Sulphonylurea-sensitive Channels and NO-cGMP Pathway Modulate the Heart Rate Response to Vagal Nerve Stimulation in vitro

Sulphonylurea-sensitive K+channels (KATP) have been implicated in the release 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 modulation could interact with stimulation of the NO-cGMP pathway that facilitates the decrease in heart rate (HR) in response to vagal nerve stimulation (VNS). We studied the effect of activation (diazoxide, 100 μ ) and inhibition (glibenclamide 30 μ or tolbutamide 5 μ ) of KATPchannels, and activation of the NO-cGMP pathway with the NO donor, sodium nitroprusside (SNP, 20 μ ) or the cGMP analogue, 8-Br-cGMP (0.5 m ) on the HR response to VNS in the isolated guinea pig (Cavia porcellus) double atrial/right vagus preparation (n=40). Tolbutamide increased the bradycardia in response to vagal stimulation at 3 and 5 Hz (P<0.05); effects that were reversed by diazoxide. Glibenclamide also significantly increased the HR response to VNS at 1 and 3 Hz (P<0.05). Diazoxide alone significantly attenuated the HR response to VNS at 5 Hz (P<0.05). Neither glibenclamide nor diazoxide affected the HR response to carbamylcholine (CCh, 50–200 n ). In the presence of a maximal 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 response to VNS by a pre-synaptic mechanism, and that this modulation may be independent of activation of the NO-cGMP pathway.