Pulmonary actions of anandamide, an endogenous cannabinoid receptor agonist, in guinea pigs.
Anandamide (arachidonylethanolamide), 5,8,11,14-eicosatetraenamide, (N-2-hydroxyethyl), was tested for bronchodilator and anti-inflammatory activities. Conscious guinea pigs were given cumulative i.v. doses of anandamide (1.0, 3.0, and 10.0 mg/kg) to assess its effect on dynamic compliance (Cdyn), total pulmonary resistance (RL), tidal volume (VT) and breathing frequency (f). Other guinea pigs were exposed to an aerosol of A23187 (6S-[6alpha(2S*,3S*),8beta(R*),9beta,11alpha]-5- (methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)e thyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazole carboxylic acid) until Cdyn decreased by 50% (approximately 5 min) and at 20 min, cumulative i.v. doses of anandamide (1.0, 3.0, and 10.0 mg/kg) were administered and reversal of Cdyn examined. After the final dose of anandamide, the animals were killed and excised lung gas volumes (ELGV), i.e., pulmonary gas trapping, measured. Other animals were treated i.v. with anandamide (10.0 mg/kg), exposed to an aerosol of A23187 until labored breathing began, and then killed 1 h later. Anandamide did not significantly affect Cdyn, RL, VT and f. ELGV values of anandamide-treated guinea pigs were not different from those of vehicle-treated animals. Anandamide failed to reverse A23187-induced decreases in Cdyn and to reduce A23187-associated ELGV increases. Also, it did not prevent the prolonged airway obstruction caused by A23187. Histological evaluation revealed that anandamide significantly reduced A23187-related airway epithelial injury and pulmonary leukocytosis. However, it did not prevent A23187-induced peribronchiolar granulocytic accumulation. Our results suggest that in vivo anandamide has minimal direct airway smooth muscle-related actions, however it may possess modest anti-inflammatory properties.
Stengel
P W
PW
Eli Lilly, Lilly Research Laboratories, Neuroscience Research, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. stengel_peter_w@lilly.com
Rippy
M K
MK
Cockerham
S L
SL
Devane
W A
WA
Silbaugh
S A
SA
D000336:Aerosols; D000402:Airway Obstruction / Q000139:chemically induced; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000494:pharmacology; D000001:Calcimycin; D063388:Endocannabinoids; D006168:Guinea Pigs; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D053284:Polyunsaturated Alkamides; D012123:Pulmonary Ventilation / Q000187:drug effects; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists*; D013990:Tidal Volume / Q000187:drug effects
D000336:Aerosols; D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D001993:Bronchodilator Agents; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000001:Calcimycin; C078814:anandamide