These data suggest that increased myocyte length (an intracellular event), instead of myocyte slippage (an extracellular event), is largely responsible for the chamber dilation in ICM. Furthermore, maladaptive remodeling of myocyte shape (e.g., increased myocyte length/width ratio) may contribute to the elevated wall stress (e.g., increased chamber radius/wall thickness) in ICM.
Hypertension produces pathophysiological changes that are often responsible for the mortality associated with the disease. However, it is unclear whether normalizing blood pressure (BP) with conventional therapy is effective in reversing the pathophysiological damage. The duration and initiation of treatment, site of administration, and agent used all appear to inf luence the reversal of the pathophysiological alterations associated with hypertension. We have previously established that retrovirally mediated delivery of angiotensin II type 1 receptor antisense (AT 1 R-AS) attenuates the development of high BP in the spontaneously hypertensive (SH) rat model of human essential hypertension. Our objective was to determine whether this attenuation of high BP is associated with prevention of other pathophysiological changes induced by the hypertensive state. Intracardiac delivery of AT 1 R-AS in neonates prevented the development of hypertension in SH rats for at least 120 days. Contractile experiments demonstrated an impaired endothelium-dependent vascular relaxation (acetylcholine) and an enhanced contractile response to vasoactive agents (phenylephrine and KCl) in the SH rat renal vasculature. In addition, the voltage-dependent K ؉ current density, which is believed to contribute to smooth muscle resting membrane potential and basal tone, was decreased in renal resistance artery cells of the SH rat. AT 1 R-AS treatment prevented each of these renal vascular alterations. Finally, AT 1 R-AS delivery prevented the pathological alterations observed in the SH rat myocardium, including left ventricular 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 in SH rats.The elevation of systemic blood pressure (BP) associated with hypertension is a risk factor for cardiovascular disease and renal failure. Often it is the pathophysiological alterations and impairments associated with hypertension that lessen life expectancy. Pharmacological intervention has been relatively successful in normalizing the elevation in BP. However, the assumption that reduction of BP will totally reverse hypertension-induced pathophysiological changes remains unclear (1-4).The duration of treatment, age at which the antihypertensive therapy is initiated, site of administration, and specific agent used all appear to influence the reversal of the pathophysiological alterations associated with the disease (5-7). In some instances, reversal of pathophysiological alterations may even be unfavorable, such as when regression of left ventricular hypertrophy and peripheral resistance occur in a disproportionate manner (8). Similarly, other reports have indicated that traditional antihypertensive agents can contribute to target organ injury by altering metabolic processes (i.e., hypercholesterolemia, glucose intolerance, hyperkalemia).A...
Abstract-Intracellular Ca 2ϩ ([Ca 2ϩ ] i ) homeostasis regulates vascular smooth muscle tone, and alteration in [Ca 2ϩ ] 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 (AT 1 R-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 AT 1 R-AS gene therapy (1) could have a longer duration in the prevention of hypertension and (2) Key Words: angiotensin II Ⅲ arterioles Ⅲ calcium, intracellular Ⅲ Ca 2ϩ current Ⅲ excitation-contraction coupling Ⅲ gene therapy E ssential hypertension is characterized by normal cardiac output and an increase in total peripheral resistance. 1 Hypertension is one of the most important risk factors for stroke, congestive heart failure, myocardial infarction, endstage renal diseases, and peripheral vascular disease. 2-4 Studies from the last 2 decades have established that both circulating and tissue renin-angiotensin systems (RAS) are important, that their coordinated interaction is essential in the regulation of blood pressure, and that they play a key role in the development, establishment, and maintenance of hypertension. 2,5,6 The relevance of the RAS to blood pressure control is further supported by reports that various genes that encode renin, angiotensinogen, angiotensin-converting enzyme (ACE), and the angiotensin II type 1 receptor (AT 1 R) have been associated with hypertension in both human and animal models. 7-9 Additionally, interruption in the expression of the RAS attenuates high blood pressure and other pathophysiological aspects of hypertension. 4,10,11 In fact, blockade of the RAS has become a well-accepted treatment for Angdependent hypertension and congestive heart failure. 11 Because ACE inhibition and AT 1 R blockade are standard means to treat hypertension and because AT 1 R encoding gene polymorphism is coupled with hypertension in both humans and in animal models of hypertension, 6,9 it would appear only logical that AT 1 R is an important target in the management of high blood pressure. Although major strides have been made in developing drugs that interfere with either angiotensin II (Ang II) formation or its action toward the management of Ang-dependent hypertension, there is neither a long-term preventive measure nor a cure for this disease.The most widely used animal model for studying human essential hypertension is the spontaneously hypertensive rat (SHR). Pharmacological intervention has been relatively
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