L-type calcium channel blockers modulate the microvascular hyperpermeability induced by platelet-activating factor in vivo.
OBJECTIVE
Platelet-activating factor (PAF) is a potent phospholipid mediator of the microvascular dysfunction associated with ischemia-reperfusion injury. Because changes in cytosolic-free Ca2+ concentration are essential in PAF cellular signaling, we formulated the hypothesis that blockade of Ca2+ entry may inhibit the PAF-induced microvascular dysfunction.


METHODS
To investigate this hypothesis two L-type calcium channel blockers, verapamil and nifedipine, were applied to the hamster cheek pouch before the topical PAF challenge was undertaken. Permeability was assessed by measurement of the plasma clearance of fluorescein isothiocyanate dextran, 150,000 mol wt. The arteriolar diameter was measured simultaneously to evaluate the effects of L-type calcium channel blockers on PAF-induced vasoconstriction.


RESULTS
Baseline clearance was 498.7 +/- 225.0 nl/60 min/gm (mean +/- SE). PAF 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 reduced 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) also 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 affected PAF-induced vasoconstriction.


CONCLUSIONS
The significant inhibition of the increase in permeability by the L-type calcium channel blockers suggests that these compounds may be useful in the management of PAF-induced hyperpermeability.
Oshiro
H
H
Department of Physiology, UMDNJ-New Jersey Medical School, Newark 07103-2714, USA.
Kobayashi
I
I
Kim
D
D
Takenaka
H
H
Hobson
R W
RW
Durán
W N
WN
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D006224:Cricetinae; D003911:Dextrans; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D008297:Male; D008647:Mesocricetus; D009543:Nifedipine / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology* / Q000502:physiology; D013050:Spectrometry, Fluorescence; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D003911:Dextrans; D010972:Platelet Activating Factor; C015219:fluorescein isothiocyanate dextran; D014700:Verapamil; D016650:Fluorescein-5-isothiocyanate; D009543:Nifedipine