L-TYPE CALCIUM-CHANNEL BLOCKERS MODULATE THE MICROVASCULAR HYPERPERMEABILITY INDUCED BY PLATELET-ACTIVATING-FACTOR IN-VIVO

Purpose: Platelet-activating factor (PAF) is a potent phospholipid med iator of the microvascular dysfunction associated with ischemia-reperf usion injury. Because changes in cytosolic-free Ca2+ concentration are essential in PAF cellular signaling, we formulated the hypothesis tha t blockade of Ca2+ entry may inhibit the PAP-induced microvascular dys function. Methods: To investigate this hypothesis two L-type calcium c hannel blockers, verapamil and nifedipine, were applied to the hamster cheek pouch before the topical PAP challenge was undertaken. Permeabi lity was assessed by measurement of the plasma clearance of fluorescei n isothiocyanate dextran, 150,000 mol wt. The arteriolar diameter was measured simultaneously to evaluate the effects of L-type calcium chan nel blockers on PAE-induced vasoconstriction. Results: Baseline cleara nce was 498.7 +/- 225.0 nl/60 min/gm (mean +/- SE). PAP at 10(-8) mol/ L (n = 5) increased clearance to 3753.8 +/- 572.8 nl/60 min/gm (p < 0. 01). Pretreatment with verapamil (2 mg/kg; n = 5) significantly reduce d the increase in permeability caused by 10(-8) mol/L PAF (1909.1 +/- 620.2 nl/60 min/gm; p < 0.05). Nifedipine (5 - 10(-6) mol/L; n = 5) al so significantly attenuated the impact of 10(-8) mol/L PAF (2037.2 +/- 427.5 nl/60 min/gm; p < 0.05). Neither verapamil nor nifedipine affec ted PAF-induced vasoconstriction. Conclusion: The significant inhibiti on of the increase in permeability by the L-type calcium channel block ers suggests that these compounds may be useful in the management of P AF-induced hyperpermeability.