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British Journal of Pharmacology
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January 1999, Volume 126, Issue 1, Pages 317 - 325 |
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| Original Article |
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Studies of the role of endothelium-dependent nitric oxide release in the sustained vasodilator effects of corticotrophin releasing factor and sauvagine
Diana M. Barker & Roger Corder1 The William Harvey Research Institute, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, Charterhouse Square, London, EC1M 6BQ1Author for correspondence |
| Keywords |
| Corticotrophin-releasing factor;
sauvagine;
nitric oxide;
endothelium;
adenylate cyclase;
guanylate cyclase;
K+ channels;
vasodilatation;
CRF receptor |
| Abstract |
1 The mechanisms of the sustained vasodilator actions of corticotrophin-releasing factor (CRF) and sauvagine (SVG) were studied using rings of endothelium de-nuded rat thoracic aorta (RTA) and the isolated perfused rat superior mesenteric arterial vasculature (SMA). 2 SVG was 50 fold more potent than CRF on RTA (EC40: 0.9±0.2 and 44±9 nM respectively, P<0.05), and 10 fold more active in the perfused SMA (ED40: 0.05±0.02 and 0.6±0.1 nmol respectively, P<0.05). Single bolus injections of CRF (100 pmol) or SVG (15 pmol) in the perfused SMA caused reductions in perfusion pressure of 23±1 and 24±2% that lasted more than 20 min. 3 Removal of the endothelium in the perfused SMA with deoxycholic acid attenuated the vasodilatation and revealed two phases to the response; a short lasting direct action, and a sustained phase which was fully inhibited. 4 Inhibition of nitric oxide synthase with L-NAME (100 µM) L-NMMA (100 µM) or 2-ethyl-2-thiopseudourea (ETPU, 100 µM) had similar effects on the vasodilator responses to CRF as removal of the endothelium, suggesting a pivotal role for nitric oxide. However the selective guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 µM) did not affect the response to CRF. 5 High potassium (60 mM) completely inhibited the vasodilator response to CRF in the perfused SMA, indicating a role for K+ channels in this response. 6 Compared to other vasodilator agents acting via the release of NO, the actions of CRF and SVG are strikingly long-lasting, suggesting a novel mechanism of prolonged activation of nitric oxide synthase. |
Received 29 April 1998; Revised 10 September 1998; Accepted 5 October 1998
