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

Intracellular Ca2+ ([Ca2+](i)) homeostasis regulates vascular smooth muscle tone, and alteration in [Ca2+](i) handling is associated with the developm ent and establishment of hypertension. We have previously established in th e spontaneously hypertensive rat (SHR) that virally mediated delivery of an giotensin II type 1 receptor antisense (AT(1)R-AS) prevents the development of high blood pressure and some pathophysiology associated with hypertensi on for 120 days. In light of this, our objectives in this study were to det ermine whether AT(1)R-AS gene therapy (1) could have a longer duration in t he prevention of hypertension and (2) would attenuate the alterations in re nal vascular Ca2+ homeostasis and therefore vasoconstriction, characteristi cs of hypertension, Intracardiac delivery of AT(1)R-AS in neonates prevente d the development of hypertension in SHR for at least 210 days. At this tim e, untreated SHR renal resistance arterioles showed a significantly enhance d contractile response to KCl and angiotensin II (Ang II) when compared wit h 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. A T(1)R-AS treatment prevented all of the above vascular alterations associat ed with the hypertensive state in SHR. Finally, Western blot analysis of L- type Ca2+ channel (alpha(1C)) protein levels in renal resistance arterioles of untreated SHR showed no significant difference when compared with contr ol. These results are novel and demonstrate that viral-mediated delivery of AT(1)R-AS not only attenuates the development of hypertension on a long-te rm basis but prevents changes in renal vascular Ca2+ homeostasis associated with the disease.