Angiotensin II inhibits ADH-stimulated cAMP: role on O2- and transport-related oxygen consumption in the loop of Henle.

Dehydration and acute reductions of blood pressure increases ADH and Ang II levels. These hormones increase transport along the distal nephron. In the thick ascending limb (TAL) ADH increases transport via cAMP, while Ang II acts via superoxide (O2-). However, the mechanism of interaction of these hormones in this segment remains unclear. The aim of this study was to explore ADH/Ang II interactions on TAL transport. For this, we measured the effects of ADH/Ang II, added sequentially to TAL suspensions from Wistar rats, on oxygen consumption (QO2) -as a transport index-, cAMP and O2-. Basal QO2 was 112+-5 nmol O2/min/mg protein. Addition of ADH (1nM) increased QO2 by 227 percent. In the presence of ADH, Ang II (1nM) elicited a QO2 transient response. During an initial 3.1+-0.7 minutes after adding Ang II, QO2 decreased 58 percent (p less than 0.03 initial vs. ADH) and then rose by 188 percent (p less than 0.03 late vs initial Ang II). We found that Losartan blocked the initial effects of Ang II and the latter blocked ADH and forskolin-stimulated cAMP. The NOS inhibitor L-NAME or the AT2 receptor antagonist PD123319 showed no effect on transported related oxygen consumption. Then, we assessed the late period after adding Ang II. The O2- scavenger tempol blocked the late Ang II effects on QO2, while Ang II increased O2- production during this period. We conclude that 1) Ang II has a transient effect on ADH-stimulated transport; 2) this effect is mediated by AT1 receptors; 3) the initial period is mediated by decreased cAMP and 4) the late period is mediated by O2-.

Hyperkalemia, renal failure, and converting-enzyme inhibition: an overrated connection.

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(+) diet or by blocking aldosterone receptors. We found that although quinapril blocked the K(+)-induced increase in aldosterone, serum K(+) levels and K(+) balance were maintained before and during high K(+) 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.

Abnormal endothelium-dependent responses in early radiation nephropathy.

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.