Chronic effects of early started angiotensin converting enzyme inhibition and angiotensin AT1-receptor subtype blockade in rats with myocardial infarction: role of bradykinin

Abstract

Objective: The long-term effects and mechanisms of early started angiotensin converting enzyme (ACE) inhibition post myocardial infarction (MI) are not well understood. Chronic effects of early ACE inhibition on hemodynamics, left ventricular diastolic wall stress and remodeling were, therefore, compared to that of angiotensin AT -receptor subtype blockade in rats with experimental myocardial 1 infarction. The contribution of bradykinin potentiation to both ACE inhibitor and angiotensin AT -receptor subtype blockade was 1 assessed by cotreatment of rats with a bradykinin B2-receptor antagonist. Methods: MI was produced by coronary artery ligation in adult male Wistar rats. The ACE inhibitor, quinapril (6 mg / kg per day), or the angiotensin AT -receptor subtype blocker, losartan (10 mg / kg 1 per day), administered by gavage, and the bradykinin B2-receptor antagonist, Hoe-140 (500 mg / kg per day s.c.), administered either alone or in combination with quinapril or losartan, were started 30 min after MI and continued for eight weeks. Results: Quinapril and losartan reduced left ventricular end-diastolic pressure and global left ventricular diastolic wall stress only in rats with large MI. Pressure volume curves showed a rightward shift in proportion to MI size that was not prevented by quinapril or losartan treatment. Only the ACE inhibitor reduced left ventricular weight and this effect was prevented by cotreatment with the bradykinin antagonist. Baseline and peak cardiac index and stroke volume index, as determined using an electromagnetic flowmeter before and after an acute intravenous volume load, were restored by quinapril, whereas losartan had no effects. Conclusion: Treatments starting 30 min after coronary artery ligation, with either quinapril or losartan, reduced preload only in rats with large MI. Despite this unloading of the heart, structural dilatation was not prevented by this early treatment. Only quinapril improved cardiac performance and reduced left ventricular weight and this effect was abolished by cotreatment with Hoe-140, suggesting an angiotensin II blockade-independent, but bradykinin potentiation-dependent, mechanism.

Effects of Bradykinin on Cardiovascular Remodeling in Renovascular Hypertensive Rats

“…Gohlke et al showed that the anti-hypertrophic effect of the ACE inhibitor, ramipril, was prevented by co-treatment with HOE140 in spontaneously hypertensive rats (10) and Hu et al showed that cardiac remodeling after myocardial infarction was prevented by the same drug treatment (11). In agreement with these results, our study showed that the administration of BK prevented cardiac remodeling in RHT rats.…”

“…In the present study, the inhibition of NOS by treatment with L-NAME completely blocked the cardioprotection of BK. Even if NO had accumulated or eNOS was activated in this experiment, previous studies have shown that the concentration of BK used in our experiment was sufficient to produce NO in rat models (11,28). The direct effect of HOE140 or L-NAME was notable because these drugs directly induce cardiac hypertrophy and stimulate humoral factors (29,30).…”

“…Various studies have noted the contribution of BK to the cardioprotective effect in a variety of cardiac disease models (5,11,12). To our knowledge, there have been very few reports that examine the direct effect of BK on cardiac disease Table 2.…”

“…Several studies have indicated that the addition of BK B2 receptor antagonist, D-arginyl-[Hyp ]-bradykinin (HOE140) or NO synthase (NOS) inhibition blocks the cardioprotective effect of ACE inhibitor in several cardiac disease models, including models of cardiac hypertrophy (10), myocardial infarction (11) and ischemic injury (12,13).…”

Regulation of the kinin receptors after induction of myocardial infarction: a mini-review

“…BK has been hypothesized to be a reciprocal regulator of collagen turnover by suppressing fibroblast/myofibroblast-induced growth in the heart (8,31,43,44). Studies with angiotensin-converting enzyme inhibitors and/or B2R antagonists extended the knowledge of the anti-proliferative B2R-regulated effect (45)(46)(47)(48).…”