Effects of LP-805, a new vasodilating agent, on rat thoracic aorta.
1. In canine coronary arteries, the contraction induced by prostaglandin F2 alpha (PGF2 alpha), but not by 65.9 mM K+, were relaxed by LP-805 (0.01-10 microM) in a concentration-dependent manner. 2. In rat thoracic aorta, LP-805 (0.1-10 microM) also relaxed the preparations contracted with norepinephrine (NE) and PGF2 alpha, but did not relax the contraction produced by 65.9 mM K+. 3. LP-805 (3-10 microM) inhibited the increase in cytosolic Ca2+ levels and contractions evoked by NE (1 microM) in the absence or presence of external Ca2+ in rat thoracic aorta. 4. LP-805 (0.1-10 microM) inhibited synthesis of IP3 induced by NE (0.3 microM) and cyclic AMP phosphodiesterase activity, and increased intracellular cyclic AMP levels in rat thoracic aorta. 5. These results suggest that a vasodilatory effect of LP-805 is due to inhibiting the increase in cytosolic Ca2+ levels via stimulation of various receptors, modulating second messenger synthesis.
POLA Pharmaceutical R&D Laboratory, Yokohama, Japan.
K
K
Kishii
M
M
Inazu
T
T
Morimoto
M
M
Tsujitani
I
I
Takayanagi
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D015290:Second Messenger Systems / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D011506:Proteins; 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; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D002118:Calcium; D009638:Norepinephrine