Comparative in Vitro Myocardial Inotropic Effects and in Vivo Hemodynamic Effects of Forskolin and Isoproterenol in Young Lambs

ABSTRACT: Previous studies have shown a decreased responsiveness of young lambs to isoproterenol, a ß-adrenergic agonist, when compared to older lambs. To see if this decreased responsiveness of immature lambs is secondary to an abnormality of the ß-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 ß-adrenergic stimulation with isoproterenol. This suggests that the decreased ß-adrenergic responsiveness in newborn lambs is secondary to abnormalities that exist beyond the level of the ß-adrenergic receptor/adenylate cyclase complex.