REDUCTION OF COLD-INDUCED HYPERTENSION BY ANTISENSE OLIGODEOXYNUCLEOTIDES TO ANGIOTENSINOGEN MESSENGER-RNA AND AT(1)-RECEPTOR MESSENGER-RNAIN BRAIN AND BLOOD

Rats exposed chronically to mild cold (5 degrees C/41 degrees F) devel op hypertension and cardiac hypertrophy. This provides a unique model of hypertension that is environmentally induced. The blood renin-angio tensin system (RAS) has been shown to play a role in both initiating a nd maintaining the high blood pressure (BP) in cold-induced hypertensi on. The mechanism also appears to involve both the tissue and brain RA S because there is increased mRNA for angiotensinogen (AGT) and angiot ensin type 1 (AT(1)) receptors in brain and peripheral tissues, an inc reased spontaneous drinking response, and an increased dipsogenic resp onse to acute administration of angiotensin II (Ang II) in cold-treate d rats. Antisense oligodeoxynucleotides (AS-ODN), targeted to the RAS, have been shown to reduce BP in spontaneously hypertensive rats. Ther efore, we injected AS-ODN in rats with cold-induced hypertension to te st whether antisense inhibition was effective in reducing this nongene tic nonsurgical hypertension. Sprague-Dawley rats were made hypertensi ve by cold exposure and injected intracerebroventricularly with AS-ODN to AGT mRNA (n=6) or AT(1) receptor mRNA (n=6). Systolic BP was recor ded by tail cuff 24 hours later for 2 or 7 days, respectively. Systoli c BP decreased significantly in response to AGT-AS-ODN (40+/-6 mm Hg, P<0.01) within 1 day after injection and to AT(1) receptor-AS-ODN (P<0 .05) for 3 days after injection. The maximum decrease was 41+/-10 mm H g. Systolic BP then gradually increased to the preinjection level. The spontaneous drinking response to cold treatment also decreased signif icantly (P<0.05) after AGT-AS-ODN or AT(1) receptor-AS-ODN intracerebr oventricular injection. Intracardiac injection of AT(1)-AS-ODN (n=6) r educed systolic BP by 36+/-8 mmHg (P<0.05) and decreased AT(1) recepto r as measured by autoradiography in aorta, adrenal glands, and kidneys 24 hours after injection. These data show that AS-ODN reduces BP in c old-induced hypertension and that the hypertension involves both perip heral tissues and central RAS in addition to blood-borne RAS mechanism s.