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Published on: December 10, 2020
Protective effects of cyclosporin-A in splanchnic artery occlusion shock
F Squadrito1, D Altavilla, G Squadrito
1Institute of Pharmacology, School of Medicine, University of Messina, Italy. squadrito@csnet.it
Abstract:
Cyclosporin A (CsA) is an immunosuppressant drug that inhibits nitric oxide (NO) synthase induction in vascular smooth muscle cells. Splanchnic artery occlusion (SAO) shock is a lethal type of shock characterized by a marked vascular dysfunction in which the L-arginine/nitric oxide pathway plays an important role. We investigated whether CsA exerts protective effects in SAO shock by interfering with the L-arginine/nitric oxide pathway. Male anaesthetized rats (n=156) were subjected to clamping of the splanchnic arteries for 45 min. This surgical procedure resulted in an irreversible state of shock (SAO shock). Sham operated animals were used as controls. SAO shocked rats had a decreased survival (86+/-6 min, while sham shocked rats survived more than 240 min), marked hypotension, increased serum levels of TNF-alpha, enhanced plasma nitrite/nitrate concentrations (75+/-7.1 microM; sham shocked rats=1.6+/-0.5 microM) and enhanced inducible NO synthase (iNOS) protein induction and activity in the aorta. Moreover aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (PE, 1 nM - 10 microM). CsA (0.25, 0.5 and 1 mg kg(-1), 5 min after reperfusion) increased survival rate (SAO+CsA=236+/-9 min following the highest dose), reverted the marked hypotension, reduced plasma nitrite/nitrate concentration (11+/-5.2 microM following the highest dose), restored to control values the hyporeactivity to PE, and blunted iNOS protein induction and activity in aortic rings. The present data indicate that in an experimental rat model CsA may have antishock properties related to inhibition of L-arginine/nitric oxide pathway.
Insights
Cyclosporin A (CsA) demonstrates protective effects against splanchnic artery occlusion (SAO) shock in rats by inhibiting the nitric oxide (NO) pathway. This immunosuppressant drug improved survival rates and vascular function in a preclinical model of shock.
Area of Science:
- Pharmacology
- Immunology
- Physiology
Background:
- Splanchnic artery occlusion (SAO) shock induces lethal vascular dysfunction.
- The L-arginine/nitric oxide (NO) pathway is implicated in SAO shock pathophysiology.
- Cyclosporin A (CsA) is known to inhibit nitric oxide synthase.
Purpose of the Study:
- To investigate the potential protective effects of CsA in a rat model of SAO shock.
- To determine if CsA interferes with the L-arginine/NO pathway during SAO shock.
Main Methods:
- Rats were subjected to SAO or sham operation.
- CsA was administered post-reperfusion at varying doses.
- Survival, blood pressure, plasma nitrite/nitrate, aortic iNOS expression, and vascular reactivity were assessed.
Main Results:
- SAO shock significantly decreased survival and caused hypotension, increased TNF-alpha, elevated plasma nitrite/nitrate, and enhanced aortic iNOS.
- CsA treatment dose-dependently increased survival, reversed hypotension, reduced plasma nitrite/nitrate, and blunted iNOS induction and activity.
- Aortic rings from SAO rats showed hyporeactivity to phenylephrine, which was restored by CsA.
Conclusions:
- CsA exhibits antishock properties in experimental SAO shock.
- These protective effects are associated with the inhibition of the L-arginine/NO pathway.
- CsA may represent a therapeutic strategy for managing shock involving vascular dysfunction.
