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(Hypertension. 1998;31:1317-1323.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Reduction of Cold-Induced Hypertension by Antisense Oligodeoxynucleotides to Angiotensinogen mRNA and AT₁-Receptor mRNA in Brain and Blood

Jian-Feng Peng; Birgitta Kimura; Melvin J. Fregly¹; ; M. Ian Phillips

From the Department of Physiology, College of Medicine, University of Florida (Gainesville).

Correspondence to Dr M. Ian Phillips, Department of Physiology, Box 100274, College of Medicine, University of Florida, Gainesville, FL 32610. E-mail MIP{at}phys.med.ufl.edu

Abstract—Rats exposed chronically to mild cold (5°C/41°F) develop hypertension and cardiac hypertrophy. This provides a unique model of hypertension that is environmentally induced. The blood renin-angiotensin system (RAS) has been shown to play a role in both initiating and maintaining the high blood pressure (BP) in cold-induced hypertension. The mechanism also appears to involve both the tissue and brain RAS because there is increased mRNA for angiotensinogen (AGT) and angiotensin type 1 (AT₁) receptors in brain and peripheral tissues, an increased spontaneous drinking response, and an increased dipsogenic response to acute administration of angiotensin II (Ang II) in cold-treated rats. Antisense oligodeoxynucleotides (AS-ODN), targeted to the RAS, have been shown to reduce BP in spontaneously hypertensive rats. Therefore, we injected AS-ODN in rats with cold-induced hypertension to test whether antisense inhibition was effective in reducing this nongenetic nonsurgical hypertension. Sprague-Dawley rats were made hypertensive by cold exposure and injected intracerebroventricularly with AS-ODN to AGT mRNA (n=6) or AT₁ receptor mRNA (n=6). Systolic BP was recorded by tail cuff 24 hours later for 2 or 7 days, respectively. Systolic BP decreased significantly in response to AGT–AS-ODN (40±6 mm Hg, P<0.01) within 1 day after injection and to AT₁ receptor–AS-ODN (P<0.05) for 3 days after injection. The maximum decrease was 41±10 mm Hg. Systolic BP then gradually increased to the preinjection level. The spontaneous drinking response to cold treatment also decreased significantly (P<0.05) after AGT–AS-ODN or AT₁ receptor–AS-ODN intracerebroventricular injection. Intracardiac injection of AT₁–AS-ODN (n=6) reduced systolic BP by 36±8 mm Hg (P<0.05) and decreased AT₁ receptor as measured by autoradiography in aorta, adrenal glands, and kidneys 24 hours after injection. These data show that AS-ODN reduces BP in cold-induced hypertension and that the hypertension involves both peripheral tissues and central RAS in addition to blood-borne RAS mechanisms.

Key Words: hypertension, cold-induced • angiotensinogen • angiotensin II • RNA • receptors • antisense elements

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