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Adrenomedullin-Induced Endothelium-Dependent Relaxation in Porcine Ciliary Arteries

From the Laboratory of Ocular Pharmacology and Physiology, University Eye Clinic Basel, Basel, Switzerland.

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 (Rel_max): 85.5 ± 3.0%; negative log M concentration inducing 50% of Rel_max (pD₂): 7.4 ± 0.1] in comparison to time-controls (Rel_max: 19.2 ±4.8%; P < 0.001). Relaxation was inhibited by 3 µM CGRP[8-37] (CGRP₁ receptor antagonist; Rel_max: 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 (Rel_max: 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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