Angiotensin I–Converting Enzyme Antisense Prevents Altered Renal Vascular Reactivity, but Not High Blood Pressure, in Spontaneously Hypertensive Rats

Abstract

Abstract-The renin-angiotensin system plays a critical role in the control of blood pressure, and its hyperactivity is associated with the development of human primary hypertension. Because low-dose angiotensin I-converting enzyme (ACE) inhibitors cause small reductions in blood pressure that are associated with the complete reversal of altered vascular pathophysiology, our objective in this study was to determine whether ACE antisense (ACE-AS) gene delivery prevents alterations in renal vascular physiology in the parents and F 1 offspring of AS-treated spontaneously hypertensive rats (SHR). A single bolus intracardiac injection of ACE-AS (2ϫ10 8 colony-forming units) in SHR neonates caused a modest (18Ϯ3 mm Hg, nϭ7 to 9) lowering of blood pressure, which was maintained in the F 1 generation offspring (nϭ7 to 9). Alterations in renal vascular reactivity, electrophysiology, and [Ca 2ϩ ] i homeostasis are underlying mechanisms associated with the development and establishment of hypertension. Renal resistance arterioles from truncated ACE sense-treated SHR showed a significantly enhanced contractile response to KCl and phenylephrine (nϭ24 rings from 6 animals, PϽ0.01) and significantly attenuated acetylcholine-induced relaxations (nϭ24 rings from 6 animals, PϽ0.01) compared with arterioles from ACE-AS-treated SHR. In addition, compared with cells dissociated from arterioles of ACE-AS-treated SHR, cells from truncated ACE sense-treated animal vessels had a resting membrane potential that was 22Ϯ4 mV more depolarized (nϭ38, PϽ0.01), an enhanced L-type Ca 2ϩ current density Key Words: hypertension, renal Ⅲ calcium channels Ⅲ potassium channels Ⅲ arterioles Ⅲ gene therapy H ypertension is a complex disease that is manifested as chronically high blood pressure (BP) and is a major risk factor in many cardiovascular pathophysiological states, including arteriosclerosis, stroke, heart failure, coronary artery disease, and progressive renal damage. 1-3 Evidence has established that a dysfunctional renin-angiotensin system (RAS) is one of the many physiological alterations that contribute to the development and maintenance of hypertension. 4 -6 This is based on the fact that pharmacological interruption in the activity of the RAS has proven to be highly successful in the treatment and management of hypertension in a significant population of hypertensive patients. 7-10 However, this pharmacological intervention has major limitations, which include compliance, side effects, and relatively short duration of antihypertensive effects. 11,12 As a result of these limitations, we have begun to use an antisense (AS) gene therapy approach to determine whether targeting RAS at a genetic level would be a step forward in the long-term control of hypertension. These studies have revealed that a single intracardiac administration of retroviral vector containing angiotensin II type 1 receptor (AT 1 R) AS results in long-term prevention of high BP in the spontaneously hypertensive rat (SHR), which is an animal model associated with stud...

Gene Therapy for Cardiovascular Disease

“…Retroviral-mediated ACE antisense delivery in SHR elicited a modest antihypertensive response lasting up to 100 days. 63 An optimistic evaluation of these results is tempered by the transient and modest nature of the therapeutic response. This may reflect the multifactorial nature of the disease as well as limited gene transfer efficiency.…”

Gene therapy for hypertension and restenosis

“…This effect persisted for 100 days. [42][43][44] More interestingly, pathophysiological changes such as ventricular hypertrophy, endothelial dysfunction, increased vascular reactivity, and ion channel activity were prevented. These results provide experimental data to support the results of the HOPE trial and for the participation of the RAAS at the tissue level in the pathophysiology of hypertension.…”

“…Perhaps the most impressive example of the power of antisense gene therapy directed at the RAAS is seen in the F 1 and F 2 generations offspring of ACE-or AT 1 -receptor-AS treated SHR adults. 43,44 The F 1 and F 2 generations have lower blood pressure and normal renal artery excitation-contraction coupling, Ca 2+ current, membrane potential, Kv current and intracellular Ca 2+ concentration when compared with offspring of SHR treated with virus only. Additionally, the offspring exhibit none of the cardiovascular remodelling normally associated with hypertension.…”