Mechanisms involved in norepinephrine-induced hypertension in rats

Abstract

Chronic norepinephrine (NE) infusion in rats results in an increase in blood pressure, but the mechanisms responsible for this effect remain unclear. To investigate these mechanisms and determine whether angiotensin II (AII) and endothelin-1 (ET-1) are involved, we infused NE intravenously in adult male Sprague Dawley rats (1, 24 or 48μg/kg/hr or vehicle) for 14 days. Blood pressure was monitored by telemetry throughout and 24hr average mean arterial pressures (MAP) calculated. Anesthetized pressure-natriuresis relationships for the left kidney were determined at the end of the 14-day infusion. Mean arterial pressure increased in a biphasic manner in the 24 and 48μg/kg/hr NE groups, with an initial peak on days 2-3 (ΔMAP 10±1 and 14±2mmHg respectively; P<0.01 vs vehicle) followed by a fall (day 5 ΔMAP 6±1 and 6±2mmHg respectively; P<0.05 vs vehicle) and then a small but significant and sustained elevation (days 13-14 ΔMAP 3±1 and 10±1mmHg respectively; P<0.05 vs vehicle). Infusion of vehicle or 1μg/kg/hr NE had no effect on MAP. Pressure-natriuresis relationships were not altered by 14 days NE infusion. In separate groups of rats, 48μg/kg/hr NE was infused for 14 days during AT1 receptor blockade, ETA&B receptor blockade or vehicle treatment. The initial peak in MAP was not affected by ETA&B receptor blockade (ΔMAP 14±2mmHg for NE plus ETA&B receptor blockade and 13±3mmHg for 48μg/kg/hr NE only) but was blunted by AT1 receptor blockade (ΔMAP 4±2mmHg for NE plus AT1 receptor blockade and 14±1mmHg for 48μg/kg/hr NE only, P<0.001). The fall in MAP following the initial peak did not occur in the rats with ETA&B receptor blockade (day 5 ΔMAP 13±2mmHg for NE plus ETA&B receptor blockade and 4±1mmHg for 48μg/kg/hr NE only). The rise in MAP achieved at days 13-14 during ETA&B receptor blockade was not significantly different to that in the 48μg/kg/hr NE only group (12±2 and 9±1mmHg respectively). Following cessation of 48μg/kg/hr NE infusion, MAP dropped rapidly below pre-infusion levels and seven days after cessation MAP was not significantly different to pre-NE infusion levels. Thus intravenous infusions of 24 and 48μg/kg/hr NE significantly increased MAP, an effect apparently involving at least 2 phases. The initial rise in MAP does not appear to involve ET-1 but may be partly mediated by AII, while the subsequent fall in MAP appears to be due to ET-1. The sustained rise in MAP does not appear to be mediated by a shift in the pressure-natriuresis relationship.