Article

Addition of angiotensin II receptor antagonist to an ACE inhibitor in heart failure improves cardiovascular function by a bradykinin-mediated mechanism.

First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan.
Journal of Cardiovascular Pharmacology (Impact Factor: 2.38). 05/2003; 41(4):632-9.
Source: PubMed

ABSTRACT Whether cardiovascular responses to bradykinin are augmented by additional treatment with angiotensin II receptor antagonism (ATRA) to angiotensin-converting enzyme inhibition (ACEI) in congestive heart failure (CHF) is unknown. To clarify the level and functional effects of endogenous bradykinin in CHF with combined ATRA and ACEI, 35 dogs were assigned to the following treatment protocols: 1). rapid ventricular pacing (240 bpm), 2). concomitant ATRA (TCV116, 1.5 mg x kg-1.day-1) and rapid pacing, 3). concomitant ACEI (enalapril 1.9 mg x kg-1.day-1) and rapid pacing, 4). concomitant combined ATRA (TCV116, 0.75 mg x kg-1.day-1) and ACEI (enalapril 0.95 mg x kg-1.day-1) and rapid pacing, and 5). sham-operated control. Plasma bradykinin levels were increased and B(2) receptors were synergistically upregulated in CHF groups treated with combined ATRA and ACEI compared with those treated with ATRA or ACEI alone. HOE-140 (0.3 mg/kg), a bradykinin B(2) receptor antagonist, produced an increase in total systemic resistance and a decrease in left ventricular contractility in CHF with combined therapy compared with either monotherapy. Thus, endogenous bradykinin partially contributes to the synergistic improvement of cardiovascular function in CHF with additional treatment with ATRA to ACEI.

0 Bookmarks
 · 
119 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The goal of this study was to determine whether an Angiotensin II receptor antagonist, candesartan, prevents myocardial fibrosis more effectively than enalapril in animals with a non-ACE pathway during the progression of congestive heart failure (CHF). Dogs were randomly assigned to one of four groups: (1) rapid ventricular pacing (240 bpm); (2) concomitant candesartan cilexetil (1.5 mg/kg/d) and rapid pacing; (3) concomitant enalapril (1.9 mg/kg/d) and rapid pacing; (4) sham-operated control. The expression of collagen type I & III mRNA and the collagen volume fraction, which were significantly increased in the pacing-only group, were suppressed by both treatments; it was lower in the candesartan than the enalapril group. Although there were no differences in the LV stiffness coefficient (beta) among all pacing groups, the absolute changes in beta from the control values were smaller in the candesartan group, but not the enalapril group, compared with the rapid-pacing-only group. The present study demonstrates that in animals with a non-ACE pathway, candesartan suppressed myocardial fibrosis during the progression of CHF in comparison with enalapril. Furthermore, candesartan prevented an increase in LV stiffness. These findings imply potential clinical applications for candesartan in the management of CHF to prevent myocardial fibrosis. Further prospective evaluation and clinical study will be necessary before deciding on the net benefits of candesartan in comparison to enalapril.
    Journal of Cardiovascular Pharmacology 06/2004; 43(6):860-7. · 2.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It has been suggested that proangiotensin-12 (proang-12), a novel angiotensin peptide recently discovered in rat tissues, may function as a component of the tissue renin-angiotensin system (RAS). To investigate the role of proang-12 in the production of angiotensin II (Ang II), we measured its plasma and tissue concentrations in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, with and without RAS inhibition. The 15-week-old male WKY and SHR rats were left untreated or were treated for 7 days with 30 mg kg(-1) per day losartan, an angiotensin receptor blocker, or with 20 mg kg(-1) per day imidapril, an angiotensin-converting enzyme (ACE) inhibitor. Both treatments increased renin activity and the concentrations of angiotensin I (Ang I) and Ang II in the plasma of WKY and SHR rats, but neither affected plasma proang-12 levels. In contrast to the comparatively low level of proang-12 seen in plasma, cardiac and renal levels of proang-12 were higher than those of Ang I and Ang II. In addition, despite activation of the RAS in the systemic circulation, tissue concentrations of proang-12 were significantly reduced following treatment with losartan or imidapril. Similar reductions were also observed in the tissue concentrations of Ang II in both strains, without a reduction in Ang I. These results suggest that tissue concentrations of proang-12 and Ang II are regulated independently of the systemic RAS in WKY and SHR rats, which is consistent with the notion that proang-12 is a component of only the tissue RAS.
    Hypertension Research 02/2012; 35(2):234-8. · 2.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Activation of renin-angiotensin system has been linked to cardiovascular and autonomic dysfunctions in diabetes. Experiments were performed to investigate the effects of angiotensin-converting enzyme inhibitor (ACEI), enalapril, on cardiac and autonomic functions in diabetic rats. Diabetes was induced by streptozotocin (50 mg/kg), and rats were treated with enalapril (1 mg · kg(-1) · d(-1)). After 30 days, evaluations were performed in control, diabetic, and enalapril-treated groups. Cardiac function was evaluated by echocardiography and through cannulation of the left ventricle (at baseline and in response to volume overload). Heart rate and systolic blood pressure variabilities were evaluated in the time and frequency domains. Streptozotocin rats had left ventricular systolic and diastolic dysfunctions, expressed by reduced ejection fraction and increased isovolumic relaxation time. The ACEI prevented these changes, improved diastolic cardiac responses to volume overload and total power of heart rate variability, reduced the ACE1 activity and protein expression and cardiac angiotensin (Ang) II levels, and increased angiotensin-converting enzyme 2 activity, despite unchanged blood pressure. Correlations were obtained between Ang II content with systolic and diastolic functions and heart rate variability. These findings provide evidence that the low-dose ACEI prevents autonomic and cardiac dysfunctions induced by diabetes without changing blood pressure and associated with reduced cardiac Ang II and increased angiotensin-converting enzyme 2 activity.
    Journal of cardiovascular pharmacology 09/2011; 59(1):58-65. · 2.83 Impact Factor

Full-text

View
20 Downloads
Available from
May 29, 2014