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Effects of CD-349, a new calcium entry blocker, on contraction induced by vasoconstricting agents in canine basilar artery after subarachnoid hemorrhage
1250 References Brock, T,A. and Capasso, E.A., 1988, J. Cell Physiol. 136, 54-62. De Nucci, G. et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85, 2334-2338. Weinhehner, (3. et al., 1986, Eur. J. Pharmacol. 130, 319-322.
i
MPC-1304, a novd calcim entry blocker, inhibits vasospasm induced by 3,~diaminopyridine in isolated canine coronary arteries Tajima, K., Oda, N., Miyake *, H. and Nagasaka * *, M. • Biological Research Lab., Taiho Pharmaceutical Co., Ltd, Tokushima and * * Research Lab., Maruko Pharmaceutical Co., Ltd., Kasugai, Japan
3,4-Diaminopyridine (DAP), K-channel blocker which decreases conductance, has been reported to cause phasic spasm in isolated canine and porcine coronary arteries, and membrane depolarization may trigger the rhythmic contractions, In this study we examined the effect of MPC-1304, (+)-methyl 2-oxopropyl 1,4-dilaydro-2,6-dirnethyl4(2-nitrophenyl)-3,5-pyridinedicarboxylate, a novel calcium entry blocker, on rhythmic contractions induced by DAP in canine coronary arteries and compared with those of other calcium entry blockers, nitroglycerin (NTG) and K-channel openers. MPC-1304 significantly reduced the tension of peak and relaxation phases, and ceased the rhythmic contractions without any effect on the frequency of contrac'~ions. Nifedipine and diltiazem significantly reduced the tension of peak phase, but increased the tension of relaxation phase and the frequency. NTG significantly reduced the tension of peak and relaxation phases, and decreased the frequency. Nicorandil significantly reduced the tension of peak and relaxation phases and had little effect on the frequency. BRL 34915, K-channel opener, decreased the frequency, and ceased the rhythm.ie contractions without any effect on the tension. The BRL 34915-haduced decreases in frequency was canceled by diltiazem, and the diltiazem-induced increases in frequency was inhibited by nicorandil. On the other hand, MPC-1304 and nifedipine inhibited calcium-induced contractions of feline coronary arteries. In summary, MPC-1304 inhibited the DAP-induced rhythmic contractions, significantly reduced the tension of relaxation phase as same as NTG and nieorandil, and did not show a marked effect on the frequency. These results suggest that MPC-1304 may have some modulative action on K-channel in coronary spasm induced by DAP in addition to its calcium antagonistic action. [P'we.092 ]
Effects of CD-349, a new calcium entry blocker, on contraction induced by vasoconstricting agents in canine basilar artery after subarachnoid hemorrhage Kamata, K., Nishiyama, H. and Kasuya, Y. Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo 142, Japan
It has been reported that calcium antagonists may not be useful agents for treating cerebral vasospasm after subarachnoid hemorrhage (SAIl). In the present study, we examined a new calcium antagonist, CD-349, 2-nitratopropyl 3-nitratopropyl 2,6-dimethyl-4-(3-nitrophenyl)-l,4-dihydropyridine.3,5.dicarboxylate, on the contraction induced by vasoconstricting agents in canine basilar artery after SAH. The canine model of experimental SAH was employed in the present s~udy because of its wide acceptability. Adult mongrel dogs with body weights ranging from 7 to 18 kg were anesthetized with intravenous pentobarbital. Experimental SAH was induced by an intracisternal injection of fresh arterial blood, carried out in an isovolemic
1251 fashion through a needle inserted in the cisterna magana: 8 ml of clear cerebrospinal fluid was withdrawn and replaced by an equivalent amount of the autogenous arterial blood. Three days after, the injection of fresh blood into the cisterna magna was repeated under anesthesia with pentobarbital. Changes in the contraction response of canine basilar artery after SAH are shown in Table 1. Table 1 Contractions induced by vasoconstricting agents in canine basilar artery in untreated and SAH groups. Agents
Control (g/rag)
SAH (g/mg)
P
PAF (1-6 M) Endothelin (10 -7 M) KCI (80 mM) Serotonin (10- 5 M) RGF2a (3 x 10- 6 M)
0.074+0.018 0.928 +0.046 0.863 + 0.050 0.193 4-0.058 0.159 + 0.027
0.211 +0.042 0.363 4-0.095 0.328 + 0.049 0.432 4-0.079 0.262 + 0,028
< 0.01 < 0.001 < 0.01 < 0.05 < 0.05
In untreated animals, serotonin caused a biphasic response as previously reported (Kim et al., 1988): at lower concentration (10 -9 to 3 x 10 -6 M), concentration-dependent contractions were observed, which were reversed at higher doses (10 -5 to 10 -4 M). The relaxations elicited by higher concentrations of serotonin were significantly reduced after SAH or treatment with methylene blue (10 -5 M) in untreated animals. When CD-349 (1 mg/kg, dayly for 7 days) was chronically given to the animals just after SAH, the relaxations induced by higher concentrations of serotonin were significantly reduced. Dose-response curve for the serotonin-induced contractile response after SAH was shifted to the left and maximal response of the basilar artery to serotonin was also increased. These increased contractile response to serotonin after SAH was significantly reduced by treatment with CD-349 (10-9). These results suggest that CD-349 may be useful for the treatment of serotonin-induced post-SAH vasospasm and that chronic treatment with CD-349 just after SAH may improve the endothelial damage.
