Inhibition of nitric oxide synthesis following severe hypoxia-ischemia restores autoregulation of cerebral blood flow in newborn lambs

Abstract

Birth asphyxia impairs the autoregulatory ability of the cerebral blood flow. Inappropriate synthesis of vasodilatory nitric oxide may be important in this respect. We investigated if nitric oxide synthesis inhibition by N^ω-nitro-l-arginine (NLA) could restore cerebral autoregulation after severe hypoxia-ischemia (HI). HI was induced in 15 newborn lambs. Cerebral blood flow (carotid artery blood flow [ml/min]: Q_car) and mean aortic blood pressure [mmHg]: MABP) were measured over a 30 min period before HI (pre-HI), 0–30 min after completion of HI (0–30 post-HI) and from 60 to 120 min post-HI (60–120 post-HI). Immediately after completion of HI, 5 lambs received a placebo (PLAC), 5 low dose NLA (10 mg/kg/iv: NLA-10) and 5 high dose NLA (40 mg/kg/iv: NLA-40). Pre-HI, all groups showed cerebral autoregulation with an upper limit of regulatory ability between 75 and 90 mm Hg. At 0–30 post-HI, all groups lacked autoregulatory ability of the cerebral vascular bed and showed an aortic blood pressure-passive Q_car. At 60–120 post-HI autoregulation was restored in NLA-10 and NLA-40-treated lambs (upper limit of autoregulation was shifted to higher MABP in NLA40-treated lambs), but not in placebo-treated lambs. At 60–120 post-HI MABP was higher in both NLA-groups than in PLAC group (83±15 [NLA-10] and 78±14 [NLA-40] vs. 65±9 mmHg [PLAC], P<0.05). We conclude that severe HI in newborn lambs induces impairment of the autoregulatory ability of the cerebral vascular bed. Even low-dose nitric oxide-synthesis inhibition started upon reperfusion restored autoregulation, suggesting a role for nitric oxide-induced vasodilation in the impairment of autoregulation of the cerebral blood flow after birth asphyxia.

Introduction

Following severe perinatal hypoxia-ischemia (birth asphyxia) the autoregulatory ability of the neonatal cerebral vascular bed is often impaired [1], [2]. There is an increasing body of evidence that excess production of nitric oxide is important in this respect because of its strong vasodilatory action [3], [4]. Earlier studies in newborn animals reported indeed an substantial increase of nitric oxide during, especially following reperfusion and reoxygenation after perinatal hypoxia and ischemia [5], [6], [7]. Since an appropriate cerebral perfusion is mandatory to prevent further brain damage in the early post-hypoxic-ischemic period, prompt recovery of the autoregulatory ability of the cerebral vascular bed is essential.

In the present study we investigated whether or not inhibition of nitric oxide synthesis upon reperfusion and reoxygenation after severe hypoxia-ischemia in newborn lambs restores cerebral blood flow autoregulation in the early post-ictal period. We hypothesized that NLA restores post-hypoxia-ischemia autoregulatory ability of the cerebral vascular bed. Inhibition of nitric oxide synthesis was performed with an analog of l-arginine (the precursor of nitric oxide), N^ω-Nitro-l-Arginine (NLA), which is a non-selective nitric oxide synthase inhibitor. Since nitric oxide has also a physiological role [8], [9] and recent studies suggested that partial rather than total nitric oxide synthase inhibition shows a neuroprotective effect after hypoxia-ischemia [10], [11], we divided our treatment group into a low dose (10 mg NLA/kg: partial nitric oxide synthase inhibition) and a high dose (40 mg NLA/kg: total nitric oxide synthase inhibition [12]) subgroup.