The effects of dihydropyridine Ca2+ channel blockers (DHP) and ACE inhibitors on superoxide formation and nitric oxide (NO) bioavailability were compared in human EA.Hy926 endothelial cells (EC). EC were stimulated 4 h with angiotensin II (Ang II, 10 nM) ± study drugs. Specific superoxide formation was measured by lucigenin-enhanced chemiluminescence, reduction of cytochrome c and rhodamine-123 fluorescence. Free NO release was determined with an amperometric NO sensor. NADPH oxidase subunits expression was examined with Western Blot. In untreated EC the intracellular superoxide is –64.3 ± 6.0% decreased compared to Ang II stimulated EC. Elevated extracellular superoxide formation was on a –43.0 ± 1.7% lower level in untreated EC. The DHP Ca2+-channel agonist BayK8644 and ACE inhibitors captopril and ramiprilat led extracellular superoxide concentration to control level. Enalaprilat blocked extracellular superoxide, the DHP amlodipine and nisoldipine prevented intracellular increases only (n = 8–9, p < 0.05). Icatibant (HOE 140), a kinin-B2 receptor antagonist, attenuated antioxidant actions of all tested agents except of nisoldipine. Ang II-induced superoxide was elevated by the phorbolester PMA and blocked by the protein kinase C (PKC) inhibitor chelerythrine. Suppression of substance P-evoked NO release by Ang II (>70%, n = 6) was reversed by the PKC inhibitor chelerythrine, the DHP amlodipine and nisoldipine and the ACE inhibitor ramiprilat. Further, Ang II reduces Nox-4 expression by 34.5 ± 4.9. Nox-2 expression was not regulated. DHP and ACE inhibitors exert different antioxidant effects in human EC stimulated with Ang II, but both improve NO bioavailability via bradykinin and modulation of redox-regulating enzymes.

1987-09-01·Journal of Cardiovascular Pharmacology4区 · 医学

Effect of DHP-218, a Novel Dihydropyridine Phosphonate, on Atrioventricular Nodal Conductivity Compared with Its Vascular Effect in Dogs

4区 · 医学

Article

作者: Hosono, Makoto ; Takahashi, Kenzo ; Taira, Norio

The effect of DHP-218, a dihydropyridine phosphonate Ca2+ channel blocker, on atrioventricular (AV) nodal conductivity was compared with its vascular effect in dogs. In isolated, blood-perfused AV node preparations, a long-lasting increase in AV conduction time which culminated in second- or third-degree AV block at large doses occurred when DHP-218 was injected into the AV node artery, but not when injected into the artery that supplies the His-Purkinje-ventricular system. However, with DHP-218, a far longer-lasting increase in blood flow through both arteries occurred, and at smaller doses it occurred with little effect on AV conduction. In anesthetized, open-chest dogs of which heart rate was controlled at 150 beats/min, intravenous DHP-218 produced an initially rather quick and later very slowly developing and long-lasting fall in blood pressure. AV conduction time was prolonged only after the largest dose. The functional refractory period of the AV conduction system was rather shortened in all doses examined except for the largest dose. A marked increase in AV conduction time which culminated in third-degree AV block was seen in one of six dogs, only under conditions in which the heart was deprived of central neural control. These results indicate appreciable selectivity of DHP-218 for vasculature versus the AV node.

1987-01-01·Chemical and Pharmaceutical Bulletin4区 · 医学

Syntheses and antihypertensive activities of 1,4-dihydropyridine-5-phosphonate derivatives. III.

4区 · 医学

Article

作者: Tsuda, Masami ; Kimura, Kiyoshi ; Kandori, Kazuhisa ; Haruta, Yuko ; Tomita, Toshio ; Kise, Masahiro ; Morita, Iwao

Phenyldihydropyridinephosphonates I [RR = (CH₂)₃, CH₂CMe₂CH₂; R = CO₂Me, allyl; R¹ = 2-NO₂, 2-CF₃, 2-OCHF₂, 3-NO₂; R² = Me, CH₂CHMe₂, CH₂CH₂OCH₂Ph, CH₂CH₂OMe, CH₂CH₂NMeCH₂Ph, allyl; R³ = Me, Et, Pr, allyl, CH₂Ph, CH₂CH₂OMe, NMe₂; R⁴ = Me] were prepared by the cyclocondensation reaction of R³NHCMe:CHCO₂R² with R¹C₆H₄CH:CAcP(O)(OR)₂ (II).I [R = allyl, RR = (CH₂)₃; R¹ = 2-NO₂, 3-NO₂, 2-CF₃; R² = Me; R³ = H; R⁴ = CH(OMe)₂] were prepared similarly by the reaction of II with (MeO)₂CHC(NH₂):CHCO₂Me.I [R⁴ = CH(OMe)₂] was deprotected to give I (same R-R³; R⁴ = CHO).The latter were converted to I (R⁴ = CH₂OH, CH:NOH, cyano).I were all tested for antihypertensive activity in normotensive and spontaneously hypertensive rats.I [RR = (CH₂)₃, R¹ = 2-NO₂, R² = Me, R³ = R⁴ = Me] shows higher antihypertensive activity than nifedipine, but lower than DHP-218.

100 项与 DHP-218 相关的药物交易

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