The involvement of ATP-sensitive potassium channels in beta 2-adrenoceptor agonist-induced vasodilatation on rat diaphragmatic microcirculation.
1. The effects of glibenclamide (GLB), a blocker of ATP-sensitive potassium (KATP) channels, on diaphragmatic microcirculation in male Sprague-Dawley rats were assessed under basal conditions and after beta 2-adrenoceptor-agonist stimulation. In addition, forskolin was used to bypass beta-adrenoceptors and GTP-binding proteins (G-protein) to explore the possible mechanism of GLB effects. For comparison, the relationships between KATP channel activity and cyclic GMP-mediated vasodilator responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were also assessed. 2. Male Sprague-Dawley rats were anaesthetized with urethane and mechanically ventilated. The left hemi-diaphragm of each rat was prepared and microvascular blood flow (QLDF) was recorded with laser-Doppler flowmetry during continuous superfusion with bicarbonate-buffered, prewarmed Ringer solution. The drugs were topically applied to the surface of the hemi-diaphragm. 3. Salbutamol (0.32-32 microM), terbutaline (0.32 microM-0.32 microM) and forskolin (0.32-10 microM) each elicited a concentration-dependent increase in QLDF. 4. Baseline microvascular blood flow was unaffected by a 30 min suffusion of 1 microM GLB (295 +/- 51 mV vs 325 +/- 62 mV. P = 0.738). 5. The vasodilator response elicited by salbutamol (0.32 microM, 1 microM and 3.2 microM and 10 microM), was significantly attenuated by a 30 min superfusion with 1 microM GLB; this salbutamol-induced vasodilatation was mediated via an interaction with beta-adrenoceptor receptors, as in other experiments it was greatly inhibited by 30-min superfusion with propranolol (10 microM). 6. Similarly, following 30-min superfusion with GLB (1 microM), the terbutaline (1 microM, 3.2 microM and 10 microM)-induced vasodilator response was almost abolished and the vasodilator responses induced by incremental concentrations of forskolin (0.32 microM, 1 microM and 3.2 microM) were also significantly attenuated. 7. Cromakalim (1.5 microM, 3 microM and 3.2 microM) produced an increase of QLDF in a dose-dependent manner, which was virtually abolished by GLB (1 microM). In contrast, the vasodilator responses induced by acetylcholine (32 microM, 0.1 mM, and 0.32 mM) or sodium nitroprusside (3.2 microM, 10 microM and 20 microM) were independent of GLB (1 microM). 8. In conclusion, KATP channels may be functional, but tonically inactive in the resting diaphragmatic microcirculation and the vasodilator effect of beta 2-adrenoceptor agonists may be partly mediated by KATP channels; the activation of KATP channels may involve the accumulation of cyclic AMP in vascular smooth muscle cells.
Chang
H Y
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Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C.
D000255:Adenosine Triphosphate / Q000502:physiology*; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003964:Diaphragm / Q000098:blood supply / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D017078:Laser-Doppler Flowmetry; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D005905:Glyburide