K+ channel-opening properties of a novel compound, NIP-121, in guinea pig myocardium as compared with those of cromakalim.
Myocardial effects of NIP-121, a novel compound with potent vasorelaxant activity, were examined in comparison with those of cromakalim in isolated tissue and cells from guinea pig hearts. NIP-121 and cromakalim concentration-dependently reduced the action potential duration (APD) of isolated papillary muscle; the effect was antagonized by glibenclamide. In isolated ventricular tissue, NIP-121 and cromakalim decreased the contractile force concentration dependently. In these two experiments, the potency of NIP-121 was approximately 20 times higher than that of cromakalim. The effects of NIP-121 and cromakalim on membrane currents were examined in voltage-clamped ventricular myocytes. NIP-121 (10(-6) M) and cromakalim (3 x 10(-5) M) increased the steady-state outward currents. The normal inwardly rectifying current-voltage relationship changed to a linear relationship that reversed at the K+ current reversal potential. The current activated by NIP-121 and cromakalim was inhibited either by glibenclamide or by increased intracellular ATP concentration. NIP-121, at this concentration, had little effect on the calcium current. Thus, NIP-121 was demonstrated to produce AP shortening and decrease in contractile force through activation of ATP-sensitive K+ currents in cardiac muscle, with a potency approximately 20 times higher than that of cromakalim.
Matsuda
T
T
Department of Pharmacology, Toho University School of Pharmaceutical Sciences, Chiba, Japan.
Okazaki
K
K
Kato
Y
Y
Tanaka
H
H
Shigenobu
K
K
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D019806:Cromakalim; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D007004:Hypoglycemic Agents / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology; D010069:Oxadiazoles / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D007004:Hypoglycemic Agents; D010069:Oxadiazoles; D010880:Piperidines; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; C070366:NIP 121; D000255:Adenosine Triphosphate; D005905:Glyburide