Effect of the isoprostanes, 8-iso prostaglandin E2 and 8-iso prostaglandin F2 alpha on the rabbit lung in vivo.
8-Iso-prostaglandin (PG)E2 and 8-iso-PGF2 alpha are members of the isoprostane class of prostanoids which are formed by free radical mediated oxidation of arachidonic acid. Both E2- and F2-isoprostanes are potent vasoconstrictors and are believed to act through the prostanoid TP-receptors or a closely related receptor. In lightly anaesthetised, spontaneously breathing rabbits, aerosolised administration of histamine (1.25-40 mg ml-1, n = 8) caused a modest dose-dependent increase in total lung resistance (RL) and a concomitant fall in dynamic lung compliance (CL dyn). Aerosolised methacholine (0.625-20 mg ml-1, n = 6) caused considerable bronchoconstriction, with a dose-dependent increase in RL, and a corresponding fall in CL dyn. In contrast, intratracheal administration of either 8-iso PGE2 or 8-iso-PGF2 alpha (1 ng ml(-1)-100 micrograms ml-1, n = 8) had no significant effect on lung function. The TP-receptor agonist, U-46619, was similarly inactive in this model when given by aerosol. Intravenous administration of histamine or 8-iso PGF2 omega had no significant effect on the lung indices, RL and CL dyn, or on the pulmonary and systemic vasculature (n = 4 per drug group). 8-Iso-PGE2 caused a concentration-dependent decrease in the right ventricular systolic pressure from 3 nmol kg-1 to 100 nmol kg-1 (n = 43, p < 0.05), but showed no other activity. In contrast, U-46619 given intravenously caused an increase in transpulmonary pressure (n = 4, p < 0.05), but had no effect on airflow. At higher doses, it did cause a significant drop in both systemic and right ventricular systolic pressures (n = 4, p < 0.05), which were probably due to an interaction with platelets. The isoprostanes had no effect on the rabbit airway up to a concentration of 3 microM. In contrast, 3 microM U-46619 caused a modest contraction of tracheal smooth muscle, whilst 3 microM methacholine was at least five-fold more potent in contracting the same tissues. We conclude that the aerosolised isoprostanes are not broncho-constricting agents in the rabbit in vivo.
Hill
A A
AA
Department of Clinical Pharmacology, RPMS, Hammersmith Hospital, London. ahill@rpms.ac.uk
Coleman
R A
RA
Taylor
G W
GW
Moore
K P
KP
Taylor
I K
IK
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000281:Administration, Intranasal; D000818:Animals; D016084:Bronchoconstriction; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D028441:F2-Isoprostanes; D005260:Female; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D028421:Isoprostanes; D008168:Lung / Q000187:drug effects*; D009330:Nebulizers and Vaporizers; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011817:Rabbits; D012119:Respiration; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D028441:F2-Isoprostanes; D028421:Isoprostanes; D011450:Prostaglandin Endoperoxides, Synthetic; D014662:Vasoconstrictor Agents; C075750:8-epi-prostaglandin F2alpha; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost; D015232:Dinoprostone; C011987:8-isoprostaglandin E2