Responses to central NA+ and ouabain are attenuated in transgenic rats deficient in brain angiotensinogen

Abstract

Studies with angiotensin (Ang) II type 1 receptor blockers suggest that the brain renin-angiotensin system contributes to sodium-induced sympathoexcitation and hypertension. To provide more specific evidence for the involvement of Ang II, locally produced in the brain, transgenic rats were used, which express an antisense RNA against angiotensinogen mRNA specifically in the brain, reducing angiotensinogen levels in the brain by >90%. In freely moving transgenic rats and Sprague-Dawley rats as control animals, blood pressure and heart rate responses to intracerebroventricular infusion (3.8 μL/min for 10 minutes) of artificial cerebrospinal fluid and Na+-rich artificial cerebrospinal fluid (containing 0.2, 0.3, and 0.45 mol/L Na+) as well as intracerebroventricular injection of ouabain (0.3 and 0.6 μg/2 μL) were assessed. Central infusion of Na+-rich artificial cerebrospinal fluid increased blood pressure and heart rate in a dose-related manner. However, the peak increases by each dose of Na+ were attenuated by 50% to 70% in the transgenic versus Sprague-Dawley rats. Increases in blood pressure and heart rate in response to ouabain at both doses were attenuated by 55% to 70% in the transgenic versus Sprague-Dawley rats. In the hypothalamus, Ang I level was markedly lower (31±9 versus 76±13 pg/g, P