Role of endothelium and K+ channels in dobutamine-induced relaxation in rat mesenteric artery.

1. In order to examine the possible involvement of the endothelium and K+ channel activation in the relaxation induced by dobutamine, a beta 1-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 beta 1-adrenoceptor antagonist CGP 20712A (3 mumol/L) but not by the beta 2-adrenoceptor antagonist ICI 118,551 (3 mumol/L) in endothelium-denuded arteries. 3. Pretreatment with NG-nitro-L-arginine (L-NNA; 100 mumol/L) or methylene blue (3 mumol/L) induced a similar degree of inhibition of the dobutamine-induced relaxation in endothelium-intact arteries, while NG-nitro-D-arginine (100 mumol/L) and indomethacin (10 mumol/L) had no effect. In contrast, pretreatment with L-NNA (100 mumol/L) did not affect the relaxation induced by sodium nitroprusside (SNP) or forskolin. Methylene blue (3 mumol/L) inhibited the relaxant response to SNP. 4. Charybdotoxin (CTX; 100 nmol/L), iberiotoxin (IBX; 100 nmol/L) and tetraethylammonium ions (TEA+; 3 mmol/L) significantly reduced the dobutamine-induced relaxation. Tetrapentylammonium ions (TPA+; 5 mumol/L) markedly inhibited the relaxant effect of dobutamine. The pEC50 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 mumol/L) was ineffective. At 5 mumol/L, TPA+ also inhibited the relaxation induced by forskolin. 5. The maximal relaxation of PE-contracted arteries induced by 3 mumol/L dobutamine was completely abolished in the 60 mmol/L K(+)-contracted arteries with and without endothelium, while dobutamine at a concentration greater than 3 mumol/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 mumol/L may also act through K+ channels in our preparations. Higher concentrations of dobutamine may have a direct, endothelium-independent relaxant effect.