Adaptation of Fetal Pulmonary Blood Flow to Local Infusion of Tolazoline

Abstract

ABSTRAa. Although tolazoline is the most commonly used drug in the treatment of neonatal pulmonary hypertension, its mode of action and efficacy remain incompletely understood. In order to study the effects of tolazoline on a high resistance pulmonary circulation and to better understand mechanisms that control pulmonary vascular tone and reactivity in the fetus, we infused tolazoline either continuously or as bolus into the left pulmonary artery of 15 chronically instrumented, normoxic fetal lambs during late gestation. The vasodilatory effects of bolus injections of tolazoline (2.5 mg) were inhibited by the prior administration of the histaminergic receptor blockers, cimetidine (56%), diphenhydramine (56%), or both (100%). During the continuous infusion of tolazoline (4.5 mg/h for 9 min), pulmonary blood flow to the left lung increased from 61 f 6 ml/min (mean f SE; control) to 100 k 10 (peak) at 30 min ( p < 0.001). However, following this initial vasodilatation, pulmonary blood flow steadily decreased toward control values by 90 min, despite the continued infusion of tolazoline ( p < 0.001). Although the calcium channel blocker, verapamil, and the a-adrenergic blocker, phentolamine, had little effect on fetal pulmonary blood flow when infused alone, both drugs increased the vasodilatory response to tolazoline (p < 0.001). We conclude that tolazoline effects pulmonary vasodilatation by a histaminergic mechanism and that subsequent refractoriness to the drug is a calcium-dependent process which may be partially mediated by an a-adrenergic mechanism. (Pediatr Res 20: 1131-1135,1986 Abbreviations PPHN, persistent pulmonary hypertension of the newborn LPA, left pulmonary artery PPHN accompanies a variety of cardiopulmonary disorders, including asphyxia, meconium aspiration, sepsis, hyaline membrane disease, and congenital diaphragmatic hernia, or occurs as an idiopathic disorder ("persistent fetal circulation") (1-6). Morbidity and mortality of PPHN remains high despite aggressive therapeutic interventions, including hyperventilation, inotropic support of the systemic circulation, and pharmacologic manipulation of the pulmonary vascular bed (7, 8). Attempts to find a Received January 3 1. 1986; accepted June 9, 1986. Correspondence Steven H. Abman, M.D., Pediatric Pulmonary Medicine, Box C-220, University of Colorado Health Scicnces Center, 4200 East Ninth Avenue, Denver. CO 80262.Supported by grants from the American Lung Association, American Thoracic Society, the Colorado Lung Association, and National Institutes of Health Grants HD-01860 and HD-0078 1.vasodilator which selectively and consistently lowers pulmonary vascular resistance without causing systemic hypotension or other side effects have been unsuccessful. Despite its complex pharmacology, and although its current use is largely based on case reports or uncontrolled clinical studies, tolazoline has evolved as the primary vasoactive drug used in the treatment of PPHN (4, 5, 7, 9-12). Although many newborns with PPHN treated with tolazoline appear to ...

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