The effects of the dihydropyridine Bay K 8644 in guinea-pig isolated trachealis.
In trachea bathed by Krebs solution containing indomethacin 0.8 mumol l-1, Bay K 8644 (0.01-1 mumol l-1) evoked mild spasm. Peak tension was achieved after 10 min and was generally less than 20% of an acetylcholine (ACh) maximum. The effect of Bay K 8644 was not potentiated by addition of 2.5 mmol l-1 potassium chloride (KCl) to the Krebs solution. Bay K 8644 (1 mumol l-1) caused a small potentiation of KCl and tetraethylammonium (TEA). In contrast it did not modify the actions of ACh or histamine. Bay K 8644 (1 mumol l-1) caused a small potentiation of the effect of calcium chloride (CaCl2) tested in trachea bathed by a K+-rich, Ca2+-free, MOPS-buffered physiological salt solution. Organic inhibitors of calcium influx such as nifedipine (0.1 mumol l-1), verapamil (1 mumol l-1) or diltiazem (10 mumol l-1) each caused marked depression of concentration-effect curves to KCl. Bay K 8644 (0.01-1 mumol l-1) provided concentration-dependent protection against this effect in all three cases. Estimation of calcium influx by the lanthanum technique revealed that Bay K 8644 (1 mumol l-1) was able to promote the cellular influx of Ca2+. Intracellular electrophysiological recording showed that Bay K 8644 (1 mumol l-1) caused no change in the resting membrane potential of trachealis cells and no change in the properties of the spontaneous electrical slow waves. However, Bay K 8644 was able to delay the slow wave suppression evoked by 1 mumol l-1 nifedipine. The ability of Bay K 8644 to promote Ca2+ influx and its ability to protect against the effects of several structurally-unrelated inhibitors of Ca2+ influx are consistent with Bay K 8644 acting as an agonist at the dihydropyridine receptor associated with the voltage-operated Ca2+ channel (VOC) of trachealis muscle. By this action it potentiates those spasmogens (KCl, TEA) which act by permitting Ca2+ influx through VOCs. In contrast it has no effect on those spasmogens (ACh, histamine) which principally act to liberate Ca2+ from intracellular sites of sequestration.
Allen
S L
SL
Foster
R W
RW
Small
R C
RC
Towart
R
R
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002122:Calcium Chloride / Q000494:pharmacology; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007811:Lanthanum / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
D002121:Calcium Channel Blockers; D013757:Tetraethylammonium Compounds; D019789:Tetraethylammonium; D011189:Potassium Chloride; D007811:Lanthanum; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D006632:Histamine; D009543:Nifedipine; D002122:Calcium Chloride; D000109:Acetylcholine