Aliskiren increases bradykinin and tissue kallikrein mRNA levels in the heart
- Author(s)
- Campbell, DJ; Zhang, Y; Kelly, DJ; Gilbert, RE; McCarthy, DJ; Shi, W; Smyth, GK;
- Details
- Publication Year 2011-09,Volume 38,Issue #9,Page 623-631
- Journal Title
- CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
- Publication Type
- Journal Article
- Abstract
- 1. Aliskiren is a renin inhibitor with an IC(50) of 0.6 nmol/L for human renin, 4.5 nmol/L for mouse renin and 80 nmol/L for rat renin. 2. In the present study, we compared the effects of aliskiren (10 mg/kg per day), the angiotensin-converting enzyme inhibitor perindopril (0.2 mg/kg per day) and their combination on angiotensin and bradykinin peptides in female heterozygous (mRen-2)27 rats, transgenic for the mouse renin gene. 3. All three treatments produced similar reductions in systolic blood pressure, heart weight and plasma aldosterone levels and reduced angiotensin II levels in lung, but only perindopril and the combination reduced angiotensin II levels in kidney of (mRen-2) 27 rats. In contrast, aliskiren and the combination, but not perindopril alone, increased cardiac bradykinin levels. Aliskiren increased immunostaining for tissue kallikrein in the heart and reduced cardiac fibrosis. 4. We investigated the mechanism underlying the increase in bradykinin levels following aliskiren treatment in Sprague-Dawley rats, in which aliskiren has a lower potency for renin inhibition. Aliskiren (10 mg/kg per day) reduced renal angiotensin levels within 24 h, but treatment for > 24 h was required to increase cardiac bradykinin levels. Moreover, 3 mg/kg per day aliskiren increased cardiac bradykinin levels, but did not reduce renal angiotensin levels. Aliskiren did not potentiate the hypotensive effects of bradykinin; however, it increased tissue kallikrein, but not plasma kallikrein, mRNA levels in the heart. 5. These data demonstrate that the aliskiren-induced increase in cardiac bradykinin levels is independent of renin inhibition and changes in bradykinin metabolism, but is associated with increased tissue kallikrein gene expression.
- Publisher
- WILEY-BLACKWELL
- Keywords
- ANGIOTENSIN-CONVERTING ENZYME; GLYCOGEN-SYNTHASE KINASE-3-BETA; RENIN INHIBITOR ALISKIREN; MYOCARDIAL-INFARCTION; RECEPTOR EXPRESSION; BLOOD-PRESSURE; IMAGE-ANALYSIS; PLASMA-RENIN; ACTIVE RENIN; RATS
- Publisher's Version
- https://doi.org/10.1111/j.1440-1681.2011.05572.x
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2011-09-01 12:00:00