Overexpression of endothelial ß3 -adrenergic receptor induces diastolic dysfunction in rats.

AIMS: Diastolic dysfunction is common in cardiovascular diseases, particularly in the case of heart failure with preserved ejection fraction. The challenge is to develop adequate animal models to envision human therapies in the future. It has been hypothesized that this diastolic dysfunction is linked to alterations in the nitric oxide (• NO) pathway. To investigate this issue further, we investigated the cardiac functions of a transgenic rat model (Tgß3 ) that overexpresses the human ß3 -adrenoceptor (hß3 -AR) in the endothelium with the underlying rationale that the • NO pathway should be stimulated in the endothelium. METHODS AND RESULTS: Transgenic rats (Tgß3 ) that express hß3 -AR under the control of intercellular adhesion molecule 2 promoter were developed for a specific expression in endothelial cells. Transcriptomic analyses were performed on left ventricular tissue from 45-week-old rats. Among all altered genes, we focus on • NO synthase expression and endothelial function with arterial reactivity and evaluation of • NO and O2 •- production. Cardiac function was characterized by echocardiography, invasive haemodynamic studies, and working heart studies. Transcriptome analyses illustrate that several key genes are regulated by the hß3 -AR overexpression. Overexpression of hß3 -AR leads to a reduction of Nos3 mRNA expression (-72%; P < 0.05) associated with a decrease in protein expression (-19%; P < 0.05). Concentration-dependent vasodilation to isoproterenol was significantly reduced in Tgß3 aorta (-10%; P < 0.05), while • NO and O2 •- production was increased. In the same time, Tgß3 rats display progressively increasing diastolic dysfunction with age, as shown by an increase in the E/A filing ratio [1.15 ± 0.01 (wild type, WT) vs. 1.33 ± 0.04 (Tgß3 ); P < 0.05] and in left ventricular end-diastolic pressure [5.57 ± 1.23 mmHg (WT) vs. 11.68 ± 1.11 mmHg (Tgß3 ); P < 0.05]. In isolated working hearts, diastolic stress using increasing preload levels led to a 20% decrease in aortic flow [55.4 ± 1.9 mL/min (WT) vs. 45.8 ± 2.5 mL/min (Tgß3 ); P < 0.05]. CONCLUSIONS: The Tgß3 rat model displays the expected increase in • NO production upon ageing and develops diastolic dysfunction. These findings provide a further link between endothelial and cardiac dysfunction. This rat model should be valuable for future preclinical evaluation of candidate drugs aimed at correcting diastolic dysfunction.

Nebivolol, a vasodilating selective beta(1)-blocker, is a beta(3)-adrenoceptor agonist in the nonfailing transplanted human heart.

OBJECTIVES: The present study was to assess whether nebivolol could activate beta(3)-adrenergic receptors (ARs) in the human heart. BACKGROUND: Nebivolol is a third-generation beta-blocker used in the treatment of heart failure. It associates selective beta(1)-adrenergic antagonist properties with endothelial and nitric oxide (NO)-dependent vasodilation. Several studies reported that this vasodilation could result from an activation of beta(3)-ARs, but no data are available in the heart. METHODS: The effect of nebivolol (0.1 nmol/l to 10 micromol/l) upon the developed peak tension was tested in endomyocardial biopsies from human nonrejecting transplanted hearts. Tension was recorded at steady state using a mechanoelectric force transducer. RESULTS: Nebivolol induced a concentration-dependent decrease in peak tension (maximum effect obtained at 10 micromol/l: -55 +/- 4%, n = 6), which was similar to that obtained with a preferential beta(3)-AR agonist, BRL 37344 (maximum effect obtained at 1 micromol/l: -45 +/- 2%, n = 12). The nebivolol effect was not modified by 10 micromol/l nadolol, a beta(1,2)-AR antagonist, but was significantly reduced in the presence of 1 micromol/l L-748,337, a selective beta(3)-AR antagonist, and after pre-treatment with 100 micromol/l N(G)-monomethyl-L-arginine, an NOS inhibitor. CONCLUSIONS: Our study demonstrated that nebivolol activated beta(3)-AR in the human ventricle. The NO-dependent negative inotropic effect of nebivolol associated with its vasodilating properties previously described in human microcoronary arteries could improve the energetic balance in heart. Those effects could explain the improvement of hemodynamic parameters obtained in patients with heart failure after nebivolol administration as previously described in clinical trials.