Catheter-based retrograde coronary sinus infusion is a practical delivery technique for introducing biological molecules into the cardiac system.

OBJECTIVES: To demonstrate coronary sinus (CS) retrograde catheterization as a practicable technique for delivering biologics into the heart. BACKGROUND: There are many options to deliver biologics into the heart. However, there is no single optimal technique when considering safety, biologic retention, and reproducibility. Retrograde delivery has the potential to address many of these concerns. This study evaluated retrograde CS infusion of luciferase-expressing plasmid in a porcine model using the Advance® CS Coronary Sinus Infusion Catheter and bioluminescence imaging to track the expression of the infused biological markers. METHODS: Plasmid was delivered retrograde into the CS in one of three infusion volumes. Twenty-four hours post-infusion, hearts were excised and underwent bioluminescence imaging to characterize the expression of the infusates. Heart and lung biopsies were also assessed for luciferase expression using RT-qPCR. RESULTS: Retrograde infusion was safe and successful in all nine test subjects. Luciferase detection was inconsistent in the low volume group. Bioluminescence was confined predominantly along the posterolateral left ventricle for medium volume infusions and was more broadly dispersed along the anterior side of the heart for high volume infusions. Tissue mRNA analysis corroborated the bioluminescence results, with the highest concentration of luciferase expression localized in the left ventricle. CONCLUSIONS: Retrograde CS infusion is a promising technique for delivering biological molecules to the heart. Specifically, this study demonstrated that the low pressure coronary venous system accommodates a wide range of infusion volumes and that biological infusates can be maintained in situ following the resumption of coronary venous flow.

MK-801 administration during neonatal ethanol withdrawal attenuates interpositus cell loss and juvenile eyeblink conditioning deficits.

Binge-level doses of ethanol have been demonstrated to severely disrupt the cerebellum and cerebellum-dependent tasks when administered to rodent subjects during the early postnatal period. N-methyl-d-aspartic acid (NMDA) receptor-mediated excitotoxicity associated with ethanol withdrawal has been implicated as a significant component contributing to neurotoxic effects resulting from early ethanol exposure, and studies using MK-801 (dizocilpine) have reported protection from ethanol-induced damage. The present study examined whether the administration of MK-801 during ethanol withdrawal would ameliorate ethanol-associated cell death in the interpositus nucleus of the cerebellum and behavioral deficits in a cerebellar dependent task. Long Evans rat pups were treated with ethanol (5.25 g/kg) in a binge-like manner on postnatal day 6 using intragastric intubation. Subjects then received an injection of MK-801 (0.5mg/kg) or vehicle during withdrawal, 30h after ethanol exposure. Rats were then trained on an eyeblink classical conditioning task as juveniles (40 days of age), and cerebellar interpositus nucleus numbers were assessed after conditioning. Ethanol-exposed subjects exhibited reductions in neuronal populations and behavioral deficits during eyeblink conditioning. However, MK-801 administration significantly attenuated observed deficiencies, suggesting a protective effect resulting from MK-801 treatment during ethanol withdrawal. These results support the role of NMDA receptor-mediated excitotoxicity as a component mechanism by which ethanol produces teratogenicity. Additionally, our findings support previous reports that have shown correlations between dependent measures of eyeblink classical-conditioning behavior and unbiased cell counts in the interpositus nucleus.