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Aminophylline, a methyl xanthine, has been used for many years in the treatment of apnea of prematurity and bronchospasm. Aminophylline relaxes smooth muscle through several proposed mechanisms. We hypothesized that aminophylline might be effective in relaxing preconstricted pulmonary vascular smooth muscle and would be ideally suited for clinical trial in babies with pulmonary hypertension. To test this hypothesis, the haemodynamic response of chronically instrumented newborn lambs to injections of heat-killed Group B beta-hemolytic Streptococcus (GBS) and leukotriene (LT) D4, potent pulmonary vasoconstrictors was compared before and after pretreatment with a clinically therapeutic dose of intravenous aminophylline. GBS (10(9)cfu) significantly increased pulmonary arterial pressure 130%. LTD4 (1.0 microgram/kg) significantly increased pulmonary arterial pressure 142% and systemic arterial pressure 23% and decreased cardiac output 47%. Aminophylline did not significantly affect the baseline variables or alter the pulmonary or systemic haemodynamic response to either stimuli. Therefore, it is unlikely that aminophylline will be clinically useful in the treatment of babies with persistent pulmonary hypertension whose etiology is infectious or leukotriene-mediated.

Group B beta-hemolytic streptococcus (GBS) infection is an important cause of neonatal pneumonia and sepsis. GBS infection is frequently associated with persistent pulmonary hypertension of the newborn. To better understand the early pulmonary hypertension phase of GBS-induced acute lung injury in a conscious animal, we characterized the pulmonary and systemic hemodynamic response of spontaneously breathing, chronically instrumented newborn lambs to injections of heat-killed type Ib GBS, 0.1-9.0 x 10(9) colony forming units. Heat-killed GBS caused marked dose-dependent increases in mean pulmonary arterial pressure and calculated pulmonary vascular resistance, 190 and 370% at the maximum dose, respectively. Similarly, GBS caused dose-dependent increases in mean systemic arterial pressure and systemic vascular resistance (28.5 and 108% at the maximum dose, respectively) and a decrease in cardiac output (33.5%). Arterial oxygen tension worsened at the higher doses. GBS-induced pulmonary hypertension was decreased by two structurally unrelated, putative leukotriene D4 receptor antagonists. Pretreatment with LY171883 blocked GBS-induced pulmonary hypertension by 95%, and WY48,252 attenuated this effect by 27%. Both drugs completely blocked the hemodynamic effects of exogenous leukotriene D4. For comparison, several lambs received bolus injections of live GBS, either alone or after pretreatment with LY171883. The hemodynamic response to live GBS and attenuation of that response by LY171883 were similar to those caused by similar doses of heat-killed GBS. Thus, bolus injections of heat-killed GBS provide a reproducible model of pulmonary hypertension in conscious newborn lambs. In addition, the sulfidopeptide leukotrienes appear to be important mediators of GBS-induced pulmonary hypertension in newborn lambs.