Effects of LP-805, a new vasodilating agent, on cytosolic Ca2+ and contraction in vascular smooth muscle of rat aorta.
1. LP-805 (0.1-10 microM) caused the reduction in norepinephrine (NE)-and serotonin (5-HT)-induced maximum response, a parallel shift of the concentration-response curve for prostaglandin F2 alpha (PGF2 alpha), in a concentration-dependent manner, but not K(+)-induced maximum response. 2. In Ca(2+)-free solution, LP-805 (0.1-10 microM) markedly inhibited the phasic contraction induced by 0.3 microM NE and the contraction induced by Ca2+ (0.1-2 mM) in the presence of 0.3 microM NE, in a concentration-dependent manner. Similar results were obtained in the presence of 5-HT (10 microM) or PGF2 alpha (10 microM). 3. In fura-2 loaded strips, ryanodine (10 microM) and LP-805 (10 microM) abolished 1 microM NE- and 30 microM 5-HT-induced phasic contractions, and inhibited the increase in cytosolic Ca2+ levels by both the agonists in the absence of external Ca2+, but had no influence on the following sustained contractions. 4. The effects of LP-805 on PGF2 alpha-induced Ca2+ transient and large sustained contraction were similar to those of ryanodine. 5. These results suggest that a vasodilatory effect of LP-805 might account for inhibiting the mobilization of external Ca2+ through receptor mediated passway and the Ca2+ release from a ryanodine sensitive Ca2+ store.
Kishii
K
K
POLA Pharmaceutical R&D Laboratory, Yokohama, Japan.
Inazu
M
M
Morimoto
T
T
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*; D015237:Dinoprost / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012433:Ryanodine / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D011720:Pyrazoles; D011743:Pyrimidines; D014665:Vasodilator Agents; C073993:8-tert-butyl-6,7-dihydropyrrolo(3,2-e)-5-methylpyrazolo(1,5-a)pyrimidine-3-carbonitrile; D012433:Ryanodine; D012701:Serotonin; D011189:Potassium Chloride; D015237:Dinoprost; D002118:Calcium; D009638:Norepinephrine