Secretory dysfunction of vascular endothelium limits the effect of angiotensin converting enzyme inhibitor quinapril on aggregation of erythrocytes in experimental hypertension.
Using automatic erythrocyte aggregometer type MA-1 (Myrenne gmbh, Germany), we investigated the hypothesis that therapeutic effectiveness of quinapril--angiotensin converting enzyme inhibitor (ACEI)--in the treatment of hypertension would correlate with improvement of red blood cell (RBC) aggregability. Experiments were performed on commercially available inbred strain of spontaneously hypertensive male rats (SHR) aged 19-21 weeks. Age-matched normotensive Wistar-Kyoto (WKY) rats genetically related to SHR were used as a control. Aggregability of RBC in hypertensive rats was significantly higher than in control WKY animals. Quinapril (100 microg/kg) administered i.p. for 8 days improved RBC aggregability in normotensive rats but surprisingly not in SHR animals. Beneficial effect of quinapril on RBC aggregation observed in normotensive animals did not occur when this drug was injected in combination with aspirin (1 or 50 mg/kg) or with indomethacin (20 mg/kg) or with L-NAME (10 mg/kg). However, much the same damaging effects on RBC aggregability were observed when aspirin, indomethacin or L-NAME were each administered into normotensive animals without quinapril. In contrast with normotensive rats, aggregability of RBC in SHR was not affected either by quinapril or by indomethacin and by L-NAME, given separately or in combination. The only compound significantly worsening RBC aggregability in SHR was aspirin but this effect was not dose-dependent. Quinapril-induced improvement of RBC aggregability in normotensive rats (but not in SHR) was completely abolished by simultaneous administration of B2 receptor antagonist icatibant and successfully mimicked by 8 days of treatment with bradykinin. In vitro aggregability of RBC isolated from WKY was not affected by previous incubation (30 min at 37 degrees C) with quinapril, indomethacin or L-NAME. Only aspirin (3 mM) significantly increased RBC aggregability as compared to placebo. It is concluded that under physiological conditions quinapril efficiently inhibits RBC aggregability and this effect is modulated by secretion of endothelial mediators, mainly prostacyclin and nitric oxide. In hypertension quinapril, in spite of lowering of arterial blood pressure, is unable to display its beneficial effects on RBC aggregability possibly due to the hypertension-induced/accompanied dysfunction of vascular endothelium. Aspirin revealed unique erythrocyte damaging properties, presumably independent of inhibition of cyclooxygenase but related to a direct membrane protein acetylation.
Korbut
R A
RA
Department of Internal Medicine, J Dietl Hospital, CMUJ, Poland.
Madej
J
J
Adamek-Guzik
T
T
Korbut
R
R
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D001241:Aspirin / Q000009:adverse effects; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology*; D011464:Epoprostenol / Q000096:biosynthesis / Q000378:metabolism; D004903:Erythrocyte Aggregation / Q000187:drug effects*; D006973:Hypertension / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D007213:Indomethacin / Q000009:adverse effects; D007274:Injections, Intraperitoneal; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000009:adverse effects; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D000077583:Quinapril; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*
D000806:Angiotensin-Converting Enzyme Inhibitors; D044005:Tetrahydroisoquinolines; D009569:Nitric Oxide; C065679:icatibant; D011464:Epoprostenol; D001241:Aspirin; D000077583:Quinapril; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin