Selective Kinin Receptor Agonists as Cardioprotective Agents in Myocardial Ischemia and Diabetes

Abstract

Cardiac ischemia is a leading cause of death, especially in diabetic patients. The diabetic ischemic heart is resistant experimentally to established cardioprotective treatments. New pharmacological approaches to cardiac protection are warranted. The kallikrein-kinin system is involved in myocardial protection in ischemia. Respective roles of B1 (B1R) and B2 (B2R) receptors remain controversial. We tested whether pharmacological activation of kinin receptors may have therapeutic effect in cardiac ischemia-reperfusion in nondiabetic (NDiab) and diabetic (Diab) mice. We assessed effect on infarct size (IS) and signaling pathways involved in myocardial protection of potent selective pharmacological agonists of B1R or B2R given at reperfusion. In NDiab mice, a B2R agonist reduced IS significantly by 47%, similarly to ramiprilat or ischemic postconditioning, via activation of phosphoinositide 3 kinase/Akt pathway leading to inhibition of glycogen synthase kinase-3b (GSK-3b). B1R agonist had no effect on IS. In contrast, in Diab mice, the B2R agonist, ramiprilat, or ischemic postconditioning failed to reduce IS but a B1R agonist significantly reduced IS by 44% via activation of phosphoinositide 3 kinase/Akt and extracellular signal-regulated kinase 1/2, both leading to GSK3b inhibition. Differential effect of B2R or B1R agonists in NDiab and Diab mice can be linked to inactivation of B2R signaling and induction of B1R in heart of Diab mice. Thus, a pharmacological B2R agonist is cardioprotective in acute ischemia in nondiabetic animals. B1R agonist overcomes resistance of diabetic heart to cardioprotective treatments. Pharmacological activation of B1R and B2R may become a treatment for diabetic and nondiabetic patients, respectively, in acute coronary syndromes.

Kinin Receptor Agonism Restores Hindlimb Postischemic Neovascularization Capacity in Diabetic Mice

“…This is in contrast with cardiac ischemia where B1R, but not B2R, activation reduces ischemia-reperfusion damage in diabetic mice (Potier et al, 2013). These findings indicate that, although diabetes suppresses B2R signaling in the heart, it does not alter B2R function in proangiogenic cells.…”

“…As the B2R agonist dose dependently decreases blood pressure during acute administration in mice (Potier et al, 2013), we assessed the blood pressure effect of chronic B2R agonist treatment in dedicated groups of mice. In brief, four groups of 10-week-old male C57BL/6J mice, diabetic or not (n 5 10/group; Charles River Laboratories), were treated with 720 nmol/kg×day 21 or vehicle (saline) for 5 weeks via Alzet minipump.…”

“…Developing new pharmacological interventions for KKS activation has potential therapeutic interest. Kallikrein cannot be easily targeted for pharmacological activation, but recently, potent selective and long-acting B1R and B2R agonists have been synthesized and their therapeutic efficacy has been documented in experimental cardiac ischemia (Belanger et al, 2009;Cote et al, 2009;Potier et al, 2013).…”

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…This was associated with a failure of these anesthetic agents to activate Akt, ERK1/2, GSK-3b (Tai et al, 2012), and STAT3 (Drenger et al, 2011). An interesting study by Potier et al (2013) suggested that there may be differential effects in the response to cardioprotection using different bradykinin receptor agonists in the presence of diabetes. It was shown that ischemic postconditioning, the angiotensin-converting enzyme (ACE) inhibitor ramiprilat or a bradykinin B 2 receptor agonist, all reduced infarct size and activated Akt, ERK1/2, and GSK-3b in the nondiabetic heart but failed to do so in the diabetic heart (Potier et al, 2013).…”

“…An interesting study by Potier et al (2013) suggested that there may be differential effects in the response to cardioprotection using different bradykinin receptor agonists in the presence of diabetes. It was shown that ischemic postconditioning, the angiotensin-converting enzyme (ACE) inhibitor ramiprilat or a bradykinin B 2 receptor agonist, all reduced infarct size and activated Akt, ERK1/2, and GSK-3b in the nondiabetic heart but failed to do so in the diabetic heart (Potier et al, 2013). In contrast, the diabetic heart, but not the nondiabetic heart, was found to be amenable to pharmacologic postconditioning using a bradykinin B 1 receptor agonist (Potier et al, 2013).…”