Antagonistic actions of S(-)-Bay K 8644 on cyclic nucleotide-induced inhibition of voltage-dependent Ba(2+) currents in guinea pig gastric antrum.
(+/-)-Bay K 8644, a conventional racemic mixture of Bay K 8644, is widely used as an L-type Ca(2+) channel agonist. Although interactions between Bay K 8644 and cyclic nucleotide have been described, they have not been properly characterized. We have investigated whether two optical isomers of Bay K 8644 (i.e., R(+)- and S(-)-Bay K 8644) modify cyclic nucleotide (cAMP and cGMP)-induced inhibitory effects on nifedipine-sensitive voltage-dependent Ba(2+) currents (I (Ba)) recorded from guinea pig gastric myocytes. Conventional whole-cell recordings were used to compare the effects of R(+)-Bay K 8644 and S(-)-Bay K 8644 on I (Ba). S(-)-Bay K 8644 enhanced the peak amplitude of I (Ba) evoked by depolarizing pulses to +10 mV from a holding potential of -70 mV in a concentration-dependent manner (EC(50) = 32 nM), while R(+)-Bay K 8644 inhibited I (Ba) (IC(50) = 975 nM). When R(+)-Bay K 8644 (0.5 microM) was applied, I (Ba) was suppressed to 71 +/- 10% of control. In the presence of R(+)-Bay K 8644 (0.5 microM), additional application of forskolin and sodium nitroprusside (SNP) further inhibited I (Ba). Conversely, in the presence of S(-)-Bay K 8644 (0.5 microM), subsequent application of forskolin and SNP did not affect I (Ba). Similarly, in the presence of 0.5 microM S(-)-Bay K 8644, db-cAMP and 8-Br-cGMP had no effect on I (Ba). These results indicate that S(-)-Bay K 8644, but not R(+)-Bay K 8644, can prevent the inhibitory actions of two distinct cyclic nucleotide pathways on I (Ba) in gastric myocytes of the guinea pig antrum.
Zhu
Hai-Lei
HL
Department of Pharmacology, Kyushu University, Fukuoka, 812-8582, Japan.
Teramoto
Noriyoshi
N
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001464:Barium / Q000502:physiology*; D003994:Bucladesine / Q000378:metabolism / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000737:chemistry / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D005576:Colforsin / Q000378:metabolism / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009599:Nitroprusside / Q000378:metabolism / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011706:Pyloric Antrum / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology
D002120:Calcium Channel Agonists; D020746:Calcium Channels, L-Type; D014665:Vasodilator Agents; D009599:Nitroprusside; D005576:Colforsin; D001464:Barium; C016276:8-bromocyclic GMP; D003994:Bucladesine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D006152:Cyclic GMP