Nitric oxide synthase inhibition accelerates the pressor response to low-dose angiotensin II, exacerbates target organ damage, and induces renin escape

Abstract

Because nitric oxide may attenuate both the pressor and cytotoxic effects of angiotensin II (Ang II), we investigated whether nitric oxide synthase (NOS) inhibition might accelerate the slow pressor effect of Ang II, and augment target organ damage. Using conscious, chronically catheterized rats, we previously observed that low-dose Ang II (10 ng/kg/min) rapidly increased mean arterial pressure (MAP) by approximately 25 mm Hg. The MAP then remained at this level for 2 to 4 days, and then increased again during the next 5 days by a further 25 mm Hg to a second plateau. In the present study, 7 days of N(omega)-nitro-l-arginine methyl ester (L-NAME; 10 microg/kg/min) alone increased MAP by 16 mm Hg. When Ang II was added to L-NAME, MAP increased as much as with Ang II alone, but then continued to increase until day 4, reaching a plateau as high as that reached only on day 9 of Ang II alone. In approximately half the rats infused with L-NAME + Ang II, plasma renin escaped from Ang II-induced suppression after day 4 of Ang II, and continued to increase for the duration of the study. On the first day that Ang II was added to L-NAME, urinary protein excretion and plasma cardiac troponin T increased, indicating early target organ damage. By the end of the study, all rats treated with L-NAME + Ang II developed tubulointerstitial and glomerular injuries, fibrosis of the renal and cardiac arteries, and cardiac interstitial fibrosis. Target organ damage was greater in rats that developed renin escape than in those in which plasma renin remained suppressed, but was minimal in rats infused with Ang II or L-NAME alone. Taken together, these findings suggest that endogenous NO normally attenuates the pressor response to low-dose Ang II for several days, and protects from Ang II-induced target organ damage. Under conditions of reduced NO bioavailability, which may result from endothelial insufficiency, relatively small changes in circulating Ang II levels may damage target organs. Moreover, renal damage leading to renin escape may initiate a vicious cycle of elevated Ang II production, leading to higher blood pressure and greater target organ damage.

Angiotensin II, interstitial inflammation, and the pathogenesis of salt-sensitive hypertension

“…Thus we can only suggest a defective autoregulatory response to the fall in blood pressure in Sham and ANG IIϩMMF groups, since TGF is the main component of the autoregulatory response. In addition, it should be recognized that while our results suggest that renal ANG II is responsible for the glomerular hemodynamic findings in the salt-driven hypertension that follows exogenous angiotensin administration, the potential role of incomplete suppression of circulating angiotensin levels (12) was not addressed in this investigation.…”

Renal injury in angiotensin II+l-NAME-induced hypertensive rats is independent of elevated blood pressure

“…Although not an extensively studied model of hypertension, previous groups have investigated the chronic effects of ANG IIϩL-NAME administration on renal injury. Hu et al (13) demonstrated that the administration of pressor doses of L-NAME (10 g·kg Ϫ1 ·min Ϫ1 ) in combination with a small dose of ANG II (10 ng· kg Ϫ1 ·min Ϫ1 ) in rats exacerbated both the hypertension and renal injury compared with rats made hypertensive with L-NAME or ANG II alone; however, the magnitude of BP-dependent vs. BPindependent renal injury was not determined. Particularly relevant to the results of our study, Henke et al (12) reported that suppression of endothelial NF-B, a master regulatory transcription factor influencing several potential pathways of injury (i.e., oxidative stress, inflammation, etc.)…”

A new role for vitamin D receptor activation in chronic kidney disease

“…In addition to ANG II, renin may have direct effects to increase proteinuria in CKD, acting through the (pro)rennin receptor (48). Interestingly, the combination of enalapril and paricalcitol showed a larger decrease in renal glomerulosclerosis in experimental CKD, possibly by decreasing TGF-␤ expression and macrophage infiltration (ED1 positive) (78).…”