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Biphasic Response to Bradykinin in Isolated Porcine Iliac Arteries is Mediated by Bradykinin B1 and B2 Receptors
Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
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.

Place, publisher, year, edition, pages
1998. Vol. 32, no 2, 306-313 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-79491OAI: diva2:543032
Available from: 2012-08-06 Created: 2012-08-06 Last updated: 2012-08-06Bibliographically 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.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 630
angiotensin-converting enzyme, angiotensin-converting enzyme inhibitors, atherosclerosis, bradykinin, endothelium, in vitro, nitric oxide
National Category
Medical and Health Sciences
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)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-08-06Bibliographically approved

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