Coronary β2-adrenoreceptors mediate endothelium-dependent vasoreactivity in humans: novel insights from an in vivo intravascular ultrasound study

• Published in: European heart journal 2012-02, Vol.33 (4), p.495-504
• Main Authors: Puri, Rishi, Liew, Gary Y.H., Nicholls, Stephen J., Nelson, Adam J., Leong, Darryl P., Carbone, Angelo, Copus, Barbara, Wong, Dennis T.L., Beltrame, John F., Worthley, Stephen G., Worthley, Matthew I.
• Format: Article
• Language: English
• Subjects: Adrenergic beta-2 Receptor Agonists - administration & dosage; Adrenergic beta-2 Receptor Agonists - adverse effects; Adrenergic beta-2 Receptor Agonists - pharmacology; Albuterol - administration & dosage; Albuterol - adverse effects; Albuterol - pharmacology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Coronary Circulation - drug effects; Coronary heart disease; Dose-Response Relationship, Drug; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Female; Heart; Humans; Male; Medical sciences; Microcirculation - drug effects; Microvascular Angina - etiology; Microvascular Angina - physiopathology; Middle Aged; Nitric Oxide - physiology; Observer Variation; omega-N-Methylarginine - pharmacology; Plaque, Atherosclerotic - physiopathology; Receptors, Adrenergic, beta-2 - drug effects; Receptors, Adrenergic, beta-2 - physiology; Ultrasonography, Interventional - adverse effects; Ultrasonography, Interventional - methods; Vasodilator Agents - administration & dosage; Vasodilator Agents - adverse effects; Vasodilator Agents - pharmacology
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehr359

Aims The interaction between coronary β2-adrenoreceptors and segmental plaque burden is complex and poorly understood in humans. We aimed to validate intracoronary (IC) salbutamol as a novel endothelium-dependent vasodilator utilizing intravascular ultrasound (IVUS), and thus assess relationships between coronary β2-adrenoreceptors, regional plaque burden and segmental endothelial function. Methods and results In 29 patients with near-normal coronary angiograms, IVUS-upon-Doppler Flowire imaging protocols were performed. Protocol 1: incremental IC salbutamol (0.15, 0.30, 0.60 μg/min) infusions (15 patients, 103 segments); protocol 2: salbutamol (0.30 μg/min) infusion before and after IC administration of N G-monomethyl-l-arginine (l-NMMA) (10 patients, 82 segments). Vehicle infusions (IC dextrose) were performed in 4 patients (21 segments). Macrovascular response [% change segmental lumen volume (▵SLV)] and plaque burden [per cent atheroma volume (PAV)] were studied in 5-mm coronary segments. Microvascular response [per cent change in coronary blood flow (▵CBF)] was calculated following each infusion. Intracoronary salbutamol demonstrated significant dose-response ▵SLV and ▵CBF from baseline, respectively (0.15 μg/min: 3.5 ± 1.3%, 28 ± 14%, P = 0.04, P = NS; 0.30 μg/min: 5.5 ± 1.4%, 54 ± 17%, P = 0.001, P < 0.0001; 0.60 μg/min: 4.8 ± 1.6%, 66 ± 15%, P = 0.02, P < 0.0001), with ▵SLV responses further exemplified in low vs. high plaque burden groups. Salbutamol vasomotor responses were suppressed by l-NMMA, supporting nitric oxide-dependent mechanisms. Vehicle infusions resulted in no significant ▵SLV or ▵CBF. Multivariate analysis including conventional cardiovascular risk factors, PAV, segmental remodelling and plaque eccentricity indices identified PAV as the only significant predictor of a ▵SLV to IC salbutamol (coefficient −0.18, 95% CI −0.32 to −0.044, P = 0.015). Conclusions Intracoronary salbutamol is a novel endothelium-dependent epicardial and microvascular coronary vasodilator. Intravascular ultrasound-derived regional plaque burden is a major determinant of segmental coronary endothelial function.