Contribution of Endothelial Nitric Oxide Synthase in the Blunted Renal Responses to Volume Expansion in Diabetic Rats

Abstract

The renal excretory responses to volume expansion (VE), by 10% body wt, were determined in groups of anaesthetised streptozotocin‐induced diabetic rats with one denervated and one innervated kidney in the presence and absence of nitric oxide synthase (NOS) inhibitors. VE in diabetic rats increased (P < 0.001) cumulative urine sodium excretion (CuUNaV) to 104 ± 9 and 69 ± 6 μmol min−1 (g kidney wt)−1 in the denervated and in the innervated kidneys, respectively, which were both less (P < 0.001) than in the non‐diabetic rats, at 225 ± 14 and 148 ± 14 μmol min−1 (g kidney wt)−1, respectively, in the denervated and the innervated kidney. The non‐selective NOS inhibitor, NG‐nitro‐L‐arginine‐methyl‐ester (L‐NAME) given to the diabetic rats with intact renal innervation enhanced CuUNaV after VE by 43% (P < 0.001), while the combination of L‐NAME and renal denervation restored CuUNaV to a value comparable to that of non‐diabetic rats. In diabetic rats treated with either a relatively selective inhibitor for the neuronal isoform of NOS, 7‐nitroindazole, or a relatively selective inhibitor for the inducible isoform of NOS, aminoguanidine, CuUNaV after VE was similar to the untreated diabetic rats irrespective of whether or not the renal nerves were present. This investigation demonstrated that NO production contributed, at least partly, to the depressed ability to excrete a saline load in diabetes mellitus. The endothelial isoform of NOS was most probably responsible for generating NO which caused the blunted excretory responses. The ability of NO to attenuate the excretory responses to volume expansion was an action independent of the renal innervation status.

Nitric oxide inhibition and the impact on renal nerve‐mediated antinatriuresis and antidiuresis in the anaesthetized rat

“…Under these conditions, l ‐NAME had no measurable effect on basal renal haemodynamics or sodium and water excretion from either kidney compared with the group of rats given saline only, and these observations were comparable with those of Lahera et al (1991). Moreover, this dosing regime has been used previously in this laboratory to study the role of NOS in the control of renal function (Wongmekiat & Johns, 2001 a , b , c ).…”

“…This compound was utilized in preference to 7‐NI used previously (Wu et al 1999; Wu & Johns, 2002), which has only a 5‐fold greater inhibitory action on nNOS compared with eNOS, and has to be dissolved in oil and given i.p. to obtain sufficient systemic concentrations (Wongmekiat & Johns, 2001 a , b , c ). Again, it was apparent from the basal values that the compound did not result in any major differences in renal haemodynamic or excretory function compared with the control group of rats receiving saline, although blood pressure was higher.…”

Endothelin as a causative factor of blunted volume reflex in diabetic rats

“…This series of experiments explored the role of ET on systemic and renal haemodynamics and renal excretory function either at the basal state or in response to VE by blocking ET actions with a nonselective ET A /ET B receptor antagonist, SB209670 (SmithKline Beecham Pharmaceuticals, King, PA, U.S.A.). Previously reported groups of nondiabetic rats (Wongmekiat & Johns, 2001a, b) and two groups of diabetic rats ( n =7–9) in the current study were treated with SB209670 at 10 or 30 μ g kg −1 min −1 . SB209670 at 10 μ g kg −1 min −1 has been reported in the rats to reverse completely the haemodynamics effects of an infusion of exogenous ET (Douglas et al ., 1995; Gardiner et al ., 1995), but the higher dose was also employed to ascertain that the maximal effects were achieved.…”

“…This possibility is based on a substantial body of evidence, which demonstrated that both diabetic animals and humans have an impaired ability to excrete an acute saline load (Patel & Zhang, 1989; Zhang et al ., 1991; Beretta‐Piccoli et al ., 1994; Patel et al ., 1997). The deficits in the reflex fall into three main categories; a failure to suppress renal sympathetic nerve activity, tubular deficiencies, and an inappropriate release or response to natriuretic factors (Zhang et al ., 1991; Patel & Zhang, 1994; Patel et al ., 1997; Wongmekiat & Johns, 2001a). Nevertheless, the mechanisms involved in the altered volume reflex seen in diabetes remain uncertain and need to be examined further.…”

Role of neuronal nitric oxide synthase in response to hypertonic saline loading in rats

“…Studies exploring the acute and chronic effects of systemic nNOS inhibition have not provided unequivocal evidence on its effects on BP. Thus, Wongmekiat & Johns (2001a,b) observed a mild (8 mmHg), but significant, BP increase after the administration of 7NI to anaesthetized volume expanded rats. However, other authors found no rise in blood pressure in response to acute (Beierwaltes 1995, 1997) or chronic (Ollerstam et al.…”