Reference Kim et al., 1988, J. Neurosurg. 69, 239.
P.we.093 [
Lack of calcium-antagonist effects of PCA-4230, a novel 1,4-dihydropyridine derivative on several animal isolated tissues Villarroya, M., L6pez, M.G., Cillero, F.J., Sunkel, C.E. a n d Priego, J.G. Research Department. ALTER S.A., Mateo lnurria, 30, Madrid 28036, Spain
PCA-4230 (2•(••••3-Tri•x•-2•3•dihydr•-••2-benzis•thiaz•••2-y•)ethy•2•6•dimethy••5-(eth•xycarb•ny•)•4•methy• 1,4dihydropyridine-carboxylate) is a new 1,4-dihydropyridine derivative with antiplatelet and antithrombotic properties (SurLkel et al., 1988). Pig coronary art:ry, rabbit aorta and guinea pig ileum were depolarized with 35 mM K + and the effects of the compounds were as;es~ed after contracting under 1.5 mM Calcium. The antiserotoniaergic effect of PCA-4230 was tested in isolated guinea-pig ileum as compared with cyproheptadine. The anticholi~ergic effect of PCA-4230 and Atropine was assayed on isolated guinea-pig ileum and rat uterus. The effect of PCA-4230 on isolated guinea-pig trachea was analyzed in comparison with isoproterenol. PCA-4230 was compared with phentolamine in rabbit thoracic aorta and guinea-pig was deferens. 45-Calcium uptake experiments were performed on rabbit aorta strips according to Terai (1981). 3H-Nitrendipin~ binding experiments were carried out in rabbit skeletal muscle microsomes according to Ferry and 31ossman (1982).
i
MPC-1304, a novd calcim entry blocker, inhibits vasospasm induced by 3,~diaminopyridine in isolated canine coronary arteries Tajima, K., Oda, N., Miyake *, H. and Nagasaka * *, M. • Biological Research Lab., Taiho Pharmaceutical Co., Ltd, Tokushima and * * Research Lab., Maruko Pharmaceutical Co., Ltd., Kasugai, Japan
3,4-Diaminopyridine (DAP), K-channel blocker which decreases conductance, has been reported to cause phasic spasm in isolated canine and porcine coronary arteries, and membrane depolarization may trigger the rhythmic contractions, In this study we examined the effect of MPC-1304, (+)-methyl 2-oxopropyl 1,4-dilaydro-2,6-dirnethyl4(2-nitrophenyl)-3,5-pyridinedicarboxylate, a novel calcium entry blocker, on rhythmic contractions induced by DAP in canine coronary arteries and compared with those of other calcium entry blockers, nitroglycerin (NTG) and K-channel openers. MPC-1304 significantly reduced the tension of peak and relaxation phases, and ceased the rhythmic contractions without any effect on the frequency of contrac'~ions. Nifedipine and diltiazem significantly reduced the tension of peak phase, but increased the tension of relaxation phase and the frequency. NTG significantly reduced the tension of peak and relaxation phases, and decreased the frequency. Nicorandil significantly reduced the tension of peak and relaxation phases and had little effect on the frequency. BRL 34915, K-channel opener, decreased the frequency, and ceased the rhythm.ie contractions without any effect on the tension. The BRL 34915-haduced decreases in frequency was canceled by diltiazem, and the diltiazem-induced increases in frequency was inhibited by nicorandil. On the other hand, MPC-1304 and nifedipine inhibited calcium-induced contractions of feline coronary arteries. In summary, MPC-1304 inhibited the DAP-induced rhythmic contractions, significantly reduced the tension of relaxation phase as same as NTG and nieorandil, and did not show a marked effect on the frequency. These results suggest that MPC-1304 may have some modulative action on K-channel in coronary spasm induced by DAP in addition to its calcium antagonistic action. [P'we.092 ]
Effects of CD-349, a new calcium entry blocker, on contraction induced by vasoconstricting agents in canine basilar artery after subarachnoid hemorrhage Kamata, K., Nishiyama, H. and Kasuya, Y. Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo 142, Japan
