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Endothelial‐Independent Prevention of High Blood Pressure in L‐Name‐Treated Rats by Angiotensin II type I Receptor Antisense Gene Therapy
Author(s) -
Reaves Phyllis Y.,
Beck Caren R.,
Wang HongWei,
Raizada Mohan K.,
Katovich Michael J.
Publication year - 2003
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/eph8802579
Subject(s) - medicine , endocrinology , angiotensin ii , blood pressure , renin–angiotensin system , phenylephrine , endothelial dysfunction , muscle hypertrophy , left ventricular hypertrophy , endothelium , angiotensin receptor
It has previously been established that a single systemic administration of retroviral vector containing angiotensin II type I receptor antisense (AT 1 R‐AS) in the neonatal spontaneously hypertensive rat (SHR) prevents development of hypertension, and in addition cardiac hypertrophy and endothelial dysfunction. However, these studies could not determine whether the effects of AT 1 R‐AS on high blood pressure (BP) and endothelial function were independent. Angiotensin receptor blockers have been shown to reduce BP in the L‐NAME (N ω ‐nitro‐L‐arginine methyl ester hydrochloride)‐induced rat model of hypertension. Our objective in the present study was to use the L‐NAME model of hypertension to determine whether AT 1 R‐AS treatment would lower high BP and attenuate cardiac hypertrophy under conditions of permanent endothelial damage. A single bolus of LNSV‐AT 1 R‐AS viral particles in neonatal Wistar‐Kyoto (WKY) rats was without affect on basal BP. Efficacy of the transgene incorporation was assessed by observing a significant reduction in angiotensin‐induced dipsogenic response in the AT 1 R‐AS‐treated animals. Introduction of L‐NAME in the drinking water for 10 weeks resulted in the establishment of hypertension only in the WKY rats treated with vector alone. These hypertensive (BP, 179 ± 4 mmHg) animals showed a 17% increase in heart weight/body weight ratio and a 60% reduction in ACh‐induced vasorelaxation in phenylephrine‐preconstricted arteries. The L‐NAME‐induced high BP and cardiac hypertrophy were attenuated in rats expressing AT 1 R‐AS. However, endothelial dysfunction could not be prevented with the antisense therapy. These observations demonstrate that attenuation of endothelial dysfunction is not a prerequisite for the antihypertensive effects of AT 1 R‐AS treatment.