Endothelin resets renal blood flow autoregulatory efficiency during acute blockade of NO in the rat

Abstract

Renal blood flow (RBF) autoregulatory efficiency may be enhanced during NO inhibition in the rat, as recently reported. Under these conditions, endothelin (ET) synthesis and release may be increased. Our purpose was therefore to determine the role of ET in RBF autoregulatory changes induced by NO inhibition. To address this point, ET(A/B) receptors were blocked in anesthetized rats with bosentan, or selectively with BQ-610 or BQ-788. NO synthesis was inhibited with N(G)-nitro-L-arginine methyl ester (L-NAME). Mean arterial pressure (MAP) was decreased after bosentan (-10 mmHg; P < 0.01) or increased after L-NAME (25 mmHg; P < 0.001). RBF measured with an electromagnetic flow probe was reduced by L-NAME (-50%) and by BQ-788 (-24%). The pressure limits of the autoregulatory plateau (P(A) approximately 100 mmHg) and of no RBF autoregulation (P(o) approximately 80 mmHg) were significantly lowered by 15 mmHg after L-NAME but were unchanged after bosentan, BQ-610, or BQ-788. During NO inhibition, autoregulatory resetting was completely hindered by bosentan (P(A) approximately 100 mmHg) and by ET(B) receptor blockade with BQ-788 (P(A) approximately 106 mmHg), but not by ET(A) receptor blockade with BQ-610 (P(A) approximately 85 mmHg). These results suggest that the involvement of ET in the RBF autoregulatory resetting occurs during NO inhibition, possibly by preferential activation of the ET(B) receptor. However, the relative contribution of ET receptor subtypes remains to be further specified.

The Acute Physiological Effects of the Vaso-Active Drug, L-NNA, a Nitric Oxide Synthase Inhibitor, on Renal and Tumour Perfusion in Human Subjects

“…Consistent with published results in animal and clinical studies, we have demonstrated a reduction in renal blood flow, blood volume, and extraction fraction within one hour of L-NNA administration [22][23][24][25][26], and a transient increase in the systemic arterial blood pressure following the blockade of the nitric oxide synthase pathway [21]. Blood pressure began to normalise two hours after L-NNA administration, and renal perfusion returned to baseline by 24 hours post L-NNA.…”

“…Expression of nitric oxide synthase (NOS), which catalyses the conversion of L-arginine into nitric oxide, is up-regulated by VEGF [18,19], whilst VEGF expression is down-regulated by nitric oxide [20]. Blockade of the NOS pathway has been shown to result in hypertension in humans [21] and impact on renal blood flow and its autoregulation in animals [22][23][24][25][26]. Thus it has been suggested that the development of hypertension in patients on long term VEGF inhibitor treatment may in part be secondary to the suppression of nitric oxide production due to VEGF inhibition.…”

Assessment of renal autoregulation

“…Using their formal interpretation procedures, they demonstrated a significant shift of the lower limit of autoregulation to reduced arterial pressure (196), a finding that was also reported by Kramp et al (102,103). In addition, time-series analysis showed that the myogenic system is augmented during NOS inhibition (88,213,210).…”

Salt-resistant blood pressure and salt-sensitive renal autoregulation in chronic streptozotocin diabetes

“…This conclusion, although reasonable at the time it was drawn, is difficult to reconcile with current understanding of the role of nitric oxide in renal autoregulation. First, nonselective inhibition of NOSs causes a pronounced left shift of the lower limit of autoregulation (31,43,44,64,79). Second, inhibition of NOSs enhances autoregulation within the normal autoregulatory range of renal perfusion pressure (44,64,79).…”