Beta-Adrenoceptor Agonists (β-agonists)
Beta-adrenoceptor agonists (β-agonists) bind to β-receptors on cardiac and smooth muscle tissues. They also have important actions in other tissues, especially bronchial smooth muscle (relaxation), the liver (stimulate glycogenolysis) and kidneys (stimulate renin release). Beta-adrenoceptors normally bind to norepinephrine released by sympathetic adrenergic nerves, and to circulating epinephrine. Therefore, β-agonists mimic the actions of sympathetic adrenergic stimulation acting through β-adrenoceptors. Overall, the effect of β-agonists is cardiac stimulation (increased heart rate, contractility, conduction velocity, relaxation) and systemic vasodilation. Arterial pressure may increase, but not necessarily because the fall in systemic vascular resistance offsets the increase in cardiac output. Therefore, the effect on arterial pressure depends on the relative influence on cardiac versus vascular β-adrenoceptors. Long-term exposure to β-agonists can cause β-receptor down-regulation, which limits their therapeutic efficacy to short-term application. Beta-agonists, because they are catecholamines, have a low bioavailability and therefore must be given by intravenous infusion.
- Increase contractility
- Increase relaxation rate
- Increase heart rate
- Increase conduction velocity
- Smooth muscle relaxation
- Hepatic glycogenolysis
- Pancreatic release of glucagon
- Renin release by kidneys
The heart has both β1 and β2 adrenoceptors, although the predominant receptor type in number and function is β1. These receptors primarily bind norepinephrine that is released from sympathetic adrenergic nerves. Additionally, they bind norepinephrine and epinephrine that circulate in the blood.
Beta-adrenoceptors are coupled to Gs-proteins, which activate adenylyl cyclase to form cAMP from ATP. Increased cAMP activates a cAMP-dependent protein kinase (PK-A) that phosphorylates L-type calcium channels, which causes increased calcium entry into the cells. Increased calcium entry during action potentials leads to enhanced release of calcium by the sarcoplasmic reticulum in the heart; these actions increase inotropy (contractility). Gs-protein activation also increases heart rate by opening ion channels responsible for pacemaker currents in the sinoatrial node. PK-A phosphorylates sites on the sarcoplasmic reticulum, which enhances the release of calcium through the ryanodine receptors (ryanodine-sensitive, calcium-release channels) associated with the sarcoplasmic reticulum. This provides more calcium for binding the troponin-C, which enhances inotropy. Finally, PK-A can phosphorylate myosin light chains, which may also contribute to the positive inotropic effect of beta-adrenoceptor stimulation. In summary, the cardiac effects of a β-agonist are increased heart rate, contractility, conduction velocity, and relaxation rate.
Vascular smooth muscle has β2-adrenoceptors that have a high binding affinity for circulating epinephrine and a relatively lower affinity to norepinephrine released by sympathetic adrenergic nerves.
These receptors, like those in the heart, are coupled to a Gs-protein, which stimulates the formation of cAMP. Although increased cAMP enhances cardiac myocyte contraction (see above), in vascular smooth muscle an increase in cAMP leads to smooth muscle relaxation. The reason for this is that cAMP inhibits myosin light chain kinase that is responsible for phosphorylating smooth muscle myosin. Therefore, increases in intracellular cAMP caused by β2-agonists inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation).
Activation of β2-adrenoceptors in the lungs causes bronchodilation. β2-adrenoceptor activation leads to hepatic glycogenolysis and pancreatic release of glucagon, which increases plasma glucose concentrations. β1-adrenoceptor stimulation in the kidneys causes the release of renin, which stimulates the production of angiotensin II and the subsequent release of aldosterone by the adrenal cortex.
Specific Drugs and Therapeutic Uses
There are several different β-agonists that are used clinically for the treatment of heart failure or circulatory shock, all of which are either natural catecholamines or analogs. Nearly all of these β-agonists, however, have some degree of α-agonist activity. These drugs along with their agonist properties are given in the table below. Note that for some of the drugs the receptor selectivity is highly dose-dependent. (Go to www.rxlist.com for specific drug information).
|Drug||Receptor Selectivity||Clinical Use||Comments|
|Epinephrine||β1 = β2 > α1* = α2*||Anaphylactic shock; cardiogenic shock; cardiac arrest||Low doses produce cardiac stimulation and vasodilation, which turns to vasoconstriction at high doses. *At high plasma concentrations, α = β selectivity.|
|Norepinephrine|| β1 = α1 >
β2 = α2
|Severe hypotension; septic shock||Reflex bradycardia masks direct stimulatory effects on sinoatrial node.|
|Dopamine||β1 = β2 > α1*||Acute heart failure, cardiogenic shock and acute renal failure||Biosynthetic precursor of norepinephrine; stimulates norepinephrine release. *At low doses, it stimulates the heart and decreases systemic vascular resistance; at high doses, vasodilation becomes vasoconstriction as lower affinity α-receptors bind to the dopamine; also binds to D1 receptors in kidney, producing vasodilation.|
|Dobutamine||β1 > β2 > α1||Acute heart failure; cardiogenic shock; refractory heart failure||Net effect is cardiac stimulation with modest vasodilation.|
|Isoproterenol||β1 = β2||Bradycardia and atrioventricular block||Net effect is cardiac stimulation and vasodilation with little change in pressure.|
Side Effects and Contraindications
A major side effect of β-agonists is cardiac arrhythmia. Because these drugs increase myocardial oxygen demand, they can precipitate angina in patients with coronary artery disease. Headache and tremor are also common.