Several cannabinoids elicit systemic vasodilation, mainly via CB 1 cannabinoid and vanilloid receptors. However, effects in the pulmonary circulation are unknown. Using the isolated, ventilated, buffer-perfused rabbit lung, we have shown that the endocannabinoids arachidonyl ethanolamide (anandamide) and 2-arachidonyl glycerol (2-AG) dose-dependently increase pulmonary arterial pressure (+19.9 ± 3.4 mmHg, 5 µM, and +39.5 ± 10.8 mmHg, 0.4 µM, respectively). 2-AG induced lung edema. The CB 1 receptor antagonist AM-251 (0.1 and 5 µM) and the VR 1 vanilloid receptor antagonist capsazepine (10 µM) failed to reduce anandamide's effects. The metabolically stable anandamide and 2-AG analogs R -methanandamide and noladin ether, Δ 9 -tetrahydrocannabinol, and the synthetic cannabinoid HU-210, which is no arachidonic acid product, were without effect. The unspecific cyclooxygenase (COX) inhibitor aspirin (100 µM, P < 0.001) and the specific COX-2 inhibitor nimesulide (10 µM, P < 0.01) completely prevented pulmonary hypertension after 5 µM anandamide. COX-2 RNA was detected in rabbit lungs. The synthetic thromboxane receptor antagonist SQ 29,548 was without effect, but the specific EP1 prostanoid receptor antagonist SC-19220 (100 µM) inhibited the pressure increase after anandamide ( P < 0.05). PCR analysis detected fatty acid amidohydrolase (FAAH), an enzyme that degrades endocannabinoids, in rabbit lung tissue. Furthermore, the specific FAAH inhibitor methyl arachidonyl fluorophosphonate (0.1 µM) blocked pressure effects of anandamide ( P < 0.01). Finally, anandamide (99 ± 55 pmol/g) and 2-AG (19.6 ± 8.4 nmol/g) were found in native lungs. We conclude that anandamide increases pulmonary arterial pressure via COX-2 metabolites following enzymatic degradation by FAAH into arachidonic acid products. pulmonary hypertension; cannabinoid receptors; vanilloid receptors; prostaglandins Address for reprint requests and other correspondence: J. A. Wagner, Medizinische Universitaetsklinik, Josef-Schneider-Str. 2, 97080 Würzburg, Germany (e-mail: email@example.com )
AJP - Heart and Circulatory Physiology – The American Physiological Society
Published: Dec 1, 2005
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