caa a22 4500 469077778 CHVBK 20180323132940.0 cr unu---uuuuu 170328e19920701xx s 000 0 eng 10.1007/BF00167577 doi (NATIONALLICENCE)springer-10.1007/BF00167577 Vasodilating properties of KRN2391: structural basis of a new pyridine-type potassium channel opener with a nitrate moiety [Elektronische Daten] [Takaharu Ishibashi, Masami Hamaguchi, Shoichi Imai] Summary: The vasodilating mechanism of a new compound, cyanoimino-3-pyridylmethylaminoethyl nitrate methanesulfonate (KRN2391), a derivative of nicorandil, was examined in the isolated rabbit aorta. To elucidate the structure activity relationship, a comparison was made with the two denitrated derivatives: cyanoimino-3-pyridylmethylaminoethyl acetate methanesulfonate (Ki4032) and cyanoimino-3-pyridylmethylaminoethyl alcohol (Ki3315). In preparations precontracted with phenylephrine (10−7 mol/l), KRN2391, Ki4032 and Ki3315 caused concentration-dependent relaxation. pD2 values (−log [EC50]) were 6.74 ± 0.03, 5.67 ± 0.05 and 3.63 ± 0.03, respectively. Both methylene blue and glibenclamide produced a shift to the right of the concentration-response curves for KRN2391. The shift by glibenclamide became greater in the presence of methylene blue. An elevation of the cGMP content was not detected until the concentration of KRN2391 was increased to a level enough to produce a full relaxation (3 × 10−6 mol/l). In contrast, in the case of Ki3315 a parallel shift to the right of the concentration-response curve was observed after glibenclamide (10−5 mol/l). Methylene blue (10−5 mol/l) had no effect on the concentration-response curve, and there was no increase in cyclic GMP (cGMP) with 10−5 mol/l of the compound. The concentration-response curve of Ki4032 was also attenuated by glibenclamide. Though this compound lacks the nitrate moiety, it (10−4 mol/l) showed a slight tendency to increase the cGMP content, and methylene blue slightly but significantly modified the concentration-response curve of this compound. However, the co-administration of glibenclamide and methylene blue resulted in no further modification of the concentration-relaxation curve. These results indicate that both the opening of potassium channels and the activation of the soluble guanylate cyclase are responsible for the vasorelaxant effect of KRN2391. These two mechanisms are operative at similar concentrations of KRN2391. In contrast, Ki3315 and Ki4032 are exclusive potassium channel openers. Although KiA032 produced a slight increase in cGMP, this is probably not due to the activation of soluble guanylate cyclase. Springer-Verlag, 1992 KRN2391 nationallicence Ki3315 nationallicence Ki4032 nationallicence Cyclic GMP nationallicence Isolated rabbit aorta nationallicence Ishibashi Takaharu Department of Pharmacology, Niigata University School of Medicine, Asahimachi-Dori 1-757, 951, Niigata, Japan aut Hamaguchi Masami Department of Pharmacology, Niigata University School of Medicine, Asahimachi-Dori 1-757, 951, Niigata, Japan aut Imai Shoichi Department of Pharmacology, Niigata University School of Medicine, Asahimachi-Dori 1-757, 951, Niigata, Japan aut Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 346/1(1992-07-01), 94-101 0028-1298 346:1<94 1992 346 210 https://doi.org/10.1007/BF00167577 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00167577 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Ishibashi Takaharu Department of Pharmacology, Niigata University School of Medicine, Asahimachi-Dori 1-757, 951, Niigata, Japan aut NATIONALLICENCE 700 1- Hamaguchi Masami Department of Pharmacology, Niigata University School of Medicine, Asahimachi-Dori 1-757, 951, Niigata, Japan aut NATIONALLICENCE 700 1- Imai Shoichi Department of Pharmacology, Niigata University School of Medicine, Asahimachi-Dori 1-757, 951, Niigata, Japan aut NATIONALLICENCE 773 0- Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 346/1(1992-07-01), 94-101 0028-1298 346:1<94 1992 346 210 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer