NO-independent mechanism mediates tempol-induced renal vasodilation in SHR

Abstract

. NO-independent mechanism mediates tempol-induced renal vasodilation in SHR. Am J Physiol Renal Physiol 289: F1227-F1234, 2005. First published July 20, 2005; doi:10.1152/ajprenal.00116.2005.-We investigated whether tempol, a superoxide dismutase mimetic, affected renal hemodynamics and arterial pressure in spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. We also examined whether tempol affected exaggerated renal vasoconstrictor responses to ANG II in SHR. To test whether the effects of tempol were due to a restored NO system, we used the NOS inhibitor N w -nitro-L-arginine methyl ester (L-NAME). Renal blood flow (RBF) and mean arterial pressure (MAP) were measured in vivo by electromagnetic flowmetry and arterial catheterization in 10-to 12-wk-old anesthetized SHR and SD rats. Systolic arterial pressure (SAP) was measured in conscious rats using the tail cuff method. Tempol (1 mM) was given in the drinking water to SD (SD-T) and SHR (SHR-T) for 5-7 days for RBF measurements and for 15 days for SAP measurements. Age-matched SD (SD-C) and SHR (SHR-C) were used as controls. ANG II (1-4 ng) was administered as a bolus via a renal artery catheter. L-NAME was administered intravenously for 15-20 min. Renal vascular resistance (RVR) was elevated in SHR-C compared with SD-C. In SHR-T, baseline RVR was not different from SD-C and SD-T rats. Tempol had no effect on RVR in SD. L-NAME elevated RVR to the same extent in all four groups. Arterial pressure was not affected by tempol. The RVR responses to ANG II were higher in SHR-C than in the SD-C group. ANG II responses were not different between SHR-T and SD-T. Overall, tempol reduced the renovascular responses to ANG II in SHR. L-NAME elevated the effects of ANG II in SD-C rats but had no effect on the ANG II responses in the other groups. Thus L-NAME treatment did not influence tempol's effects on baseline RVR or ANG II responses. We conclude that in SHR, tempol has a significant renal vasodilator effect and that it normalizes the increased renovascular ANG II sensitivity. As the effects of L-NAME are not greater in SHR-T rats, it is not likely that the elevated renal resistance and ANG II sensitivity in SHR are due to reactive oxygen speciesinduced quenching of nitric oxide. angiotensin II; hypertension; nitric oxide; oxidative stress; renal hemodynamics; spontaneously hypertensive rats KIDNEY FUNCTION IS of central importance in the control of normal blood pressure and in the development of essential hypertension (35,36). Spontaneously hypertensive rats (SHR) have an elevated renal vascular tone compared with normotensive rats (7,14,24). Also, an augmented response to vasoconstrictors, among them ANG II, has been observed in the genetically hypertensive rats (8,14,15,26,50). Despite intensive research, the reason for this enhanced renal vascular tone and reactivity in hypertensive animals is still not resolved.Elevated oxidative stress and high levels of reactive oxygen species (ROS) have been suggested to play a role in the pathogenesis of hyperten...

Predicted effects of nitric oxide and superoxide on the vasoactivity of the afferent arteriole

“…Stated differently, if the rate of NO scavenging by O 2 Ϫ were the same in SHR as in normotensive rats, the SHR afferent arteriolar diameter would only be 0.5 m higher than its base-case value; i.e., the reduced diameter in SHR does not appear to stem mostly from NO scavenging. These predictions accord with experimental observations suggesting that elevated renal resistance in SHR is unlikely to stem from ROS-induced quenching of NO (8).…”

“…Studies in isolated afferent arterioles suggest that pressure-induced constriction is enhanced in SHR (29,46), but other investigations, performed on isolated perfused kidneys, indicate that the autoregulatory response of the afferent arteriole is similar in SHR and WKY (21,45). Additionally, several investigations indicate that Tempol induces vasodilation of the afferent arteriole in SHR at normal perfusion pressures (8,17,26), but at least one study found no effect of Tempol on the basal arteriolar diameter of these rats (46).…”

Reactive oxygen species participate in acute renal vasoconstrictor responses induced by ETAand ETBreceptors

“…This agrees with our previous observations of the NO-independent influence of O 2 Ϫ on the acute renal constrictor responses to ANG II and NE (29). Our findings also are congruent with the observations of other investigators that the attenuating effect of tempol on the acute renal vasoconstrictor response to ANG II is not impaired in the absence of NO in dogs (43) or rats (9). It is important to appreciate that the latter two studies as well as our work were conducted using intact kidneys of anesthetized animals and that acute vasoconstrictor responses were recorded over a shortterm time range of a few seconds to 30 min.…”

“…In particular, superoxide (O 2 Ϫ ) mediates a significant portion of the acute vasoconstriction elicited by ANG II and NE in the kidney of normotensive as well as hypertensive animals (9,29,29,40,43,50,50,54). Based on these findings, we queried whether ROS are more universally associated with vasoconstriction triggered by stimulation of other G proteincoupled receptors, in particular those activated by endothelin-1 (ET-1).…”

Acute antihypertensive action of Tempol in the spontaneously hypertensive rat

“…Since 80% of the antihypertensive response is blocked by hexamethonium ϩ L-NAME, we conclude that the majority of the acute antihypertensive and bradycardic responses in vivo can be attributed to independent effects of Tempol on these systems. Prior reports of the effect of NOS inhibition on the antihypertensive response to Tempol range from complete blockade of the short-term response to Tempol in the SHRs (39) to a not-significant effect during more prolonged Tempol infusions (8).…”