Labedipinedilol-C: A Third-Generation Dihydropyridine-Type Calcium Channel Antagonist Displaying K+ Channel Opening, NO-Dependent and Adrenergic Antagonist Activities

Abstract

Intravenous and oral labedipinedilol-C showed a dose-dependent long-lasting hypotension and a decrease of heart rate in normotensive and conscious spontaneously hypertensive rats (SHR). In isolated Wistar rat and guinea pig tissues, labedipinedilol-C competitively antagonized (-)isoproterenol-induced cardiac stimulation, tracheal relaxation, and phenylephrine-, CaCl2-, and high-K-induced aorta contractions in a concentration-dependent manner. The estimated pA2 and pKCa values were 8.22+/-0.04 and 7.11+/-0.52, respectively. [H]CGP-12177 binding to ventricle and lung tissues as well as [H]prazosin and [H]nitrendipine binding to brain membranes were inhibited by labedipinedilol-C with Ki values of 2.86, 9.03, 0.39, and 0.05 muM, respectively. The vasorelaxant effects of labedipinedilol-C on phenylephrine (10 microM)-induced contractions were attenuated by removing endothelium, by pretreatment with soluble guanylyl cyclase (sGC) inhibitors ODQ (10 microM) and methylene blue (10 microM), a NOS inhibitor L-NAME (100 microM), a K channel blocker TEA (10 mM), a KATP channel blocker glibenclamide (1 microM), and Ca-dependent K channel blockers apamin (1 microM) and charybdotoxin (0.1 microM). In human umbilical vein endothelial cells (HUVECs), labedipinedilol-C increased NO release, which was significantly inhibited by L-NAME. The Western blot analysis on HUVECs indicated that labedipinedilol-C increased the expression of eNOS. These results indicate that hypotension effects of labedipinedilol-C result from alpha-adrenoceptor and Ca entry-blocking activities and release of NO or NO-related substance from vascular endothelium. The endothelium-independent relaxation of vascular smooth muscle is probably linked to K channel opening and alpha-adrenoceptor-blocking activities.

Endotoxemia-Mediated Induction of Cardiac Inducible Nitric-Oxide Synthase Expression Accounts for the Hypotensive Effect of Ethanol in Female Rats

“…It is noteworthy that there are similarities between the cardiovascular effects of ethanol and estrogen, which include inhibition of calcium influx (Turlapaty et al, 1979;Zhang et al, 1994), enhancement of NOS activity (Weiner et al, 1994;Wang and Abdel-Rahman, 2005;Zhang et al, 2005), and reduction of ␣-adrenergic receptor responsiveness (Abdel-Rahman et al, 1985;Sudhir et al, 1997). Indeed, the NOS-derived NO seems to be the major mediator of the estrogen-dependent hypotensive effect of ethanol because NO is directly or indirectly linked to vasodilation and reduces cardiac contractility (Yeh et al, 2005). It is possible, therefore, that ethanol may interact synergistically with estrogen to produce vascular and/or cardiac changes that might lead to hypotension.…”

Terminalia fagifolia Mart. & Zucc. elicits vasorelaxation of rat thoracic aorta through nitric oxide and K+ channels dependent mechanism

“…The presence of nitric oxide in the vascular smooth muscle activates the sGC that act over the guanosine triphosphate, converting it to cGMP, which is important in the regulation of vascular tonus. The inhibition of the soluble guanylyl cyclase enzyme can be performed with the use of ODQ (Yeh et al, 2005; Hipólito et al, 2009), and when the aorta rings were pre-incubated with ODQ, the curve of relaxation induced by Tf-AQF moved significantly to the right with attenuation of the relaxing efficacy, in the presence of that inhibitor (Fig. 2B).…”

“…The activation of K ATP channels can stem from the release of endothelium-derived factors, such as NO. NO and cGMP may promote a hyperpolarization and relaxation of the smooth muscular cells by means of the opening of K ATP channels (Feleder and Adler-Graschinsy, 1997; Yeh et al, 2005). Therefore, nitric oxide donor substances have been shown as activators of the K ATP independently on cGMP (Murphy and Brayden, 1995), and by an independent mechanism of cGMP in the rat mesenteric artery (Weidelt et al, 1997).…”

The Novel Analogue of Hirsutine as an Anti-Hypertension and Vasodilatary Agent Both In Vitro and In Vivo

“…Endothelium-intact aortic rings were pre-incubated for 15 min, respectively with L-NAME, a NO synthase inhibitor (10 –4 mol·L -1 )[ 10 , 11 ] and ODQ, a specific inhibitor of soluble guanylyl cyclase (10 –6 mol·L -1 )[ 12 ]. After that, aortic rings prior to contraction with PE (10 −6 mol·L -1 ) to get to the plateau, then continuously add cumulative concentrations of compound 1 (10 -11 -10 -4 mol·L -1 ) to the bath so as to obtain the concentration–response curve of compound 1 -induced relaxation.…”