Contractile actions of epidermal growth factor-urogastrone in isolated smooth muscle preparations from guinea pig stomach: structure-activity relationships and comparison with the effects of human transforming growth factor-alpha.
In two distinct isolated guinea pig stomach smooth muscle preparations, we have studied the contractile effects of intact human epidermal growth factor-urogastrone (mEGF-URO) and murine epidermal growth factor-urogastrone (mEGF-URO), along with the actions of derivatives (hEGF-URO1-47; mEGF-URO1-47) lacking the C-terminal pentapeptide. The effects of these polypeptides were compared with the actions of human transforming growth factor-alpha (TGF-alpha). In the longitudinal muscle preparation, wherein the contractile actions of agonists were abolished by 1 microM indomethacin, the order of potency was: hEGF-URO = mEGF-URO greater than TGF-alpha greater than hEGF-URO1-47 greater than or equal to mEGF-URO1-47. In this longitudinal muscle preparation, reproducible contractions could be obtained by rinsing the preparation free of agonist and by maintaining intermittent dose intervals of 1 hr or more. In contrast, in the circular muscle preparation, all agonists elicited a contractile effect that was present in the presence of 1 microM indomethacin. In this indomethacin-treated preparation, when an intermittent dosing regimen was used, repeated exposure to either human or murine EGF-URO caused a persistent desensitization. However, in the indomethacin-treated circular muscle preparation, repeated exposure to TGF-alpha and hEGF-URO1-47 during an intermittent dosing schedule caused only a low degree of persistent desensitization. In the indomethacin-treated circular muscle preparation, the order of potency for the contractile effect was: TGF-alpha = hEGF-URO1-47 greater than or equal to hEGF-URO.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Therapeutics, University of Calgary, Faculty of Medicine, Alberta, Canada.
M D
MD
Hollenberg
I
I
Muramatsu
H
H
Itoh
P
P
Patel
S G
SG
Yang
K
K
Lederis
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D013270:Stomach / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D015291:Transforming Growth Factors / Q000494:pharmacology*
D004815:Epidermal Growth Factor; D015291:Transforming Growth Factors; D007213:Indomethacin