Introduction

Beta-1 receptors, along with beta-2, alpha-1, and alpha-2 receptors, are adrenergic receptors primarily responsible for signaling in the sympathetic nervous system. Beta-agonists bind to the beta receptors on various tissues throughout the body. Beta-1 receptors are predominantly found in three locations: the heart, the kidney, and the fat cells.

The beta-1 adrenergic receptor is a G-protein-coupled receptor communicating through the Gs alpha subunit. By signaling Gs, a cAMP-dependent pathway is initiated through adenylyl cyclase, and this results in potentiation of the receptor’s function. 

Targeted activation of the beta-1 receptor in the heart increases sinoatrial (SA) nodal, atrioventricular (AV) nodal, and ventricular muscular firing, thus increasing heart rate and contractility. With these two increased values, the stroke volume and cardiac output will also increase. This effect clearly shows in the cardiac output equation. Cardiac output equals the product of stroke volume and heart rate. As either stroke volume or heart rate increase, both of which will increase with targeted activation of the beta-1 receptor, cardiac output will increase, thus increasing perfusion to tissues throughout the body.

In the kidney, smooth muscle cells in the juxtaglomerular apparatus contract and release renin. This cascading effect will eventually increase blood volume through the actions of angiotensin II and aldosterone. In the adipocyte[1], the beta-1 receptor is targeted to upregulate lipolysis. 

Various hormones may target the adrenoreceptors with different affinities. In this article, we will focus on the beta receptors, in particular, beta-1 adrenergic receptors. The chemicals epinephrine, dopamine, and isoproterenol[2] target beta-1 and beta-2 receptors almost equally. Norepinephrine and dobutamine target beta-1 to a greater degree than beta-2.

While hormones are the normal pathway by which these systems typically activate, they can also be activated or blocked medically through a multitude of pharmacologic therapies, some of which will be discussed below.

Function

The Gs subunit of the beta-1 adrenoreceptor upon activation upregulates adenylyl cyclase which converts ATP to cAMP. With the increased presence of cAMP, cAMP-dependent protein kinase A (PKA) phosphorylates calcium channels, thus increasing cellular calcium influx. Increased concentrations of intracellular calcium increase inotropy in the heart through calcium exchange in the sarcoplasmic reticulum. PKA also phosphorylates myosin light chains which lead to contractility in smooth muscle cells. 

Issues of Concern

The beta-1 receptor is an integral part of the normal function of the sympathetic nervous system. The sympathetic nervous system, more colloquially known as the ‘fight or flight’ system, is the body’s way of recruiting extraordinary function in a short amount of time. When a person experiences fear or extreme excitement, the body will quickly releases catecholamines (epinephrine and norepinephrine) that will target one of many receptors including the beta-1 receptor. By increasing heart rate and contractility, for example, the blood pumps faster throughout the body allowing a person to run faster, jump higher, and accomplish things not typically within their physiologic capacity for a short duration; it is a primary survival mechanism. 

Day-to-day maintenance of blood pressure is accomplished with the constant opposition of the sympathetic and parasympathetic systems. Baroreceptors[3], located in the carotid sinus near the bifurcation of the common carotid artery, are stretch receptors that will sense any deviation from the set point (about 100 mm Hg) with decreased stretch on the receptor. The baroreceptors innervated by the herring nerve decrease parasympathetic outflow to the heart through cranial nerve X, the vagus nerve. With decreased parasympathetic outflow, the sympathetic nervous system runs less opposed, increasing heart rate, contractility, and stroke volume through the function of the beta-1 receptor. Through a similar mechanism, decreased renal perfusion causes the release of renin from the juxtaglomerular apparatus. Through a cascading effect, aldosterone is released, and blood volume increases through sodium retention.

Although these are only two examples, the sympathetic nervous system, through the activation of adrenergic receptors, helps maintain a constant blood pressure.

Clinical Significance

Various substances including many medications can be used to manipulate the beta-1 receptor. They can be used to block or potentiate the effects to treat certain conditions. 

Beta-blockers, like propranolol (nonselective, beta-1 and beta-2 receptor antagonists) and atenolol and landiolol[4] (cardioselective and have very little affinity for the beta-2 receptor), are widely used for medical conditions including hypertension[5], arrhythmias, heart failure[6], chest pain, myocardial infarctions, migraines, and anxiety. By blocking the normal function of the receptor, there is a decrease in the binding of epinephrine and norepinephrine at the targeting the receptor. Blocking the receptor can be thought of as producing the opposite effect. Thus, the heart will generally beat more slowly and with less force. In turn, lowering blood pressure. 

Beta-agonists, like dopamine (a beta-1 selective agonist) and isoproterenol (a non-selective beta agonist), on the other hand, are used to mimic and potentiate the effects of sympathomimetic agents like epinephrine and norepinephrine. These agents increase heart rate and ventricular oxygen consumption thus increasing contractility and are commonly used in heart failure or cardiogenic shock. 

Illicit drug use is of particular note when talking about the beta-1 receptor. Cocaine increases the plasma concentrations of catecholamines including epinephrine and norepinephrine by inhibition of peripheral re-uptake and central sympathetic system stimulation. Increased levels of these catecholamines potentiate activation of the beta-1 receptor and thus lead to increased heart rate. In some patients, and in overdose, these increased levels can contribute to the onset of ventricular fibrillation (V-fib). With the rapid onset of cocaine effects, use of this drug can quickly become a medical emergency. Although increases in beta activation can precipitate an arrhythmia, beta-blocking agents are not recommended. Instead, treatment with alpha-blocking agents to prevent hypertension and malignant arrhythmias is the recommended therapeutic course. 

Other Issues

The beta 1 receptor is vital for the normal physiological function of the sympathetic nervous system. Through various cellular signaling mechanisms, hormones and medications activate the beta-1 receptor. Targeted activation of the beta-1 receptor increases heart rate, renin release, and lipolysis. From day-to-day maintenance of blood pressure to manipulation of the receptor by recreational substances like cocaine and pharmacologic therapy including agonists like isoproterenol and antagonists like propranolol, the beta-1 receptor is essential to everyday clinical medicine. 

Enhancing Healthcare Team Outcomes

The healthcare team, e.g., physicians, nurses, and pharmacists must know the basics of the autonomic nervous system in order to correctly chose the correct pharmacologic treatments for patients experiencing a cocaine overdose or anaphylactic shock for example.