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NO donors and ACE inhibitors act in concert to inhibit human ACE activity and platelet aggregation in vitro
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0003-3184-0427
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

This study investigates the effects of exogenous and endogenous nitric oxide (NO) on human circulating and endothelial angiotensin-converting enzyme (ACE) activity, and platelet aggregation. The NO donor S-nitroso N-acetylpenicillamine SNAP (10-8-10-6 M) significantly and dose-dependently inhibited serum ACE activity. The concomitant addition of SNAP to ACE inhibitor-treated (captopril or enalaprilat) serum, further reduced ACE activity. In cultured endothelial cells from human umbilical veins (HUVEC), both SNAP and 3-morpholinosydnonimine (SIN-1) significantly reduced ACE activity. An additative effect was seen with a combined treatment of captopril and SNAP. Treatment with the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) did not affect ACE activity. Thrombin inhibited endothelial ACE activity, an effect that was abolished when cells were pretreated with L-NMMA. ADP-induced platelet aggregation was inhibited with SNAP, SIN-1 and nitroglycerine (GTN). Captopril did not affect aggregation, while a high concentration of enalaprilat (10-4 M) reduced it. The concomitant addition of 10-5 M ACE inhibitor to NO donor-treated platelets resulted in a further reduction of platelet aggregation. This effect was most evident with SIN-I and enalaprilat. In conclusion, both exogenous and endogenous NO inhibit human ACE activity. NO donors and ACE inhibitors act in concert to inhibit ACE and platelet aggregation. 

Keyword [en]
angiotensin-converting enzyme, ACE inhibitors, HUVEC, nitric oxide, platelet aggregation
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-79493OAI: oai:DiVA.org:liu-79493DiVA: diva2:543045
Available from: 2012-08-06 Created: 2012-08-06 Last updated: 2013-09-03Bibliographically approved
In thesis
1. Pharmacological interactions between angiotensin-converting enzyme (ACE) inhibitors, bradykinin and nitric oxide
Open this publication in new window or tab >>Pharmacological interactions between angiotensin-converting enzyme (ACE) inhibitors, bradykinin and nitric oxide
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cardiovascular diseases are a major cause of death in Western countries. Angiotensin-converting enzyme (ACE) is as a key enzyme in the renin-angiotensin system involved in the regulation of blood pressure, and water and electrolyte balance in the body. ACE not ouly increases the conversion of angiotensin I to the active angiotensin II, but also degrades bradykinin. ACE inhibitors, like captopril, are today first-line treatment in hypertension and heart failure.

We have shown that two structurally different ACE inhibitors, captopril and fosinopril, exhibit anti-atherosclerotic effects in hypercholesterolemic mini pigs. Captopril, but not fosinopril, improved endothelial function in the iliac arteries from the mini pigs.

Bradykinin-induced relaxation of porcine iliac arteries was mediated by bradykinin B2 receptors and the subsequent release of nitric oxide (NO). ACE inhibitors did not affect the bradykinin-induced relaxation, implying that other enzymes than ACE (e. g. carboxypeptidase M; CPM) are involved in bradykinin degradation in these vessels. Bradykinin B, and B2 receptors on the vascular media elicited a contraction mediated by cyclooxygenase metabolite(s). Treatment with captopril potentiated bradykinin B, receptor-mediated contraction, due to CPM becoming responsible for bradykinin degradation.

Captopril potentiated bradykinin- and inhibited angiotensin I-induced contractions only in arteries with intact NO synthesis. This implied that NO synthesis is necessary for an effective ACE inhibition. ACE activity analyses did reveal that both exogenous and endogenous NO are able to inhibit porcine and human ACE activity. It was also shown that this inhibition is additative with captopril and enalaprilat. This additative effect of NO and ACE inhibitors on ACE activity affected not only angiotensin I- and bradykinin- mediated contractions of porcine iliac arteries, but also reduced human platelet aggregation.

In summary, ACE inhibitors show anti-atherosclerotic properties in hypercholesterolemic mini pigs. ACE inhibitor treatment of porcine iliac arteries did not affect bradykinin-induced relaxation, but instead shunted over bradykinin to other enzymes generating the bradykinin B 1 receptor agonist desArg9 -bradykinin. NO was found to be an endogenous inhibitor of ACE, acting in concert with therapeutically used ACE inhibitors to decrease vascular tone and human platelet aggregation.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2000. 105 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 630
Keyword
angiotensin-converting enzyme, angiotensin-converting enzyme inhibitors, atherosclerosis, bradykinin, endothelium, in vitro, nitric oxide
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27536 (URN)12193 (Local ID)91-7219-587-8 (ISBN)12193 (Archive number)12193 (OAI)
Public defence
2000-05-25, Elsa Brändströms Sal, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-08-06Bibliographically approved

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Persson, KarinWhiss, Per A.Nyhlén, KristinaAndersson, Rolf G. G.

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