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- Title
Involvement of soluble guanylate cyclase and calcium-activated potassium channels in the long-lasting hyporesponsiveness to phenylephrine induced by nitric oxide in rat aorta.
- Authors
Terluk, M. R.; da Silva-Santos, J. E.; Assreuy, J.
- Abstract
Excessive nitric oxide (NO) production by inducible NO synthase has been implicated in the hyporesponsiveness to vasoconstrictors present in septic shock. Here we show that a brief incubation (30 min) of rat aorta rings with NO donors renders the vessels hyporesponsive to phenylephrine for several hours. Contraction of rings without endothelium by phenylephrine (0.1 nM to 100 µM) was decreased by 50–60% after incubation (30 min) with sodium nitroprusside (3–300 µM) or S-nitroso-acetyl-d,l-penicillamine (SNAP; 70–200 µM). This decrease was characterized by reductions in maximal response and rightwards shifts of phenylephrine concentration/response curves, present even 130 min after NO donor removal. Soluble guanylate cyclase inhibitors methylene blue (10 µM) and 1H-(1,2,4)-oxadiazol-(4,3-a)-quinoxalin-1-one (ODQ, 1 µM) or the potassium channel blockers TEA (tetraethylammonium; 10 mM) and charybdotoxin (100 nM) inhibited the hyporesponsiveness to phenylephrine induced by the NO donors. In contrast, 4-aminopyridine (1 mM) and glibenclamide (10 µM) had no effect. Our results show that incubation with NO donors reproduces the hyporesponsiveness to phenylephrine and that NO alone accounts for most, if not all, the refractoriness to vasoconstrictors present in septic shock. In addition, soluble guanylate cyclase activation and opening of potassium channels, more specifically the calcium-activated subtype, play a predominant role in this NO-induced hyporesponsiveness to phenylephrine in the rat aorta.
- Subjects
CARDIOVASCULAR agents; BACTERIAL disease complications; ARTERIES; BLOOD circulation; CHELATION therapy; ENDOTHELIUM
- Publication
Naunyn-Schmiedeberg's Archives of Pharmacology, 2000, Vol 361, Issue 5, p477
- ISSN
0028-1298
- Publication type
Article
- DOI
10.1007/s002100000216