Cilostazol induces vasorelaxation through the activation of the eNOS/NO/cGMP pathway, prostanoids, AMPK, PKC, potassium channels, and calcium channels
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1Bursa Uludag University Medicine School, Physiology Department, 16059, Bursa, Turkey.
Objective:
This study aimed to investigate vasoactive effect mechanisms of cilostazol in rat thoracic aorta.
Materials And Methods:
The vessel rings prepared from the thoracic aortas of the male rats were placed in the chambers of the isolated tissue bath system. The resting tone was adjusted to 1 g. Following the equilibration phase, potassium chloride or phenylephrine was used to contract the vessel rings. When achieving a steady contraction, cilostazol was applied cumulatively (10-8-10-4 M). In the presence of potassium channel blockers or signaling pathway inhibitors, the same experimental procedure was performed.
Results:
Cilostazol exhibited a significant vasorelaxant effect in a concentration-dependent manner (pD2: 5.94 ± 0.94) (p < .001). The vasorelaxant effect level of cilostazol was significantly reduced by the endothelial nitric oxide synthase inhibitor L-NAME (10-4 M), soluble guanylate cyclase inhibitor methylene blue (10 µM), cyclooxygenase 1/2 inhibitor indomethacin (5 µM), adenosine monophosphate-activated protein kinase inhibitor compound C (10 µM), non-selective potassium channel blocker tetraethylammonium chloride (10 mM), large-conductance calcium-activated potassium channel blocker iberiotoxin (20 nM), voltage-gated potassium channel blocker 4-Aminopyridine (1 mM), and inward-rectifier potassium channel blocker BaCl2 (30 µM) (p < .001). Moreover, incubation of cilostazol (10-4 M) significantly reduced caffeine (10 mM), cyclopiazonic acid (10 µM), and phorbol 12-myristate 13-acetate-induced (100 µM) vascular contractions (p < .001).
Conclusions:
In the rat thoracic aorta, the vasodilator action level of cilostazol is quite noticeable. The vasorelaxant effects of cilostazol are mediated by the eNOS/NO/cGMP pathway, prostanoids, AMPK pathway, PKC, potassium channels, and calcium channels.
Insights
Cilostazol demonstrates significant vasodilation in rat aorta, primarily through the eNOS/NO/cGMP pathway. Its effects are also mediated by prostanoids, AMPK, potassium channels, and calcium channels, highlighting its complex vasodilatory mechanisms.
Area of Science:
- Pharmacology and Physiology
- Vascular Biology
- Drug Mechanisms
Background:
- Cilostazol is a medication used to treat symptoms of intermittent claudication.
- Understanding its precise vasodilatory mechanisms is crucial for optimizing its therapeutic applications.
- Previous studies suggest potential roles in various signaling pathways, but comprehensive investigation is needed.
Purpose of the Study:
- To elucidate the specific vasoactive effect mechanisms of cilostazol in rat thoracic aorta.
- To identify the key signaling pathways and ion channels involved in cilostazol-induced vasodilation.
Main Methods:
- Isolated rat thoracic aorta rings were used in a tissue bath system.
- Vessel rings were contracted using potassium chloride or phenylephrine.
- Cilostazol was applied cumulatively in the presence and absence of various channel blockers and pathway inhibitors.
Main Results:
- Cilostazol induced a significant, concentration-dependent vasorelaxant effect (pD2: 5.94 ± 0.94).
- This effect was notably reduced by inhibitors of endothelial nitric oxide synthase (L-NAME), soluble guanylate cyclase (methylene blue), cyclooxygenase (indomethacin), and AMPK (compound C).
- Blockade of various potassium channels (TEA, iberiotoxin, 4-AP, BaCl2) and modulation of calcium channels also significantly impacted cilostazol's vasorelaxant activity.
Conclusions:
- Cilostazol exhibits a pronounced vasodilator action in the rat thoracic aorta.
- The vasorelaxant effects are mediated through a complex interplay of the eNOS/NO/cGMP pathway, prostanoids, AMPK pathway, protein kinase C, potassium channels, and calcium channels.
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