S-51-6: RENOVASCULAR HYPERTENSION AND BRAIN: ROLE OF THE RENIN-ANGIOTENSIN SYSTEM AND SODIUM

Abstract

Renovascular hypertension is a type of secondary hypertension. Renovascular hypertensive 2-kidney, 1-clip (2K1C) rats have an increased activity of the renin-angiotensin system, and it is an experimental model to study renovascular hypertension. Renovascular hypertensive 2K1C rats have an imbalance of RAS components in the brain, an impairment of the baroreflex and they present an increase in daily intake of hypertonic NaCl solution. Therefore, we focused on studying: 1) the effects of overexpression of RAS components in the in the nucleus of the solitary tract (NTS), a brainstem area involved with cardiovascular control, 2) the brain mechanisms involved with the sodium appetite (operationally defined as an ingestion of hypertonic NaCl solution) in 2K1C rats. In adult Holtzman rats, the left renal artery was partially occluded by a silver clip with an opening of 0.2 mm to induce 2K1C. The experiments started after 6 weeks (hypertension plateau). We observed that increasing angiotensin type 2 receptor (AT2R) expression in the NTS attenuated the development of renovascular hypertension and also reversed the impairment of the baroreflex observed in 2K1C rats. Furthermore, an observed decrease in mRNA levels of angiotensin-converting enzyme 2 in the NTS of 2K1C rats was restored to control levels after viral-mediated increases in AT2R at this site. Virally mediated blockade of an intracellular pathway activated by angiotensin II (ANG II) acting in type 1 receptor (AT1R) in the NTS attenuated the development of renovascular hypertension and also reversed the impairment of the baroreflex. Daily 0.3 M NaCl intake transiently increased from the 2nd to the 5th week after 2K1C surgery. On the 6th week, in spite of comparable daily 0.3 M NaCl intake between 2K1C and sham rats, water deprivation (used to induce sodium appetite) produced a greater increase 0.3 M NaCl intake in 2K1C rats. Moreover, this intake is totally blocked by central AT1R and mineralocorticoid receptor antagonism. These data demonstrated that ANG II acting in the AT1R in the NTS is involved with the development of hypertension and baroreflex impairment in 2K1C and that AT2 overexpression at the same site can counteract these effects. In addition, the results demonstrated the participation of ANG II and aldosterone acting centrally in the enhanced sodium intake in water deprived 2K1C rats.