Mepacrine attenuates pulmonary vasoreactivity in rabbits

Area of Science:

• Pharmacology
• Pulmonary Medicine
• Biochemistry

Background:

• Organic peroxides like tert-butyl hydroperoxide (t-bu-OOH) trigger pulmonary vasoconstriction.
• This vasoconstriction is linked to thromboxane production, potentially via phospholipase A2 activation.
• Inhalational anesthetics can amplify t-bu-OOH effects, possibly by altering membrane lipids.

Purpose of the Study:

• To investigate the role of phospholipase A2 in t-bu-OOH-induced pulmonary vasoconstriction.
• To examine the mechanism of thromboxane generation using the phospholipase A2 inhibitor, mepacrine.
• To explore mepacrine's effects on other vasoconstrictors and its reversibility.

Main Methods:

• Administered mepacrine, a phospholipase A2 inhibitor, to rabbit lungs.
• Measured pulmonary arterial vasoconstriction induced by t-bu-OOH, arachidonic acid, angiotensin II (ANG II), and KCl.
• Assessed thromboxane production and mepacrine's inhibitory effects.
• Evaluated the reversibility of mepacrine's actions.

Main Results:

• Mepacrine (10(-4) M) completely inhibited t-bu-OOH-induced vasoconstriction.
• Mepacrine inhibited arachidonic acid-induced vasoconstriction but not thromboxane production.
• Mepacrine also inhibited ANG II and KCl-induced vasoconstriction, which are independent of arachidonic acid metabolites.
• The inhibitory effect of mepacrine was reversible upon washout.

Conclusions:

• Mepacrine's complete inhibition of t-bu-OOH-induced vasoconstriction suggests a role beyond just phospholipase A2 inhibition.
• The findings indicate that mepacrine may directly prevent smooth muscle contraction.
• Mepacrine's effects are not solely mediated by inhibiting thromboxane production via arachidonic acid pathways.