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Acute effects of cyclosporin and cremophor EL on endothelial function and vascular smooth muscle in the isolated rat heart

  • Experimental Pharmacology
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Summary

We studied the effects of cyclosporin dissolved in the vehicle used as an intravenous preparation, namely, cremophor EL, and cremophor alone on the basal coronary flow plus endothelial function and vascular smooth muscle response by examining their influence on 5-hydroxytryptamine (5-HT) and nitroglycerine (GTN) induced changes in coronary flow in the isolated rat heart. A total of 72 rat hearts were perfused with a modified Langendorf preparation. There was a 12.8±3% reduction in the basal coronary flow after 60 minutes of perfusion with the drug-free buffer (p=ns). A dose of 50 ng/ml of cremophor or cyclosporin gave a similar reduction in the flow (cremophor 9.2±0.7%, cyclosporin 12.7±2%). However, at higher concentrations cremophor caused dose-dependent coronary vasodilation, while cyclosporin had the opposite effect. The maximum effect after 1000 ng/ml of cyclosporin was a 48.7±0.6% decrease, and after an equivalent dose of cremophor a 24.8±2.2% increase in the flow. The vasodilatory response to 5-HT and GTN remained unchanged after 60 minutes of perfusion with the drug-free buffer (5-HT, before 33.3±2.5%, after 37.7±4.2%; GTN, before 34.3±2.5%, after 33.7±1.5%). A period of 60 minutes of perfusion with 500 ng/ml and 1000 ng/ml of cremophor caused a significant reduction in the 5-HT response without an appreciable change in the effect of GTN (500 ng/ml—5-HT, before 29.9±0.9% after 10.7±3.7%; GTN, before 32.3±1.9% after 31.8±3.5%; 1000 ng/ml—5-HT, before 29.7±0.6%, after 12.3±2.7%; GTN, before 33.3±2.8%, after 32.7±1.4%; p<0.001). The same concentration of cyclosporin not only reduced the 5-HT response but also reduced the vasodilation induced by GTN (500 ng/ml—5-HT, before 35.3±3.7%, after 1.6±5%; GTN, before 30.8±1.5%, after 11.2±2.7%; 1000 ng/ml—5-HT, before 32.8±1.9%, after -32.3±1.1%; GTN, before 35.7±0.8%, after 10.0±1.3%). We conclude that cremophor EL causes endothelial dysfunction in the isolated rat heart, and this effect may be aggravated by cyclosporin dissolved in cremophor. Cyclosporin with cremophor also leads to injury to vascular smooth muscle. The direct effect of cremophor is to cause coronary vasodilation, while cyclosporin causes dose-dependent coronary vasoconstriction.

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Authors and Affiliations

  1. National Heart and Lung Institute, London

    Pankaj Mankad, Jaroslav Spatenka, Zdenek Slavik, Gregory O'Neil, Adrian Chester &  Magdi Yacoub

  2. Harefield Hospital, Middlesex, UK

    Pankaj Mankad, Jaroslav Spatenka, Zdenek Slavik, Gregory O'Neil, Adrian Chester &  Magdi Yacoub

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  1. Pankaj Mankad
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  2. Jaroslav Spatenka
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  3. Zdenek Slavik
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  4. Gregory O'Neil
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  5. Adrian Chester
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  6. Magdi Yacoub
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Mankad, P., Spatenka, J., Slavik, Z. et al. Acute effects of cyclosporin and cremophor EL on endothelial function and vascular smooth muscle in the isolated rat heart. Cardiovasc Drug Ther 6, 77–83 (1992). https://doi.org/10.1007/BF00050920

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