Coronary vascular hemodynamic and permeability changes during reperfusion after no-flow ischemia in isolated, diltiazem-treated rabbit hearts

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 (t_BSA), vascular volume (V₁), and vascular into extravascular space clearance (F₂₁) for [¹²⁵I]BSA. Perfusion pressure, left ventricular (LV) enddiastolic pressure, LV developed pressure, maximum +dP/dt, and V₁ remained constant during 5 h of continuous perfusion, while t_BSA and F₂₁ 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 V₁, extracellular space, t_BSA, or albumin permeation. During reperfusion after 30 min of ischemia, V₁ increased 40% and perfusion pressure increased 60%, while t_BSA and F₂₁ 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, V₁, 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.