Inhibitory effect of dithiothreitol on angiotensin II-induced contractions mediated by AT1-receptors in rat portal vein and rabbit aorta.
The disulfide-reducing agent dithiothreitol (DTT) has been shown to reduce angiotensin II (Ang II) subtype 1 receptor (AT1) binding sites in various tissues. Its effect on Ang II-induced contractions was studied in the rat portal vein and rabbit aorta. In the isolated rat portal vein, DTT shifted the concentration-response curve for Ang II to the right (DTT 0.5-3 mmol/l) and depressed the maximal response (DTT 1-3 mmol/l). DTT 5 mmol/l almost abolished the effect of Ang II. In the isolated rabbit aorta, the inhibitory effect of DTT was more pronounced and its pattern of effect was different, since DTT 0.3 and 0.5 mmol/l caused a progressive flattening of the concentration-response curve of Ang II. DTT (1 mmol/l) fully suppressed the effect of Ang II. A biphasic curve consisting of a high sensitivity component and a component of low sensitivity for Ang II was observed after pretreatment with DTT 1 mmol/l in the rat portal vein but not in the rabbit aorta. In the presence of DTT 1 mmol/l, the AT1-receptor antagonist losartan antagonized the high sensitivity response to Ang II in a competitive manner with a pA2 value very similar to that obtained in the absence of DTT, suggesting that this response to Ang II is mediated by those AT1-receptors which were not inactivated by DTT. The biphasic curve may be explained by the occurrence of a single AT1-receptor subtype existing in two different states. Another possibility might be the involvement of two AT1-receptor subpopulations.(ABSTRACT TRUNCATED AT 250 WORDS)
Zhang
J S
JS
Department of Pharmacotherapy, Academic Medical Centre, University of Amsterdam, The Netherlands.
van Meel
J C
JC
Pfaffendorf
M
M
van Zwieten
P A
PA
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D008297:Male; D008782:Methylurea Compounds / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011169:Portal Vein / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D008782:Methylurea Compounds; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C077353:BIBS 222; D019808:Losartan; D004229:Dithiothreitol