1. The microcirculation of the kidney is arranged in a manner that facilitates separation of blood flow to the cortex, outer medulla and inner medulla. 2. Resistance vessels in the renal vascular circuit include arcuate and interlobular arteries, glomerular afferent and efferent arterioles and descending vasa recta. 3. Vasoactive hormones that regulate smooth muscle cells of the renal circulation can originate outside the kidney (e.g. vasopressin), can be generated from nearby regions within the kidney (e.g. kinins, endothelins, adenosine) or they can be synthesized by adjacent endothelial cells (e.g. nitric oxide, prostacyclin, endothelins). 4. Vasoactive hormones released into the renal inner medullary microcirculation may be trapped by countercurrent exchange to act upon descending vasa recta within outer medullary vascular bundles. 5. Countercurrent blood flow within the renal medulla creates a hypoxic environment. Relative control of inner versus outer medullary blood flow may play a role to abrogate the hypoxia that arises from O2 consumption by the thick ascending limb of Henle. 6. Cortical blood flow is autoregulated. In contrast, the extent of autoregulation of medullary blood flow appears to be influenced by the volume status of the animal. Lack of medullary autoregulation during volume expansion may be part of fundamental processes that regulate salt and water excretion.

Pericytes are contractile smooth muscle-like cells that surround descending vasa recta (DVR) and provide their capability for vasomotion. The importance of the medullary pericyte derives from the role of DVR to distribute most or all of the blood flow from juxtamedullary cortex to the renal inner and outer medulla. Physiological processes that are likely to be influenced by pericyte constriction of DVR include the urinary concentrating mechanism and pressure natriuresis. Oxygen tensions in the medulla are low, so that subtle variation of pericyte vasomotion might play a role to abrogate hypoxia and prevent insult to the medullary thick ascending limb of Henle. Known vasoconstrictors of DVR include angiotensin II, endothelins, norepinephrine, acetylcholine, and adenosine. Vasodilators include prostaglandin E₂, adenosine, acetylcholine, bradykinin, and nitric oxide.

Deletion of AQP1 in mice results in diminished urinary concentrating ability, possibly related to reduced NaCl-and urea gradient-driven water transport across the outer medullary descending vasa recta (OMDVR). To quantify the role of AQP1 in OMDVR water transport, we measured osmotically driven water permeability in vitro in microperfused OMDVR from wild-type, AQP1 heterozygous, and AQP1 knockout mice. OMDVR diameters in AQP1 -/-mice were 1.9-fold greater than in AQP1 +/+ mice. Osmotic water permeability (P f ) in response to a 200 mM NaCl gradient (bath > lumen) was reduced about 2-fold in AQP1 +/-mice and by more than 50-fold in AQP1 -/-mice. P f increased from 1015 to 2527 µm/s in AQP1 +/+ mice and from 22 to 1104 µm/s in AQP1 -/-mice when a raffinose rather than an NaCl gradient was used. This information, together with p-chloromercuribenzenesulfonate inhibition measurements, suggests that nearly all NaCl-driven water transport occurs by a transcellular route through AQP1, whereas raffinose-driven water transport also involves a parallel, AQP1-independent, mercurial-insensitive pathway. Interestingly, urea was also able to drive water movement across the AQP1-independent pathway. Diffusional permeabilities to small hydrophilic solutes were comparable in AQP1 +/+ and AQP1 -/-mice but higher than those previously measured in rats. In a mathematical model of the medullary microcirculation, deletion of AQP1 resulted in diminished concentrating ability due to enhancement of medullary blood flow, partially accounting for the observed urine-concentrating defect.

Endothelins (ET) and prostaglandin E2 are synthesized in the inner medulla by collecting duct epithelium and interstitial cells, respectively. All ascending vasa recta (AVR) blood returns from the inner medulla to the cortex in outer medullary vascular bundles. We reasoned that hormones might influence medullary blood flow by diffusing across AVR fenestrations to modulate vasoconstriction of outer medullary descending vasa recta (OMDVR). To investigate this possibility, OMDVR dissected from vascular bundles were exposed to ET-1, 2, or 3. Each endothelin isoform induced stable vasoconstriction with potency, ET-1 > ET-2 > ET-3 (EC5, 1.8 x 10-15, 5.9 x 10-12, and 8.8 x 10-10 M, respectively). The ETA receptor antagonists BQ-123 and BQ-610 (10-6 M), as well as an ETA and ETB receptor antagonist combination, attenuated vasoconstriction due to ET-1 (10-12 M). BQ-123 had no effect on the response to ET-3 (10 -M). The ETB receptor antagonist BQ-788 (10-6 M) attenuated the response to ET-3 (1010 M), but not that to ET-1 (10-2 M). Finally, PGE2 (10-6 M) reversibly dilated OMDVR preconstricted with ET-1 (1012 M) or ET-3 (10-8 M) but not ET-1 (1010 M). We conclude that ET-1, 2, and 3 are potent constrictors of OMDVR and the response to ET-1 is mainly ETA receptor subtype mediated, while ET-3 acts via the ETB. PGE2 modulates ET induced constriction. These findings are consistent with interactive feedback and control of medullary perfusion by locally synthesized hormones. (J. Clin. Invest. 1995Invest. . 95:2734Invest. -2740

The intracellular calcium ([Ca(2+)](i)) response of outer medullary descending vasa recta (OMDVR) endothelia to ANG II was examined in fura 2-loaded vessels. Abluminal ANG II (10(-8) M) caused [Ca(2+)](i) to fall in proportion to the resting [Ca(2+)](i) (r = 0. 82) of the endothelium. ANG II (10(-8) M) also inhibited both phases of the [Ca(2+)](i) response generated by bradykinin (BK, 10(-7) M), 835 +/- 201 versus 159 +/- 30 nM (peak phase) and 169 +/- 26 versus 103 +/- 14 nM (plateau phase) (means +/- SE). Luminal ANG II reduced BK (10(-7) M)-stimulated plateau [Ca(2+)](i) from 180 +/- 40 to 134 +/- 22 nM without causing vasoconstriction. Abluminal ANG II added to the bath after luminal application further reduced [Ca(2+)](i) to 113 +/- 9 nM and constricted the vessels. After thapsigargin (TG) pretreatment, ANG II (10(-8) M) caused [Ca(2+)](i) to fall from 352 +/- 149 to 105 +/- 37 nM. This effect occurred at a threshold ANG II concentration of 10(-10) M and was maximal at 10(-8) M. ANG II inhibited both the rate of Ca(2+) entry into [Ca(2+)](i)-depleted endothelia and the rate of Mn(2+) entry into [Ca(2+)](i)-replete endothelia. In contrast, ANG II raised [Ca(2+)](i) in the medullary thick ascending limb and outer medullary collecting duct, increasing [Ca(2+)](i) from baselines of 99 +/- 33 and 53 +/- 11 to peaks of 200 +/- 47 and 65 +/- 11 nM, respectively. We conclude that OMDVR endothelia are unlikely to be the source of ANG II-stimulated NO production in the medulla but that interbundle nephrons might release Ca(2+)-dependent vasodilators to modulate vasomotor tone in vascular bundles.