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1 Biology, Concordia University, Montreal, Quebec, Canada; Lady Davis Institute, SMBD-Jewish General Hospital, Montreal, Quebec, Canada
2 Smooth Muscle Research Group, University of Calgary, Calgary, Alberta, Canada
3 Biomedical Engineering, Physiology, SUNY, Stony Brook, Stony Brook, NY, USA
4 Lady Davis Institute, SMBD-Jewish General Hospital, Montreal, Quebec, Canada; Centre for Biomedical Research, Biology, University of Victoria, Victoria, BC, Canada
* To whom correspondence should be addressed. E-mail: wcupples{at}uvic.ca.
Non-selective inhibition of nitric oxide synthase augments myogenic autoregulation, an action that implies enhancement of both pressure-induced constriction and pressure-induced dilatation. This pattern is not susceptible to explanation solely by interaction with a vasoconstrictor pathway. To test involvement of the Rho-Rho kinase pathway in modulation of autoregulation by nitric oxide, the selective Rho kinase inhibitor, Y-27632, and the nitric oxide synthase inhibitor L
-nitro-arginine methyl-ester (L-NAME) were infused into the left renal artery of anesthetized rats alone and in combination. They were also infused into isolated, perfused hydronephrotic kidneys to assess myogenic autoregulation over a wide range of perfusion pressure. In vivo, L-NAME alone reduced renal vascular conductance and augmented myogenic autoregulation, shown by increased slope of gain reduction and associated phase peak in the pressure-flow transfer function. Y-27632 (10 µmol/L) strongly dilated the renal vasculature and profoundly inhibited autoregulation in the absence or presence of L-NAME in vivo and in vitro. Afferent arteriolar constriction induced by 30 mmol/L KCl was reversed (-92 ± 3%) by Y-27632. Phenylephrine caused strong renal vasoconstriction, but did not affect autoregulation. In contrast inhibition of neuronal nitric oxide synthase by N5-(1-imino-3-butenyl)-L-ornithine (L-VNIO) did not cause significant vasoconstriction but did augment myogenic autoregulation. Thus vasoconstriction is neither necessary (L-VNIO) nor sufficient (phenylephrine) to explain the augmented myogenic autoregulation induced by L-NAME. The effect of L-VNIO implicates tubuloglomerular feedback and neuronal nitric oxide synthase at the macula densa in regulation of the myogenic mechanism. This conclusion was confirmed by demonstrating that systemic furosemide removed the tubuloglomerular feedback signature from the pressure-flow transfer function and significantly inhibited myogenic autoregulation. Furthermore in the presence of furosemide the augmentation of myogenic autoregulation by L-NAME was significantly reduced. These results provide a potential mechanism to explain interaction between myogenic and TGF-mediated autoregulation.
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