Epidermal growth factor-urogastrone (murine EGF-URO) caused concentration-dependent contractile responses in preparations of longitudinal and circular smooth muscle derived from guinea pig stomach. The actions of EGF-URO in these two preparations were distinguished in terms of the ability of indomethacin to block EGF-URO-mediated contraction completely in the longitudinal muscle preparation but not in the circular muscle preparation. The EC50 for EGF-URO was 2 to 5 nM in the longitudinal muscle preparations and 20 to 50 nM in the indomethacin-treated circular muscle preparation. The action of EGF-URO in the longitudinal preparation also was inhibited by ibuprofen, aspirin and by anti-inflammatory steroids possessing an 11-beta-hydroxyl; the corresponding steroids lacking the 11-beta-hydroxyl substituent were inactive. In contrast, little or no effect of the anti-inflammatory steroids on the EGF-URO-mediated response was observed in the indomethacin-treated circular muscle preparation. Partial inhibition (about 30%) of the EGF-URO-mediated contraction of the indomethacin-sensitive longitudinal preparation was caused by mepacrine and p-bromophenyl-acylbromide, whereas esculetine, tranylcypromine, prazosin, yohimbine and cyproheptadine had no effect. The action of EGF-URO in both preparations exhibited marked tachyphyllaxis, which could not be attributed either to the production of inhibitory factors or to the disappearance of EGF-URO from the organ bath. The response of both preparations required the presence of extracellular calcium and was inhibited largely (90%, longitudinal preparation) or in part (69%, indomethacin-treated circular preparation) by verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)
[Show abstract][Hide abstract] ABSTRACT: To evaluate further the action of epidermal growth factor - urogastrone (EGF-URO) in smooth muscle systems, we examined the effect of the peptide on guinea pig tracheal strips. The cumulative addition of EGF-URO to the organ bath resulted in a concentration-dependent tonic contraction without tachyphylaxis. The half-maximal contraction was obtained at 13 +/- 3 ng/mL EGF-URO (2 nM). The maximum contraction at 100 ng/mL approached 60% of that induced by 1 microM histamine. No significant difference in the EGF-URO-induced contraction was observed in the presence or absence of a functional epithelium. Preincubation with 1 microM indomethacin for 20 min abolished the action of EGF-URO. The contractile effect of EGF-URO was not affected by yohimbine, propranolol, atropine, tetrodotoxin, and esculetin. However, mepacrine caused inhibition by 37 +/- 7% (mean +/- SEM for n = 3). Verapamil (10 microM) inhibited the EGF-induced response by 62 +/- 5% (mean +/- SEM for n = 4); the response was also absent in Ca-free (1 mM EGTA) buffer. However, the response was restored after the readdition of calcium. Our results suggest that EGF-URO can modulate tracheal smooth muscle contractility via a cyclooxygenase product and raise the possibility that EGF-URO might play a role in controlling pulmonary smooth muscle tone in vivo.
Canadian Journal of Physiology and Pharmacology 11/1988; 66(10):1308-12. DOI:10.1139/y88-214 · 1.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A10 cultured smooth muscle cells from rat embryonic thoracic aorta bound 125I-labelled epidermal growth factor (125I-EGF), and responded to EGF by an increase in DNA synthesis. Scatchard analysis of binding data obtained at 4 degrees C showed curvilinearity consistent with there being two affinity classes of binding site. The amount of 125I-EGF that bound was decreased by treatment of the A10 cells at 37 degrees C with [Arg8]vasopressin or with 5-hydroxytryptamine (5-HT). Scatchard analysis of binding (at 4 degrees C after pretreatment at 37 degrees C) revealed this effect to be due to a loss of the high-affinity component of 125I-EGF binding, with no change in total receptor number. The presence of vasopressin or 5-HT raised the concentration of EGF required for the stimulation of DNA synthesis. Cultured A10 aortic smooth muscle cells therefore have receptors for EGF that mediate an increase in cell proliferation. EGF receptor function is modified by vasopressin and 5-HT, probably as a consequence of their effects on EGF receptor affinity.
European Journal of Pharmacology 04/1989; 172(1):1-7. DOI:10.1016/0922-4106(89)90039-4 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have examined the ability of epidermal growth factor (EGF) to regulate prostacyclin production by cultured A10 smooth muscle cells. EGF by itself had no effect on prostacyclin production, but it augmented the response to arg8-vasopressin. An AGF stimulation of prostacyclin production was also observed in the presence of the calcium ionophore A23187; it therefore seemed likely that the key event required for EGF to stimulate prostacyclin production might be an increase in the available cellular Ca2+. Studies with 45Ca2+ showed that vasopressin both mobilised Ca2+ from intracellular stores and increased the influx of extracellular Ca2+ into A10 cells. The increase in prostacyclin production caused by vasopressin and the augmentation by EGF were both abolished by TMB-8, an antagonist of Ca2+ mobilisation, by EGTA, a chelator of Ca2+ ions, or by incubating cultures in the absence of added Ca2+. These results were consistent with a central role for Ca2+ in the responses and showed that both intracellular and extracellular sources of Ca2+ were important for the triggering of prostacyclin production. The increases in prostacyclin production were only marginally affected by nifedipine, and no responses were seen (either in the absence or presence of EGF) when KCl was used to depolarise the cell membrane. These data indicated that uptake of Ca2+ ions via voltage-dependent channels was unlikely to be a major factor in the stimulation of prostanoid production. We conclude that the ability of EGF to stimulate prostacyclin production in A10 smooth muscle cells depends upon a concurrent stimulus that will increase available intracellular Ca2+ levels.
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