Objective: Obstructive sleep apnea chronically increases blood pressure through sympathetic nervous system activation. In animals, hypertension and sympathetic activity are restrained by cannabinoid receptor activation. Therefore, we hypothesized that increased blood pressure in patients with obstructive sleep apnea is associated with increased circulating endocannabinoid concentrations.
Methods: Arterial oxygen saturation and apnea/hypopnea episodes were recorded in 29 patients with normal glucose tolerance, 26 patients with type 2 diabetes mellitus, and 21 patients obese subjects without sleep apnea. We determined seated blood pressure, insulin, glucose, and high-sensitive C-reactive protein in the morning, and insulin sensitivity by euglycemic-hyperinsulinemic clamp the next day. Anandamide, the sum of 1-arachidonoylglycerol and 2-arachidonoylglycerol, and oleoylethanolamide were measured in plasma by liquid chromatography-tandem mass spectrometry.
Results: Endocannabinoid concentrations in sleep apnea patients were increased compared to obese individuals without disordered nocturnal breathing. Correction for variables of obesity and insulin resistance almost completely abrogated this difference in endocannabinoids. Anandamide strongly correlated with blood pressure in sleep apnea patients (r = 0.60 for SBP and r = 0.58 for DBP, P < 0.001). In multivariate regression analysis, anandamide was a stronger determinant of blood pressure than sleep apnea severity, obesity, insulin resistance, and inflammation.
Conclusion: Obstructive sleep apnea patients show positive correlations between blood pressure and venous anandamide concentrations independent of confounding factors. Our data suggest a previously not recognized role of the endocannabinoid system for blood pressure regulation in patients with high risk for hypertension and cardiovascular disease.
aInstitute of Clinical Pharmacology, Hannover Medical School, Hannover
bDepartment of Medicine, University of Leipzig, Leipzig
cClinic for Endocrinology, Diabetes and Nutrition, Experimental & Clinical Research Center, Charité University Medicine, Berlin
dInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany
eLaboratory of Physiologic Studies, NIAAA, Bethesda, Maryland, USA
Correspondence to Stefan Engeli, MD, Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Tel: +49 511 532 2796; fax: +49 511 532 2750; e-mail: firstname.lastname@example.org
Abbreviations AEA, anandamide; CB1, cannabinoid type 1 receptor; FAAH, fatty acid amide hydrolase; OEA, oleoyl ethanolamide; OSA, obstructive sleep apnea; RDI, respiratory distress index; SaO2, arterial oxygen saturation; T90, time with SaO2 less than 90%
Received 4 August, 2011
Revised 16 July, 2012
Accepted 8 August, 2012