Inhibition of voltage-gated L-type calcium channels by labedipinedilol-A involves protein kinase C in rat cerebrovascular smooth muscle cells.
Labedipinedilol-A, a novel calcium channel blocker with alpha/beta-adrenoceptor blockade properties, inhibits L-type calcium channels (LTCCs) in rat cerebrovascular smooth muscle cells (CSMCs). We used conventional whole cell patch-clamp electrophysiology to investigate Ba(2+) currents (I(Ba)) through LTCCs in rat CSMCs enzymatically dissociated from rat cerebral arteries. Labedipinedilol-A (1, 10 microM) reversibly inhibited I(Ba) in a voltage-dependent manner without modifying the I(Ba) current-voltage relationship. The I(Ba) was also abolished by the LTCC blocker nifedipine (1 microM), but enhanced by the LTCC activator Bay K8644 (100 nM). Labedipinedilol-A shifted the steady-state inactivation curve of I(Ba) to more negative potentials. Additionally, labedipinedilol-A had greater inhibitory activity on I(Ba) holding at -40 mV than at -80 mV. This might contribute to labedipinedilol-A's more selective effect on vascular muscles compared to cardiac muscles. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) and norepinephrine-enhanced I(Ba) were also inhibited by labedipinedilol-A. Pretreatment with the PKC inhibitor chelerythrine (5 microM) attenuated labedipinedilol-A-mediated I(Ba) inhibition. However, the Rho kinase inhibitor Y-27632 (30 microM) had little effect on labedipinedilol-A inhibition of I(Ba). Labedipinedilol-A inhibition of voltage-dependent LTCCs may be, at least in part, due to its modulation of the PKC pathway.
Wu
Bin-Nan
BN
Department of Pharmacology, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan.
Chen
Mu-Long
ML
Dai
Zen-Kong
ZK
Lin
Yi-Ling
YL
Yeh
Jwu-Lai
JL
Wu
Jiunn-Ren
JR
Chen
Ing-Jun
IJ
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002536:Cerebral Arteries / Q000166:cytology / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D004789:Enzyme Activation; D005260:Female; D008564:Membrane Potentials; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
D000317:Adrenergic alpha-Antagonists; D000840:Anisoles; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers; C500368:labedipinedilol A; D054460:rho-Associated Kinases; D011493:Protein Kinase C