Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals

Abstract

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals. Am J Physiol Renal Physiol 294: F362-F370, 2008. First published November 21, 2007 doi:10.1152/ajprenal.00410.2007.-Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N G -nitro-L-arginine methyl ester (L-NAME) or L-arginine. Blood samples for ADMA, SDMA, and L-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. L-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.ADMA; tubuloglomerular feedback; L-arginine; L-NAME; telemetry; blood pressure HYPERTENSION IS THE MOST COMMON chronic disorders worldwide and secondary forms of hypertension are found in 5-10% of the hypertensive population, of which most can be linked to renal disease (24). In humans, as well as in experimental models of salt-sensitive hypertension, there is a growing body of evidence pointing at a close relationship between nitric oxide (NO) deficiency and development of hypertension (37).Hydronephrosis due to obstruction at the level of the pelvicureteric junction is a common condition in children, with an incidence in newborns of ϳ1%. The obstruction is mostly partial and congenital of origin. Unilateral hydronephrosis causes salt-sensitive hypertension in both rats (5) and mice (7).The renal function in hydronephrotic animals, measured as renal blood flow and glomerular filtration rate (GFR), is rather...

Nitric Oxide Deficiency and Increased Adenosine Response of Afferent Arterioles in Hydronephrotic Mice With Hypertension

“…20,26 Hydronephrotic kidneys display reduced renal NO availability, which is associated with a sensitized TGF response. 5 In the present study, unspecific NOS inhibition with L-NAME did not cause any significant constriction of AAs from the hydronephrotic kidneys of wild-type mice, but the controls constricted Ϫ12% and the AAs of the contralateral kidney constricted as much as Ϫ43% after 15 minutes of treatment. Moreover, a stronger effect must be assumed in contralateral arterioles, because a steady state of arteriolar diameter was not reached at this time.…”

“…4 The mechanisms are thought to be associated with increased activity of the renin-angiotensin system, 2 increased oxidative stress, and reduced NO availability in the diseased kidney. 5 In micropuncture studies of hydronephrotic animals, the tubuloglomerular feedback (TGF) has a higher responsiveness in the hydronephrotic kidney. 5,6 An increased TGF response, as seen in hydronephrotic kidneys, has also been described in spontaneously hypertensive rats, 7 Milan hypertensive rats 8 during development of hypertension, and in animals subjected to neuronal NO synthase (NOS) inhibition.…”

“…5 In micropuncture studies of hydronephrotic animals, the tubuloglomerular feedback (TGF) has a higher responsiveness in the hydronephrotic kidney. 5,6 An increased TGF response, as seen in hydronephrotic kidneys, has also been described in spontaneously hypertensive rats, 7 Milan hypertensive rats 8 during development of hypertension, and in animals subjected to neuronal NO synthase (NOS) inhibition. 9 These studies suggest an important role for changes of the TGF function in the pathophysiology of hypertension.…”

Hypertension and Hydronephrosis: Rapid Resolution of High Blood Pressure Following Relief of Bilateral Ureteric Obstruction

“…Increased activity of both the TGF system and RAA axis are thought to play an important role in this process. 6 TGF is a physiological process involved in autoregulation of glomerular blood flow (Fig. 3).…”

“…11 In the hydronephrotic state, there is increased activity of the TGF system, 1 which appears to be due to reduced nitric oxide availability. 6 This pathologically increased activity of TGF reduces urine volume and thus may ameliorate the deleterious effect of high pressure within the renal pelvis that occurs in hydro- nephrosis, 12 but also results in salt and water retention and development of salt-sensitive hypertension. 6 Increased activity of the RAA axis in hydronephrotic states also contributes to the development of hypertension.…”