Salt reabsorption by the loop of Henle controls NaCl handling and blood pressure regulation. Increased oxidative stress stimulates NaCl transport in one specific segment of the loop of Henle called the thick ascending limb (TAL). The isoprostane 8-iso-prostaglandin-F2α (8-iso-PGF2α) is one of the most abundant nonenzymatic lipid oxidation products and has been implicated in the development of hypertension. However, it is not known whether 8-iso-PGF2α regulates transport or the mechanisms involved. Because protein kinase A (PKA) stimulates NaCl transport in several nephron segments, we hypothesized that 8-iso-PGF2α increases NaCl transport in the cortical TAL (cTAL) via a PKA-dependent mechanism. We examined the effect of luminal 8-iso-PGF2α on NaCl transport by measuring chloride absorption (J(Cl)) in isolated microperfused cTALs. Adding 8-iso-PGF2α to the lumen increased J(Cl) by 54% (from 288.7 ± 30.6 to 446.5 ± 44.3 pmol·min(-1)·mm(-1); P < 0.01), while adding it to the bath enhanced J(Cl) by 35% (from 236.3 ± 35.3 to 319.2 ± 39.8 pmol·min(-1)·mm(-1); P < 0.05). This stimulation was blocked by Na-K-2Cl cotransporter inhibition. Next, we tested the role of cAMP. Basal cAMP in the cTAL was 18.6 ± 1.6 fmol·min(-1)·mm(-1), and 8-iso-PGF2α raised it to 35.1 ± 1.4 fmol·min(-1)·mm(-1), an increase of 94% (P < 0.01). Because cAMP stimulates PKA, we measured J(Cl) using the PKA-selective inhibitor H89. In the presence of H89 (10 μM), 8-iso-PGF2α failed to increase transport regardless of whether it was added to the lumen (216.1 ± 16.7 vs. 209.7 ± 23.8 pmol·min(-1)·mm(-1); NS) or the bath (150.4 ± 32.9 vs. 127.1 ± 28.6 pmol·min(-1)·mm(-1); NS). We concluded that 8-iso-PGF2α stimulates cAMP and increases Cl transport in cTALs via a PKA-dependent mechanism.

While arterial hypertension and renal dysfunction are well recognized complications of renal irradiation, the mechanisms that trigger the development of these complications are unknown. Recently, it was reported that the endothelium is a major target in radiation injury. Because dysfunction of the endothelial cells may lead or contribute to the development of hypertension and renal dysfunction in radiation nephropathy, we tested the hypothesis that endothelium-dependent vasodilation is impaired in radiated kidneys prior to the onset of hypertension. To test this hypothesis, we used Long-Evans rats that had undergone left nephrectomy (3 weeks earlier) and irradiation (3000 r's) to the right kidney 8 days earlier (mean blood pressures in the irradiated rats were not different than in the controls). We then measured the changes in renal blood flow (RBF) induced by endothelium-dependent (acetylcholine and bradykinin) and -independent (nitroprusside, norepinephrine, and angiotensin II) vasoactive agents. We found that the increases in RBF induced by the endothelium-dependent but not independent vasodilators were markedly impaired in the irradiated kidneys. Blocking nitric oxide synthesis with nitro L-arginine methyl ester in sham rats mimicked the blunted responsiveness of the irradiated rats, whereas indomethacin (an inhibitor of prostaglandin synthesis) had no effect on either sham or irradiated rats. Finally, the RBF responses to the endothelium-independent vasoconstrictors, norepinephrine and angiotensin II, were not altered in the irradiated kidneys. These results suggest that renal irradiation causes endothelial dysfunction (prior to the onset of hypertension) but spares the vascular smooth muscle cells.

Abstract-Hyperkalemia is widely viewed as a common complication of ACE inhibition in azotemic patients. These renal failure patients are the patients who benefit most from ACE inhibition. Because we could not confirm this notion after a retrospective evaluation of 236 azotemic patients, we studied 2 models of renal mass reduction. In the first, we did a 5/6 nephrectomy (Nx) on rats and studied them 2 weeks after surgery (before chronic renal changes had developed). A second group was studied 16 weeks after Nx, once chronic renal failure was established. Rats in both models were treated with quinapril in drinking water. After baseline evaluation, we challenged them either by a high-K ϩ diet or by blocking aldosterone receptors. We found that although quinapril blocked the K ϩ -induced increase in aldosterone, serum K ϩ levels and K ϩ balance were maintained before and during high K ϩ intake or during simultaneous spironolactone administration. We conclude that in hemodynamically stable rats with reduced renal mass and renal dysfunction, the administration of an ACE inhibitor does not cause severe hyperkalemia.

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