Selective kinin receptor agonists as cardioprotective agents in myocardial ischemia and diabetes
Louis Potier1, Ludovic Waeckel, Marie-Pascale Vincent
1INSERM U872, Research Center les Cordeliers, Paris, France.
Insights
Pharmacological activation of B2 receptors protects nondiabetic hearts from ischemia, while B1 receptor agonists protect diabetic hearts, offering new treatments for acute coronary syndromes.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Diabetology
Background:
- Cardiac ischemia is a major cause of mortality, particularly in diabetic patients, whose hearts show resistance to standard cardioprotective therapies.
- The kallikrein-kinin system plays a role in myocardial protection during ischemia, but the specific roles of B1 receptors (B1R) and B2 receptors (B2R) are debated.
- Novel pharmacological strategies are needed to protect the diabetic heart from ischemic injury.
Purpose of the Study:
- To investigate the therapeutic potential of pharmacological kinin receptor activation in non-diabetic (NDiab) and diabetic (Diab) mice subjected to cardiac ischemia-reperfusion.
- To assess the effects of selective B1R and B2R agonists on infarct size (IS) and key signaling pathways involved in myocardial protection.
Main Methods:
- Administered potent selective pharmacological agonists of B1R or B2R at the time of reperfusion in NDiab and Diab mouse models.
- Quantified infarct size (IS) and analyzed signaling pathways, including phosphoinositide 3 kinase/Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), and glycogen synthase kinase-3β (GSK-3β).
Main Results:
- In NDiab mice, a B2R agonist significantly reduced IS by 47% via the phosphoinositide 3 kinase/Akt/GSK-3β pathway.
- In Diab mice, B2R agonists and standard treatments failed to reduce IS, but a B1R agonist significantly reduced IS by 44% through phosphoinositide 3 kinase/Akt and ERK1/2/GSK-3β pathways.
- Differential receptor effects in Diab mice are attributed to B2R signaling inactivation and B1R induction.
Conclusions:
- Pharmacological B2R activation provides cardioprotection in non-diabetic acute cardiac ischemia.
- B1R agonist therapy effectively overcomes the resistance of the diabetic heart to cardioprotective treatments.
- Targeting B1R and B2R pathways offers potential therapeutic avenues for non-diabetic and diabetic patients with acute coronary syndromes, respectively.
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-3β (GSK-3β). 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 GSK-3β 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.
Related Concept Videos
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
01:26Heart Failure Drugs: Inotropic Agents
01:16Antianginal Drugs: Nitrates and β-Blockers
Organic nitrates, such as nitroglycerin, play a pivotal role. Once metabolized, they liberate nitric oxide, a molecular marvel. Nitric oxide triggers guanylyl cyclase and augments cGMP production. This biochemical cascade orchestrates the relaxation of vascular smooth muscles, ushering in vasodilation and enhancing coronary blood flow. Administered...
01:27Transducer Mechanism: Enzyme-Linked Receptors
Major types that are helpful drug targets include:
01:25Antihypertensive Drugs: Direct Renin Inhibitors
01:30Antihypertensive Drugs: Angiotensin-Converting Enzyme Inhibitors