Losartan reduces constrictor responses to endothelin-1 and the thromboxane A2 analogue in aortic rings from spontaneously hypertensive rats: role of nitric oxide.
OBJECTIVE
Our study was designed to investigate whether angiotensin II subtype 1 (AT1) receptors are involved in the constrictor responses evoked by endothelin-1 and the thromboxane A2 analogue U46619 in aortic rings from spontaneously hypertensive rats (SHR), by studying the effect of the AT1 receptor antagonist losartan. In addition, since nitric oxide seems to participate in the mechanism of action of losartan, we studied the effect of the nitric oxide synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), on the action of losartan.


METHODS
Dose-response curves of either endothelin-1 (10(-10) to 10(-7) mol/l) or U46619 (10(-10) to 10(-6) mol/l) were studied in the presence or absence of losartan (10(-5) mol/l) in aortic rings from SHR. Likewise, similar experiments were done in aortic rings pretreated with the nitric oxide synthesis inhibitor, L-NAME (10(-4) mol/l).


RESULTS
Pre-incubation with losartan significantly reduced the contractile response to endothelin-1 compared with control rings, without modifying the value represented by 50% of the maximal response (pD2). The concentration-response curve to U46619 was shifted to the right in the presence of losartan, reducing the pD2 compared with control rings. The presence of captopril (10(-5) mol/l) in the incubation media did not alter the response to either endothelin-1 or U46619. The diminished response to both endothelin-1 and U46619 in the presence of losartan was reversed in L-NAME-pretreated rings.


CONCLUSIONS
Angiotensin II seems to participate in the vasoconstriction induced by both endothelin-1 and the thromboxane A2 analogue through the stimulation of AT1 receptors in SHR aortic rings, because losartan inhibited this effect. Moreover, nitric oxide appears to be involved in this action of losartan.
Maeso
R
R
Department of Physiology, School of Medicine, Universidad Complutense, Madrid, Spain.
Rodrigo
E
E
Muñoz-Garcia
R
R
Navarro-Cid
J
J
Ruilope
L M
LM
Lahera
V
V
Cachofeiro
V
V
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000502:physiology; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester