Forskolin inhibits leukotriene D4-induced thromboxane B2 release from guinea-pig lung parenchyma

PROSTAGLANDINS

FORSKOLIN INHIBITS LEUKOTRIENE 04-INWCED

THROMBOXANE 8,

RELEASE FROM GUINEA-PIG LUNG PARENCHYMA Mark A. Giembycz h Ian W. Rodger Department of Physiology and Pharmacology, University of Strathclyde, Glasgow Gl 1XW. The efficacy of 8-adrenoceptor

agonists in reversing bronchoconstriction

in asth-

matic individuals is thought to reside solely in their ability to activate the biochemical mechanisms which initiate relaxation. have reported that the leukotriene(LT)-induced from guinea-pig lung parenchyma

However, Zijlstra -et al (1) (TX) A,

release of thromboxane

(GPLP) is inhibited by &adrenoceptor

agonists

Since TXA, appears to contribute significantly to the -in vivo bronchoconstriction induced by LTD4in the guinea-pig inhibition of TXA,release may represent an additional mechanism of action of sympathomimetic

bronchodilators.

We present here the

results from a study in which we have investigated the possible role that cyclic AMP plays in the B-adrenoceptor-mediated

inhibition of TXB, release.

Portions of GPI-P were incubated for 90 min in oxygenated

(5% CO,; 95X 0,) Krebs-

Tissues were then transferred to

Henseleit Solution (KHS) maintained at 32OC.

KHS containing either no drug, 3-isobutyl-l-methyl

xanthine (IBEX; 1 n-M for 60 min),

isoprenaline

for 60 min).

(10FIM for 2 min) or forskolin(100 m

After this period

tissues were transferred to an identical medium containing LTD4 (100 nM). GPLP released TXB, spontaneously

into the bathing medium.

This release was linear

(r=0.98) over the 15 min period studied.

LTQ, significantly enhanced (_l4 fold

over basal levels) this release of TXB,.

Forskolin and IBEX markedly inhibited

LTD4-induced

Isoprenaline on the other

TXB, release by 61% and 99% respectively.

hand was without significant effect.

All three drugs significantly elevated

tissue cyclic AMP levels with respect to control (Rank order:Forskolin >> isoprenaline

> IBMX).

These data illustrate that inhibition of LTD4 -induced TXB, release does not correlate with changes in cyclic AMP levels in GPLP. bline do not support the observations

whilst our results with isopren-

of Zijlstra &al

(1) they are nevertheless

consistent with those of Dahlen -et al (2) who employed a similar method. The inhibitory action of both forskolin and IBEX on LTD4-induced TXB, release may reflect mechanisms of action that are independent of cyclic AMP formation. (1) Zijlstra, F.J., Bonta, I.L., Adolfs, M.J.P. h Vincent, J.E. inhibits leukotriene C4-induced parenchyma.

Eur.J.Pharmacol.,

26,

297-298, 1981.

(2) Dahlen, S-E., Hedqvist, P., Westlund, P Lindgren, J.A. & Radmark, 0.

Isoprenaline

thromboxane A, release from guinea-pig

,

Grandstrom, E., Hammarstrom,

Mechanisms of leukotriene-induced

S.,

contractions

of guinea-pig airways: leukotriene C4 has a potent direct action whereas leukotriene 84 acts indirectly.

NOVEMBER

1984 VOL. 28 NO. 5

Acta Physiol.Scand.,

12,

393-403, 1983.

651