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

• Published in: Journal of hypertension Vol. 23; no. 4; p. 779
• Main Authors: Shinde, Urmila A, Desai, Kaushik M, Yu, Changhua, Gopalakrishnan, Venkat
• Format: Journal Article
• Language: English
• Published: England 01.04.2005
• Subjects: Anesthesia; Animals; Apamin - pharmacology; Blood Pressure - drug effects; Charybdotoxin - pharmacology; Drug Synergism; Enzyme Inhibitors - pharmacology; Ghrelin; Heart Rate - drug effects; Hypotension - chemically induced; Hypotension - physiopathology; Injections, Intravenous; Male; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide Synthase - antagonists & inhibitors; Peptide Hormones - pharmacology; Potassium Channels, Calcium-Activated - physiology; Rats; Rats, Sprague-Dawley
• ISSN: 0263-6352
• DOI: 10.1097/01.hjh.0000163146.20330.bc

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. 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-Dawley rats subjected to pretreatment with either the nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME; 0.7 mg/ml by mouth for 5 days), or vehicle (control). 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 mug/kg each of apamin and charybdotoxin (ChTX), a combination that is known to block Ca-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. These data suggest that the Ca-activated, K-channel-mediated, ghrelin-evoked decrease in MAP may be significant in states of endothelial dysfunction associated with reduced nitric oxide availability.