Effects of LP-805, a novel vasorelaxant agent, a potassium channel opener, on rat thoracic aorta.
1. In rat thoracic aorta, LP-805 (0.1-10 microM) caused the marked reduction of NE-induced maximum response and relaxed the low K+ (less than 35.9 mM)-induced contraction, in a concentration-dependent manner, but failed to relax the high K+ (65.9 mM)-induced contraction. 2. Glibenclamide (0.3-1 microM) caused a parallel shift of concentration-response curve produced by LP-805 for 25.9 mM K(+)-induced contraction and prevented the LP-805-induced reduction in maximum response evoked by NE in a concentration-dependent manner. 3. Glibenclamide (10 microM) prevented the LP-805 (10 microM)-induced decrease in cytosolic Ca2+ levels which was increased by 1 microM NE or 25.9 mM K+. 4. LP-805 (10 microM) increased basal 86Rb efflux, which was completely inhibited by 10 microM glibenclamide. 5. The results suggest that LP-805 causes a vasorelaxation as a consequence of the decrease in cytosolic Ca2+ levels due to the increase in K+ efflux via opening ATP-dependent K+ channels.
Kishii
K
K
POLA Pharmaceutical R&D Laboratory, Yokohama, Japan.
Morimoto
T
T
Nakajima
N
N
Yamazaki
K
K
Tsujitani
M
M
Takayanagi
I
I
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D016257:Fura-2 / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012414:Rubidium Radioisotopes; D014665:Vasodilator Agents / Q000494:pharmacology*
D015221:Potassium Channels; D011720:Pyrazoles; D011743:Pyrimidines; D012414:Rubidium Radioisotopes; D014665:Vasodilator Agents; C073993:8-tert-butyl-6,7-dihydropyrrolo(3,2-e)-5-methylpyrazolo(1,5-a)pyrimidine-3-carbonitrile; D011188:Potassium; D005905:Glyburide; D002118:Calcium; D016257:Fura-2; D009638:Norepinephrine