Characterization of the Relaxant Response to N,N′-Dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine in Porcine Coronary Arteries

Abstract

N, ethylenediamines show structural analogy with estrogens and selective estrogen receptor modulators. Because the vasodilator properties of these compounds are unknown, we investigated their potential to relax porcine coronary arteries and determined the mechanism(s) of relaxation. Isolated porcine coronary arterial rings were suspended in organ chambers, precontracted with KCl (30 mM), and the relaxant response was determined by measurement of changes in isometric force. Dependent on the chemical structure, the drugs induced concentration-dependent relaxation in rings with and without endothelium. N,NЈ-Dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (8) was most potent and showed a 12-to 15-fold higher vasodilatory effect than 17␤-estradiol (E2). The vasorelaxation was independent of endothelium. Calcium concentrationdependent contractions in high-potassium depolarizing me- . Western blot analysis demonstrated that 8, unlike E2, raloxifene, and tamoxifen, failed to stimulate p38 MAPK. It is concluded that N,NЈ-dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine induces endothelium-independent relaxation of coronary arteries; the mechanism apparently involves inhibition of L-type Ca 2ϩ channels. The drug may be protective against cardiovascular diseases.N, ethylenediamines (Table 1) represent a class of compounds that are structurally similar to synthetic estrogens such as diethylstilbestrol (DES) and hexestrol (HEX) and to selective estrogen receptor modulators (SERMs) such as tamoxifen and the red wine polyphenol resveratrol (Fig. 1) (Metzler and Pfeiffer, 2001). For some of these ethylenediamines, a highestrogen receptor affinity of both diastereomeric forms with a preference for the meso isomer over the d,l-isomer has been reported previously. In addition, a strong inhibitory effect on the 7,12-dimethylbenz[a]anthracene-induced hormone-dependent mammary carcinoma in rats and a high potency in Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.107.120337.ABBREVIATIONS: DES, diethylstilbestrol; HEX, hexestrol; SERM, selective estrogen receptor modulator; E2, 17␤-estradiol; MAPK, mitogenactivated protein kinase; KHS, Krebs-Henseleit solution; PGF 2␣ , prostaglandin F 2␣ ; ICI 182,780,[7][8][9]4,5,5,