Valsartan improves fibrinolytic balance in atherosclerotic rabbits.
OBJECTIVE
To examine the long-term effects of the angiotensin type I (AT1) receptor antagonist, valsartan, on fibrinolytic balance, coagulation parameters, endothelial function and structural alterations in atherosclerotic rabbits.


METHODS
Animals were submitted to a 1% cholesterol-enriched diet for 10 weeks. Half of the animals were treated with valsartan (3 or 10 mg/kg per day). Systolic arterial pressure was directly measured in awake rabbits. Tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor (PAI-1) activities were measured. Plasma concentrations of cholesterol, D-dimer, factor VIII and fibrinogen, as well as thrombin time, were also determined. Responses to acetylcholine, sodium nitroprusside and angiotensin II were evaluated in aortic rings. Morphometric analysis of aortic segments was also performed to calculate atherosclerotic lesion.


RESULTS
Cholesterol-fed rabbits presented systolic arterial pressure levels comparable to controls. These animals presented aortic atherosclerotic lesions. Treatment with valsartan did not alter plasma cholesterol levels or arterial pressure in any group. Acetylcholine-induced relaxations and D-dimer and t-PA activity were lower (P < 0.05) in atherosclerotic than in normal rabbits. In contrast, PAI-1 activity was higher (P < 0.05) in atherosclerotic rabbits than in controls. Valsartan increased (P < 0.05) acetylcholine-induced relaxations, D-dimer concentration and t-PA activity, and reduced intimal thickening and PAI-1 activity in cholesterol-fed rabbits. Fibrinogen concentrations and factor VIII concentrations were lower (P < 0.05) and thrombin time was higher (P < 0.05) in atherosclerotic rabbits compared to controls. Valsartan did not affect factor VIII in any group, but reduced fibrinogen levels only in hypercholesterolemic rabbits. Valsartan 10 mg/kg per day reduced (P < 0.05) thrombin time in cholesterol-fed rabbits.


CONCLUSIONS
Impairment of fibrinolytic balance, associated with atherosclerosis in rabbits, appears to be related with angiotensin II via AT1receptors. The beneficial effect of valsartan on fibrinolysis seems to be related to the concomitant amelioration of endothelial dysfunction and reduction of intimal thickening, further supporting the importance of the blockade of angiotensin II actions to prevent thrombotic alterations associated with atherosclerosis.
Oubiña
M Pilar
MP
Departmento de Fisiología, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
de Las Heras
Natalia
N
Vázquez-Pérez
Sandra
S
Cediel
Eva
E
Sanz-Rosa
David
D
Ruilope
Luis M
LM
Cachofeiro
Victoria
V
Lahera
Vicente
V
D000109:Acetylcholine / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000187:drug effects; D005338:Fibrin Fibrinogen Degradation Products / Q000187:drug effects; D005340:Fibrinogen / Q000187:drug effects; D005342:Fibrinolysis / Q000187:drug effects*; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy / Q000209:etiology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011817:Rabbits; D013777:Tetrazoles / Q000627:therapeutic use*; D013995:Time; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D000068756:Valsartan
D000959:Antihypertensive Agents; D015415:Biomarkers; D002791:Cholesterol, Dietary; D005338:Fibrin Fibrinogen Degradation Products; D013777:Tetrazoles; C036309:fibrin fragment D; D000068756:Valsartan; D005169:Factor VIII; D005340:Fibrinogen; D002784:Cholesterol; D014633:Valine; D000109:Acetylcholine