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Pharmacological reactivity of human epicardial coronary arteries: characterization of relaxation responses to endothelium‐derived relaxing factor
Author(s) -
Stork Andrew P.,
Cocks Thomas M.
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.tb17109.x
Subject(s) - bradykinin , endothelium derived relaxing factor , histamine , medicine , sodium nitroprusside , endocrinology , thromboxane a2 , contraction (grammar) , endothelium , chemistry , substance p , vasodilation , nitric oxide , receptor , neuropeptide
1 Human epicardial coronary artery rings, freshly obtained from cardiac transplantation patients, commonly examined for their responses to endothelium‐derived relaxing factor (EDRF)‐releasing agents. 2 Functional antagonism profoundly influenced relaxation responses in this tissue. Increasing force with concentrations of U46619 above 3 n m (40% of maximum contraction response) resulted in a reduction of the maximum response to four vasorelaxants which relax vascular smooth muscle via different mechanisms: the EDRF‐releasing agents, substance P and bradykinin; the endothelium‐independent nitro‐vasodilator, sodium nitroprusside (SNP); and the β‐adrenoceptor agonist, isoprenaline. 3 Substance P, histamine, bradykinin and the Ca 2+ ionophores ionomycin and A23187 all caused concentration‐ and endothelium‐dependent relaxation in vessels pre‐contracted with the thromboxane A 2 ‐mimetic, U46619 (3 n m ) to an active force optimal for relaxation responses. Nifedipine (0.1 μ m ), added to prevent spontaneous contractions, had no effect on relaxation responses to substance P, bradykinin and histamine. 4 Substance P was the most potent of the EDRF‐releasing agents examined and all agents except for bradykinin caused near‐maximal relaxation. Bradykinin caused only 46.2% ± 7.3% relaxation. Responses were abolished when the endothelium was removed and, except for histamine, were not significantly affected by indomethacin (3–10 μ m , P >0.05). Histamine (0.1–10 μ m ) caused a concentration‐dependent contraction of arterial rings without endothelium. 5 The L‐arginine analogues N G ‐nitro‐L‐arginine (L‐NOARG, 0.1 μ m ) and N G ‐monomethyl‐L‐arginine (L‐NMMA, 0.1 μ m ) both caused no further contraction in arteries precontracted with U46619 (3 n m ) and were in general, poor inhibitors of responses to EDRF agonists. L‐NMMA, but not L‐NOARG, caused small but significant decreases in the maximum responses to substance P, bradykinin (18.5 ± 6.9% and 27.6 ± 10.9% relaxation with L‐NMMA and L‐NOARG, respectively), histamine and A23187 ( P < 0.05). The analogues had no effect on SNP responses. 6 In conclusion, EDRF release in human isolated coronary artery is only poorly antagonized by the nitric oxide synthase inhibitors L‐NOARG and L‐NMMA. These results indicate that either the nitric oxide transduction pathway present in human coronary artery is different from that in other tissues or that another factor(s) (e.g. endothelium‐derived hyperpolarizing factor) is also released in response to EDRF‐releasing agents and augments the relaxation to nitric oxide.