Coronary Vascular Hemodynamic and Permeability Changes During Reperfusion After No-Flow Ischemia in Isolated, Diltiazem-Treated Rabbit Hearts

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Abstract
Summary: Effects of diltiazem on coronary vascular functional integrity were assessed in isolated rabbit hearts during reperfusion after 30 min of global, no-flow ischemia. External detection of radiolabeled albumin, [125I]bovine serum albumin ([125I]BSA), and compartmental-model analysis were used to estimate the mean transit time of [125I]BSA (BSA), vascular volume (1), and vascular into extravascular space clearance (21) for [125I]BSA. Perfusion pressure, left ventricular (LV) enddiastolic pressure, LV developed pressure, maximum +dP/dt, and 1 remained constant during 5 h of continuous perfusion, while BSA and 21 gradually increased (1.5 and 2.4 times baseline, respectively). Diltiazem, 4 μM, increased total water content (8.5%) and decreased perfusion pressure (11%), LV developed pressure (22%), and +dP/dt (24%) in nonischemic control experiments, but did not significantly affect estimates of 1, extracellular space, BSA, or albumin permeation. During reperfusion after 30 min of ischemia, 1 increased 40% and perfusion pressure increased 60%, while BSA and 21 increased three and eight times baseline, respectively. LV developed pressure and +dP/dt returned to control levels, even though the water content and extracellular space of ischemic hearts were increased significantly. Diltiazem, 4 μM, blocked ischemia–reperfusion-induced increases in water content, extracellular space, vascular resistance, 1, and vascular permeability to [125I]BSA, without reducing LV developed pressure or +dP/dt relative to nonischemic diltiazem controls. These results suggest that protection of ischemic myocardium by diltiazem is mediated, at least in part, by preservation of vascular functional integrity.