The Importance of Medullary Blood Flow and Nitric Oxide in Hypertension

Renal medullary NOS activity and NO production exceeds that in the cortex. NO acts in autocrine and paracrine fashion to modulate both vasoconstriction and epithelial NaCl reabsorption. NOS isoforms have specific effects [18]. NOS1 inhibition reduces NO levels in the medulla and induces salt-sensitive hypertension without altering medullary perfusion. Global inhibition of NOS1, NOS2, and NOS3 isoforms decreases medullary NO levels, medullary blood flow, and tissue oxygen tension and leads to salt-dependent hypertension [19]. NO generation may be important to abrogate tissue hypoxia that would otherwise arise from release of vasoconstrictors. Angll, norepineph-rine, and vasopressin stimulate release of NO in the medulla. Subpressor infusion of N(w)-nitro-L-arginine methyl ester (LNAME) into the renal interstitium does not affect medullary blood flow or pO2 but enables otherwise ineffective doses of Angll, norepinephrine, or vasopressin to reduce perfusion. Data broadly support the conclusion that medullary NO production has a tonic effect to maintain perfusion, favor saliuresis, and protect from ischemic injury and hypertension.

Glossary

Hydraulic conductivity: Proportionality constant generally denoted Lp that relates the rate of vectorial water flux that occurs across a membrane in response to driving forces imposed by osmotic, oncotic, and hydraulic pressures.

Juxtamedullary: Refers to the deepest region of the renal cortex. Glomeruli that lie in the deep, juxtamedullary cortex have efferent arteri-oles that extend into the outer stripe of the outer medulla where they break up like a horse's tail to form descending vasa recta.

Osmotic water permeability: Proportionality constant generally denoted Pf that relates the rate of vectorial water flux that occurs across a membrane in response to driving forces imposed by osmotic, oncotic, and hydraulic pressures. Can be converted to hydraulic conductivity by the relationship Lp = (Pf Vw)/(R T), where Vw is the partial molar volume of water, R is the universal gas constant, and T is absolute temperature.

Solute permeability: Proportionality constant for the ith solute generally denoted Pi that relates the rate of diffusive solute flux across a membrane that occurs when a transmural concentration difference of that solute exists across the membrane.

Vasa recta: System of parallel microvessels that traverse the renal outer and inner medulla. Descending vasa recta carry blood flow from the juxtamedullary cortex to the medulla and are sometimes referred in older literature to as arteriolar vasa recta. Ascending vasa recta carry blood flow from the inner and outer medulla back to the cortex and are sometimes referred to as venous vasa recta.

References

1. Lemley, K. V., and Kriz, W. (1987). Cycles and separations: the histo-topography of the urinary concentrating process. Kidney Int. 31, 538-548.

2. Pallone, T. L., Zhang, Z., and Rhinehart, K. (2003). Physiology of the renal medullary microcirculation. Am. J. Physiol. 284, F253-F266.

3. Pallone, T. L., Edwards, A., Ma, T., Silldorff, E. P., and Verkman, A. S. (2000). Requirement of aquaporin-1 for NaCl-driven water transport across descending vasa recta. J. Clin. Invest. 105, 215-222.

4. Pallone, T. L., Work, J., Myers, R. L., and Jamison, R. L. (1994). Transport of sodium and urea in outer medullary descending vasa recta. J. Clin. Invest. 93, 212-222.

5. Pallone, T. L., Kishore, B. K., Nielsen, S., Agre, P., and Knepper, M. A. (1997). Evidence that aquaporin-1 mediates NaCl-induced water flux across descending vasa recta. Am. J. Physiol. 272, F587-F596.

6. Pallone, T. L., Turner, M. R., Edwards, A., and Jamison, R. L. (2003). Countercurrent exchange in the renal medulla. Am. J. Physiol. 284, R1153-R1175.

7. Edwards, A., Delong, M. J., and Pallone, T. L. (2000). Interstitial water and solute recovery by inner medullary vasa recta. Am. J. Physiol. 278, F257-F269.

8. Pallone, T. L. (1991). Resistance of ascending vasa recta to transport of water. Am. J. Physiol. 260, F303-F310.

9. MacPhee, P. J. and Michel, C. C. (1995). Fluid uptake from the renal medulla into the ascending vasa recta in anaesthetized rats. J. Physiol. 487, 169-183.

