Role of prostaglandin, endothelin and sympathetic nervous system on the l-NAME-induced pressor responses in spontaneously hypertensive rats

Abstract

We tested the hypothesis that in spontaneously hypertensive rat (SHR) NO produced centrally influences the resting arterial blood pressure by attenuating mechanisms involving prostaglandins, angiotensin II, endothelin and sympathetic nervous system. l-NAME (200 μg/5 μl), an inhibitor of NO synthase, administered intracerebroventricularly (i.c.v.) to awake and freely moving rats increased mean arterial blood pressure (MABP) in a biphasic pattern: an early transient increase within 1 min and a late prolonged response starting at 45 min and persisting for the duration of experiment (180 min). The two pressor responses involve different neurochemical mechanisms and, based on their latencies, they appear to reflect different anatomical sites of action of l-NAME. The late, but not the early pressor response, was prevented by pretreatment with chlorisondamine (2.5 mg/kg, i.v.), a ganglionic blocker, indicating its dependence on the sympathetic nervous system. Both pressor responses were abolished by i.c.v. pretreatment with indomethacin (200 μg/5 μl, i.c.v.), an inhibitor of cyclo-oxygenase, showing that they are mediated by prostaglandin(s). In contrast, losartan (25 μg/5 μl), an angiotensin II AT 1 receptor antagonist, had no effect. The initial pressor response was also attenuated by pretreatment with the endothelin ET A/ET B receptor antagonist, PD 145065 (48 μg/2 μl, i.c.v.). Intravenous pretreatment with another ET A/ET B receptor antagonist, L-754,142 (15 mg/kg as a bolus+15 mg/kg/h for 180 min), however, attenuated both responses to l-NAME. It is possible that L-754,142 crossed the blood–brain barrier and blocked, in addition, central ET A/ET B receptors. These studies show that NO synthesized in the brain attenuates pressor mechanisms involving prostaglandin, endothelin and sympathetic nervous system, but not angiotensin II, to modulate resting arterial blood pressure.