Abstract 21483: In vivo and in vitro Cardiac Responses to Beta-adrenergic Stimulation in Volume-Overload Heart Failure
Volume overloaded hearts undergo progressive left ventricular (LV) failure and decreased β-adrenergic responsiveness; however little is known regarding the mechanisms involved. In the present study we evaluated contractile function and the response of adult rat LV myocytes (ARLVMs) to β-adrenergic agonists.
Objective: We hypothesize that defective cell to cell communication in vivo contributes to β-adrenergic unresponsiveness in VO hearts.
Methods and results: Aorto-caval fistula (ACF) or sham surgery was performed on 200g male rats. All studies were performed 21-weeks post surgery. Echocardiography analyses showed increased LV systolic and diastolic diameter (LVSD and LVDD, respectively), decreased fractional shortening (%FS) and increased Tei index in ACF compared to sham rats. In vivo treatment with a β-adrenergic agonist (dobutamine) caused typical inotropic and chronotropic responses in sham rats while ACF rats were unresponsive to adrenergic stimulation. ARLVM contractility was evaluated at 1–2Hz ± isoproterenol (ISO, β-adrenergic agonist; 10–100 nM). Video edge detection and fura-2 fluorescence microscopy were used to measure single cell contractility and [Ca2+]i, respectively. Interestingly, we observed that in vitro treatment of ACF ARLVMs with ISO exhibited a similar response to β-adrenergic stimulation as sham ARLVMs (comparable %PS). These changes in ACF myocytes were associated with increased tau and decreased SERCA-2 expression. Moreover, connexin-43, a major LV gap junction protein, was significantly downregulated while the tight junction protein, N-cadherin was unchanged in VO hearts.
Conclusion: These results demonstrate that in vivo unresponsiveness to β-adrenergic agonists in VO heart failure may involve impaired gap junction communication.
- Cardiac volume
- Ventricular function
- Myocardial contraction
- Beta-adrenergic receptor agonists
- Contractile proteins
- © 2010 by American Heart Association, Inc.