Combination Angiotensin Converting Enzyme and Direct Renin Inhibition in Heart Failure following Experimental Myocardial Infarction

Abstract

SUMMARYAims: Diminishing the activity of the renin-angiotensin system (RAS) plays a pivotal role in the treatment of heart failure. In addition to angiotensin converting enzyme (ACE) inhibitors and angiotensin-receptor blockers, direct renin inhibition has emerged as a potential adjunctive treatment to conventional RAS blockade. We sought to determine the effectiveness of this strategy after myocardial infarction (MI) in the setting of preexisting hypertension, a common premorbid condition in patients with ischemic heart disease. Methods and Results: Ten-week-old female heterozygous hypertensive (mRen-2)27 transgenic rats (Ren-2), were randomized to one of five groups (n = 8 per group); sham, MI, MI + aliskiren, MI + lisinopril and MI + combination lisinopril and aliskiren. Cardiac function was assessed by echocardiography and in vivo cardiac catheterization. Untreated MI animals developed heart failure with hypotension, dilation, reduced ejection fraction (EF), and raised left ventricular end-diastolic pressure (LVEDP). Treatment with single agent treatment had only modest effect on cardiac function though combination therapy was associated with significant improvements in EF and LVEDP when compared to untreated MI animals (P < 0.05). Histologic analysis demonstrated increase extracellular matrix deposition and cardiomyocyte hypertrophy in the noninfarct region of all MI groups when compared with sham operated animals (P < 0.05) that was reduced by ACE inhibitor monotherapy and combination treatment but not by aliskiren alone. Conclusion:In a hypertensive rat model that underwent experimental MI, EF, and LVEDP, key functional indices of heart failure, were improved by treatment with combination ACE and direct renin inhibition when compared with either agent used alone.

Evaluating Molecular Mechanism of Hypotensive Peptides Interactions with Renin and Angiotensin Converting Enzyme

“…Renin cleaves angiotensinogen to yield angiotensin-I, which is subsequently converted by the action of ACE to angiotensin-II, a potent vasoconstrictor that up-regulates blood pressure. Therefore, simultaneous inhibition of renin and ACE activities would prevent the formation of both angiotensin-I and angiotensin-II, which produces a more efficient regulation of RAS when compared to the use of individual enzyme inhibitors alone [2]. The simultaneous inhibition of renin and ACE activities could provide a new alternative way to treat hypertension efficiently without severe negative side effects [3].…”

Intermedin improves cardiac function and sympathetic neural remodeling in a rat model of post myocardial infarction heart failure

“…Angiotensin II (Ang II) is hypothesized to serve a major role in ventricle remodeling in heart failure, which promotes myocardium hypertrophy ( 24 ). Blockade of the renin-angiotensin system attenuates cardiomyocyte hypertrophy in post-MI HF ( 18 ). It has been reported that the cell size of H9c2 cells was increased by Ang II treatment, while IMD significantly attenuates hypertrophy in these cells ( 25 ).…”

“…Rats were lightly anesthetized with 1% sodium pentobarbital, (40 mg/kg; Sinopharm Chemical Reagent Co., Ltd.) and transthoracic echocardiography was performed with a 30 MHz high frequency transducer (VisualSonics Vevo770; VisualSonics, Inc., Toronto, ON, Canada) as previously described ( 18 ). End-diastolic and end-systolic left ventricle diameters were measured by M-mode tracing.…”

Dipeptidyl peptidase‐4 inhibition improves cardiac function in experimental myocardial infarction: Role of stromal cell‐derived factor‐1α

“…Expression of SDF-1α is induced by hypoxiainducible factor-1α-dependent mechanisms in response to ischemia, 20,23 and increases markedly following MI, 11,22 where several lines of evidence support its role in mediating cardiac protection by protecting cardiac myocytes against apoptosis and enhancing angiogenesis. 11,20,27 For example, both recombinant and degradation-resistant SDF-1α improved cardiac function and structure after experimental MI in rodents. [24][25][26]28 Conversely, blocking CXCR4 in this setting enhanced apoptosis, worsened scar formation, diminished the angiogenic response, and adversely affected cardiac function.…”

“…11,[24][25][26] Two weeks after randomization to vehicle, saxagliptin or liraglutide treatment, MI (complete left anterior descending [LAD] ligation) or sham surgery was performed as described previously. 11,27 Two days later, rats were subjected to echocardiography, 28 and then followed for a further 4 weeks. Prior to being killed, rats underwent cardiac catheterization and echocardiography and tail blood collection.…”