Adenosine kinase inhibition enhances microvascular dilator function and improves left ventricle diastolic dysfunction

Area of Science:

• Cardiovascular Physiology
• Pharmacology
• Metabolic Disease Research

Background:

• Adenosine kinase (ADK) inhibition increases endogenous adenosine levels, which is known to provide cardiovascular protection.
• The role of ADK in regulating microvascular and left ventricle (LV) function under stress remains incompletely understood.

Purpose of the Study:

• To investigate the effects of ADK inhibition on microvascular dilator function and LV contractile performance during metabolic and hemodynamic stress.
• To determine if targeting ADK can ameliorate cardiac dysfunction in disease models.

Main Methods:

• Treatment of obese diabetic rats with a selective ADK inhibitor (ABT-702) to assess coronary arteriole function and LV parameters.
• Analysis of microvascular responses in mice with endothelial-specific ADK deletion (ADK^VEC KO) compared to wild-type (WT) mice.
• Evaluation of LV function in WT and ADK^VEC KO mice subjected to transverse aortic constriction (TAC) surgery.

Main Results:

• ADK inhibition with ABT-702 restored acetylcholine-, sodium nitroprusside-, and adenosine-induced dilations in coronary arterioles of obese diabetic rats.
• Treatment normalized end-diastolic pressure and improved LV relaxation (Tau) in these rats.
• ADK^VEC KO mice showed enhanced acetylcholine-induced dilation in gracilis muscle and mesenteric arterioles compared to WT mice.
• ADK^VEC KO mice exhibited preserved LV systolic and diastolic function following TAC surgery compared to WT mice.

Conclusions:

• ADK inhibition selectively improves microvascular vasodilator function.
• Enhanced microvascular function translates to improved LV perfusion and contractile performance under stress.
• Targeting ADK represents a potential therapeutic strategy for cardiovascular protection in metabolic and hemodynamic stress conditions.