EDRF release in human isolated coronary arteries is poorly antagonized by nitric oxide synthase inhibitors L-NOARG and L-NMMA, suggesting an alternative pathway or additional relaxing factors.
Nitric oxide synthase inhibitors poorly antagonize EDRF-mediated relaxation in human coronary arteries, suggesting alternative transduction pathways or the involvement of endothelium-derived hyperpolarizing factor.
Human epicardial coronary artery rings, freshly obtained from cardiac transplant patients, were 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 nM (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 beta-adrenoceptor agonist, isoprenaline. 3. Substance P, histamine, bradykinin and the Ca2+ ionophores ionomycin and A23187 all caused concentration- and endothelium-dependent relaxation in vessels pre-contracted with the thromboxane A2-mimetic, U46619 (3 nM) to an active force optimal for relaxation responses. Nifedipine (0.1 microM), added to prevent spontaneous contractions, had no effect or 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 microM, P > 0.05). Histamine (0.1-10 microM) caused a concentration-dependent contraction of arterial rings without endothelium. 5. The L-arginine analogues NG-nitro-L-arginine (L-NOARG, 0.1 mM) and NG-monomethyl-L-arginine (L-NMMA, 0.1 mM) both caused no further contraction in arteries precontracted with U46619 (3 nM) 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 nitricoxide 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.
Stork et al. (Thu,) conducted a other in Cardiac transplant patients (tissue source). EDRF-releasing agents (substance P, bradykinin, histamine, A23187, ionomycin) vs. Nitric oxide synthase inhibitors (L-NOARG, L-NMMA) or endothelium removal was evaluated on Relaxation responses. EDRF release in human isolated coronary arteries is poorly antagonized by nitric oxide synthase inhibitors L-NOARG and L-NMMA, suggesting an alternative pathway or additional relaxing factors.