Comparative vasodepressor effects of 3-pyridine derivatives possessing the cyanoamidine or amide structure in pithed rats.
The potency and mechanism of the vasodepressor action of N-cyano-3-pyridinecarboximidamide and nicotinamide, which are 3-pyridine derivatives possessing cyanoamidine and amide structures, respectively, were studied in pithed rats infused with phenylephrine. The N-substituents of cyanoamidine and amide in the derivatives studied comprised 2-nitroxyethyl (KRN2391 and nicorandil), phenethyl (Ki769 and Ki765) and 2-(2-chlorophenyl)ethyl (Ki3005 and Ki4261) moieties. These derivatives produced vasodepressor actions in a dose-dependent manner, except for Ki4261 which did not show any action below the solubility limit. When the vasodepressor effects of compounds possessing the same N-substituents in cyanoamidine and amide derivatives were compared, the potency of cyanoamidine derivatives was greater than that of amide derivatives, Ki3005 being the most potent. The vasodepressor effects of cyanoamidine and amide derivatives were antagonized by glibenclamide, although the antagonism of the depressor effects of KRN2391 and nicorandil was less pronounced than that of the other derivatives. These results suggest that N-substituents, in addition to the cyanoamidine structure, play an important role in determining the vasodepressor potencies of 3-pyridine derivatives. Furthermore, the vasodepressor effects of these derivatives appear to be based on their K+ channel-opening actions, although those of KRN2391 and nicorandil seem to be partly mediated by a nitrate-like action in addition to their K+ channel-opening action.
Kashiwabara
T
T
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
Nakajima
T
T
Hasegawa
S
S
Tanaka
Y
Y
Okada
Y
Y
Izawa
T
T
Ogawa
N
N
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D003655:Decerebrate State; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000008:administration & dosage / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D008297:Male; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D020108:Nicorandil; D010656:Phenylephrine / Q000008:administration & dosage / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014655:Vascular Resistance / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D015221:Potassium Channels; D011725:Pyridines; D014665:Vasodilator Agents; C084622:Ki 1769; C070492:N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonate; D010656:Phenylephrine; D009536:Niacinamide; D020108:Nicorandil; D005905:Glyburide