Effects of potassium channel blockers on the negative inotropic responses induced by cromakalim and pinacidil in guinea pig atrium.
The K+ channel openers cromakalim and pinacidil induced a concentration-dependent reduction in atrial contraction force with EC50 values of 25 +/- 2 and 37 +/- 2 mumol/l, respectively. This depressant effect was antagonised by 50 mumol/l tacrine which displaced the concentration-response curves of cromakalim and pinacidil to the right. The respective DR50 values were 3.8 and 2.3. Increasing the tacrine concentration (100 and 500 mumol/l) produced no additional effect on the concentration-response relationships. Addition of 1 mumol/l atropine enhanced the antagonism due to tacrine by increasing the DR50 value from 3.8 to 6.5 for cromakalim and from 2.3 to 5.2 for pinacidil. Glibenclamide, an ATP-sensitive K+ channel blocker, competitively inhibited the negative inotropic effects of cromakalim and pinacidil. The respective dissociation constants for glibenclamide against cromakalim and pinacidil were 0.57 and 0.35 mumol/l. Neither apamin nor variation in external Ca2+ concentration affected the negative inotropic effects of the K+ channel openers. It was suggested that the mechanical effects of cromakalim and pinacidil are mediated through the ATP-sensitive K+ channels in the heart.
Lau
W M
WM
Materials Research Laboratory, Defence Science and Technology, Organisation, Ascot Vale, Victoria, Australia.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019806:Cromakalim; D003864:Depression, Chemical; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects* / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects*; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013237:Stereoisomerism; D013619:Tacrine / Q000494:pharmacology
D000959:Antihypertensive Agents; D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D013619:Tacrine; D020110:Pinacidil; D000255:Adenosine Triphosphate; D005905:Glyburide