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Eike S. Dettmann, Ineta Vysniauskiene, Renyi Wu, Josef Flammer, Ivan O. Haefliger; Adrenomedullin-Induced Endothelium-Dependent Relaxation in Porcine Ciliary Arteries. Invest. Ophthalmol. Vis. Sci. 2003;44(9):3961-3966. doi: 10.1167/iovs.02-1312.
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purpose. To investigate adrenomedullin-induced relaxation in isolated porcine ciliary arteries.
methods. In a myograph system (isometric force measurement), precontracted vessels (∼0.1 μM U46619; thromboxane A2 analogue or ∼10 nM endothelin-1) were exposed, in a cumulative manner, to increasing concentrations of adrenomedullin (1 nM to 1 μM) in the presence or absence of different drugs. Some experiments were conducted in vessels with nonfunctional (intentionally mechanically damaged) endothelium.
results. Adrenomedullin evoked marked relaxation [maximum relaxation (Relmax): 85.5 ± 3.0%; negative log M concentration inducing 50% of Relmax (pD2): 7.4 ± 0.1] in comparison to time-controls (Relmax: 19.2 ±4.8%; P < 0.001). Relaxation was inhibited by 3 μM CGRP[8-37] (CGRP1 receptor antagonist; Relmax: 27.2% ± 5.3%; P < 0.001) but not by 3 μM adrenomedullin[22-52] (presumed adrenomedullin receptor antagonist; P = 0.75). Adrenomedullin-induced relaxation was less pronounced in nonfunctional endothelium vessels (Relmax: 67.6% ± 3.1%; pD2: 6.9 ± 0.1; P < 0.01). In vessels with functional endothelium, relaxation was not significantly influenced by 0.1 mM N G-nitro-l-arginine methyl ester (l-NAME; a nitric oxide synthesis inhibitor), 10 μM indomethacin (a cyclooxygenase inhibitor), or 10 μM 17-octadecynoic acid (a cytochrome P450 inhibitor). In contrast, relaxation was significantly inhibited by either 10 mM tetraethylammonium (nonselective potassium channel inhibitor; P < 0.01) or 50 nM apamin (small conductance potassium channel inhibitor), together with 50 nM charybdotoxin (large and intermediate potassium channel inhibitor; P < 0.01). In the presence of these potassium channel inhibitors, the amount of relaxation was not significantly different (P > 0.50) from that observed in vessels with nonfunctional endothelium.
conclusions. In isolated porcine ciliary arteries, adrenomedullin induces relaxation that involves CGRP1 receptors and is in part endothelium dependent. Endothelium-dependent relaxation was blocked by some potassium channel inhibitors, suggesting the possible release of an endothelium-derived hyperpolarizing factor (EDHF).
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