Inhibition of field stimulation-evoked relaxations in rat oesophageal smooth muscle by the calcium antagonist PN 200-110.
1. The inhibitory effects of the 1,4-dihydropyridine calcium channel antagonist, PN 200-110 (isradipine), on field stimulation-evoked tetrodotoxin (TTX)-sensitive and -insensitive relaxations were studied in rat oesophageal smooth muscle of the tunica muscularis mucosae. 2. The TTX-insensitive relaxation was inhibited by PN 200-110 in a stereoselective manner with the (+)-(S)-isomer displaying a 1000 fold greater inhibitory potency than the (--)-(R) isomer. A similar potency was noted for inhibition of high K+ -evoked contractions. 3. TTX-sensitive relaxations evoked by field stimulation and contractions elicited by the muscarinic cholinoceptor agonist, cis-2-methyl-4-dimethylamino-methyl-1,3-dioxolane methiodide (cisdioxolane) were considerably less sensitive to inhibition by PN 200-110, although, again, stereoselectivity for PN 200-110 was apparent. 4. Pretreatment with (+)-(S)-PN 200-110 resulted in a non-competitive displacement of the Ca2+ concentration-response curves obtained in the presence of either isotonic 50 mM KCl or cisdioxolane. The effect of K+ was 10 fold more sensitive than that of cis-dioxolane. 5. The potency rank orders for inhibition of TTX-insensitive field stimulation-evoked relaxations and K+ -mediated contractions in a series of calcium channel antagonists were closely correlated; (+)-(S)-PN 200-110 showing highest potency followed by nifedipine, verapamil, diltiazem, (--)-(R)-PN 200-110. 6. It is concluded that TTX-insensitive relaxations are dependent upon an influx of extracellular Ca2+ through potential-operated calcium channels.
Akbarali
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HI
Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
Bieger
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D
Triggle
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CR
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004148:Dioxolanes / Q000494:pharmacology; D004558:Electric Stimulation; D004947:Esophagus / Q000187:drug effects; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D017275:Isradipine; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010069:Oxadiazoles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013779:Tetrodotoxin / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004148:Dioxolanes; D010069:Oxadiazoles; D013779:Tetrodotoxin; D017275:Isradipine