Effect of angiotensin II receptor blockade on the interaction between enalaprilat and doxazosin in rat tail arteries.
1. Previous work has shown that enalaprilat, an inhibitor of angiotensin-converting enzyme (ACE), potentiated the actions of alpha 1-adrenoceptor antagonists; it was hypothesized that angiotensin II (AngII) modulated the activity of alpha 1-adrenoceptors. This hypothesis was tested in Sprague-Dawley rat isolated perfused tail arteries using the AT1 receptor antagonist losartan and the AT2 receptor antagonist PD123319. 2. Losartan had no alpha 1-adrenoceptor antagonist effects at concentrations below 1 mumol/L. Similarly, losartan (0.1 mumol/L) had no effect on the alpha 1-adrenoceptor antagonist action of doxazosin (1, 10 nmol/L) nor on the potentiation of doxazosin by enalaprilat (1 mumol/L). 3. PD123319 (0.1 mumol/L) had no alpha 1-adrenoceptor antagonist effect but altered the mode of action of the alpha 1-adrenoceptor antagonist doxazosin: PD123319 changed doxazosin from a competitive to a non-competitive antagonist, as evidenced by the reduced slope of the dose-response curve for the alpha 1-adrenoceptor agonist phenylephrine. 4. These results suggest that AngII can modulate alpha 1-adrenoceptor function in rat tail arteries via an indirect action at AT2 receptors. However, the present results do not rule out the involvement of bradykinin, endothelin or prostaglandin in the modulation of alpha 1-adrenoceptor function by angiotensin II.
Marwood
J F
JF
Hypertension Unit, Royal North Shore Hospital, St Leonards, New South Wales, Australia. jmarwood@doh.health.nsw.gov.au
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001158:Arteries / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D017292:Doxazosin / Q000494:pharmacology*; D004347:Drug Interactions; D015773:Enalaprilat / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013623:Tail / Q000098:blood supply
D000317:Adrenergic alpha-Antagonists; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D007093:Imidazoles; D011725:Pyridines; D000804:Angiotensin II; C073402:PD 123319; D000803:Angiotensin I; D015773:Enalaprilat; D019808:Losartan; D017292:Doxazosin