Adenosine Receptors: The A₁-Receptor Target

The Science of the A₁-receptor

Scientists at CV Therapeutics believe that selectively stimulating or blocking specific A₁-receptor subtypes may have beneficial physiological effects. A three-pronged research effort is underway.

One of our programs aims to determine the complete agonistic, or stimulatory, effects of the A₁-receptor in the heart. The rhythmic beating of the heart is created by an electrical current produced by specialized pacemaker cells. The movement of the current from the atria to the ventricles is regulated by a grouping of specialized pacemaker cells called the atrioventricular node, where the A₁-receptor is located. Our scientists believe that fully stimulating the
A₁-receptor could help bring abnormally fast and uncoordinated beating of the atria (including conditions such as atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardias) back to more normal levels. In addition, this action might not have the undesirable side effects of existing therapies, including unwanted and/or excessive lowering of blood pressure.

More than 2 million people in the United States have some type of atrial arrhythmia. After the age of 60, the prevalence of atrial arrhythmias increases dramatically. If left uncontrolled, atrial arrhythmias can place patients at risk for thromboembolism, stroke, and death. View an image series on
A₁-receptors in the heart.

Another one of our programs investigates the potential use of selective
A₁-receptor partial agonists as antilipolytic agents. Full agonists for the
A₁-receptors may cause a physiologic response in the heart and possibly other organs. However, a partial agonist may demonstrate more focused specificity and lead to desired outcomes while potentially avoiding unwanted effects in other organ systems.

During periods of increased energy requirements, the body requires fuels in the form of glucose and free fatty acids to maintain high energy output. Triglycerides in fatty (adipose) tissue are broken down to free fatty acids by a process called lipolysis and released into the system. An excess of free fatty acids during periods of lower energy requirements is known to lead to insulin resistance associated with Type 2 diabetes as well as lipid profile irregularities. A₁-adenosine receptor agonists have been shown to inhibit lipolysis in adipose tissue, and researchers at CV Therapeutics believe that partial agonists of the A₁-receptor subtype may have potential therapeutic utility in the management of metabolic disorders.

A third area of research involves the blockade, or antagonism of the
A₁-receptor in the kidneys. Fluid overload is a common medical complication of heart failure, a condition in which the heart is so weak it is unable to effectively pump blood to the rest of the body. Stimulation of the A₁-receptor in the kidney may lead to worsening of fluid overload.

Some therapies for heart failure may tend to have an adverse effect on kidney function, as measured by changes in the glomerular filtration rate. Therefore, our scientists believe that blocking, or antagonizing, the A₁-receptor in the kidneys may help remove excess fluids from the body without affecting glomerular filtration rate, and may present a potential new approach to the treatment of heart failure.