Response of the Neonatal Heart to a New Inotropic Agent, RO2-2985 (X537A)

Abstract

Extract: The ionophore RO2-2985 did not produce a positive inotropic response in 1-day-old canine isolated ventricle. A gradual increase in inotropic response was seen with age. Isolated atria, however, exhibited a positive inotropic response at birth (50% increased dF/dt), which became progressively greater with age (100% increase in dF/dt at 15 days of age). In the neonatal heart in situ there was a positive inotropic response in 1-day-old puppies (40% increase in left ventricular dF/dt) with progressively greater responses with age (135% increase in left ventricular dF/dt at 11 days of age). There was a positive chronotropic (75–125% increase) response to RO2-2985 at all ages studied. The drug elevated systemic arterial pressure (150% increase in mean arterial pressure) to a similar degree in all ages studied. RO2-2985 depressed total calcium binding by both neonatal and adult isolated cardiac sarcoplasmic reticulum approximately 50%. Speculation: Although the exact mechanism of action of RO2-2985 on the heart remains unproven, the temporal association of the increase in ventricular and atrial sympathetic nerve endings with development reported by previous authors and the increase in response to RO2-2985 and tyramine suggest that the drug might act in part by releasing a humoral substance. The discrepancy between in situ and isolated studies tends to support this view. A more complete delineation of all subcellular fractions of the developing heart will be necessary to clarify the differential actions of this and other drugs on the developing heart. RO2-2985 may be of value in the treatment of low cardiac output states in neonates as well as adults, but specific testing in neonates will be necessary.