: Angiotensin II (Ang II) type I (AT1) receptor antagonists are the most recent addition to the arsenal of drugs used n treating hypertension and associated cardiovascular disease. Although these pharmaceutical agents also elicit large increases in circulating Ang II, clinical trials indicate no serious side effects associated with raised levels of this hormone. In fact, recent studies have suggested that this AT, receptor antagonist-induced increase in plasma Ang II may be cardioprotective via its vasodilatory actions mediated by Ang II type 2 (AT2) receptor. Indeed, gene """"""""knockout' studies indicate that mutant mice lacking the AT2 receptor exhibit increased basal BP and pressor responses to Ang II. We have used a novel approach to """"""""knockdown"""""""" AT2R by in vivo gene transfer technology to further support this view. Based upon this and the fact that AT2 receptors are predominant in neonatal expression of AT2 receptors, we have developed the following hypotheses concerning the roles of AT2 receptors in cardiovascular regulation. We propose that in neonatal rats AT2 receptors participate in normal development of the cardiovascular system and allow it to operate within physiological boundaries throughout life. WE further propose that this includes a vasodilatory counterbalance to the AT1 receptor-mediated pressor actions of Ang II, Thus, """"""""knocking down"""""""" AT2 receptors in neonatal life with AT2R-AS would allow vasoconstrictor mechanisms to predominate, resulting in increased basal blood pressure (BP) and pressor responses in adults. Conversely, over expression of AT2 receptors in neonatal life with AT2R-5 would allow vasodilator mechanisms to predominate, resulting in decreased pressor responses in adults. Finally, we propose that BP can be lowered in SHR rats by over expression of AT2 receptor5 in neonatal life. We will test these hypotheses using a combination of molecular, in vitro and in vivo physiological approaches, centered around the retroviral delivery of AT2R-AS and AT2 receptor sense (AT2R-S) into young rats to elicit maximal effects on AT2 receptors.
The specific aims are as follows:
Aim 1 : To determine the optimal conditions for modulation of AT2 receptor function in vitro.
Aim 2 : To define the physiological role of the AT2 receptor in the cardiovascular system by utilizing systemic delivery of AT2R-AS in the young rat.
Aim 3 : To investigate whether over expression of AT; receptors in young rats attenuates the development of hypertension. The proposal is innovative in its approach because it will allow, for the first time, an in depth analysis of the functions of the AT2 receptor in a relatively normal setting, without germ line manipulation. We believe that the studies are low risk in nature and will have a high impact on the development of new strategies based on gene targeting, for the treatment of hypertension and cardiovascular disease.
