AT-1 receptor antagonism modifies the mediation of endothelin-1, thromboxane A2, and catecholamines in the renal constrictor response to angiotensin II.
OBJECTIVE
The present study investigated the consequences of partial AT(1) receptor blockade on the participation of catecholamines, thromboxane A(2) (TXA(2)), and endothelin-1 (ET-1) in the renal vasoconstriction induced by angiotensin II (Ang II).


METHODS
For this purpose, the increase in renal perfusion pressure (RPP) produced by Ang II was studied in isolated kidneys from untreated or irbesartan-treated Wistar Kyoto and spontaneously hypertensive rats (SHR), in absence or presence of the alfa-1 receptor antagonist, prazosin, the TXA(2) receptor antagonist, ifetroban, or the ET(A)/ET(B) receptor antagonist, PD145065.


RESULTS
Systolic arterial pressure (SAP) was higher (P < 0.05) in SHR than in WKY. Increases in RPP produced by Ang II were comparable in kidneys from both untreated groups. Treatment with irbesartan reduced SAP and RPP in both strains in a comparable extent. Presence of prazosin, ifetroban, or PD145065 in perfusion media reduced (P < 0.05) Ang II maximal response in all groups. Maximal inhibition of Ang II-induced vasoconstriction produced by the 3 antagonists was comparable in untreated WKY, but that of ifetroban and PD145065 was lower (P < 0.05) than that of prazosin in untreated SHR. Maximal inhibition of Ang II-induced vasoconstriction produced by the 3 antagonists was comparable in WKY treated with irbesartan, and not different to that observed in untreated WKY. Maximal inhibitory effect of the 3 antagonists was higher (P < 0.05) in treated than in untreated SHR.


CONCLUSIONS
The study further supports the importance of catecholamines, TXA(2), and ET-1 as mediators of the renal vasoconstriction induced by Ang II in both normotensive and hypertensive rats. Hypertensive conditions appeared to reduce the participation of TXA(2) and ET-1 in Ang II-induced vasoconstriction when compared with normotensive conditions. Chronic partial blockade of AT(1) receptors did not affect the participation of catecholamines, TXA(2), and ET-1 in normotensive rats, but increased the participation of the 3 mediators in SHR. This suggests that when AT(1) receptors are partially blocked, other vasoconstrictor factors could exert part of the renal vasoconstrictor effects of Ang II.
Cediel
Eva
E
Departamento Científico, BMS España SA, Madrid, Spain.
de Las Heras
Natalia
N
Sanz-Rosa
David
D
Velasco
Olga
O
Cachofeiro
Victoria
V
Lahera
Vicente
V
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002395:Catecholamines / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D000077405:Irbesartan; D008297:Male; D011189:Potassium Chloride / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D012079:Renal Circulation / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D002395:Catecholamines; D019332:Endothelin-1; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D013928:Thromboxane A2; D011189:Potassium Chloride; D000077405:Irbesartan; D011224:Prazosin