Angiotensin II type 1 receptor antisense gene therapy prevents altered renal vascular calcium homeostasis in hypertension

Abstract

Intracellular Ca2+ ([Ca2+](i)) homeostasis regulates vascular smooth muscle tone, and alteration in [Ca2+](i) handling is associated with the development and establishment of hypertension. We have previously established in the spontaneously hypertensive rat (SHR) that virally mediated delivery of angiotensin II type 1 receptor antisense (AT1R-AS) prevents the development of high blood pressure and some pathophysiology associated with hypertension for 120 days. In light of this, our objectives in this study were to determine whether AT1R-AS gene therapy (1) could have a longer duration in the prevention of hypertension and (2) would attenuate the alterations in renal vascular Ca2+ homeostasis and therefore vasoconstriction, characteristics of hypertension. Intracardiac delivery of AT1R-AS in neonates prevented the development of hypertension in SHR for at least 210 days. At this time, untreated SHR renal resistance arterioles showed a significantly enhanced contractile response to KCl and angiotensin II (Ang II) when compared with normotensive Wistar-Kyoto rats. In addition, L-type Ca2+ current density and Ang II-dependent increases in [Ca2+](i) were significantly increased in cells dissociated from renal resistance arterioles of the untreated SHR. AT1R-AS treatment prevented all of the above vascular alterations associated with the hypertensive state in SHR. Finally, Western blot analysis of L-type Ca2+ channel (α(1C)) protein levels in renal resistance arterioles of untreated SHR showed no significant difference when compared with control. These results are novel and demonstrate that viral- mediated delivery of AT1R-AS not only attenuates the development of hypertension on a long-term basis but prevents changes in renal vascular Ca2+ homeostasis associated with the disease.