Peng J F, Kimura B, Fregly M J, Phillips M I
Department of Physiology, College of Medicine, University of Florida, Gainesville 32610, USA.
Hypertension. 1998 Jun;31(6):1317-23. doi: 10.1161/01.hyp.31.6.1317.
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.
长期暴露于轻度寒冷环境（5摄氏度/41华氏度）的大鼠会出现高血压和心脏肥大。这提供了一种由环境诱发的独特高血压模型。血液肾素-血管紧张素系统（RAS）已被证明在冷诱导高血压的起始和维持高血压（BP）过程中均发挥作用。该机制似乎还涉及组织和脑RAS，因为在脑和外周组织中血管紧张素原（AGT）和1型血管紧张素（AT1）受体的mRNA增加，冷处理大鼠的自发饮水反应增加，并且对急性给予血管紧张素II（Ang II）的致渴反应增加。已证明靶向RAS的反义寡脱氧核苷酸（AS-ODN）可降低自发性高血压大鼠的血压。因此，我们向冷诱导高血压大鼠注射AS-ODN，以测试反义抑制在降低这种非遗传性非手术性高血压方面是否有效。通过冷暴露使Sprague-Dawley大鼠患高血压，并向AGT mRNA（n = 6）或AT1受体mRNA（n = 6）的大鼠脑室内注射AS-ODN。分别在24小时后通过尾袖法记录收缩压2天或7天。注射后1天内，AGT-AS-ODN使收缩压显著降低（40±6 mmHg，P<0.01），注射后3天内，AT1受体-AS-ODN使收缩压显著降低（P<0.05）。最大降幅为41±10 mmHg。然后收缩压逐渐升至注射前水平。脑室内注射AGT-AS-ODN或AT1受体-AS-ODN后，对冷处理的自发饮水反应也显著降低（P<0.05）。心内注射AT1-AS-ODN（n = 6）使收缩压降低36±8 mmHg（P<0.05），并在注射24小时后通过放射自显影法测量主动脉、肾上腺和肾脏中的AT1受体减少。这些数据表明，AS-ODN可降低冷诱导高血压中的血压，并且除了血源性RAS机制外，高血压还涉及外周组织和中枢RAS。
