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Pharmacological interactions between angiotensin-converting enzyme (ACE) inhibitors, bradykinin and nitric oxide
Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
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 [en]
angiotensin-converting enzyme, angiotensin-converting enzyme inhibitors, atherosclerosis, bradykinin, endothelium, in vitro, nitric oxide
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-27536Local ID: 12193ISBN: 91-7219-587-8 (print)OAI: oai:DiVA.org:liu-27536DiVA: diva2:248088
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
List of papers
1. Antiatherosclerotic Effects of the Angiotensin-Converting Enzyme Inhibitors Captopril and Fosinopril in Hypercholesterolemic Minipigs
Open this publication in new window or tab >>Antiatherosclerotic Effects of the Angiotensin-Converting Enzyme Inhibitors Captopril and Fosinopril in Hypercholesterolemic Minipigs
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1994 (English)In: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 24, no 4, 670-677 p.Article in journal (Refereed) 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.

Keyword
Angiotensin, converting enzyme inhibitors, Atherosclerosis, Captopril, Cholesterol, Fosinopril, lntimal thickening, Minipigs
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79490 (URN)
Available from: 2012-08-06 Created: 2012-08-06 Last updated: 2017-12-07Bibliographically approved
2. Biphasic Response to Bradykinin in Isolated Porcine Iliac Arteries is Mediated by Bradykinin B1 and B2 Receptors
Open this publication in new window or tab >>Biphasic Response to Bradykinin in Isolated Porcine Iliac Arteries is Mediated by Bradykinin B1 and B2 Receptors
1998 (English)In: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 32, no 2, 306-313 p.Article in journal (Refereed) Published
Abstract [en]

Bradykinin-induced responses were studied in isolated porcine iliac arteries. Relaxation was endothelium dependent and seen at low concentrations (10-10-10-8 M) of bradykinin. It was inhibited by the bradykinin B2-receptor antagonist icatibant (HOE-140) and by the nitric oxide synthase inhibitor Nω-nitro-L-arginine. Bradykinin-induced relaxation was significantly potentiated by the kininase I carboxypeptidase inhibitor mergepta (10-6 M). Bradykinin (>10-7M) elicited contraction of preparations with or without endothelium. The contraction was abolished by indomethacin but was not affected by the thromboxane A2/prostaglandin H2-receptor antagonist SQ 29,548. Icatibant and the bradykinin B1-receptor antagonist desArg9[Leu8]bradykinin significantly decreased bradykinin-induced contraction regardless of endothelial function. The contraction also was decreased by treatment with mergepta. The bradykinin B1-receptor agonist desArg9-bradykinin contracted endothelium-denuded arterial strips. This contraction was significantly decreased by desArg9 [Leu8] bradykinin but not by icatibant. The desArg9-bradykinin-induced contraction also was inhibited by the protein-synthesis inhibitor cycloheximide. Neither bradykinin-induced relaxation nor contraction was affected by the ACE inhibitors enalaprilat or cilazaprilat. In conclusion, bradykinin-induced relaxation of isolated porcine iliac arteries was mediated by endothelial bradykinin B2 receptors and mainly nitric oxide. Bradykinin-induced contraction was endothelium independent, indomethacin sensitive, and probably mediated by bradykinin B1 (inducible) and B2 receptors located in the vascular smooth-muscle layer. Kininase I carboxypeptidase, and not ACE, is the main enzyme responsible for bradykinin degradation in these vessels.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79491 (URN)
Available from: 2012-08-06 Created: 2012-08-06 Last updated: 2017-12-07Bibliographically approved
3. Nitric oxide modulates captopril-mediated angiotensin-converting enzyme inhibition in porcine iliac arteries
Open this publication in new window or tab >>Nitric oxide modulates captopril-mediated angiotensin-converting enzyme inhibition in porcine iliac arteries
1999 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 385, no 1, 21-27 p.Article in journal (Refereed) Published
Abstract [en]

The influence of the angiotensin-converting enzyme inhibitor captopril on bradykinin-and angiotensin I-induced responses with special regard to nitric oxide (NO) was studied. Auxometric tension and angiotensin-converting enzyme activity was studied in isolated porcine iliac arteries. Captopril potentiated bradykinin-induced contraction of preparations with intact endothelium; this potentiation was not seen with the kininase I inhibitor mergepta or a bradykinin B1-receptor antagonist. Captopril did not affect bradykinin-induced relaxation. The captopril-mediated increase of bradykinin-induced contraction was only seen in preparations with intact endothelium, while captopril did not affect arterial strips treated with Nω-nitro-L-arginine. Angiotensin I-induced contractions was less reduced by captopril when the strips were pretreated with Nω-nitro-L-arginine. Both captopril and the NO donor S-nitroso-N-acetyl-penicillamine inhibited angiotensin-converting enzyme activity. An additional reduction in angiotensin-converting enzyme activity was seen when S-nitroso-N-acetyl-penicillamine was added to captopril-treated preparations. In conclusion, captopril increased bradykinin-induced contraction in a NO-dependent manner. This potentiation is probably mediated by the increased metabolism of bradykinin by kininase I, and the additive angiotensin-converting enzyme inhibitory effect of captopril and NO.

Place, publisher, year, edition, pages
Elsevier, 1999
Keyword
Angiotensin-converting enzyme activity, Bradykinin, Captopril, Contraction, Nitric oxide (NO), Relaxation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79492 (URN)10.1016/S0014-2999(99)00689-5 (DOI)
Available from: 2012-08-06 Created: 2012-08-06 Last updated: 2017-12-07Bibliographically approved
4. NO donors and ACE inhibitors act in concert to inhibit human ACE activity and platelet aggregation in vitro
Open this publication in new window or tab >>NO donors and ACE inhibitors act in concert to inhibit human ACE activity and platelet aggregation in vitro
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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
angiotensin-converting enzyme, ACE inhibitors, HUVEC, nitric oxide, platelet aggregation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79493 (URN)
Available from: 2012-08-06 Created: 2012-08-06 Last updated: 2013-09-03Bibliographically approved

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