Impairment of pressure-natriuresis and renal autoregulation in ANG II-infused hypertensive rats

Abstract

Chronic infusions of initially subpressor doses of angiotensin II (ANG II) lead to progressive hypertension over a 2-wk period and to augmented intrarenal ANG II levels. The present study was performed to investigate total renal blood flow (RBF) and medullary blood flow (MBF) autoregulatory behavior and pressure-natriuresis in ANG II-infused hypertensive rats and how these are modified by concomitant treatment with an ANG II AT(1) receptor antagonist. ANG II-infused rats (n = 27) were prepared by administration of ANG II at 60 ng/min via osmotic minipump for 13 days. Twelve of the ANG II-infused hypertensive rats were treated with losartan in the drinking water (30 mg. kg.(-1) day(-1)). Rats were anesthetized with pentobarbital sodium (50 mg/kg, ip) and prepared for renal function measurements. An aortic clamp was placed above the junction of the left renal artery to reduce renal arterial pressure. Autoregulatory responses for renal plasma flow, overall RBF, and glomerular filtration rate were impaired in ANG II-infused hypertensive rats; however, MBF autoregulation was not disrupted. Most strikingly, pressure-natriuresis was markedly suppressed in ANG II-infused hypertensive rats. Chronic treatment with losartan prevented the impairment of the pressure-natriuresis relationship caused by chronic ANG II infusion. These findings demonstrate that chronic ANG II infusion leads to marked impairment of sodium excretion and suppression of the pressure-natriuresis relationship, which may contribute to the progressive hypertension that occurs in this model. These renal effects are prevented by simultaneous treatment with an AT(1) receptor blocker.

Impaired Ca 2+ Signaling Attenuates P2X Receptor–Mediated Vasoconstriction of Afferent Arterioles in Angiotensin II Hypertension

“…Consistent with our findings of impaired autoregulation and impaired P2 receptor-mediated vascular responses, Wang et al demonstrated that whole kidney autoregulation of renal blood flow was impaired in Ang II-infused rats. 28 These data support our hypothesis that angiotensin hypertension attenuates preglomerular autoregulatory responses and calcium signaling and is responsible for the decreased afferent arteriolar responses to purinoceptor stimulation.…”

“…4,5,28 Casellas et al demonstrated that autoregulatory responses were impaired in juxtamedullary afferent arterioles and interlobular arteries and that the greatest degree of impairment was observed in close proximity to the glomerulus. 4 Similar impairment was noted in 2K1C Goldblatt hypertensive rats.…”

AT 1 Receptor Mediated Augmentation of Intrarenal Angiotensinogen in Angiotensin II-Dependent Hypertension

“…The increased tubular Ang II formation may be partially responsible for the elevated intrarenal Ang II content and the enhanced fractional sodium reabsorption found in this model. 33 Recent studies support these interpretations. Peti-Peterdi et al 9 reported that Ang II directly stimulates the amiloride-sensitive epithelial sodium channel activity in the cortical collecting duct via activation of AT 1 receptor.…”

Renal Renin-Angiotensin System

“…In Ang IIdependent hypertension, the elevated Ang II concentrations acting on vascular and tubular basolateral receptors may contribute to enhanced sodium transport and impaired pressure natriuresis as well as the increased vascular resistance [42,61,62]. Micropuncture studies by Mitchell and Navar [63] demonstrated that peritubular capillary infusion of 10−7 mol/l Ang II resulted in increases in fractional proximal tubular fluid reabsorption and decreases in tubule fluid flow, stop-flow pressure, and single nephron glomerular filtration rate.…”