Action of AT1 receptor antagonists on angiotensin II-induced tone in human isolated subcutaneous resistance arteries.
1. Human isolated subcutaneous arteries were studied under isometric conditions in a myograph. 2. Addition of angiotensin II (AII) induced a concentration-dependent increase in tone in isolated arteries. The active metabolite of candesartan (CV 11974), losartan and the active metabolite of losartan, E-3174 antagonized AII-induced tone in a non-competitive manner, but the AT2 selective antagonist, PD123319, was without effect on responses to AII. The effects of candesartan, losartan and E-3174 were analysed using a classical model of non-competitive antagonism and a two-state receptor model. 3. Mechanical removal of the endothelium; pre-incubation with Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME); pre-incubation with indomethacin, a cyclo-oxygenase inhibitor; or pre-incubation with BQ 485, an endothelin antagonist; had no significant effect on contractions induced by AII. 4. Our results suggest AII contracts human isolated resistance arteries by an action on AT1 receptors and does not involve release of endothelial factors. Use of a two-state receptor model successfully described the action of the AT1 antagonists without sacrificing assumptions regarding the competitive nature of binding of these antagonists.
Garcha
R S
RS
Clinical Pharmacology, National Heart & Lung Institute, Imperial College of Science, Technology & Medicine, St Mary's Hospital, South Wharf Road, London W2 1NY.
Sever
P S
PS
Hughes
A D
AD
D000804:Angiotensin II / Q000494:pharmacology* / Q000502:physiology; D057911:Angiotensin Receptor Antagonists; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D009129:Muscle Tonus / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C066026:losartan carboxylic acid; D019808:Losartan; C081643:candesartan