[Effect of cyclosporin A on the reactivity of the pulmonary vascular network in dogs].
Aside to its immunosuppressive effects, cyclosporine A (CyA) is known as a vasoconstrictor agent. The vasoconstriction appears to be related to an endothelial release of thromboxane A2 (TxA2) and endothelium as well as a decrease endothelial production of nitric oxide. However, no data is available on the effects of CyA on pulmonary artery (PA) network. We designed experiments to study the CyA effects on canine pulmonary artery vasoregulation. Resistance vessels were studied in vivo using a lung (n = 6) steady rate delivery autoperfusion model. The CyA was infused in the left pulmonary artery at incremental doses of 5, 10, and 20 mg; CyA dosage, sampled in the left atrium, were respectively 515 +/- 67, 580 +/- 97, and 1024 +/- 84 nmol/L. No significant increase in tension were registered regardless of the dose infused. Conductance vessels were studied in vitro using third division PA segments (n = 6) suspended for isometric force measurement in organ chambers. PA segments were precontracted (phenylephrine 10(-6) M) and subsequently exposed to incremental dose of CyA and cremophor (CR), the CyA vehicle. CyA specifically induced a dose-dependent contraction. The maximal contraction observed were 159 g +/- 13% with CyA exposure and 106 +/- 3% with the CR (p < 0.05). This contraction was abolished by indomethacin (cyclooxygenase inhibitor), pinane thromboxane A2 (TxA2 antagonist), dexamethasone (phospholipase A2 inhibitor), neomycin (phospholipase C inhibitor), and endothelial mechanical denudation.


CONCLUSIONS
In the canine model, in vivo infusion of CyA does not affect pulmonary resistance arteries. However, in vitro, on pulmonary conductance arteries, CyA induces an endothelium-dependent vasoconstriction. This constriction appears to be related to a TxA2 release mediated by a phospholipase A2 phospholipase C pathway.
Mathieu
P
P
Département de Chirurgie, Institut de Cardiologie de Montréal, Québec, Canada.
Cartier
R
R
Carrier
M
M
Pelletier
L C
LC
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004285:Dogs; D014677:Pharmaceutical Vehicles / Q000494:pharmacology; D010741:Phospholipases A / Q000378:metabolism / Q000494:pharmacology; D054467:Phospholipases A2; D011092:Polyethylene Glycols / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects*; D013928:Thromboxane A2 / Q000378:metabolism / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D014677:Pharmaceutical Vehicles; D014662:Vasoconstrictor Agents; C022131:cremophor; D011092:Polyethylene Glycols; D013928:Thromboxane A2; D016572:Cyclosporine; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases