The effects of KRN2391 (N-cyano-N'-(nitroxyethyl)-3-pyridine carboximidamide methane-sulfonate), which possesses ATP-sensitive potassium (K+) channel opening (KCO) activity and nitrate activity; Ki1769 (N-cyano-N'-(phenylethyl)-3-pyridinecarboximidamide methanesulfonate), which possesses only KCO activity; and nitroglycerin (NG) were determined on the motility of the ureter, urinary bladder and urethra of rats. Bladder contraction was induced by infusion of fluid into the bladder of conscious rats and recorded on a cystometrogram. KRN2391 and Ki1769 (both 0.3 mg/kg, i.v.) prolonged the micturition interval immediately after the injection, but NG (5 mg/kg, i.v.) did not. Peristaltic movement of the ureter, recorded in anesthetized rats, was inhibited by i.v. injection of KRN2391 and Ki1769 (both 0.03 mg/kg). However, when NG, NaNO2, N-nitro L-arginine methylester and methylene blue were applied directly to the ureter, no change in movement of the ureter was detected. KRN2391 (0.03 mg/kg, i.v.) and Ki1769 (0.3 mg/kg, i.v.) reduced the resistance to fluid infusion through the urethral lumen in anesthetized rats, whereas NG (0.5 mg/kg, i.v.) only reduced this resistance transiently. These results indicate that KCO activity had an inhibitory effect on the motility of the ureter, bladder and urethra. On the other hand, nitrate activity had an inhibitory effect on urethral tonus, corresponding to that induced by KCO activity.

12 Nov 1997·Fundamental & Clinical PharmacologyQ3 · MEDICINE

In vitro and in vivo vasodilating effects of KRN4884, Ki1769 and Ki3005, pyridinecarboxamidine derivatives

Q3 · MEDICINE

Article

Author: A Takeuchi ; J Kawahara ; N Ogawa ; T Izawa ; H Izumi

Summary— The vasodilating potencies and mechanism of action of a novel pyridinecarboxamidine derivative, KRN4884 (5‐amino‐N‐(2‐(2‐chlorophenyl)ethyl]‐N'‐cyano‐3‐pyridinecarboxamidine] were compared with those of Ki 1769 [N‐cyano‐N'‐(2‐phenylethyl)‐3‐pyridinecarboxamidine] and Ki3005 [N‐[2‐(2‐chlorophenyl)ethyl]‐N'‐cyano‐3‐pyridinecarboxamidine] in rat isolated aortas and in anesthetized normotensive rats. In vitro, KRN4884 (10‐10‐10‐6 M), Ki3005 (10‐10‐10‐6 M) and Ki30O5 (10‐10‐10‐6 M) produced concentration‐dependent relaxations. KRN4884 was about 100‐ and 10‐fold more potent than KU769 and Ki3005, respectively. The relaxant effects of these compounds were antagonized by glibenclamide. In vivo, KRN4884 (1–10 μg/kg, intravenously [iv]), KM769 (10–100 μg/kg, iv) and Ki3005 (3–30 μg/kg, iv) produced dose‐dependent decreases in mean blood pressure with slight increases in heart rate. At 10 μg/kg, iv, the hypotensive effect of KRN4884 was about the same as that of Ki3005 and about 5‐fold more pronounced than that of Ki 1769.The hypotensive action remained for a longer period after KRN4884 administration. In rats pre‐treated with glibenclamide (20 mg/kg, iv), the hypotensive effect of KRN4884 was abolished. These results suggest that the effect of KRN4884 in vitro and in vivo is based on its K channel opening action and that the in vitro vasorelaxant effect of these compounds in aortic rings does not predict their relative hypotensive effect in vivo.

01 Sep 1994·General Pharmacology: The Vascular System

Comparative analysis of vasodilating Mechanisms of Kil769, Ki3315 and KRN2391, pyridinecarboximidamide derivatives, in porcine isolated coronary artery

Article

Author: Okada, Yuji ; Izawa, Toshio ; Jinno, Yasuhiro ; Izumi, Hideakira ; Yokoyama, Takashi ; Ogawa, Nobuyuki

1. The vasodilating mechanisms of pyridinecarboximidamide derivatives which have a nitroxyl group (KRN2391), a phenyl group (Ki1769) or a hydroxyl group (Ki3315) were studied in porcine isolated coronary artery. 2. KRN2391 (10(-6) M) increased cyclic GMP formation but did not affect intracellular cyclic AMP level. Ki1769 (10(-5) M) and Ki3315 (10(-3) M) had no effect on intracellular cyclic GMP and cyclic AMP levels. 3. Despite producing submaximal relaxation at KRN2391 (10(-6) M) and nitroglycerin (10(-6) M), the increase in cyclic GMP caused by KRN2391 was lower than that caused by nitroglycerin. 4. Methylene blue (10(-5) M) inhibited KRN2391- and nitroglycerin-induced relaxations but did not affect Ki1769- and Ki3315-induced relaxation. 5. Glibenclamide (10(-6) M) inhibited KRN2391-, Ki1769- and Ki3315-induced relaxation but did not affect nitroglycerin-induced relaxation. 6. These results suggest that the nitroxyl group of KRN239 contributes to its nitrate action and the pyridinecarboximidamide moiety plays an important role of developing a K channel opening action.

100 Deals associated with Ki-1769

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Preclinical	JP	Kirin Holdings Co., Ltd.	-
Hypertension	Preclinical	-	Kirin	-
Myocardial Ischemia	Preclinical	-	Kirin	-
Myocardial Ischemia	Preclinical	JP	Kirin Holdings Co., Ltd.	-

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