PREVENTION OF RENOVASCULAR AND CARDIAC PATHOPHYSIOLOGICAL CHANGES IN HYPERTENSION BY ANGIOTENSIN-II TYPE-1 RECEPTOR ANTISENSE GENE-THERAPY

Hypertension produces pathophysiological changes that are often respon sible for the mortality associated with the disease, However, it is un clear whether normalizing blood pressure (BP) with conventional therap y is effective in reversing the pathophysiological damage, The duratio n and initiation of treatment, site of administration, and agent used all appear to influence the reversal of the pathophysiological alterat ions associated with hypertension, We have previously established that retrovirally mediated delivery of angiotensin II type 1 receptor anti sense (AT(1)R-AS) attenuates the development of high BP in the spontan eously hypertensive (SH) rat model of human essential hypertension, Ou r objective was to determine whether this attenuation of high BP is as sociated with prevention of other pathophysiological changes induced b y the hypertensive state, Intracardiac delivery of AT(1)R-AS in neonat es prevented the development of hypertension in SH rats for at least 1 20 days, Contractile experiments demonstrated an impaired endothelium- dependent vascular relaxation (acetylcholine) and an enhanced contract ile response to vasoactive agents (phenylephrine and KCl) in the SH ra t renal vasculature. In addition, the voltage-dependent K+ current den sity, which is believed to contribute to smooth muscle resting membran e potential and basal tone, was decreased in renal resistance artery c ells of the SH rat, AT(1)R-AS treatment prevented each of these renal vascular alterations, Finally, AT(1)R-AS delivery prevented the pathol ogical alterations observed in the SH rat myocardium, including left v entricular hypertrophy, multifocal fibrosis, and perivascular fibrosis , These observations demonstrate that viral-mediated delivery of AT(1) R-AS attenuates the development of hypertension on a long term basis, and this is associated with prevention of pathophysiological changes i n SH rats.