An extension of Satterthwaite's approximation applied to pharmacokinetics

Central inhibition of nitric oxide synthase (NOS) by intracerebroventricular (i.c.v.) administration of NG-nitro-l-arginine methyl ester (L-NAME; 150 microg/5 microl) to conscious rats produced a biphasic pressor response characterized by an initial transient increase within 5 min, and a delayed response starting between 60-90 min. The effect was stereospecific, as D-NAME (250 microg/5 microl) did not modify the resting arterial blood pressure, nor did L-arginine (323 microg/5 microl, i.c.v.), indicating the substrate for NOS is not rate-limiting. Intracerebroventricular pretreatment with losartan (25 microg/5 microl), a non-peptide antagonist of the angiotensin II AT1 receptor subtype, or indomethacin (100 microg/5 microl), a blocker of cyclooxygenase, however, prevented the initial increase in blood pressure without affecting the delayed pressor response. In contrast, neither intravenous losartan (10 mg/kg b.wt) nor prazosin, an alpha1 adrenergic receptor antagonist, at doses of 5 microg/5 microl (i.c.v.) or 0.3 mg/kg b.wt (i.v.) were effective in altering the pressor responses. These results indicate that centrally produced NO maintains the resting arterial blood pressure at least partially through modulation of the brain angiotensin system and prostaglandins.