Antithrombotic effect of captopril and losartan is mediated by angiotensin-(1-7).
It is well established that renin-angiotensin system blockers exert NO/prostacyclin-dependent antithrombotic effects. Because some beneficial effects of these drugs are mediated by angiotensin (Ang)-(1-7), in the present study we examined if their antithrombotic action could be mediated by Ang-(1-7). Intravenous infusion of Ang-(1-7) (1, 10, or 100 pmol/kg per minute for 2 hours) into rats developing venous thrombosis caused 50% to 70% reduction of the thrombus weight. This effect was dose-dependently reversed by cotreatment with A-779 (selective Ang-[1-7] receptor antagonist) or EXP 3174 (angiotensin type 1 receptor antagonist) but not by PD 123,319 (angiotensin type 2 receptor antagonist). Similarly, the antithrombotic effects of captopril (ACE inhibitor) and losartan (angiotensin type 1 receptor blocker) were attenuated by A-779 in a dose-dependent manner. The effect of Ang-(1-7) was completely abolished by concomitant administration of NO synthase inhibitor (N(G)-nitro-L-arginine methyl ester) and prostacyclin synthesis inhibitor (indomethacin), as has been shown previously for captopril and losartan. Thus, the antithrombotic effect of renin-angiotensin system blockers involves Ang-(1-7)-evoked release of NO and prostacyclin.
Kucharewicz
Iwona
I
Department of Pharmacodynamics, Medical Academy of Bialystok, Bialystok, Poland.
Pawlak
Robert
R
Matys
Tomasz
T
Pawlak
Dariusz
D
Buczko
Wlodzimierz
W
D000803:Angiotensin I / Q000378:metabolism* / Q000494:pharmacology; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006977:Hypertension, Renal / Q000188:drug therapy / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007262:Infusions, Intravenous; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D012084:Renin-Angiotensin System / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology; D020246:Venous Thrombosis / Q000188:drug therapy*
C092006:7-Ala-angiotensin (1-7); D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D007093:Imidazoles; D010446:Peptide Fragments; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D009569:Nitric Oxide; D000803:Angiotensin I; D002216:Captopril; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; C066026:losartan carboxylic acid; C118790:angiotensin I (1-7); D019808:Losartan