SummaryUsing a piglet model of neonatal sepsis, we have determined that Group B streptococcal (GBS) bacteremia is associated with a state of vascular hyper‐resistance in both the pulmonary and systemic circulations. This elevated vascular resistance is accompanied by a significant fall in cardiac output despite the assurance of constant intravascular fluid volume. Pulmonary artery pressure rises extensively while systemic blood pressure remains essentially unchanged during this GBS infusion protocol.We report here our attempts to relieve the vascular hyperresistance of GBS infusion by administration of an &agr;‐sympathetic antagonist, tolazoline (Tz). We found that Tz, in a dose‐related fashion, decreased both systemic and pulmonary vascular resistance over the entire range from 2 to 25 mg/kg. Further, at all doses tested, the resistance‐reducing effect of Tz was equal in the systemic and pulmonary vascular beds. No selective pulmonary or systemic vasodilatory effect was demonstrated by Tz in this model of neonatal pulmonary hypertension.The reduction of systemic vascular resistance was accompanied by a significant elevation in total body cardiac output at all Tz doses. Compared to pre‐Tz values, cardiac output rose by 24, 55, and 55% after Tz at 2, 8.3, and 25 mg/kg respectively. In addition, administration of Tz to septic normovolemic piglets reliably produced a transient decrease of systemic blood pressure. For Tz doses of 2 and 8.3 mg/kg, steady state systemic blood pressure returned to pre‐Tz levels within 10 min. However, after Tz at 25 mg/kg, steady state systemic blood pressure remained significantly below pre‐Tz levels.AbbreviationsAOP, aortic pressurePAP, pulmonary artery pressureLAP, left atrial pressureCVP, central venous pressurePVR, pulmonary vascular resistanceSVR, systemic vascular resistanceGBS, Group B streptococciTz, tolazoline