Nitric Oxide in the Renal Medulla Protects From Vasopressin-Induced Hypertension

Abstract

Abstract-In the present study, we assessed whether activation of the nitric oxide (NO) system within the renal medulla could serve as a buffer against the chronic hypertensive effects of arginine vasopressin (AVP). NO concentration in the renal medulla of Sprague-Dawley rats was measured with in vivo microdialysis/oxyhemoglobin NO trapping. The results showed that medullary interstitial [NO] was increased after 2 hours of AVP infusion and remained elevated even after 10 days (by 62Ϯ8% and 42Ϯ13%, respectively). Western blot analysis showed that 2 days of AVP infusion was insufficient to increase protein expression of any of the NO synthase (NOS) isoforms, but after 10 days of AVP infusion, endothelial NOS expression was significantly increased in the inner medulla with no significant changes in noninducible NOS and inducible NOS levels. When renal medullary NOS enzyme activity was blunted with a nonpressor dose of) that was chronically infused locally into the renal medulla, intravenous AVP infusion (which was shown earlier to be subpressor in chronic studies) produced a sustained elevation in arterial pressure (from 107Ϯ2 to 121Ϯ2 mm Hg). These data indicate that chronic elevations in plasma AVP enhance renal medullary endothelial NOS protein expression, which enables sustained elevations of NO concentrations in this region of the kidney to buffer the hypertensive effects of AVP. Key Words: arterial pressure Ⅲ kidney Ⅲ vasopressins Ⅲ nitric oxide Ⅲ endothelium Ⅲ nitric oxide synthase Ⅲ arginine A rginine vasopressin (AVP) is one of the most potent circulating vasoconstrictor hormones, 1-6 and it has long been recognized as the antidiuretic hormone. 2 Its combined vasoconstrictor and volume-retaining actions suggest that chronic elevations in circulating AVP should result in hypertension. Hypertension would also be predicted on the basis of observations that small elevations in AVP can significantly reduce medullary blood flow (MBF) and blunt pressure natriuresis, 4,6 both of which generally lead to hypertension. 3 However, AVP does not produce sustained hypertension in normal rats, dogs, or humans 3,7,8 maintained on a normal sodium intake.Recent studies in conscious rats in which changes in regional renal blood flow were determined with laser-Doppler flowmetry provide, in part, an answer to this puzzle. It was found that although AVP produced immediate reductions in MBF, the reductions were not sustained during a chronic 5-day medullary interstitial infusion of AVP, nor was hypertension observed. 8 In contrast, a medullary infusion of a vasopressin V 1 receptor (V 1 R) agonist produced a sustained reduction in MBF with a corresponding chronically sustained increase in mean arterial pressure (MAP). The results of these studies suggested that a parallel stimulation of both V 1 R and vasopressin V 2 receptors (V 2 Rs) with endogenous AVP resulted in an increase in a V 2 R-induced counterregulatory system. This was shown to be a V 2 R-mediated increase in medullary nitric oxide (NO) production. 9 These studies al...

Role of renal NO production in the regulation of medullary blood flow

“…Also shown in Fig. 7, hypertension occurred associated with sustained reductions of MBF (not shown) only when medullary NOS activity was blunted by the medullary interstitial infusion of L-NAME (116,117).…”

“…However, as seen in Fig. 7, in rats that received the subpressor chronic medullary infusion of L-NAME, AVP led to a sustained elevation of blood pressure (117). Similar studies were carried out to determine the responses to chronic intravenous infusions of subpressor doses of ANG II (116) and NE (118).…”

“…A dose of L-NAME (75 g ⅐ kg Ϫ1 ⅐ h Ϫ1 ) was used that did not reduce basal MBF Ͼ5% when administered into the medullary interstitial space chronically for 2 wk (118). The same dose of L-NAME that significantly attenuated acute increases of medullary [NO] produced by intravenous infusions of subpressor amounts of ANG II, NE, and AVP (116)(117)(118). Doses of ANG II (3.0 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ), NE (0.1 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ), and AVP (2.0 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) were determined that when administered intravenously did not result in elevations of mean arterial pressure Ͼ5 mmHg when infused for 5-7 days to normal Sprague-Dawley rats (see Fig.…”

“…Influence of NO blockade by L-NAME delivered chronically into the renal interstitium on the blood pressure response to vasoconstrictors given intravenously. MAP was normalized to allow comparison between the individual studies using nonpressor doses of ANG II (116), NE (118), and arginine vasopressin (117). F, Saline ri; E, L-NAME ri.…”

Physiology of the renal medullary microcirculation

“…NO generation may be important to abrogate tissue hypoxia that would otherwise arise from release of vasoconstrictors. ANG II, norepinephrine, and vasopressin stimulate release of NO in the medulla (121,150,151,181,185). Subpressor infusion of N G -nitro-Larginine methyl ester into the renal interstitium does not affect medullary blood flow or PO 2 but enables otherwise ineffective doses of ANG II (185) norepinephrine (151,181), or vasopressin (150) to induce a fall in these parameters.…”