Long-term intensive BP lowering in the hypertensive patients was associated with a significant reduction in aortic stiffness distinct from its acute depressor effect.

Abstract-This study was designed to determine the influence of increased superoxide anion in neuronal nitric oxide synthase (nNOS)-dependent regulation of afferent arterioles in spontaneously hypertensive rats (SHR). Afferent arteriolar diameters of male Wistar-Kyoto rats (WKY) and SHR were assessed in vitro with the blood-perfused juxtamedullary nephron technique and averaged 21.6Ϯ1.6 (nϭ6) and 18.8Ϯ1.2 (nϭ7) m, respectively. The superoxide dismutase mimetic Tempol (1, 10, and 100 mol/L) did not influence afferent arterioles of WKY but significantly increased afferent arteriolar diameters of SHR by 20.6Ϯ5.5%, 25.2Ϯ5.4%, and 23.3Ϯ4.9%, respectively. In WKY (nϭ6), the nNOS inhibitor S-methyl-L-thiocitrulline (L-SMTC; 10 mol/L) and the NOS inhibitor N -nitro-L-arginine (L-NNA; 100 mol/L) significantly decreased afferent arteriolar diameters (19.6Ϯ1.6 m) by 11.9Ϯ3.1% and 21.0Ϯ3.9%, respectively. In SHR (nϭ7), L-SMTC did not influence afferent arteriolar diameters (21.0Ϯ1.5 m), but L-NNA exerted an afferent arteriolar constriction (14.8Ϯ3.2%) that was similar to the response observed in WKY. Experiments were also performed in the presence of 100 mol/L Tempol. In afferent arterioles of WKY (nϭ6), Tempol treatment did not modulate the basal diameters (21.5Ϯ1.2 m) or the constrictor response to L-SMTC (10.6Ϯ2.1%) or L-NNA (19.3Ϯ3.3%). In SHR (nϭ8), Tempol significantly increased afferent arteriolar diameters by 22.5Ϯ4.3% and enhanced afferent arteriolar constrictor responses to L-SMTC (18.4Ϯ2.7%) and L-NNA (31.9Ϯ2.6%). However, the nitric oxide donor S-nitroso-N-acetylpenicillamine (10 mol/L), which similarly increased afferent arteriolar diameters (17.2Ϯ2.3%, nϭ6), did not affect afferent arteriolar responses to L-SMTC (1.5Ϯ2.7%) or L-NNA (18.6Ϯ2.3%). These suggest that superoxide anion inhibits the control of afferent arteriolar diameters by nNOS in SHR. Key Words: Tempol Ⅲ nitric oxide synthase Ⅲ arterioles Ⅲ rats, spontaneously hypertensive Ⅲ kidney N itric oxide (NO) is recognized as a major paracrine regulator of renal microvascular tone. 1 Inhibition of NO synthase (NOS) causes renal microvascular constriction with consequent decreases in renal blood flow and glomerular filtration rate. Therefore, renal NO deficiency may theoretically lead to the development of hypertension. However, constitutive NOS activity has been reported to be maintained in the kidneys of various models of hypertension. [2][3][4][5] In kidneys of spontaneously hypertensive rats (SHR), constitutive NOS activity is also maintained or elevated, 6 -9 suggesting that renal NO production is not reduced. However, the endothelium-dependent relaxation of renal vasculatures has been reported to be impaired in this model of hypertension. 10,11 This finding can be explained by the reduced production of NO-independent vasodilators, such as endothelium-derived hyperpolarizing factor, or a decrease in NO bioavailability. Recent studies have demonstrated that superoxide anion (O 2 Ϫ ) production is increased in the aorta of stroke-prone SHR 12,13 and in...

Abstract-To define the role of angiotensin type 1A (AT 1A ) receptor in modulating tubuloglomerular feedback signals and to determine its relationship to neuronal NO synthase (nNOS), the diameter of the afferent arterioles of wild-type and AT 1A receptor-deficient mice was measured by the blood-perfused juxtamedullary nephron technique. The afferent arteriolar diameter of wild-type and AT 1A receptor-deficient mice averaged 16.7Ϯ0.6 (nϭ9) and 16.8Ϯ0.7 m (nϭ9), respectively. In the wild-type mice, addition of 10 mol/L acetazolamide to the blood perfusate exerted a biphasic afferent arteriolar constriction, with the initial response and sustained response averaging 47.2Ϯ3.8% and 33.9Ϯ3.3%, respectively. In AT 1A receptor-deficient mice, the initial response and sustained response averaged 51.6Ϯ3.6% and 9.5Ϯ1.3%, respectively, and the sustained response was significantly attenuated compared with that of wild-type mice. Inhibition of nNOS with 10 mol/L S-methyl-L-thiocitrulline significantly decreased the afferent arteriolar diameter of AT 1A receptor-deficient mice, from 15.1Ϯ1.2 to 5.0Ϯ0.3 m (nϭ7), and the decrease was significantly greater than that observed in wild-type mice (from 15.9Ϯ1.2 to 10.6Ϯ1.3 m; nϭ8). During nNOS inhibition, the initial and sustained afferent arteriolar constrictor responses to acetazolamide in wild-type mice averaged 54.4Ϯ6.4% and 44.8Ϯ11.3%; respectively, and were similar to those in AT 1A receptor-deficient mice (53.2Ϯ6.4% and 59.5Ϯ4.4%, respectively). These results suggest that AT 1A receptors enhance tubuloglomerular feedback-mediated afferent arteriolar constriction, at least in part, through reducing the counteracting modulation by nNOS. Key Words: arterioles Ⅲ autoregulation Ⅲ mice Ⅲ nitric oxide synthase Ⅲ receptors, angiotensin II T he tubuloglomerular feedback (TGF) mechanism is recognized as the main mechanism responsible for the intrarenal vascular resistance adjustments that occur in response to increases in distal volume and sodium chloride/ bicarbonate delivery. 1 Peritubular perfusion of angiotensin II enhances TGF responses, 2 and TGF responses do not occur in angiotensin type 1A (AT 1A ) receptor-deficient mice 3 or in ACE-deficient mice. 4 These findings suggest that angiotensin II is a significant constituent of the TGF control system.Immunohistochemical studies have demonstrated the specific localization of neuronal NO synthase (nNOS) in macula densa cells, 5,6 which serve as the sensing site of the TGF mechanism by monitoring flow-mediated changes in tubular fluid composition to the distal nephron and, in turn, by releasing vasoactive paracrine signals that alter afferent arteriolar resistance. 1 NO produced in response to activation of macula densa nNOS affects the diameter of afferent and efferent arterioles 7 and contributes to the counteracting resetting process of the TGF-mediated autoregulatory response, resulting in a biphasic afferent arteriolar constriction. 8 Thus, macula densa nNOS activity plays an important role in the counteracting modulation of TGF ...

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