Development of Cardiovascular Dysfunction in a Rat Spinal Cord Crush Model and Responses to Serotonergic Interventions.

Abstract

Selection of a proper spinal cord injury (SCI) rat model to study therapeutic effects of cell transplantation is imperative for research in cardiovascular functional recovery, due to the local harsh milieu inhibiting cell growth. We recently found that a crushed spinal cord lesion can minimize fibrotic scarring and grafted cell death compared with open-dura injuries. To determine if this SCI model is applicable for studying cardiovascular recovery, we examined hemodynamic consequences following crushed SCI and tested cardiovascular responses to serotonin (5-HT) or dopamine (DA) receptor agonists. Using a radio-telemetric system, multiple cardiovascular parameters were recorded prior to, 2, and 4 weeks after SCI, including resting mean arterial pressure (MAP) and heart rate (HR), as well as spontaneous or colorectal distension (CRD)-induced autonomic dysreflexia (AD). The results showed that this injury caused tachycardia at rest as well as the occurrence of spontaneous or artificially induced dysreflexic events. Four weeks post-injury, specific activation of 5-HT2A receptors by subcutaneous (s.c.) or intrathecal (i.t.) delivery of Dimethoxy-4-iodoamphetamine (DOI) remarkably increased resting MAP levels in a dose-dependent fashion. During CRD-induced autonomic dysreflexia, systemic administration of DOI alleviated the severity of bradycardia responsive to episodic hypertension. In contrast, selective stimulation of 5-HT1A receptors with 8-OH-DPAT or non-selective activation of DA receptors with apomorphine did not affect cardiovascular performance. Thus, crush injuries induce cardiovascular abnormalities in rats that are sensitive to 5-HT2A receptor stimulation, indicating a reliable SCI model to study how cell-based approaches impact the severity of autonomic dysreflexia and identify a possible target for pharmacological interventions.