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This Article Full Text Full Text (PDF) All Versions of this Article: 289/6/H2491    most recent 00718.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Wahn, H. Articles by Wagner, J. A. Search for Related Content PubMed PubMed Citation Articles by Wahn, H. Articles by Wagner, J. A.

The endocannabinoid arachidonyl ethanolamide (anandamide) increases pulmonary arterial pressure via cyclooxygenase-2 products in isolated rabbit lungs

Department of Internal Medicine I/Center of Cardiovascular Medicine, University of Würzburg, Germany

Submitted 5 July 2005 ; accepted in final form 25 July 2005

Several cannabinoids elicit systemic vasodilation, mainly via CB₁ 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 CB₁ receptor antagonist AM-251 (0.1 and 5 µM) and the VR₁ 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, 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