title: Differential inhibition by tedisamil (KC 8857) and glibenclamide of the responses to cromakalim and minoxidil sulphate in rat isolated aorta.
abstract: The effects of the K+ channel blockers tedisamil and glibenclamide on cromakalim- and minoxidil sulphate-induced 42K+ and 86Rb+ efflux and vasorelaxation in rat aorta, were investigated. In aortic strips preloaded with 42K+ or 86Rb+, cromakalim (1 mumol/l) induced increases in tracer efflux, which were concentration-dependently inhibited by tedisamil with similar potencies (pD2 approximately 7.3) but different amplitudes (maximum inhibition of 86Rb+ efflux to 0% of control, 42K+ efflux to 10 +/- 1%). The 42K+ efflux elicited by a low concentration of cromakalim (100 nmol/l) was, however, fully inhibited by tedisamil. The tracer effluxes induced by minoxidil sulphate were fully inhibited by tedisamil and glibenclamide (300 nM). Cromakalim and minoxidil sulphate, produced a concentration-dependent inhibition of noradrenaline (100 nmol/l)-induced tone, with pD2 values of approximately 7.3. Tedisamil (300 nmol/l) and glibenclamide (300 nmol/l), which inhibited cromakalim- and minoxidil sulphate-induced 42K+ and 86Rb+ efflux by greater than or equal to 80%, produced 2-fold and 40-fold shifts in the concentration-relaxation curve for cromakalim, and 3.5-fold and 2200-fold shifts in the concentration-relaxation curve for minoxidil sulphate, respectively. Similar shifts of the cromakalim concentration-relaxation curve in the presence of tedisamil and glibenclamide were also observed when the tissues were precontracted with potassium chloride (25 mmol/l). The results show that tedisamil and glibenclamide inhibit the cromakalim- and minoxidil sulphate-induced tracer effluxes with similar potencies whereas they differ greatly in their ability to inhibit the vasorelaxant effects of the two K+ channel openers.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Cardiovascular Department, Sandoz Pharma Ltd., Basel, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Bray
authors.forename: U
authors.initials: U
authors.lastname: Quast
mesh_terms: D000818:Animals; D001011:Aorta; D001578:Benzopyrans / Q000037:antagonists & inhibitors*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019806:Cromakalim; D003521:Cyclopropanes / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D008297:Male; D008914:Minoxidil / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects; D011758:Pyrroles / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D012413:Rubidium / Q000378:metabolism
chemical_list: D001578:Benzopyrans; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; C039516:minoxidil sulfate ester; D008914:Minoxidil; C059921:tedisamil; D012413:Rubidium; D011188:Potassium; D005905:Glyburide