Sensitization of Slow Pressor Angiotensin II (Ang II)–Initiated Hypertension

Abstract

Sensitization involving the central nervous system has been studied in many conditions but has received little attention in investigation of the pathogenesis of hypertension. Our experiments were initiated to determine whether angiotensin II (Ang II)–induced hypertension can be sensitized by prior Ang II treatment and the role of the brain renin-angiotensin-aldosterone system (RAAS) in this process. To demonstrate Ang II–induced sensitization, we used an experimental design of induction-delay-expression. Male rats were implanted for telemetered blood pressure (BP) recording. During induction (I), low doses of subcutaneous or intracerebroventricular Ang II were delivered for 1 week, and then the rats were rested for 1 week (delay [D]) to ensure that any exogenous Ang II was metabolized. After this, a second higher dose of Ang II was given subcutaneously for 2 weeks (expression [E]). During I and D, the low doses of Ang II had no sustained effects on BP. However, during E, the Ang II–induced BP increase was greater in the groups that had received low doses of Ang II during I in comparison to the group receiving saline during I. Central angiotensin type 1 receptor antagonist delivery blocked this sensitization. Brain tissue collected at the end of D and E showed increased mRNA expression of several RAAS components in key forebrain regions of sensitized rats. Fos-related antigen–like immunoreactivity was also increased at the end of E in the sensitized forebrain. These results indicate that subpressor doses of Ang II act on the brain to sensitize the hypertensive response to subsequent Ang II and that sensitization is associated with altered expression of RAAS components in forebrain cardiovascular control structures.