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Cyclic GMP‐independent relaxation and hyperpolarization with acetylcholine in guinea‐pig coronary artery
Author(s) -
Eckman D.M.,
Weinert J.S.,
Buxton I.L.O.,
Keef K.D.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb14851.x
Subject(s) - hyperpolarization (physics) , acetylcholine , cyclic gmp , guinea pig , medicine , chemistry , cardiology , endocrinology , biophysics , biology , nitric oxide , stereochemistry , nuclear magnetic resonance spectroscopy
1 The effects of acetylcholine (ACh) on membrane potential, relaxation and cyclic GMP levels were compared to the NO donor l ‐nitrosocysteine (Cys‐NO) in segments of guinea‐pig coronary artery. 2 ACh and Cys‐NO produced concentration‐dependent relaxations of muscles contracted with the H 1 receptor agonist, 2‐(2‐aminoethyl)pyridine (AEP, 0.35 m m ). The relaxation to ACh was unchanged in the presence of N G ‐monomethyl‐ l ‐arginine ( l ‐NMMA; 350 μ m ) or indomethacin (3 μ m ). 3 Oxyhaemoglobin (HbO; 20 μ m ) alone or in combination with l ‐NMMA increased the EC 50 for ACh‐induced relaxation whereas relaxation with Cys‐NO was almost completely abolished with HbO. 4 Scorpion venom (SV; 8.7 μg ml −1 ) increased the EC 50 for relaxation with ACh but not Cys‐NO. Combined l ‐NMMA, HbO and SV produced nearly complete abolition of ACh‐induced relaxations. 5 Basal cyclic GMP levels (i.e., 20 pmol mg −1 protein) were significantly increased following addition of either ACh (190 pmol mg −1 protein) or Cys‐NO (240 pmol mg −1 protein). l ‐NMMA significantly reduced the rise of cyclic GMP with ACh but not Cys‐NO. In contrast, SV did not significantly reduce the rise in cyclic GMP produced with ACh. In the combined presence of l ‐NMMA and HbO neither ACh nor Cys‐NO produced a significant increase in cyclic GMP levels. 6 ACh gave rise to significantly greater membrane hyperpolarization than Cys‐NO both in the presence and absence of AEP. Combined l ‐NMMA and HbO did not reduce the amplitude of hyperpolarization with ACh. 7 These data indicate that some but not all of the actions of ACh in the coronary artery can be mimicked by the NO donor, Cys‐NO, suggesting that ACh releases NO as well as a second hyperpolarizing factor (i.e., EDHF). Release of NO results in a large increase in tissue cyclic GMP levels and minimal change in membrane potential whereas release of EDHF results in a large membrane hyperpolarization which is independent of changes in tissue cyclic GMP levels. Both of these pathways appear to contribute to relaxation throughout the entire ACh concentration‐relaxation relationship.