Reduction of cold-induced hypertension by antisense oligodeoxynucleotides to angiotensinogen mRNA and AT1-receptor mRNA in brain and blood.
Rats exposed chronically to mild cold (5 degrees C/41 degrees 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.
Peng
J F
JF
Department of Physiology, College of Medicine, University of Florida, Gainesville 32610, USA.
Kimura
B
B
Fregly
M J
MJ
Phillips
M I
MI
D000311:Adrenal Glands / Q000378:metabolism; D000803:Angiotensin I / Q000235:genetics*; D000804:Angiotensin II / Q000008:administration & dosage; D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D016375:Antisense Elements (Genetics); D001011:Aorta / Q000378:metabolism; D001345:Autoradiography; D001769:Blood / Q000378:metabolism; D001794:Blood Pressure; D001921:Brain / Q000378:metabolism*; D003080:Cold Temperature / Q000009:adverse effects*; D004326:Drinking; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D007668:Kidney / Q000378:metabolism; D008297:Male; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000502:physiology; D013997:Time Factors
D016375:Antisense Elements (Genetics); D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D000808:Angiotensinogen; D000804:Angiotensin II; D000803:Angiotensin I