AT2-antagonist sensitive potentiation of angiotensin II-induced vasoconstrictions by blockade of nitric oxide synthesis in rat renal vasculature

1. Although the actions of angiotensin II (Ang II) on renal haemodynamics appear to be mediated by activation of the AT1 receptor subtype, AT2 binding sites have also been evidenced in the adult kidney vasculature. As NO is known to mask part of the renal effects of vasoconstrictor drugs, we queried whether the Ang II-induced vasoconstrictions could occur via multiple receptor subtypes during inhibition of NO synthesis. We explored the effect of AT1 and AT2 receptor (AT-R) antagonists on Ang II-induced pressure increases during NO synthase or soluble guanylyl cyclase inhibition in rat isolated kidneys perfused in the presence of indomethacin at constant flow in a single-pass circuit. 2. In the absence of NO blockade, the AT1-R antagonist L-158809 (500 nM) antagonized the Ang II-induced vasoconstrictions, while the AT2-R antagonist PD-123319 (500 nM) had no effect. 3. Perfusing kidneys in the presence of either NO synthase inhibitors, L-NAME (100 microM) or L-NOARG (1 mM), or soluble guanylyl cyclase inhibitor, LY-83583 (10 microM), significantly increased both molar pD2 (from 9.40+/-0.25 to 10.36+/-0.11) and Emax values (from 24.9+/-3.1 to 79.9+/-4.9 mmHg) of the concentration-response curve for Ang II-induced vasoconstriction. 4. In the presence of L-NAME, 500 nM L158809 abolished the Ang II-induced vasoconstrictions whatever the concentration tested. On the other hand, 500 nM PD-123319 reversed the left shift of the concentration-response curve for Ang II (molar pD2 value 9.72+/-0.13) leaving Emax value unaffected (91.3+/-7.6 mmHg). 5. In the presence of L-NAME, the potentiated vasoconstriction induced by 0.1 nM and the augmented vasoconstriction induced by 10 nM Ang II were fully inhibited in a concentration-dependent manner by L-158809 (0.05-500 nM). By contrast, PD-123319 (0.5-500 nM) did not affect the 10 nM Ang II-induced vasoconstriction and concentration-dependently decreased the 0.1 nM Ang II-induced vasoconstriction plateauing at 65% inhibition above 5 nM antagonist. 6. Similar to PD-123319, during NO blockade the AT2-R antagonist CGP-42112A at 5 nM decreased by 50% the 0.1 nM Ang II-induced vasoconstriction and at 500 nM had no effect on 10 nM Ang II-induced vasoconstriction. 7. In conclusion, the renal Ang II-induced vasoconstriction, which is antagonized only by AT1-R antagonist in the presence of endogenous NO, becomes sensitive to both AT1- and AT2-R antagonists during NO synthesis inhibition. While AT1-R antagonist inhibited both L-NAME-potentiated and -augmented components of Ang II-induced vasoconstriction, AT2-R antagonists inhibited only the L-NAME-potentiated component.     

cAMP pathway in podocytes

Podocytes possess receptors for a variety of hormones. The following receptors whose stimulation results in increased cAMP levels have been detected in podocytes: adrenergic beta(2) receptor, dopamine D(1) receptor, prostaglandin IP and EP(4) receptors, and parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor. Besides activating protein kinase A, increased levels of cAMP depolarize podocytes via opening of chloride channels. Relatively little is known about the impact of the cAMP pathway on podocyte function. Results obtained in a limited number of studies indicate that cAMP in podocytes may regulate cell morphology, actin assembly, and matrix production. In addition, cAMP seems to attenuate the action of hormones, which activate the Ca(2+)/protein kinase C pathway. Effects of the cAMP pathway on further aspects of podocyte biology, such as contractility, phosphorylation state of slit membrane-associated proteins, glomerular permeability, cell cycle control, and synthesis of reactive oxygen species can be anticipated from studies on other cell types and from studies on isolated glomeruli. In summary, the data available indicate that the cAMP pathway affects several aspects of podocyte biology in an overall glomerulo-protective manner.     

Gebrauchswertprüfung bei Feinseifen

Testing of Fine Quality Soaps At present, no obligatory standards exist on test for the determination of properties of tabletted soaps and pieces of syndets, although various test procedures have been reported in the literature. An uniform standardization is desireable. The author has reported various methods and results of test procedures that permit the determination of water uptake during wetting, drying time of wetted pieces, stability against wear and tear, homogenity and the mechanical stability of peletted soaps under the action of a temperature- and pressure-adjusted conical water jet.