[New AT1 receptor antagonist. Rapid and effective blood pressure decrease].

OBJECTIVES: We investigated the vascular effects of candesartan in hypertensive patients. BACKGROUND: The renin-angiotensin system may contribute to atherogenesis through the promotion of endothelial dysfunction. The plausible mechanisms are that angiotensin II promotes superoxide anion generation, endothelial dysfunction, inflammation, and impaired fibrinolysis. The effects of candesartan on these conditions have not been clearly observed. METHODS: We administered placebo or candesartan 16 mg daily during two months to 45 patients with mild-to-moderate hypertension. This was a randomized, double-blind, placebo-controlled, crossover study in design. RESULTS: Candesartan did not significantly change lipoprotein levels. However, compared with placebo, candesartan significantly reduced plasma levels of malondialdehyde from 1.50 +/- 0.07 to 1.29 +/- 0.09 microM (p = 0.009); improved the percent flow-mediated dilator response to hyperemia from 5.17 +/- 0.24 to 6.22 +/- 0.26% (p < 0.001); and, furthermore, reduced plasma levels of monocyte chemoattractant protein (MCP-1) from 213 +/- 8 to 190 +/- 7 pg/ml (p = 0.003), tumor necrosis factor-alpha from 2.93 to 2.22 pg/ml (p = 0.026), and plasminogen activator inhibitor type 1 from 74 +/- 4 to 53 +/- 4 ng/ml (p < 0.001) but not C-reactive protein (CRP), matrix metalloproteinase protein, and fibrinogen. There were no significant correlations between these changes and reduction of systolic blood pressure (BP) (-0.247 < or = r < or = 0.195) and between these changes and reduction of diastolic BP (-0.262 < or = r < or = 0.197). There were no significant correlations between markers of inflammation and flow-mediated dilation percent or reduction of oxidant stress (-0.119 < or = r < or = 0.127). Furthermore, we observed no significant correlations between CRP and MCP-1 levels (r = -0.162). CONCLUSIONS: Inhibition of the angiotensin II type 1 (AT1) receptor in hypertensive patients reverses endothelial dysfunction, measured as an improvement in flow-mediated dilation and fibrinolysis and reduction of oxidant stress and inflammatory cytokines, suggesting that AT1 receptor blocker therapy has antiatherogenic effects.

Angiotensin Receptor Antagonists↗

PubMed2003

Angiotensin AT2 receptors directly stimulate renal nitric oxide in bradykinin B2-receptor-null mice.

Both bradykinin B2 and angiotensin II type 2 (AT2) receptors are known to stimulate renal production of nitric oxide (NO). To evaluate the individual contributions of AT2 and B2 receptors to renal NO production, we monitored renal interstitial, stable NO metabolites and cGMP by a microdialysis technique in conscious, bradykinin B2-null and wild-type mice (n=8 in each group) during low sodium intake alone or with the angiotensin AT1 or AT2 receptor blockers, valsartan (0.5 microg/min) or PD123319 (0.15 microg/min), or both. During normal salt intake, renal interstitial fluid NO and cGMP levels in B2-null mice were not different from those of wild-type mice. Low sodium intake increased NO and cGMP in wild-type mice but not in B2-null mice. Valsartan increased NO and cGMP in both wild-type and B2-null mice but to a significantly greater degree in the wild-type than in B2-null mice. PD123319 decreased NO and cGMP in both wild-type and B2-null mice. Combined valsartan and PD123319 decreased NO and cGMP in both wild-type and B2-null mice, but there was no significant difference during combined treatment from their levels after administration of PD123319 alone. Our results indicate that during ingestion of a low-salt diet, production of NO is mediated mainly via the AT2-B2 receptor cascade. Blockade of the AT1 receptor enhances the production of NO via the AT2 receptor in both wild-type and B2-null mice. We conclude that NO can be produced by 2 alternative pathways: directly through the AT2 receptor or indirectly from AT2 receptor stimulation of bradykinin via the B2 receptor.

Angiotensin Receptor Antagonists↗

PubMed2003

Experimental design approach for the optimisation of a HPLC-fluorimetric method for the quantitation of the angiotensin II receptor antagonist telmisartan in urine.

A high performance liquid chromatographic method with fluorimetric detection has been developed for the quantitation of the angiotensin II receptor antagonist (ARA II) 4-((2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)methyl)biphenyl-2-carboxylic acid (telmisartan) in urine, using a Novapak C18 column 3.9 x 150 mm, 4 microm. The mobile phase consisted of a mixture acetonitrile-phosphate buffer (pH 6.0, 5 mM) (45:55, v/v) pumped at a flow rate of 0.5 ml min(-1). Effluent was monitored at excitation and emission wavelengths of 305 and 365 nm, respectively. Separation was carried out at room temperature. Chromatographic variables were optimised by means of experimental design. A clean-up step was used for urine samples consisting of a solid-phase extraction procedure with C8 cartridges and methanol as eluent. This method proved to be accurate (RE from -12 to 6%), precise (intra- and inter-day coefficients of variation (CV) were lower than 8%) and sensitive enough (limit of quantitation (LOQ), ca. 1 microg l(-1)) to be applied to the determination of the active drug in urine samples obtained from hypertensive patients. Concentration levels of telmisartan at different time intervals (from 0 up to 36 h after oral intake) were monitored.

Angiotensin Receptor Antagonists↗