Society of Cardiovascular Anesthesiologists

Bradykinin and Myocardial Protection

Reviewer: Mark A. Chaney, M.D.

With the resurgence of minimally invasive cardiac revascularization, myocardial preconditioning (ischemic and pharmacologic) has received much attention. Recent investigations indicate that bradykinin pretreatment of the heart may be an important addition to standard methods of myocardial protection and that it plays an essential role in the preservation of myocardial structure and function. Bradykinin exerts physiologic effects via stimulation of two specific receptors. Bradykinin B1 receptors mediate inflammatory effects whereas bradykinin B2 receptors mediate most of the cardiovascular effects. Bradykinin exerts several anti-ischemic, antiproliferative, and antiatherosclerotic effects. It preserves myocardial stores of energy-rich phosphates and glycogen, increases coronary blood flow, improves ventricular performance, decreases reperfusion arrhythmias, and decreases infarct size. In the vasculature, bradykinin stimulates endogenous nitric oxide synthase, thus increasing levels of nitric oxide. The beneficial effects of ACE inhibitors (improved survival in patients with advanced heart failure and after myocardial infarction) may in fact be caused by decreased degradation of bradykinin (beneficial effects are maintained despite normal plasma and tissue angiotensin II levels). Selective blockade of bradykinin B2 receptors decreases coronary blood flow and contractility and increases left ventricular end-diastolic pressure in pacing-induced heart failure. Recent accumulating evidence shows that bradykinin improves myocardial tolerance to ischemia through molecular mechanisms likely associated with ischemic preconditioning (protein tyrosine kinase and protein kinase C activation). The cited investigation by Feng and Rosenkranz examined the myocardial protective effects of bradykinin. They found that pretreating the heart with bradykinin prior to warm cardioplegic ischemia significantly improved postischemic ventricular function, an effect that was prevented by giving a drug that inhibits protein tyrosine kinase. Specifically, in their rabbit model, pretreatment with bradykinin (via retrograde perfusion) significantly increased coronary blood flow, significantly increased left ventricular contractility, significantly increased left ventricular developed pressure, significantly increased left ventricular compliance, and significantly decreased left ventricular end-diastolic pressure during the reperfusion phase following 50 minutes of warm cardioplegic arrest when compared to control rabbits. All beneficial effects were prevented by pretreatment with a drug that inhibited protein tyrosine kinase, indicating that effects were likely mediated through this enzyme. Recent accumulating evidence also shows that bradykinin plays an essential role in the preservation of myocardial structure and function. The cited investigation by Emanueli and associates examined the effects of bradykinin on the functional and structural preservation of the heart. They found that deficiency of bradykinin B2 receptors leads to decompensated left ventricular hypertrophy and failure similar to hypertrophic hypertensive cardiomyopathy. Specifically, in their mouse model, genetically altered animals without bradykinin B2 receptors progressively developed (over one year) myocardial alterations associated with hypertrophic hypertensive cardiomyopathy such as increased systolic blood pressure, increased heart rate, increased left ventricular mass, increased left ventricular end-diastolic pressure, increased left ventricular chamber volume, and reparative fibrosis when compared to control mice. Such changes demonstrate the essential role of bradykinin in the preservation of myocardial structure and function.

Postreperfusion myocardial depression, whether associated with conventional cardiac surgery or minimally invasive cardiac surgery, remains an important clinical entity and influences postoperative morbidity and mortality. Bradykinin, by exerting a multitude of beneficial cardiovascular effects, may prove to be an important new pharmacologic adjunct to clinically improve myocardial protection in the clinical setting.

References:

Feng J, Rosenkranz ER. Bradykinin pretreatment improves ischemia tolerance of the rabbit heart by tyrosine kinase mediated pathways. Ann Thorac Surg 68:1567-72, 1999

Emanueli C, Maestri R, Corradi D, Marchione R, Minasi A, Tozzi MG, Salis MB, Straino S, Capogrossi MC, Olivetti G, Madeddu P. Dilated and failing cardiomyopathy in bradykinin B2 receptor knockout mice. Circulation 100:2359-65, 1999

Dell'Italia LJ, Oparil S. Bradykinin in the heart; friend or foe? (Editorial) Circulation 100: 2305-7, 1999

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