Objective Thymoquinone, a major component of black seed oil, has beneficial (vasodilator, antioxidative and anti-inflammatory) effects in the cardiovascular system. Previous experiments in isolated arteries indicate that thymoquinone causes augmentations… Click to show full abstract
Objective Thymoquinone, a major component of black seed oil, has beneficial (vasodilator, antioxidative and anti-inflammatory) effects in the cardiovascular system. Previous experiments in isolated arteries indicate that thymoquinone causes augmentations of contraction. The present study aims to identify the mechanisms underlying the counterintuitive augmentations caused by thymoquinone. Methods Isometric tension was measured in rings of porcine coronary arteries, and rat aortae and mesenteric arteries. Precontracted preparations were exposed to increasing concentrations of thymoquinone, in the absence/presence of endothelium and of pharmacological inhibitors/activators. Cyclic nucleotide levels in rings were measured with ultra-high performance liquid chromatography coupled with mass spectrometry (UPLC–MS/MS). Results Thymoquinone-induced augmentations in the three arteries were not observed in rings without endothelium, and were abolished by inhibitors of nitric oxide (NO) synthase and soluble guanylyl cyclase (sGC), L-NAME and ODQ respectively. Rho-kinase inhibitor and L-type voltage-dependent calcium channel (VDCC) blockers inhibited the augmentations in porcine, but not in rat arteries, while T-type VDCC blockers did so only in the latter. In L-NAME-treated rings, the NO donor detaNONOate and sGC activator YC-1 restored the augmentations; by contrast, in ODQ-treated rings, cell-permeable cyclic GMP did not. UPLC–MS/MS measurements showed that thymoquinone increased intracellular levels of cyclic IMP. Conclusion Thymoquinone causes endothelium-dependent augmentations that depend on a biased sGC activation by NO to produce cyclic IMP instead of cyclic GMP. Cyclic IMP causes contraction of the vascular smooth muscle through alteration of calcium handling. Hence, thymoquinone is the first pharmacological agent reported to cause endothelium-dependent contractions with similar characteristics as hypoxic vasoconstrictions.
               
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