Nitric oxide synthase inhibition exaggerates the hypotensive response to ghrelin: role of calcium-activated potassium channels

Objective To investigate the mechanism underlying the observation that infusion of the growth hormone secretagogue peptide, ghrelin, produces a decrease in mean arterial pressure (MAP) with no change in heart rate. Method The effect of a single bolus infusion of ghrelin (12 nmol/kg intravenously) on the changes in MAP and heart rate was determined in 12-week-old male anaesthetized Sprague-Ellawley rats subjected to pretreatment with either the nitric oxide synthase (NOS) inhibitor, N-omega-nitro-(L)-arginine methyl ester (L-NAME; 0.7 mg/ ml by mouth for 5 days), or vehicle (control). Results Ghrelin produced a significant decrease in MAP at 20 min (P < 0.05) after infusion in the control group, without any change in heart rate. The MAP recovered partially over 1 h. The ghrelin-evoked decrease in MAP was much greater (P < 0.01) and was sustained for 1 h in rats subjected to NOS inhibition. Pretreatment with the cyclo-oxygenase inhibitor, indomethacin, failed to affect the responses in either group. Intravenous infusion of 50 mu g/kg each of apamin and charybdotoxin (ChTX), a combination that is known to block Ca (2+)-activated K+ channels or the endothelium -derived hyperpolarization process, attenuated the decrease in MAP evoked by ghrelin in both control and NOS-inhibited rats. A sodium nitroprusside-induced decrease in MAP was unaffected in the presence of apamin-ChTX, but acetylcholine-evoked hypotension was significantly reduced in both groups. Conclusion These data suggest that the Ca (2+)-activated, K+-channel-mediated, ghrelin-evoked decrease in MAP may be significant in states of endothelial dysfunction associated with reduced nitric oxide availability.(c) 2005 Lippincott Williams & Wilkins.