Impaired Regulation of Renal Oxygen Consumption in Spontaneously Hypertensive Rats

Abstract

Abstract. Abnormalities of nitric oxide (NO) and oxygen radical synthesis and of oxygen consumption have been described in the spontaneously hypertensive rat (SHR) and may contribute to the pathogenesis of hypertension. NO plays a role in the regulation of renal oxygen consumption in normal kidney, so the response of renal cortical oxygen consumption to stimulators of NO production before and after the addition of the superoxide scavenging agent tempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl) was studied. Baseline cortical oxygen consumption was similar in SHR and Wistar-Kyoto (WKY) rats (SHR: 600 Ϯ 55 nmol O 2 /min per g, WKY: 611 Ϯ 51 nmol O 2 /min per g, P Ͼ 0.05). Addition of bradykinin, enalaprilat, and amlodipine decreased oxygen consumption significantly less in SHR than WKY (SHR: bradykinin Ϫ13.9 Ϯ 1.9%, enalaprilat Ϫ15.3 Ϯ 1.6%, amlodipine Ϫ11.9 Ϯ 0.7%; WKY: bradykinin Ϫ22.8 Ϯ 1.0%, enalaprilat Ϫ24.1 Ϯ 2.0%, amlodipine Ϫ20.7 Ϯ 2.3%; P Ͻ 0.05), consistent with less NO effect in SHR. Addition of tempol reversed the defects in responsiveness to enalaprilat and amlodipine, suggesting that inactivation of NO by superoxide contributes to decreased NO availability. The response to an NO donor was similar in both groups and was unaffected by the addition of tempol. These results demonstrate that NO availability in the kidney is decreased in SHR, resulting in increased oxygen consumption. This effect is due to enhanced production of superoxide in SHR. By lowering intrarenal oxygen levels, reduced NO may contribute to susceptibility to injury and renal fibrosis. Increasing NO production, decreasing oxidant stress, or both might prevent these changes by improving renal oxygenation.Nitric oxide (NO) plays an important role in regulation of vascular tone. Absence of the NO generating enzyme endothelial nitric oxide synthase (eNOS) or impairment of NO production leads to hypertension in animal models and can increase vascular tone in humans (1-4). In a model of genetic hypertension in the rat, the spontaneously hypertensive rat (SHR), abnormalities in synthesis of NO, expression of the NO-synthesizing enzymes, or both have been described both in vitro and in vivo, but with conflicting results. Thus, several studies have been performed to provide evidence of impaired vasodilation in response to acetylcholine, an effect mediated by endothelium-derived relaxing factor or NO, decreased eNOS expression, or decreased NO synthesis in SHR (5-11). These abnormalities are present as early as 5 wk of age, a period before the development of hypertension (7). However, several of these studies have shown a decreased effect of NO rather than direct evidence of decreased production.On the other hand, evidence of increased expression of NO synthesizing enzymes (eNOS and inducible NO synthase), increased NO production, or both have also been noted (12-18), both before and after the onset of hypertension. One possible explanation for this discrepancy is inactivation of NO, explaining increased production but less effect in SHR...

Physiology of the renal medullary microcirculation

“…It has been shown that both ANG II receptor blockers (ARBs) and the combination of hydrochlorothiazide, hydralazine, and reserpine (triple therapy) can normalize blood pressure in the SHR rat; however, only ARBs reduce excretion of ROS reaction product 8-iso-PGF 2␣ . Interestingly, PO 2 values are lower in the SHR, and this too is normalized by ARB therapy or treatment with the SOD mimetic tempol (1,164). Tempol also has been shown to enhance medullary perfusion (183).…”

Chronic Hypoxia and Tubulointerstitial Injury

“…Adler et al (44) showed that, because NO is a suppressor of mitochondrial respiration, depletion of NO by oxidative stress may stimulate mitochondrial respiration and uncouple it from chemical energy consumption, resulting in tissue hypoxia ( Figure 2E). Kidneys of the spontaneously hypertensive rat (SHR), which characteristically undergo oxidative stress, revealed enhanced oxygen usage relative to tubular sodium transport and lower intrarenal pO 2 (45).…”

Hypoxia: The Force that Drives Chronic Kidney Disease

“…Specifically, the oxygen tension of the kidney cortex and medulla has been shown to be approximately 10 mm Hg lower than normal in spontaneously hypertensive rats and other models of hypertension as well as in hypertensive patients. 15,89,[144][145][146] The role of hypertension in the progression of CKD was first described in 1914 by Volhard and Fahr. 13 Subsequently, it was appreciated that hypertension predisposes to kidney failure by inducing renal hypoxia.…”