10. Pallone, T. L. (1991). Transport of sodium chloride and water in rat ascending vasa recta. Am. J. Physiol. 261, F519-F525.

11. Silldorff, E. P., Yang, S., and Pallone, T. L. (1995). Prostaglandin E2 abrogates endothelin-induced vasoconstriction in renal outer medullary descending vasa recta of the rat. J. Clin. Invest. 95, 2734-2740.

12. Zhang, Z., Huang, J. M., Turner, M. R., Rhinehart, K. L., and Pallone, T. L. (2001). Role of chloride in constriction of descending vasa recta by angiotensin II. Am. J. Physiol. 280, R1878-R1886.

13. Pallone, T. L. and Huang, J. M. (2002). Control of descending vasa recta pericyte membrane potential by angiotensin II. Am. J. Physiol. 282, F1064-F1074.

14. Hansen, P. B., Jensen, B. L., Andreasen, D., and Skott, O. (2001). Differential expression of T- and L-type voltage-dependent calcium channels in renal resistance vessels. Circ. Res. 89, 630-638.

15. Zhang, Z., Rhinehart, K., and Pallone, T. L. (2002). Membrane potential controls calcium entry into descending vasa recta pericytes. Am. J. Physiol. 283, R949-R957.

16. Pallone, T. L., Silldorff, E. P., and Cheung, J. Y. (1998). Response of isolated rat descending vasa recta to bradykinin. Am. J. Physiol. 274, H752-H759.

17. Rhinehart, K., Handelsman, C. A., Silldorff, E. P., and Pallone, T. L. (2003). ANG II AT2 receptor modulates AT1 receptor-mediated descending vasa recta endothelial Ca2+ signaling. Am. J. Physiol. 284, H779-H789.

18. Mattson, D. L., and Wu, F. (2000). Control of arterial blood pressure and renal sodium excretion by nitric oxide synthase in the renal medulla. Acta Physiol. Scand. 168, 149-154.

19. Nakanishi, K., Mattson, D. L., and Cowley, A. W., Jr. (1995). Role of renal medullary blood flow in the development of L-NAME hypertension in rats. Am. J. Physiol. 268, R317-R323.

Bibliography

Bankir, L., and de Rouffignac, C. (1985). Urinary concentrating ability: Insights from comparative anatomy. Am. J. Physiol. Regul. Integr. Comp. Physiol. 249, R643-R666.

Cowley, A. W., Jr., Mori, T., Mattson, D., and Zou, A. P. (2003). Role of renal NO production in the regulation of medullary blood flow. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R1355-R1369. This review describes the important role of nitric oxide to maintain renal medullary perfusion. Important references that demonstrate the hypertensive effect of inhibiting medullary NO generation are cited.

Jamison, R. L., and Kriz, W. (1982). Urinary Concentrating Mechanism.

New York: Oxford University Press. Knepper, M. A., Saidel, G. M., Hascall, V. C., and Dwyer, T. (2003). Concentration of solutes in the renal inner medulla: Interstitial hyaluronan as a mechano-osmotic transducer. Am. J. Physiol. Renal. Physiol. 284, F433-F446.

Mattson, D. L. (2003). Importance of the renal medullary circulation in the control of sodium excretion and blood pressure. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R13-R27. Michel, C. C. (1995). Renal medullary microcirculation: Architecture and exchange. Microcirculation 2, 125-139. Pallone, T. L., and Silldorff, E. P. (2001). Pericyte regulation of renal medullary blood flow. Exp. Nephrol. 9, 165-170.

Capsule Biography

Thomas Pallone obtained the bachelor's degree in engineering at the Massachusetts Institute of Technology (1977) and the Doctor of Medicine degree from the Pennsylvania State University (1981). Subsequently, his graduate studies in the Health Science and Technology program at M.I.T. were mentored by William M. Deen, Ph.D. in Chemical Engineering. His interest in the renal medullary microcirculation was kindled as a thesis project (S.M., 1982). After completing medicine residency training at the University of Maryland (1985), he obtained clinical and laboratory fellowship training in the Nephrology Division at Stanford University under Rex L. Jamison, M.D. (1988). He has held staff positions at Penn State University (through 1995) and the University of Maryland at Baltimore, where he is currently Professor of Medicine and Physiology.

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