The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin-angiotensin system

• Published in: Diabetologia 2006-12, Vol.49 (12), p.3067-3074
• Main Authors: REUTER, H, ADAM, C, GRÖNKE, S, ZOBEL, C, FRANK, K. F, MÜLLER-EHMSEN, J, BRABENDER, J, SCHWINGER, R. H. G
• Format: Article
• Language: English
• Subjects: Aged; Angiotensin II - pharmacology; Antihypertensives; Biological and medical sciences; Biopsy; Blood pressure; Cardiovascular disease; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Glucose; Glycated Hemoglobin A - metabolism; Heart Atria - metabolism; Humans; Hypertension; Insulin; Kinases; Male; Medical sciences; Metabolism; Middle Aged; Muscle Contraction; Muscle Relaxation; Muscle, Skeletal - cytology; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Myocardium - metabolism; Protein expression; Proteins; Receptor, Angiotensin, Type 1 - genetics; Receptor, Angiotensin, Type 1 - metabolism; Reference Values; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Surgery
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-006-0444-8

The angiotensin II (type 1) (AT1) receptor mediates many biological effects of the renin-angiotensin system (RAS), leading to remodelling of cardiac tissue. The present study was designed to analyse changes in the function and expression of the AT1 receptor as principal effector of the RAS in myocardium from type 2 diabetic patients compared with non-diabetic myocardium as control. In addition, we determined the effect of treatment with ACE inhibitors or AT1 receptor blockers on expression levels of the receptor in diabetic patients. Gene expression of the AT1 receptor was analysed by quantitative RT-PCR and protein expression was determined by immunoblot analysis in human right atrial myocardium. We investigated functional coupling of the receptors by measuring contractility in isolated trabeculae stimulated with increasing concentrations of angiotensin II. Diabetic myocardium showed a significant increase in protein expression (170 +/- 16% of control) and median mRNA expression (186% of control) of the AT1 receptor. The additional receptors were functionally coupled, resulting in a stronger inotropic response upon stimulation with angiotensin II (89 +/- 5.5% vs 29 +/- 1.6% in controls), whereas receptor affinity was similar in both groups. However, myocardium from diabetic patients treated with ACE inhibitors or AT1 receptor blockers showed no increase in AT1 receptor expression. AT1 receptor expression in myocardium of type 2 diabetic patients is dynamic, depending on the level of glycaemic control and the activity of the RAS. These findings could at least in part explain the strong therapeutic benefit of RAS inhibition in diabetic patients.