Aliskiren increases bradykinin and tissue kallikrein mRNA levels in the heart

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.

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B 2 Receptor– and Angiotensin AT 2 Receptor–Mediated Mechanism

“…12 Our finding that icatibant prevented the cardioprotective effect of aliskiren is consistent with the involvement of B 2 receptors, although unlike other studies we did not detect an effect of icatibant on valsartan-induced cardioprotection. 25,[27][28][29] Many previous studies have shown interaction between the B 2 and AT 2 receptors.…”

“…Because aliskiren increases bradykinin levels in the heart 12 and bradykinin has well-established cardioprotective activity, [13][14][15][16][17][18][19][20][21][22] we compared the effects of aliskiren with valsartan and their combination on cardiac I/R injury. Myocardial infarct size relative to the area at risk was 43% in the no inhibitor vehicle-treated group (Figure 1).…”

“…[9][10][11] Recently, we reported that aliskiren increases tissue kallikrein and bradykinin levels in the rat heart at plasma levels within the therapeutic range in patients. 12 Both the dose-response and time course of the aliskiren-induced increases in cardiac bradykinin levels suggested that these actions of aliskiren were independent of renin inhibition. 12 Bradykinin has well-established cardioprotective activity [13][14][15][16][17][18][19][20][21][22] and is implicated in the reduction of myocardial ischemiareperfusion (I/R) injury by both ACE inhibitors and ARBs.…”

“…12 Both the dose-response and time course of the aliskiren-induced increases in cardiac bradykinin levels suggested that these actions of aliskiren were independent of renin inhibition. 12 Bradykinin has well-established cardioprotective activity [13][14][15][16][17][18][19][20][21][22] and is implicated in the reduction of myocardial ischemiareperfusion (I/R) injury by both ACE inhibitors and ARBs. The bradykinin receptor type 2 (B 2 ) receptor antagonist icatibant prevents the reduction in I/R injury produced by ACE inhibitors, [23][24][25][26] whereas both icatibant and the angiotensin II receptor type 2 (AT 2 ) receptor antagonist PD123319 attenuate cardioprotection by ARBs.…”

“…The bradykinin receptor type 2 (B 2 ) receptor antagonist icatibant prevents the reduction in I/R injury produced by ACE inhibitors, [23][24][25][26] whereas both icatibant and the angiotensin II receptor type 2 (AT 2 ) receptor antagonist PD123319 attenuate cardioprotection by ARBs. 25,[27][28][29] Our finding that aliskiren increases cardiac bradykinin levels 12 raised the possibility of cardioprotection, independent of any effect of aliskiren on renin.…”