Renal Medulla in Hypertension

Abstract

Studies have found that blood flow to the renal medulla is an important determinant of pressure-natriuresis and the long-term regulation of arterial pressure. First, a brief review of methods developed enabling the study of the medullary circulation is presented. Second, studies performed in rats are presented showing medullary blood flow plays a vital role in the pressure-natriuresis relationship and thereby in hypertension. Third, it is shown that chronic reduction of medullary blood flow results in hypertension and that enhancement of medullary blood flow reduces hypertension hereditary models of both salt-sensitive rats and salt-resistant forms of hypertension. The key role that medullary nitric oxide production plays in protecting this region from ischemic injury associated with circulating vasoconstrictor agents and reactive oxygen species is presented. The studies cited are largely the work of my students, research fellows, and colleagues with whom I have performed these studies dating from the late 1980s to more recent years.

Keywords: hypertension; inbred Dahl rats; inbred SHR rats; nitric oxide; reactive oxygen species; renal blood flow; renal perfusion pressure.

Figure 1.

Relationship between inner medullary flow (○) and urine osmolality (●) with small increasing levels of circulating AVP showing a coordinated action of AVP on medullary flow and collecting duct hydraulic conductivity. * Significant difference from control (P<0.05).

Figure 2.

Lack of blood flow autoregulation in the renal medulla. Relationship between renal perfusion pressure (RPP) and whole kidney renal blood flow (RBF), superficial cortical blood flow measured with an external laser-Doppler flow probe (SC_e), and outer (OM_i) inner (IM_i) medullary blood flow measured with implanted fibers for laser-doppler flowmetry in volume-expanded rats.

Figure 3.

Left upper panel: Cross section of the rat delineating the cortex (Cx), outer medulla (OM), and inner medulla (IM) illustrating implanted optical fibers placed into the Cx and IM for determination of changes in regional blood flows by laser-Doppler flowmetry. Left lower panel: Autoradiogram of a midline section of a rat kidney after outer medullary interstitial infusion of ^14Cclentiazem for 20 minutes showing the gradient of compound localization from OM to IM with no detectable accumulation of radioactivity in the cortex. Figure 3A. Effects of chronic renal medullary interstitial infusion (i.r.) of Captopril (5 mg/kg per day) in SHR rats on mean arterial pressure (MAP), medullary blood flow (MBF) and cortical blood flow (CBF). Changes in MBF and CBF (expressed in volts) were measured using implanted optical probes and laser-Doppler flowmetry. Enhanced MBF resulted in reduced MAP ( Figure 3B). Effects of i.r. infusion of L-NAME (120 mg/hour) in Sprague Dawley (SD) rats. Figure 3C. Effects of i.r. infusion of V1 agonist (2 ng/kg per min) in SD rats. Both L-NAME and the V1 agonist selectively reduced MBF and induced hypertension without altering CBF. Vertical dashed lines represent the start and end of r.i. infusions. *Significantly different from values on the final control day (P<0.05).

Figure 4.

Influence of NO blockade by L-NAME delivered chronically into the renal interstitium (r.i.) on the mean arterial pressure (MAP) responses to vasoconstrictors given intravenously. MAP was normalized to allow comparison between individual studies using normally non-pressor doses of (A) AngII, (B) NE, and (C) arginine vasopressin (AVP) . Solid circles represent saline r.i. and open circles represent L-NAME r.i..

Figure 5.

Effects of a high salt diet (4%) on changes in medullary blood flow (MBF; top panel), cortical blood flow (CBF; middle panel), and mean arterial pressure (MAP; lower panel) in unanesthetized S rats (5A) and Dahl R rats (5B). Panel 5C shows the chronic effects of renal medullary interstitial infusion of L-Arg in SS rats fed a high salt diet upon changes in MBF (top), CBF (middle), and MAP (lower) .