Endothelial-independent prevention of high blood pressure in L-NAME-treated rats by angiotensin II type I receptor antisense gene therapy.
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 (omega)-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.
Reaves
Phyllis Y
PY
Department of Physiology and Functional Genomics, Colleges of Medicine and Pharmacy, University of Florida, Gainesville, FL 32610, USA.
Beck
Caren R
CR
Wang
Hong-Wei
HW
Raizada
Mohan K
MK
Katovich
Michael J
MJ
D000818:Animals; D006332:Cardiomegaly / Q000517:prevention & control / Q000628:therapy; D016373:DNA, Antisense; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors; D015316:Genetic Therapy; D006973:Hypertension / Q000139:chemically induced / Q000517:prevention & control* / Q000628:therapy*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D051381:Rats; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics
D016373:DNA, Antisense; D004791:Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D019331:NG-Nitroarginine Methyl Ester