AJP - Lung Cellular and Molecular Physiology, Vol 266, Issue 6 620-L627, Copyright © 1994 by American Physiological Society
Roles of Ca2+ influx and intracellular Ca2+ release in agonist-induced contractions in guinea pig trachea
N. J. Cuthbert, P. J. Gardiner, K. Nash and C. T. Poll
Bayer Pharmaceutical Research Department, Stoke Poges, United Kingdom.
The contribution of receptor-operated Ca2+ channels (ROCs),
voltage-operated Ca2+ channels (VOCs), and intracellular Ca2+ release to
contractions induced by a range of stimuli in the guinea pig isolated
trachea has been evaluated. In the presence of physiological Ca2+ (1.3 x
10(-3) M), tissue pretreatment with ethylene glycol-bis(beta-aminoethyl
ether)-N,N,N',N'-tetraacetic acid (EGTA) (4 x 10(-3) M for 5 min) markedly
inhibited (> 90%) the contractile responses to a range of agonists.
Therefore, under physiological Ca2+ concentration, Ca2+ mobilization from
internal stores appeared to make little contribution to maximum
contractions. Nifedipine (10(-7) M) or verapamil (10(-5) M) abolished
KCl-induced contractions but produced variable inhibition of contractions
induced by other agonists. The ROC (and VOC) blocker, SK&F 96365
(10(-5)-10(-4) M), inhibited both KCl-induced contractions and the
nifedipine-insensitive component of contractions induced by acetylcholine
(ACh), U46619, or leukotriene D4 [half maximal inhibitory concentration
(IC50) values 1.7-3.8 x 10(-5) M]. Ni2+, which has ROC- and VOC-blocking
actions, also abolished nifedipine-insensitive contractions induced by ACh.
When Ca2+ was replaced with Ba2+, the contraction induced by ACh was
blocked by nifedipine. Also, under these conditions, ACh did not increase
the KCl maximum contraction. These data are consistent with there being
distinct ROC and VOC influx pathways in guinea pig trachea and with ROCs
playing a significant role in smooth muscle contraction.
