Effect of UK-84149 on voltage-activated calcium currents of single smooth muscle cells from guinea-pig and rabbit jejunum and rabbit coronary artery.
1. Smooth muscle cells of the longitudinal muscle of the guinea-pig and the rabbit jejunum and rabbit coronary artery were dispersed by enzyme treatment and recordings of membrane current were made in the standard whole cell voltage-clamp mode and by perforated patch technique. The effect of UK-84149 on the voltage-dependent calcium inward current of single isolated smooth muscle was studied at room temperature. 2. When inward and outward currents were evoked by stepping to 0 mV or + 10 mV from -80 mV every 20 s, UK-84149 reduced the voltage-dependent inward current in guinea-pig jejunum smooth muscle cells with a ID50 of 2.3 microM, and also reduced voltage-dependent outward current with a ID50 of 7.2 microM. The effect of UK-84149 was difficult to wash out. 3. The inactivation of the inward current was studied by holding at various potentials for 10 s before evoking inward current at a test potential of 0 mV. The voltage-inactivation curve was shifted to the left by 3 microM UK-84149. The voltage at which current was 50% available (Vh) was changed from -37 +/- 2 mV to -50 mV +/- 2.2 (n = 6, means +/- s.e. mean). 4. When inward current was evoked by stepping to 0 mV from -80 mV for 50 ms, every 20 s, nicardipine immediately, and verapamil and UK-84149 slowly, reduced the peak amplitude. Inhibition by the latter two drugs depended on the number of stimulations applied. So, like verapamil, UK-84149 had a use-dependent action. 5. The effect of UK-84149 on inward current from rabbit jejunum and coronary artery smooth muscle cells was compared with the effect of nicardipine and D600. When inward current was evoked by stepping to 0 mV from - 80 mV every 20 s, UK-84149 inhibited inward currents from both types of smooth cell with an ID50 of 1.7 microM for jejunum and an ID50 of 3.2 microM for coronary artery. ID50 values of D600 were 8.1 microM for jejunum and 3.9 microM for coronary artery. ID50 values of nicardipine were 24 nM for jejunum and 12 nM for coronary artery.6. The results of the present studies indicate that UK-84149 has a calcium-antagonist action that can explain its inhibitory action on bowel motility. Its bowel selectivity may arise due to its use-dependent,and persistent, action.
Zhang
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H
Department of Pharmacology & Clinical Pharmacology, St. George's Hospital Medical School, London.
Bolton
T B
TB
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001158:Arteries / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D003987:Dibenzothiazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005071:Evoked Potentials / Q000187:drug effects; D005711:Gallopamil / Q000494:pharmacology; D006168:Guinea Pigs; D007583:Jejunum / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009529:Nicardipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011817:Rabbits; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003987:Dibenzothiazepines; C094476:UK 84149; D005711:Gallopamil; D014700:Verapamil; D009529:Nicardipine