It has been reported that calcium antagonists may not be useful agents for treating cerebral vasospasm after subarachnoid hemorrhage (SAIl). In the present study, we examined a new calcium antagonist, CD-349, 2-nitratopropyl 3-nitratopropyl 2,6-dimethyl-4-(3-nitrophenyl)-l,4-dihydropyridine.3,5.dicarboxylate, on the contraction induced by vasoconstricting agents in canine basilar artery after SAH. The canine model of experimental SAH was employed in the present s~udy because of its wide acceptability. Adult mongrel dogs with body weights ranging from 7 to 18 kg were anesthetized with intravenous pentobarbital. Experimental SAH was induced by an intracisternal injection of fresh arterial blood, carried out in an isovolemic
1251 fashion through a needle inserted in the cisterna magana: 8 ml of clear cerebrospinal fluid was withdrawn and replaced by an equivalent amount of the autogenous arterial blood. Three days after, the injection of fresh blood into the cisterna magna was repeated under anesthesia with pentobarbital. Changes in the contraction response of canine basilar artery after SAH are shown in Table 1. Table 1 Contractions induced by vasoconstricting agents in canine basilar artery in untreated and SAH groups. Agents
Control (g/rag)
SAH (g/mg)
P
PAF (1-6 M) Endothelin (10 -7 M) KCI (80 mM) Serotonin (10- 5 M) RGF2a (3 x 10- 6 M)
0.074+0.018 0.928 +0.046 0.863 + 0.050 0.193 4-0.058 0.159 + 0.027
0.211 +0.042 0.363 4-0.095 0.328 + 0.049 0.432 4-0.079 0.262 + 0,028
< 0.01 < 0.001 < 0.01 < 0.05 < 0.05
In untreated animals, serotonin caused a biphasic response as previously reported (Kim et al., 1988): at lower concentration (10 -9 to 3 x 10 -6 M), concentration-dependent contractions were observed, which were reversed at higher doses (10 -5 to 10 -4 M). The relaxations elicited by higher concentrations of serotonin were significantly reduced after SAH or treatment with methylene blue (10 -5 M) in untreated animals. When CD-349 (1 mg/kg, dayly for 7 days) was chronically given to the animals just after SAH, the relaxations induced by higher concentrations of serotonin were significantly reduced. Dose-response curve for the serotonin-induced contractile response after SAH was shifted to the left and maximal response of the basilar artery to serotonin was also increased. These increased contractile response to serotonin after SAH was significantly reduced by treatment with CD-349 (10-9). These results suggest that CD-349 may be useful for the treatment of serotonin-induced post-SAH vasospasm and that chronic treatment with CD-349 just after SAH may improve the endothelial damage.
Reference Kim et al., 1988, J. Neurosurg. 69, 239.
P.we.093 [
Lack of calcium-antagonist effects of PCA-4230, a novel 1,4-dihydropyridine derivative on several animal isolated tissues Villarroya, M., L6pez, M.G., Cillero, F.J., Sunkel, C.E. a n d Priego, J.G. Research Department. ALTER S.A., Mateo lnurria, 30, Madrid 28036, Spain
PCA-4230 (2•(••••3-Tri•x•-2•3•dihydr•-••2-benzis•thiaz•••2-y•)ethy•2•6•dimethy••5-(eth•xycarb•ny•)•4•methy• 1,4dihydropyridine-carboxylate) is a new 1,4-dihydropyridine derivative with antiplatelet and antithrombotic properties (SurLkel et al., 1988). Pig coronary art:ry, rabbit aorta and guinea pig ileum were depolarized with 35 mM K + and the effects of the compounds were as;es~ed after contracting under 1.5 mM Calcium. The antiserotoniaergic effect of PCA-4230 was tested in isolated guinea-pig ileum as compared with cyproheptadine. The anticholi~ergic effect of PCA-4230 and Atropine was assayed on isolated guinea-pig ileum and rat uterus. The effect of PCA-4230 on isolated guinea-pig trachea was analyzed in comparison with isoproterenol. PCA-4230 was compared with phentolamine in rabbit thoracic aorta and guinea-pig was deferens. 45-Calcium uptake experiments were performed on rabbit aorta strips according to Terai (1981). 3H-Nitrendipin~ binding experiments were carried out in rabbit skeletal muscle microsomes according to Ferry and 31ossman (1982).