Bipyridine Derivatives Lower Arteriolar Resistance and Improve Left Ventricular Function in Newborn Lambs

Abstract

ABSTRACT. Milrinone may be used in the treatment of pulmonary hypertensive diseases of the newborn. We have studied its effects in chronically instrumented newborn lambs over a dose range from 1-100 pg/kg. These actions have been compared with those of amrinone. We have also tested the effect of milrinone on hypoxia and leukotriene D4-induced pulmonary vasoconstriction. Injected into the right pulmonary artery, both amrinone and milrinone cause a dose-related fall in pulmonary arteriolar resistance with milrinone being approximately 20 times more potent than amrinone and possessing an ED-of about 10 pg/kg. Both agents increase left ventricular dp/dt significantly and tend to increase cardiac output. Systemic vascular resistance falls with both drugs but the change is significant only with milrinone. While milrinone attenuates the increase in pulmonary arteriolar resistance induced by leukotriene D4 and hypoxia, this is probably an indirect effect. Milrinone does not modify either the increases in left atrial, aortic pressure, and systemic vascular resistance or the decreases in cardiac output and left ventricular dp/dt induced by leukotriene D4. These findings suggest that milrinone deserves clinical trial in newborn infants with pulmonary hypertension in whom myocardial depression often coexists. (Pediatr Res 22: 422-428, 1987) Abbreviations Impaired coronary perfusion and systemic hypoxemia often depress myocardial function in these patients, thereby adding to the therapeutic problem. Indeed, severe forms of this syndrome carry a 25 to 30% mortality (1, 2).Because active pulmonary vasoconstriction is believed to be a significant factor in the pathogenesis of persistent pulmonary hypertension, many vasodilators have been tried with inconsistent effects. With most such drugs systemic vasodilation with hypotension limits their usefulness.The bipyridine derivatives, amrinone [WIN 40680,3, 4'-bipyridine-6(1H)-one] and milrinone [WIN 47203, 1,6-dihydro-2-methyl-6-oxo(3,4'-bipyridine)-5-carbonitrile] are positive inotropic agents in animals (3) and humans (4, 5) and smooth muscle relaxants. Amrinone has been the subject of a limited trial in children with pulmonary hypertension. In neonates it was possibly harmful, while in older children its benefits were limited by the rapid onset of tachyphylaxis (6). We have therefore studied the pulmonary vascular, cardiac, and systemic effects of milrinone in conscious, chronically instrumented young lambs and its effect on pulmonary vasoconstriction due hypoxia, leukotriene D4, or both. Amrinone was also studied in one group of animals to provide comparative data. Milrinone differs from amrinone in being stable to light, it does not exhibit tachyphylaxis in adults (7) and causes fewer side-effects. It may therefore be a useful drug in pulmonary hypertensive diseases of the newborn. PE, polyethylene HPLC, high performance liquid chromatography MATERIALS AND METHODSANOVA, analysis of variance Qinj, flow in injected lung Twelve lambs of the Rambouillet breed, age 0.5-4 days (m...

Pharmacokinetics of Cardiovascular Drugs in Children

“…There has been no clinical evidence to date of a negative inotropic effect of amrinone in human neonates. This may represent species differences, as amrinone and milrinone improved left ventricular function in newborn lambs, [147] but caused a negative inotropic response in newborn dogs and pigs.…”