Inhibition of pulmonary thromboxane A2 synthase activity and airway responses by CGS 13080.

The effects of CGS 13080, a thromboxane (TXA2) synthase inhibitor, on airway responses to arachidonic acid (AA) were investigated in the anesthetized cat. Feline and human lung microsomal fraction exhibited prostaglandin I2 (PGI2, prostacyclin), and TXA2 synthase activities, and human platelet microsomal fractions exhibited TXA2 synthase activity. Cat and human lung microsomal fractions, but not human platelets, exhibited the presence of GSH-dependent PGE2 isomerase activity. CGS 13080 inhibited TXA2 synthase activity in all three microsomal fractions in a concentration-dependent manner. The increases in transpulmonary pressure and lung resistance and decreases in dynamic compliance in response to AA were decreased significantly by CGS 13080. These data suggest that the bronchoconstrictor actions of AA are mediated in large part by the formation of TXA2. The data further indicate that cyclooxygenase products other than TXA2 are involved in the bronchoconstrictor response to AA since meclofenamate had greater inhibitory activity than did CGS 13080. Moreover, the effects of CGS 13080 were due to inhibition of TXA2 synthase rather than an effect on TXA2 receptors, since airway responses to the TXA2 mimic, U46619, were not altered. The present data show that CGS 13080 inhibits TXA2 synthase activity without altering cyclooxygenase, PGI2 synthase, or GSH-dependent PGE2 isomerase activities. The data further indicate that in vivo administration of CGS 13080 may selectively increase PGI2 synthase activity.

Cyclooxygenase mediated airway response to leukotriene D4 in the cat.

The effects of leukotriene D4 (LTD4) on pulmonary mechanics were investigated in anesthetized, paralyzed cats under conditions of controlled ventilation. Intravenous injections of LTD4 in doses of 3, 10, and 30 micrograms caused significant increases in transpulmonary pressure (PTP) and lung resistance (RL) while decreasing dynamic compliance (Cdyn). LTD4 also increased systemic arterial pressure (PAo). The changes in PTP, RL, and Cdyn in response to LTD4 were blocked by sodium meclofenamate, a cyclooxygenase inhibitor. However, there was no significant change in the increase in PAo following cyclooxygenase blockade. U 46619, a thromboxane mimic, was 30 to 100 times more potent than LTD4 in increasing PTP, RL and decreasing Cdyn in the cat. These data show that LTD4 has significant smooth muscle constrictor activity in central airways as well as peripheral portions of the feline lung. In addition, these data suggest that in the cat the actions of intravenously administered LTD4 on lung mechanics are mediated by release of cyclooxygenase products while the systemic pressor effects are not dependent upon the integrity of the cyclooxygenase pathway.

Antiinflammatory fluoroalkanesulfonanilides. 3. Other fluoroalkanesulfonamido diaryl systems.

A series of isosteres of 3-benzoyltrifluoromethanesulfonanilide involving alternatives to the carbonyl linking group was synthesized and screened for antiinflammatory activity in the carrageenan rat paw edema test. The systems examined were of the type m-CF3SO2NH-C6H4-X-C6H5, where X was -CROH-, -CHR-, -CH(OH)CH2-, -COCH2-, -CH2CO-, greater than C equal to CR2, -CR equal to CH, -C identical to C-, -CH2CH2-, CONH-, -NR-, -O-, -S(O)n- (n equal to 0,1,2), and carbon-carbon single bond. Many ortho and para derivatives were also tested. Several of these new trifluoromethanesulfonanilides proved equipotent with phenylbutazone. The effects on the anticarrageenan activity of both the nature and ring position of X are discussed.