ROLE OF ENDOTHELIUM AND K+ CHANNELS IN DOBUTAMINE‐INDUCED RELAXATION IN RAT MESENTERIC ARTERY

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Abstract
1. In order to examine the possible involvement of the endothelium and K+ channel activation in the relaxation induced by dobutamine, a β‐adrenoceptor agonist, in rat isolated mesenteric arteries, the effects of inhibitors of nitric oxide (NO) activity, blockers of K+ channels and high extracellular K+ were studied by measuring isometric tension in both endothelium‐intact and ‐denuded arteries. 2. Dobutamine inhibited the phenylephrine (PE)‐induced sustained tension with a pEC50 of 7.40±0.08 in endothelium‐intact arteries. Removal of functional endothelium attenuated the effect of dobutamine. The relaxation induced by dobutamine was inhibited by the β1‐adrenoceptor antagonist CGP20712A (3μ.mol/L) but not by the β2‐adrenoceptor antagonist ICI 118 551 (3 μmol/L) in endothelium‐denuded arteries. 3. Pretreatment with NG‐nitro‐l‐arginine (l‐NNA; 100 μmol/L) or methylene blue (3 μmol/L) induced a similar degree of inhibition of the dobutamine‐induced relaxation in endothelium‐intact arteries, while NG‐nitro‐d ‐arginine (100 (μmol/L) and indomethacin (10 μmol/L) had no effect. In contrast, pretreatment with L ‐NNA (100 μmol/L) did not affect the relaxation induced by sodium nitroprusside (SNP) or forskolin. Methylene blue (3μmol/L) inhibited the relaxant response to SNP. 4. Charybdotoxin (CTX; 100nmol/L), iberiotoxin (IBX; 100nmol/L) and tetraethylammonium ions (TEA+; 3mmol/L) significantly reduced the dobutamine‐induced relaxation. Tetrapentylammonium ions (TPA+; 5μmol/L) markedly inhibited the relaxant effect of dobutamine. The pECso values for control and in the presence of TPA+ in endothelium‐intact arteries were 7.35±0.11 and 6.14±0.17, respectively, and 6.35±0.09 and 5.87±0.17 for control and in the presence of TPA+ in endothelium‐denuded arteries, respectively. In contrast, glibenclamide (3 μ‐mol/L) was ineffective. At 5 μmol/L, TPA+ also inhibited the relaxation induced by forskolin. 5. The maximal relaxation of PE‐contracted arteries induced by 3μmol/L dobutamine was completely abolished in the 60mmol/L K+‐contracted arteries with and without endothelium, while dobutamine at a concentration greater than 3 μmol/L induced inhibition of the high‐K+ response. 6. The present results indicate that endothelium, probably NO but not prostacyclin, was involved in the dobutamine‐induced relaxation in rat mesenteric arteries. Activation of CTX‐, IBX‐ and TPA+‐sensitive K+ channels contributed towards the observed relaxation. Loss of the ability to relax the 60 mmol/L K+‐contracted arteries suggests that endothelium‐derived vasoactive factors affected by concentrations of dobutamine less than 3 μmol/L may also act through K+ channels in our preparations. Higher concentrations of dobutamine may have a direct, endothelium‐independent relaxant effect.