The renal vascular response to ANG II injection is reduced in the nonclipped kidney of two-kidney, one-clip hypertension

Abstract

1R) level in the nonclipped kidney of twokidney, one-clip hypertension (2K1C) has shown to be unchanged despite a high circulating angiotensin (ANG) II level. To examine the vasoreactive response to ANG II in this kidney, injections of ANG II into renal artery were performed 6 wk after clipping of the kidney and compared with normotensive controls. The renal blood flow (RBF) response to 2.5 ng ANG II was measured by a Transonic transit-time flowmeter, before and after indomethacin and candesartan treatment, and analyzed by a computer program. The RBF response to 5 ng arginine-vasopressin (AVP) was examined for comparison with ANG II. The mRNA for AT 1A and AT1B as well as Western blotting for AT 1R in renal resistance vessels were determined, and plasma renin activity (PRA) was measured. Systolic blood pressure was 183 Ϯ 4 mmHg in 2K1C rats compared with 113 Ϯ 1 mmHg in controls (P Ͻ 0.001). PRA was significantly increased in 2K1C animals (P Ͻ 0.05). Injection of ANG II reduced RBF with 10 Ϯ 2% in the nonclipped kidney and 24 Ϯ 3% in controls (P Ͻ 0.001). After indomethacin, the RBF response increased from 10 Ϯ 2 to 20 Ϯ 3% (P Ͻ 0.02) in 2K1C rats and from 24 Ϯ 3 to 34 Ϯ 6% in controls (P Ͻ 0.01). The doses of candesartan needed to completely inhibit RBF response to ANG II were 30 g/kg in the nonclipped kidney and 100 g/kg in controls (P Ͻ 0.001). Western blotting and mRNA for AT 1A and AT1B in the nonclipped kidney were similar to the controls. The results indicate that despite no difference in total AT 1R levels, functional AT1R is downregulated in the nonclipped kidney of 2K1C rats. plasma renin activity; AT 1 receptor; renal blood flow; blood pressure TWO-KIDNEY, ONE-CLIP (2K1C) hypertension is an angiotensin II (ANG II)-dependent model of hypertension, and plasma as well as intrarenal ANG II concentrations are increased (14, 15). Removal of the clip is followed by rapid reversal of high blood pressure with normalization of renin values (14, 15). ANG II mediates its effect in the renal vasculature through two main G-coupled receptors, the AT 1 (AT 1 R) and AT 2 receptors, where AT 1 R mediates the vascular constrictor effects of ANG II (2). The rat has two types of AT 1 receptors, the AT 1A and AT 1B receptors (AT 1A and AT 1B ), which have 95% homology in their receptor amino acid sequences (16). The AT 2 receptor has only 34% homology with the AT 1 R and is expressed at a low level, particularly in the renal vasculature (7).The AT 1A receptor plays an essential role in the development of 2K1C hypertension, as knockout mice lacking this receptor do not develop hypertension (3). Usually AT 1A is downregulated when the ANG II levels are high, as during a low-salt diet, and upregulated when ANG II levels are low, as in high salt intake (25). In the nonclipped kidney, reports indicate that the modulation of the AT 1 R is different from controls and this seems also to be the case during long-term infusion of ANG II (13). The data concerning regulation of the AT 1 R in the nonclipped kidney are, however, contro...

Differential effect of tetradecythioacetic acid on the renin-angiotensin system and blood pressure in SHR and 2-kidney, 1-clip hypertension

“…Simultaneously, the mean arterial pressure (MAP) was also recorded and renal vascular resistance (RVR) was calculated based on RBF and MAP, using BOLUS program, customized software for the automated analysis of data. The experimental procedure has been described before (5). In short, anesthesia was induced by an intraperitoneal injection of pentobarbital sodium (65 mg/kg body wt) and the animals were placed on a servo-controlled heating table to keep the body temperature at 38°C.…”

“…ANG II in the nonclipped kidney of 2K1C-hypertensive has been shown before (5). It might be due to increased endogenous ANG II concentration with reduced number of available AT1 receptors and attenuated renal vascular response as a result.…”

Angiotensin II-induced calcium signaling in the afferent arteriole from rats with two-kidney, one-clip hypertension

“…Studies from our laboratory recently showed decreased responses in RBF to renal ANG II injections in the nonclipped kidney of 2K1C compared with control animals, although the preglomerular AT 1a R levels ex vivo seem to be unchanged (2). The reason for this apparent dysregulation is unclear, and further investigations are needed.…”

New insights into the importance of aminopeptidase A in hypertension

“…This results in elevated plasma renin activity and an increase in blood pressure mediated by facilitated conversion of AngI to AngII [45]. Circulating levels of renin and AngII are transiently elevated during the initial acute stage, subside during the intermediate stage, and then once again increase and remain elevated during the chronic maintenance stage.…”

“…These investigators also reported that isolated glomeruli from the groups with increased APA expression metabolized AngII to a greater extent. Recently, Bivol and colleagues [45] have noted that in the established stage of the Goldblatt hypertensive model the vascular response to AngII injection in the non-clipped kidney was substantially reduced despite normal vascular levels of AT 1 R expression. This could be due to increased APA levels as reported by Wolf et al [48,49].…”