Abstract 14972: Chamber-specific Downregulation of β1 and Dopamine Receptors in Maladaptive Models of Right Ventricular Hypertrophy and Right Heart Failure
Introduction: The autonomic nervous system is activated in patients with right ventricular hypertrophy (RVH) related to pulmonary hypertension. We have preliminary evidence that dopamine is inferior to dobutamine as an inotrope in experimental RVH models; however the molecular basis for this is unknown. We hypothesized that the decreased inotropic response to both catecholamines, and particularly dopamine, is secondary to chamber-specific downregulation of ß1 and dopaminergic receptors.
Methods: RVH in Sprague-Dawley rats was induced over four weeks using an adaptive model (RVH induced by pulmonary artery banding, PAB) and two maladaptive models in which RV failure develops: 1) RVH induced by chronic hypoxia combined with SU5416 (a VEGF receptor inhibitor injection) (CH+SU); 2) RVH induced by monocrotaline. RNA extraction was performed for analysis with quantitative RT-PCR of D1-D5 and ß1 receptors in the RV and LV of control and RVH hearts. Western blotting and immunostaining for the receptors were also performed.
Results: RVH was confirmed by increased RV/(LV+septum) ratio in all RVH models. Rats with RVH induced by CH-SU and monocrotaline had lower cardiac outputs and walked shorter distances on a treadmill. mRNA expression of dopaminergic receptors was reduced in the RV (but not the LV) of the CH+SU and monocrotaline models but not the PAB model [Table 1]. ß1 receptor expression was reduced in all RVH models. These findings were supported by the results from immunostaining and western blotting.
Conclusions: ß1 and dopaminergic receptors are selectively downregulated in RVH models. The observation that this downregulation is RV-selective and preferentially occurs in maladaptive RVH models suggests it has pathophysiologic relevance and may contribute to the decreased sensitivity of the RV, particularly to dopamine.
- © 2011 by American Heart Association, Inc.