2004 Fiscal Year Final Research Report Summary
Novel Pharmacological Protiles of Dihydropyridines
| Project/Area Number |
15590071
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Toho University |
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Principal Investigator |
TANAKA Hikaru Toho University, School of Pharmaceutical Sciences, Department of Pharmacology, Associate Professor, 薬学部, 助教授 (40236617)
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| Project Period (FY) |
2003 – 2004
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| Keywords | dihydropyridines / T-type Ca^<2+> channel / Cl^- channel / ischemia-reperfusion / heart |
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| Research Abstract |
Pharmacology of dihydropyridine compounds with blocking activity on ion channels other than the L-type Ca^<2+> channel was studied. T-type Ca^<2+> channel blockade is now receiving attention as a novel therapeutic strategy for various cardiovascular disorders. A specific T-type Ca^<2+> channel blocker has not yet been established. We found that certain dihydropyridine compounds, such as efonidipine, have blocking activity on both L-type and T-type Ca^<2+> channels which possibly underlies their excellent clinical profiles such as minimum reflex tachycardia and renal protection. A phosphonate moiety or some bulky structure at the C5 position of the dihydropyridine ring may be important for the T-type Ca^<2+> channel blocking activity. AHC-52 and PAK200 are dihydropyridine compounds which block the cAMP-dependent chloride channel but not L-type Ca^<2+> channel. These compound were shown to enhance recovery of myocardial contractile force after ishcemia -reperfusion. A remarcable feature of this cardioprotection is that it was not accompanied by cardiosuppression. These compounds were found to attenuate the decrease in cellular ATP through protection of mitochondrial function. Thus, precise pharmacological investigation of dihydropyridine compounds with blocking activity on ion channels other than the L-type Ca^<2+> channel would lead to the development of cardioprotective agents acting through novel mechanisms.
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