β2-Agonist Spillover onto Cardiac β1 Receptors
Yes, the phenomenon of β2-agonist drugs activating cardiac β1 receptors is clinically recognized and commonly referred to as "β2-agonist spillover," "cross-reactivity," or "loss of β2-selectivity." This occurs when β2-selective agonists—particularly at higher doses or therapeutic concentrations—lose their receptor selectivity and begin stimulating β1-adrenergic receptors in the heart.
Mechanism and Clinical Significance
β2-selective agonists are never absolutely selective—they exhibit dose-dependent loss of selectivity, meaning that as doses increase (especially with long-acting β2-agonists or during acute exacerbations requiring frequent dosing), these drugs increasingly activate cardiac β1 receptors. 1
Cardiac β1 receptors, located primarily in the myocardium, increase heart rate, myocardial contractility, and AV node conduction velocity when stimulated, which explains the cardiovascular adverse effects (tachycardia, palpitations, arrhythmias) seen with β2-agonist therapy. 1, 2
This spillover effect is clinically important because it can trigger atrial fibrillation—long-acting β2-agonists are associated with AF rates of 1-2.7% (OR 2.54,95% CI 1.59-4.05), while even short-acting agents like salbutamol and ipratropium can cause AF in <1% of patients. 3
Molecular Basis of Spillover
β1-adrenergic stimulation activates the β1-receptor/cAMP/PKA pathway, which phosphorylates ion channels responsible for L-type calcium current (ICa,L) and increases intracellular calcium cycling through effects on RYR2 and phospholamban. 3, 2
This increased intracellular calcium load can trigger delayed afterdepolarizations (DADs) and early afterdepolarizations (EADs), mechanisms that promote both atrial and ventricular arrhythmias—explaining why β2-agonist "spillover" onto β1 receptors shortens atrial action potential duration and increases atrial vulnerability. 3, 2
Clinical Context and Risk Factors
The arrhythmogenic risk is amplified in patients undergoing cardiac surgery or with underlying heart disease—dobutamine (which has β1 selectivity but also β2 activity) causes AF in 0-18% of patients, while dopamine at "renal doses" increases postoperative AF risk (OR 3.35,95% CI 1.38-8.12). 3
β2-agonist spillover is particularly problematic in patients with pre-existing cardiovascular disease, where the combination of increased heart rate, contractility, and myocardial oxygen demand can precipitate ischemia or worsen heart failure. 1, 2
Important Clinical Caveats
The term "spillover" is informal but widely understood—formal pharmacology literature may describe this as "loss of receptor selectivity," "non-selective β-adrenergic stimulation at therapeutic doses," or "β1-receptor cross-activation." 1
Even "selective" β2-agonists like albuterol can cause significant cardiovascular effects through this mechanism, especially when administered via nebulizer (higher systemic absorption) or in patients receiving multiple doses during acute bronchospasm. 1
Chronic β-adrenergic receptor stimulation leads to receptor downregulation and desensitization, which may paradoxically worsen outcomes in heart failure patients exposed to repeated β2-agonist therapy. 2