Vascular activity of nitrendipine (NTD) in different depolarized and prostaglandin F2 alpha (PGF2 alpha)-precontracted isolated porcine arteries was examined in the presence and absence of methylene blue (MB). Presence of MB potentiated the PGF2 alpha-induced contractions in all vessels studied and reduced the response of NTD in coronary and basilar arteries seven- to 23-fold. Only in ulnar arteries was the affinity of NTD slightly increased. In contrast, MB did not modify the affinity of papaverine under these conditions. Furthermore, MB had no influence on KCl-induced contractions and subsequent vasorelaxation by NTD. It is proposed that MB impaired endothelium derived relaxing factor, thereby stimulating and/or increasing the calcium influx through receptor-operated calcium channels.

It has been reported that the lipophilicity of dihydropyridine-type calcium entry blockers may influence both their negative inotropic and their vasodilator activities. The action of nitrendipine and six related 3-ester side-chain derivatives with increasing alkyl and aryl substituents have been investigated in isolated porcine trabecular muscles and coronary artery rings. The lipophilicity of the drugs was determined by high-pressure liquid chromatography. In addition, some sterical parameters of the ester derivatives were considered. For the drugs tested, an increase in 3-ester side chain volume correlated well with increasing lipophilicity. Compared to nitrendipine, vascular selectivity of the ester side-chain derivatives, as expressed by the ratio of their negative inotropic and vasodilator activities, was much reduced. Neither vasodilator nor negative inotropic activity was directly related to the corresponding lipophilicity. Based on these results, earlier suggestions about the influence of the ester side-chain in dihydropyridines on their cardiovascular profile are extended.

1 Dihydropyridine-type calcium entry blockers exhibit a different vasodilator potency depending on the arterial tissue (intervascular selectivity) as well as on the precontracting stimulus used (stimulus selectivity). In addition, the structure of their ester side chains seems to influence their activity. 2 Vascular activity of nitrendipine and six related 3-ester side chain derivatives was investigated in isolated coronary, ulnar and basilar arteries of the pig following precontraction with KCl or prostaglandin F2a (PGF2).3 After depolarization, all dihydropyridines exhibited a weak preferential action on coronary arteries.Bay E 6927 produced the strongest effect in all vessel types. By contrast, precontraction with PGF2, resulted in a marked preferential action in basilar arteries, although higher concentrations of the dihydropyridines were required for half maximal vasorelaxation. In each case, ulnar arteries were less sensitive. 4 Except with Bay 0 5572, the most bulky substituted and least active derivative, only moderate differences were observed within the dihydropyridines studied. On the other hand, there was a pronounced increase in the ratios of the half maximal active concentrations required after precontraction of the vessels with PGF2, compared to KCI (stimulus selectivity) following a limited prolongation of the 3-ester side chain up to an isopropyl-group. 5 It is suggested that the observed shift in the intervascular selectivity after precontraction with PGF2C, is a consequence of different contractile mechanisms in the three vessel types studied. The degree of the stimulus selectivity may also depend on the structure of the dihydropyridines.

Vascular endothelium modulates the effect of various vasoconstricting mediators as well as the affinity of dihydropyridine-type calcium entry blockers. To further investigate this influence, vasoconstriction by PGF2 alpha as opposed to KCl and the affinity of nitrendipine and some related 3-ester side-chain derivatives were determined in isolated porcine basilar arteries in the presence and in the absence of intact endothelium, as well as in the presence of methylene blue. Treatment with methylene blue or mechanical endothelial damage increased the contractile work of basilar arteries stimulated by PGF2 alpha and reduced the affinity of the dihydropyridines in such precontracted vessels. Both experimental conditions resulted in nearly the same effect. In addition, the degree of intact endothelium, as determined by substance-P-induced vasodilation, significantly correlated with the corresponding efficacy of all dihydropyridines examined. In contrast, KCl-mediated contractions remained unchanged. It is suggested that the endothelium (probably due to the production and release of endothelium-derived vasorelaxing factors, such as EDRF and/or prostacyclin) may attenuate PGF2 alpha-induced transmembrane calcium influx through receptor operated calcium channels, whereas potential operated calcium channels seems to be unaffected.

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