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Antiatherosclerotic Effects of the Angiotensin-Converting Enzyme Inhibitors Captopril and Fosinopril in Hypercholesterolemic Minipigs
Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
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1994 (Engelska)Ingår i: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 24, nr 4, s. 670-677Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

We evaluated the two angiotensin-converting enzyme (ACE) inhibitors captopril and fosinopril with regard to possible antiatherosclerotic effects in minipigs. Experimental hypercholesterolemia and atherosclerosis was produced in 33 minipigs of the Gottingen strain by an egg yolk/cholesterol-enriched diet for 1 year. One group (n = 11) was fed the atherogenic diet alone and served as a control. A second group (n = 11) received captopril (80 mg/kg/day) added to the atherogenic diet, and a third group (n = 11) was treated in the same manner but with fosinopril (8 mg/kglday). The drug treatments produced significant reduction in serum ACE activity associated with a reactive increase in plasma renin activity (PRA), but had only minor effects on plasma lipids and lipoproteins. At the end of the treatment period, all animals were killed and examined for degree of atherosclerosis. The percentage of atherosclerotic area in the abdominal aorta was significantly lower in both drug-treated groups as compared with controls. Furthermore, accumulation of cholesterol in the thoracic and abdominal aorta was inhibited by drug treatment. Finally, the percentage of intimal thickening in abdominal aorta was significantly reduced in the drug-treated groups. In conclusion, the ACE inhibitors captopril and fosinopril inhibited development of atherosclerosis in hypercholesterolemic minipigs.

Ort, förlag, år, upplaga, sidor
1994. Vol. 24, nr 4, s. 670-677
Nyckelord [en]
Angiotensin, converting enzyme inhibitors, Atherosclerosis, Captopril, Cholesterol, Fosinopril, lntimal thickening, Minipigs
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:liu:diva-79490OAI: oai:DiVA.org:liu-79490DiVA, id: diva2:543027
Tillgänglig från: 2012-08-06 Skapad: 2012-08-06 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Ingår i avhandling
1. Pharmacological interactions between angiotensin-converting enzyme (ACE) inhibitors, bradykinin and nitric oxide
Öppna denna publikation i ny flik eller fönster >>Pharmacological interactions between angiotensin-converting enzyme (ACE) inhibitors, bradykinin and nitric oxide
2000 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Linköping: Linköpings universitet, 2000. s. 105
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 630
Nyckelord
angiotensin-converting enzyme, angiotensin-converting enzyme inhibitors, atherosclerosis, bradykinin, endothelium, in vitro, nitric oxide
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-27536 (URN)12193 (Lokalt ID)91-7219-587-8 (ISBN)12193 (Arkivnummer)12193 (OAI)
Disputation
2000-05-25, Elsa Brändströms Sal, Hälsouniversitetet, Linköping, 09:00 (Svenska)
Opponent
Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2012-08-06Bibliografiskt granskad

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