Effect of cromakalim on contractions in rabbit isolated renal artery in the presence and absence of extracellular Ca2+.
1. The inhibitory effects of the K+ channel activator, cromakalim, upon contractions to noradrenaline, histamine and caffeine were examined in rabbit isolated renal artery. For comparison, the effects of pinacidil, dazodipine and sodium nitroprusside were also studied in some experiments. 2. In normal Krebs solution, cromakalim (1 microM) produced a 39.1% reduction in area under the curve (AUC) of the noradrenaline concentration-response, and a 61.8% reduction in the histamine AUC. Ca2+ removal (with EGTA 0.1 mM) gave an 80.0% reduction in the noradrenaline AUC and a 74.5% reduction in the histamine AUC. The combination of Ca2+ removal and cromakalim (1 microM) had no further effect on the noradrenaline responses (a reduction of 78.4% in AUC), but produced a significantly greater reduction in the histamine AUC (86.2%). 3. LaCl3 (1 mM) reduced the noradrenaline AUC by 74.8% and gave an 81.8% reduction in the response to a single (EC90) histamine concentration. LaCl3 (1 mM) plus cromakalim (1 microM) produced no further reduction in the noradrenaline AUC (71.9%) but gave a significant further reduction of the histamine response (94.6%). 4. Pinacidil (3 microM) reduced the noradrenaline AUC by 35.5%. Pinacidil (3 microM) plus LaCl3 (1 mM) produced the same reduction in the noradrenaline AUC (80.9%) as LaCl3 alone (80.9%). 5. In both normal and Ca2+-free Krebs solution, cromakalim (0.1, 1.0 and 10 microM) produced concentration-related inhibition of the contraction to caffeine (10 mM). This inhibition was antagonised by the K+ channel blocker, glibenclamide (3 microM). Similarly, pinacidil (0.3, 3.0 and 30 microM) produced a glibenclamide-sensitive inhibition of the caffeine contraction. At equi-vasorelaxant concentrations, dazodipine (0.01, 0.1 and 1.O microM) and sodium nitroprusside (0.03, 0.3 and 3.0 microM) had no significant effect on caffeine contractions. 6. The data show that the K+ channel activators, cromakalim and pinacidil, unlike the Ca2+ channel blocker, dazodipine, or the guanylate cyclase activator, sodium nitroprusside, can inhibit the contraction which results from caffeine-induced Ca2+ release. Cromakalim and pinacidil, however, inhibit only the component of the noradrenaline response resulting from Ca2+ influx (tonic component) and not that resulting from Ca2 + release (phasic component). Cromakalim may affect both components of the histamine contraction.
Wilson
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Beecham Pharmaceuticals Research Division, The Pinnacles, Harlow, Essex.
Cooper
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D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D019806:Cromakalim; D006146:Guanidines / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007811:Lanthanum / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D020110:Pinacidil; D011758:Pyrroles / Q000494:pharmacology*; D011817:Rabbits; D012077:Renal Artery / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D002121:Calcium Channel Blockers; D006146:Guanidines; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D009599:Nitroprusside; D002110:Caffeine; D007811:Lanthanum; D020110:Pinacidil; D006632:Histamine; D006162:Guanylate Cyclase; D009543:Nifedipine; C034600:darodipine; D002118:Calcium; D009638:Norepinephrine