISO), forskolin (FOR) and isobutyl-methylxanthine (IBMX), all of which work through the cyclic AMP-dependent pathway. Left ventricular developed pressure (LVDP) and its first derivative (dP/dt) were measured with an intraventricular fluid-filled balloon in isolated adult and newborn (ages 1-3 days) rabbit hearts under Langendorff perfusion. ISO increased LVDP and +/- dP/dtmax dose dependently, with much greater positive inotropic effect on adult than on newborn heart. Concomitant use of a subthreshold concentration of IBMX (0.1 microM), a nonselective phosphodiesterase inhibitor (PDEI), did not significantly potentiate the dose-dependent inotropic effect of ISO in adult heart, but did markedly potentiate such effect in newborn heart. ISO 10 microM and FOR 10 microM had comparable inotropic effects on adult heart, whereas 10 microM ISO had a much weaker inotropic effect than 10 microM FOR on newborn heart. However, the increase in LVDP and +dP/dtmax and the percentage increase in these values induced by 10 microM FOR in newborn heart was still significantly lower than that in adult heart. Newborn heart has less effective signal transduction from beta-adrenergic stimulation (ISO) to increased contractility than does adult heart. Although newborn heart responds more to direct stimulation of adenylyl cyclase activity (FOR) than to beta-adrenergic stimulation, it still has less overall contractile reserve than adult heart. PDE isozymes of newborn heart are much more sensitive to IBMX than are those of adult heart, producing a significant potentiation of ISO effect by low doses of IBMX in newborn, but not adult, heart.
Akita
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Todd Franklin Cardiac Research Laboratory, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Kumar
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Joyner
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RW
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine