Endothelium-derived relaxing factor and the pulmonary circulation (original) (raw)
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Anaesthesia and Intensive Care, 1993
Until just a few years ago, the extensive and purpose of nitric oxide (NO) in biological tissue was unknown, and what was then regarded by anaesthetists and intensivists as a potential noxious contaminant of nitrous oxide (N20) gas, is now a therapeutic agent. Specifically, it promises to be the first truly specific pulmonary vasodilator. The existence of NO, formerly known as endothelium-derived relaxing factor (EDRF) has been identified in many tissues. I It is a surprisingly simple molecule but functions as an important messenger in the central nervous, immune and cardiovascular systems. This review traces the series of events which led to the recognition, identification and use of NO as a therapeutic agent within the cardiovascular system and describes its relationship to a class of frequently used drugs, the nitrovasodilators. It discusses the clinical relevance of NO, in particular its efficacy in the treatment of pulmonary hypertension and in conditions such as septicaemia in which endogenous NO production may require suppression. Practical guidelines for clinical use are also discussed. DISCOVERY OF EDRF An accidental discovery in 1980 revealed that vascular endothelium is intimately involved in the regulation of the tone of vascular smooth muscle. This remarkable discovery was preceded by experiments involving preparations of isolated arteries. It had been well known that acetylcholine dilated arteries in vivo, but curiously was ineffective, or, on the contrary, caused contraction in vitro. This difference in response to acetylcholine was traced by Furchgott and Zawadzki
Pediatric Research, 1990
Endothelium-derived relaxing factor (EDRF), believed to be nitric oxide or a compound that releases nitric oxide, is a potent vasodilator produced by some arteries in response to acetylcholine (ACh) and bradykinin (BK). ACh and BK are potent dilators of perinatal pulmonary and systemic arteries. The objectives of this study were to determine if EDRF is present in newborn vessels and if EDRF mediates the vasodilator actions of ACh and BK. Arterial rings from newborn guinea pigs, 1 to 3 d old, were obtained from a branch of the main pulmonary artery and the descending aorta for isometric force bioassays. At their optimal resting tension, the rings were preconstricted with phenylephrine lo-' M in Krebs-Henseleit solution before adding incremental doses of ACh or BK. If the endothelium was intact, ACh (lo-' M) relaxed pulmonary arteries and aortas (64 f 7%, 72 f 9% relaxation, respectively, mean f SE). ACh-induced relaxation (ACh lo-' M) in the pulmonary artery and aorta, respectively, was significantly (p < 0.05) attenuated by 1) endothelial removal (11 f 9%, 28 f 10%) by rubbing the ring lumen; 2) methylene blue, 10" M, (6 f 8%, 7 f 3%) that inhibits EDRF-associated cGMP production in smooth muscle; and 3) methemoglobin, lo-' M, (13 f 9%, 17 f 7%) that binds EDRF. The results for BK were similar to ACh for the pulmonary artery but BK did not relax the aorta. Indomethacin diminished relaxation of the pulmonary artery and aorta to the submaximal dose (lo-' M) of ACh but indomethacin did not effect the relaxation to ACh lo4 M or BK. We conclude that EDRF is produced in the guinea pig pulmonary artery and descending aorta at birth and that EDRF is a mediator of the vasodilator actions of ACh and BK. Vasodilation by ACh may also involve activation of the cyclooxygenase pathway. (Pediatr Res 27: 128-132,1990) Abbreviations EDRF, endothelium-derived relaxing factor ACh, acetylcholine BK, bradykinin EDRF, now believed to be nitric oxide or a compound that releases nitric oxide, was discovered in 1980 when acetycholine
Vascular Pharmacology, 2006
Objective: To compare electrophysiological measurement of nitric oxide (NO) release and endothelium-derived hyperpolarizing factor (EDHF)mediated endothelial function in porcine pulmonary arteries and veins. Methods: Isolated pulmonary interlobular arteries (PA) and veins (PV) were obtained from a local slaughterhouse. By using a NO-specific electrode and a conventional intracellular microelectrode, the amount of NO released from endothelial cells and hyperpolarization of smooth muscle cells were investigated. The bradykinin (BK)-induced relaxation in the precontraction by U 46619 was examined in the absence or presence of N G -nitro-l-arginine (l-NNA), indomethacin (INDO) plus oxyhemoglobin (HbO). Results: The basal release of NO was 7.0 T 1.2 nmol/L in PA (n = 8) and 5.5 T 1.6 nmol/L in PV (n = 8, p < 0.05). BK-induced release of NO was 160.4 T 10.3 nmol/L in PA (n = 8) and 103.0 T 14.7 nmol/L in PV (n = 8, p < 0.001) with longer releasing duration in PA than in PV (14.3 T 1.3 vs. 12.1 T 0.8 min, p < 0.01). BK evoked an endothelium-dependent hyperpolarization and relaxation that were reduced by l-NNA, INDO, and HbO (hyperpolarization: 12.8 T 1.3 vs. 8.0 T 1.4 mV in PA, n = 6, p < 0.001 and 8.3 T 1.4 vs. 3.0 T 0.8 mV in PV, n = 6, p < 0.001; relaxation: 92.8 T 3.1% vs. 19.6 T 11.1% in PA n = 8, p < 0.001 and 70.3 T 7.9% vs. 6.0 T 6.8% in PV, n = 8, p < 0.001). Both hyperpolarization (8.0 T 1.4 vs. 3.0 T 0.8 mV, p < 0.001) and relaxation (19.6 T 11.1% vs. 6.0 T 6.8%, p < 0.01) were greater in PA than in PV. Conclusions: Both NO and EDHF play an important role in regulation of porcine pulmonary arterial and venous tones. The more significant role of NO and EDHF is revealed in pulmonary arteries than in veins. D
British Journal of Pharmacology, 1993
1 Endothelium-dependent relaxation mediated by endothelium-derived relaxing factor (EDRF) or nitric oxide (NO), is impaired in pulmonary arteries (PA) of hypoxic patients with chronic obstructive lung disease (COLD). To determine the mechanisms responsible for this impairment, we compared the response of rings of isolated PA from 12 COLD patients and 8 controls to the endothelium-dependent vasodilators acetylcholine (ACh), adenosine diphosphate (ADP), and the calcium ionophore, A23187. The response of PA rings to the endothelium-independent nitro-vasodilator sodium nitroprusside (SNP) was also studied in both groups. The PA rings had been pre-contracted by the a-adrenoceptor agonist phenylephrine (PE). 2 Endothelium-dependent relaxation was significantly reduced in PA rings from COLD patients as compared with controls when tested with ACh (37.8 ± 8.8% vs 73.4 ± 7.9%), ADP (38.4 ± 6.7% vs 80 ± 5.6%), and the calcium ionophore, A23187 (35.8 ± 6.1% vs 87 ± 6.6%). Relaxation with SNP was, however, significantly greater in PA rings from COLD patients (99.4 ± 0.6% vs 90.3 ± 3.1%), as was the contractile response to PE (1.91 ± 0.21 g vs 1.33 ± 0.15 g). Pretreatment with the specific inhibitor of NO formation, N0-monomethyl-L-arginine (L-NMMA; 10-4 M) significantly reduced the relaxation to ACh in all PA rings. This inhibition could be reversed by L-arginine (10-3 M), the substrate for NO synthesis. Pretreatment with L-arginine alone, however, did not restore the impaired endotheliumdependent relaxation of PA rings from COLD patients. 3 We conclude that EDRF (NO) production is impaired in PA rings from COLD patients and that this impairment is neither due to endothelial receptors dysfunction nor a defect of L-arginine availability and/or transport. Our hypothesis is that the abnormality must lie within the biosynthesis pathway of NO from L-arginine, possibly involving the endothelial enzyme cell, NO synthase, the normal function of which might be altered by chronic hypoxia.
Endothelium-derived vascular relaxing factor
Hypertension, 1985
A large number and variety of compounds (acetylcholine, adenosine diphosphate, adenosine triphosphate, arachidonic acid, bradykinin, Ca2+ ionophores, calcitonin gene-related peptide, histamine, hydralazine, substance P, thrombin, and vasoactive intestinal polypeptide) have been shown to relax arterial smooth muscle indirectly. The endothelium in muscular arteries from several species appears to have receptors for these vasodilators. Binding of one of these compounds to its endothelial receptors results in the release (and presumably synthesis) of substance(s) that act on arterial smooth muscle to cause relaxation. The name endothelium-derived relaxing factor (EDRF) has been proposed for the substance or substances responsible for inhibition of contraction. Studies to determine additivity of endothelium-dependent relaxing agents and sensitivity of EDRF-mediated responses to a variety of inhibitors suggest that a single factor or a single common mechanism induces relaxation of vascula...
Cardiovascular Research, 2007
Aims b-adrenoceptor (b-AR)-mediated relaxation was characterized in pulmonary arteries from normoxic and hypoxic (as model of pulmonary hypertension) mice. The endothelial NO synthase (eNOS) pathway was especially investigated because of its potential vasculoprotective effects. Methods Pulmonary arteries from control or hypoxic (0.5 atm for 21 days) wild-type or eNOS 2/2 mice were used for pharmacological characterization of b-AR-mediated relaxation in myograph, and for immunohistochemistry using anti-b-AR antibodies. Results In pulmonary arteries from normoxic mice, isoproterenol (b-AR agonist) and procaterol (selective b 2 -AR agonist) elicited relaxation, while cyanopindolol and CL316243 (b 3 -AR agonists) were ineffective. The effect of isoproterenol was antagonized by CGP20712A and ICI118551 (b 1 -or b 2 -AR antagonists, respectively) and also partially inhibited by N v -nitro-L-arginine methylester (L-NAME, a NOS inhibitor), endothelium denudation, or eNOS gene deletion. Relaxation to procaterol was abolished by L-NAME or endothelium removal. In eNOS 2/2 mice, procaterol-induced relaxation was decreased but was insensitive to L-NAME, this residual effect involving other endothelium-dependent relaxant factors as compensatory mechanisms. Immunostaining for b 2 -AR was observed in the endothelial layer, but not the medial layer of pulmonary arteries. Pulmonary arteries from hypoxic mice exhibited decreased endothelial NO-dependent relaxation to acetylcholine. However, in these arteries, relaxation to procaterol was either unaffected (extralobar segments) or even increased (intralobar segments) and was still abolished by L-NAME or endothelium removal. Conclusion b 1 -and b 2 -AR, but not b 3 -AR, mediate relaxation of mice pulmonary arteries. The b 2 -AR component is dependent on eNOS activity and is preserved following chronic hypoxia. These data highlight the role of the b 2 -AR as a pharmacological target to induce/restore endothelial NO-dependent protective effects in pulmonary circulation.
Journal of Clinical Investigation, 1988
The role of the endothelium in hypoxic constriction of the intact pulmonary vascular bed has not been clearly elucidated. To test for a possible role for endothelium-derived relaxing factor(s) (EDRF) in the hypoxic pressor response, isolated, whole blood-perfused rat lungs from male Sprague-Dawley rats treated with meclofenamate were prepared. Three protocols were performed, including: (a) normal saline (control); (b) the putative EDRF inhibitors, eicosatetraynoic acid (ETYA, 1 X 10-4 M) or nordihydroguaiaretic acid (NDGA, 1 X 10-4 M) versus vehicle DMSO; and (c) the putative EDRF inhibitor hydroquinone (HQ, 1 X 10-4 M) versus vehicle ethyl alcohol (ETOH). The pulmonary pressor response to angiotensin II (Ang II, 0.25 Mg) injections alternated with 6-min periods of hypoxic ventilation (3% 02,5% C02) was measured before and after the administration of saline, inhibitors, or vehicles. The administration of the EDRF inhibitors ETYA, NDGA, and HQ resulted in a marked accentuation of the hypoxic pressor response that was not seen in the controls (P < 0.05). In separate experiments, lungs precontracted with norepinephrine (1 X 10-6 M) were pretreated with edrophonium (1 X 10-4 M) and then observed for endothelium-dependent vasodilator responses to acetylcholine at increasing doses (1 X 10-7 X 10-4 M). Administration of ETYA, NDGA, or HQ abrogated the observed vasodilatation to acetylcholine, which was not seen with vehicles alone (P < 0.01). These studies suggest an important role for the endothelium in pulmonary vascular responsiveness to alveolar hypoxia through possible release of a relaxing factor(s) that attenuates the degree of pulmonary arterial constriction.