Sulphonylurea-sensitive channels and NO-cGMP pathway modulate the heart rate response to vagal nerve stimulation in vitro

Sulphonylurea-sensitive K+ channels (K-ATP) have been implicated in the rel ease of acetylcholine (ACh) from the vagus nerve in the heart. Our aim was to establish the functional significance of this and to test whether this m odulation could interact with stimulation of the NO-cGMP pathway that facil itates the decrease in heart rate (HR) in response to vagal nerve stimulati on (VNS). We studied the effect of activation (diazoxide, 100 muM) and inhi bition (glibenclamide 30 muM or tolbutamide 5 muM) of K+ channels, and acti vation of the NO-cGMP pathway with the NO donor, sodium nitroprusside (SNP, 20 muM) or the cGMP analogue, 8-Br-cGMP (0.5 mM) on the HR response to VNS in the isolated guinea pig (Cavia porcellus) double atrial/right vagus pre paration (n = 40). Tolbutamide increased the bradycardia in response to vag al stimulation at 3 and 5 Hz (P<0.05); effects that were reversed by diazox ide. Glibenclamide also significantly increased the HR response to VNS at 1 and 3 Hz (P<0.05). Diazoxide alone significantly attenuated the HR respons e to VNS at 5 Hz (P<0.05). Neither glibenclamide nor diazoxide affected the HR response to carbamylcholine (CCh, 50-200 nM). In the presence of a maxi mal dose of tolbutamide, SNP or 8-Br-cGMP further increased the HR response to VNS at 5 Hz (P<0.05). These results are consistent with the hypothesis that inhibition of sulphonylurea-sensitive channels can increase the HR res ponse to VNS by a pre-synaptic mechanism, and that this modulation may be i ndependent of activation of the NO-cGMP pathway. (C) 2000 Academic Press.