Nonviral monocyte chemoattractant protein-1 gene transfer improves arteriogenesis after femoral artery occlusion.

Local infusion of recombinant monocyte chemoattractant protein-1 (MCP-1) has been shown to enhance collateral artery formation in rabbit and pig hindlimb models. Owing to clinical disadvantages of protein infusion, a nonviral, liposome-based MCP-1 gene transfer was developed. Collateralization in a porcine hindlimb model served to provide a proof-of-principle for the functional benefit of MCP-1 overexpression. Development of arterial conductance as a measure of functionally relevant collateralization was evaluated in occluded as well as untreated hindlimbs in each animal. At the time of occlusion, MCP-1 and control DNA/DC-30 lipoplexes were transferred to femoral arteries of Goettingen minipigs (two therapeutic MCP-1 groups: 2 and 4 microg and one control group), using the Infiltrator local drug-delivery device. At 2 weeks following occlusion, collateralization was determined as changes in peripheral haemodynamic conductance, peripheral over aortic blood pressure ratio and angiographically visible morphology of the peripheral vessel tree. Nonviral MCP-1 gene transfer significantly improved peripheral conductance (control 11.69+/-2.78%, 2 microg 23.81+/-2.81%, P<0.05 and 4 microg 23.36+/-3.1%, P<0.05; n=12 per group) as well as the ratio of peripheral over aortic blood pressure (control 0.64+/-0.03%, 2 microg 0.75+/-0.02%, P<0.05 and 4 mug 0.75+/-0.02%, P<0.05; n=12 per group) when compared to the untreated controls 2 weeks after occlusion. Thus, it could be demonstrated for the first time that in situ overexpression of MCP-1 following local nonviral gene transfer is a potential approach to improve peripheral collateralization.

Influence of sotalol on the time constant of isovolumic left ventricular relaxation in anesthetized dogs.

OBJECTIVE: To determine the effects of various doses of sotalol on myocardial relaxation in healthy dogs. ANIMALS: 12 healthy adult mixed-breed dogs anesthetized with thiopental and alpha-chloralose. PROCEDURES: Left ventricular pressure (LVP), aortic pressure, and aortic flow velocity were measured. The time constant of isovolumic relaxation (tau) was determined by means of linear regression of the natural logarithm of LVP and by means of direct measurement from the LVP-versus-time curve. Sotalol was administered IV at cumulative doses of 1, 2, 4, and 8 mg/kg to 6 dogs; the other 6 were used as controls. Mean systolic aortic pressure was used to assess afterload, and maximal rate of increase in LVP versus time (dP/dt) was used as an index of contractility. RESULTS: After administration of the first dose of sotalol, tau was increased significantly, and maximum dP/dt was decreased significantly, compared with baseline values. Administration of additional doses of sotalol did not result in any additional change in tau, but maximum dP/dt increased, and maximum dP/dt after administration of the final dose of sotalol was significantly higher than maximum dP/dt after administration of the first dose. There were no significant changes in mean systolic aortic pressure. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy dogs, sotalol did not have any negative effect on myocardial relaxation beyond those attributable to its beta-blocking properties, despite an increase in intracellular ionized calcium concentration, as suggested by an increase in maximum dP/dt after an initial decrease.