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

Abstract

ABSTRACT. Previous studies have shown a decreased responsiveness of young lambs to isoproterenol, a P-adrenergic agonist, when compared to older lambs. To see if this decreased responsiveness of immature lambs is secondary to an abnormality of the P-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 2 84 mg, mean 2 SD) and forskolin (704 + 189 mg) was similar. However, the median effective dose for isoproterenol (5.3 f 3.4 x lo-' M ) was significantly less than the minimal median effective dose for forskolin (2.5 + 1.3 X 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 P-adrenergic stimulation with isoproterenol. This suggests that the decreased 8-adrenergic responsiveness in newborn lambs is secondary to abnormalities that exist beyond the level of the P-adrenergic receptor/adenylate cyclase complex. (Pediatr Res 25:580-584)Previous studies have shown that young lambs, when compared to older lambs, have a limited ability to increase cardiac output (1) and contractility (2) in response to inotropic stimulation with p-adrenergic agonists, such as isoproterenol. The reason for this decreased responsiveness to P-adrenergic stimulation is unclear. It has been suggested that the newborn lamb myocardium is operating at a high resting P-adrenergic state with little reserve to increase cardiac output in response to further (3-adrenergic stimulation (2). However, Friedman (3) showed the P-receptor sensitivity to catecholamines to be similar in adult and fetal myocardium, supporting the notion that sympathetic innervation is incomplete or functionally immature in the heart of the fetus or early newborn. Because of similarities in Padrenergic receptor density and affinity, and in adenylate cyclase activity between fetal and adult myocardium, it has also been suggested that this decreased responsiveness to P-adrenergic stimulation is due to developmental differences that occur at a level beyond the P-adrenergic receptor/adenylate cyclase complex (4, 5).Forskolin is a diterpene derivative with the ability to rapidly and reversibly activate the intracellular catalytic subunit of adenylate cyclase without interacting with the guanyl nucleotide regulatory subunit, thus stimulating CAMP production directly (6, 7). Forskolin stimulates adenylate cyclase to a greater extent than isoproterenol in both normal human hea...

Characterization of PGE2receptors in fetal and newborn lamb ductus arteriosus

“…As anticipated, agents that led to elevations in cAMP levels, namely forskolin and 8-Br-cAMP, relaxed the fetal DA (Fig. 2, A and B) with relatively low potency as previously described (37,41). Analogs of PGI 2 , the effects of which are also coupled to an increase in cAMP (16), relaxed the DA albeit with a potency Ͻ1,000 time less than PGE 2 (Fig.…”

In Utero Ventilation Augments the Left Ventricular Response to Isoproterenol and Volume Loading in Fetal Sheep

“…*, the presence of that intervention significantly increases heart rate. * The coefficients b (see Table I of the sacroplasmic reticulum (17)(18)(19)(20)(21), and underdevelopment of the l3-receptorjadenylate cyclase complex (22,23). However, mechanisms that are thought to accelerate myocardial maturity at birth, such as surges in thyroid hormone (23), cannot be functional in this preparation, and isoproterenol, the only intervention that should increase contractility in a manner similar to the postnatal catecholamine surge (37), only modestly increased output (36%).…”

“…Several studies point to myocardial immaturity: incomplete development of sarcomeres (17)(18)(19)(20)(21), decreased functioning of {J-receptors (22,23), and myofibrillar disarray (24,25) have all been implicated. Although fetal myocardium is certainly immature relative to that of the adult, none of these factors have been shown to change immediately at birth.…”