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The alpha(1B)-adrenergic receptor decreases the inotropic response in the mouse Langendorff heart model
Sean A Ross1, Boyd R Rorabaugh, Dan Chalothorn
1The Department of Molecular Cardiology NB50, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Insights
Increased alpha(1B)-adrenergic receptors (ARs) in the heart did not alter basal function but blunted the inotropic response to phenylephrine. This suggests alpha(1B)-AR negatively modulates alpha(1A)-AR function in cardiac muscle.
Area of Science:
- Cardiovascular Physiology
- Adrenergic Receptor Signaling
- Cardiac Pharmacology
Background:
- Alpha(1)-adrenergic receptors (ARs) mediate positive inotropy in the heart, crucial in cardiovascular disease.
- The specific roles of alpha(1A), alpha(1B), and alpha(1D)-AR subtypes in cardiac function remain unclear due to a lack of selective ligands.
Purpose of the Study:
- To investigate the role of the alpha(1B)-adrenergic receptor (AR) subtype in cardiac function using a genetically modified mouse model.
- To determine if alpha(1B)-AR overexpression impacts basal cardiac parameters and the inotropic response to adrenergic stimulation.
Main Methods:
- Utilized the Langendorff heart model in mice overexpressing alpha(1B)-AR to assess cardiac contractility.
- Evaluated cardiac function under basal conditions and following phenylephrine administration.
- Confirmed findings in isolated adult cardiac myocytes.
Main Results:
- Overexpression of alpha(1B)-AR (50% increase) did not alter basal heart rate, contractility (+/-dP/dT), or coronary flow compared to wild-type controls.
- The positive inotropic response to phenylephrine was significantly blunted in hearts with increased alpha(1B)-AR.
- This blunted response was reversed by a selective alpha(1A)-AR antagonist, indicating a compensatory downregulation of alpha(1A)-AR density.
Conclusions:
- Alpha(1B)-adrenergic receptors (ARs) do not appear to play a major direct role in positive inotropic responses in the mouse myocardium.
- Overexpression of alpha(1B)-AR may negatively modulate the function and/or density of alpha(1A)-AR, impacting overall adrenergic response.
Objective:
alpha(1)-Adrenergic receptors (ARs) are known mediators of a positive inotropy in the heart, which may play even more important roles in heart disease. Due to a lack of sufficiently selective ligands, the contribution of each of the three alpha(1)-AR subtypes (alpha(1A), alpha(1B) and alpha(1D)) to cardiac function is not clearly defined. In this study, we used a systemically expressing mouse model that overexpresses the alpha(1B)-AR to define the role of this subtype in cardiac function.
Methods:
We used the mouse Langendorff heart model to assess changes in contractility under basal and phenylephrine-induced conditions.
Results:
We find that a 50% increase of the alpha(1B)-AR in the heart does not change basal cardiac parameters compared to age-matched normals (heart rate, +/-dP/dT and coronary flow). However, the inotropic response to phenylephrine is blunted. The same results were obtained in isolated adult myocytes. The difference in inotropy could be blocked by the selective alpha(1A)-AR antagonist, 5-methylurapidil, which correlated with decreases in alpha(1A)-AR density, suggesting that the alpha(1B)-AR had caused a compensatory downregulation of the alpha(1A)-AR.
Conclusions:
These results suggest that the alpha(1B)-AR does not have a major role in the positive inotropic response in the mouse myocardium but may negatively modulate the response of the alpha(1A)-AR.
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