Comparative in vitro myocardial inotropic effects and in vivo hemodynamic effects of forskolin and isoproterenol in young lambs.

Previous studies have shown a decreased responsiveness of young lambs to isoproterenol, a beta-adrenergic agonist, when compared to older lambs. To see if this decreased responsiveness of immature lambs is secondary to an abnormality of the beta-adrenergic receptor/adenylate cyclase complex, we compared the effects of isoproterenol to forskolin, a direct activator of the catalytic subunit of adenylate cyclase. In isometrically contracting right ventricular trabeculae from five lambs (5-13 d old), the maximal developed tension with isoproterenol (875 +/- 84 mg, mean +/- SD) and forskolin (704 +/- 189 mg) was similar. However, the median effective dose for isoproterenol (5.3 +/- 3.4 X 10(-7) M) was significantly less than the minimal median effective dose for forskolin (2.5 +/- 1.3 X 10(-6) M) indicating a lesser sensitivity to forskolin. In eight conscious resting lambs (4-13 d old) we measured the hemodynamic response to graded infusions of isoproterenol and forskolin. At maximal dosage, the increase in cardiac output was significantly greater with isoproterenol (+130%) than forskolin (+55%). Heart rate also increased more with isoproterenol than forskolin. These data show that direct stimulation of adenylate cyclase in young lambs does not provide better inotropic or chronotropic responses than beta-adrenergic stimulation with isoproterenol. This suggests that the decreased beta-adrenergic responsiveness in newborn lambs is secondary to abnormalities that exist beyond the level of the beta-adrenergic receptor/adenylate cyclase complex.