Cilostazol improves endothelial dysfunction by increasing endothelium-derived hyperpolarizing factor response in mesenteric arteries from Type 2 diabetic rats

Matsumoto, Takayuki; Noguchi, Eri; Ishida, Keiko; Nakayama, Naoaki; Kobayashi, Tsuneo; Kamata, Katsuo

doi:10.1016/j.ejphar.2008.10.006

Cited by 22 publications

(14 citation statements)

References 47 publications

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“…Vascular dysfunction as a major complication of DM and is being widely studies in hope to find a therapeutic approach . Many of the published studies have focused on ROS production, abnormal endothelial function, decreased vasorelaxation, and impairment of vascular smooth muscle . Interestingly, despite vascular K + channels being a major determinant of vascular contractility, only a few studies have focused on their expression and functional changes in the vasculature in diabetes.…”

Section: Discussionmentioning

confidence: 99%

Alterations of voltage‐dependent K⁺ channels in the mesenteric artery during the early and chronic phases of diabetes

Hong

Kim

et al. 2016

Clin Exp Pharma Physio

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This study investigated the alteration of voltage-dependent K(+) (Kv) channels in mesenteric arterial smooth muscle cells from control (Long-Evans Tokushima Otsuka [LETO]) and diabetic (Otsuka Long-Evans Tokushima Fatty [OLETF]) rats during the early and chronic phases of diabetes. We demonstrated alterations in the mesenteric Kv channels during the early and chronic phase of diabetes using the patch-clamp technique, the arterial tone measurement system, and RT-PCR in Long-Evans Tokushima (LETO; for control) and Otsuka Long-Evans Tokushima Fatty (OLETF; for diabetes) type 2 diabetic model rats. In the early phase of diabetes, the amplitude of mesenteric Kv currents induced by depolarizing pulses was greater in OLETF rats than in LETO rats. The contractile response of the mesenteric artery induced by the Kv inhibitor, 4-aminopyridine (4-AP), was also greater in OLETF rats. The expression of most Kv subtypes- including Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv1.6, Kv2.1, Kv3.2, Kv4.1, Kv4.3, Kv5.1, Kv6.2, Kv8.1, Kv9.3, and Kv10.1-were increased in mesenteric arterial smooth muscle from OLETF rats compared with LETO rats. However, in the chronic phase of diabetes, the Kv current amplitude did not differ between LETO and OLETF rats. In addition, the 4-AP-induced contractile response of the mesenteric artery and the expression of Kv subtypes did not differ between the two groups. The increased Kv current amplitude and Kv channel-related contractile response were attributable to the increase in Kv channel expression during the early phase of diabetes. The increased Kv current amplitude and Kv channel-related contractile response were reversed during the chronic phase of diabetes.

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Section: Discussionmentioning

confidence: 99%

Alterations of voltage‐dependent K⁺ channels in the mesenteric artery during the early and chronic phases of diabetes

Hong

Kim

et al. 2016

Clin Exp Pharma Physio

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“…Therefore, we used available pharmacological tools to identify the role of differential PDE3B mRNA expression in the regulation of EC barrier function. Cilostazol, a putative selective PDE3 inhibitor, at 10 Ϫ6 and 10 Ϫ5 M was selected based on previous studies on the effect of PDE3 on human and rat ECs or endothelium-dependent vascular function (26,39). We found that inhibition of PDE3 caused different P s responses in XY cells vs. XX cells.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic sex-specific differences in microvascular endothelial cell phosphodiesterases

Wang

Bingaman

Huxley

2010

American Journal of Physiology-Heart and Circulatory Physiology

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The importance of gonadal hormones in the regulation of vascular function has been documented. An alternate and essential contribution of the sex chromosomes to sex differences in vascular function is poorly understood. We reported previously sex differences in microvessel permeability (P(s)) responses to adenosine that were mediated by the cAMP signaling pathway (Wang J, PhD thesis, 2005; Wang J and Huxley V, Proceedings of the VIII World Congress of Microcirculation, 2007; Wang J and Huxley VH, Am J Physiol Heart Circ Physiol 291: H3094-H3105, 2006). The two cyclic nucleotides, cAMP and cGMP, central to the regulation of vascular barrier integrity, are hydrolyzed by phosphodiesterases (PDE). We hypothesized that microvascular endothelial cells (EC) would retain intrinsic and inheritable sexually dimorphic genes with respect to the PDEs modulating EC barrier function. Primary cultured microvascular EC from skeletal muscles isolated from male and female rats, respectively, were used. SRY (a sex-determining region Y gene) mRNA expression was observed exclusively in male, not female, cells. The predominant isoform among PDE1-5, present in both XY and XX EC, was PDE4. Expression mRNA levels of PDE1A (male > female) and PDE3B (male < female) were sex dependent; PDE2A, PDE4D, and PDE5A were sex independent. Barrier function, P(s), was determined from measures of albumin flux across confluent primary cultured microvessel XY and XX EC monolayers. Consistent with intact in situ microvessels, basal monolayer P(s) did not differ between XY (1.7 +/- 0.2 x 10(-6) cm/s; n = 8) and XX (1.8 +/- 0.1 x 10(-6) cm/s; n = 10) EC. Cilostazol, a PDE3 inhibitor, reduced (11%, P < 0.05) P(s) in XX, not XY, cells. These findings demonstrate the presence and maintenance of intrinsic sex-related differences in gene expression and cellular phenotype by microvascular EC in a gonadal-hormone-free environment. Furthermore, intrinsic cell-sex likely contributes significantly to sexual dimorphism in cardiovascular function.

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“…Recent experimental and clinical studies show that cilostazol ameliorates endothelial dysfunction [8], prevents increases in endothelial permeability [29], and induces vasodilatation independent of the presence of endothelium in cerebral penetrating arterioles [7]. Moreover, cilostazol may prevent the neurological deterioration associated with acute perforating artery stroke by decreasing endothelial permeability and dilating perforating arteries independent of endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…The actions of cilostazol include platelet aggregation inhibition [6], vasodilatation [7], and amelioration of endothelial cell dysfunction [8]. A recent prospective randomized controlled trial demonstrates the non-inferiority of cilostazol to aspirin for the treatment of acute ischemic stroke [9].…”

Section: Introductionmentioning

confidence: 99%

Effect of Cilostazol in the Treatment of Acute Ischemic Stroke in the Lenticulostriate Artery Territory

et al. 2012

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Background: Cilostazol, an inhibitor of phosphodiesterase 3, has various pleiotropic effects besides its antiplatelet activity. This study examined the efficacy of cilostazol for the treatment of acute perforating artery infarction. Methods: In this prospective, randomized, open-label, blinded-end point trial, 100 patients with cerebral infarction in the territory of the lenticulostriate arteries were enrolled within 48 h of onset. Patients were randomly treated with both cilostazol and ozagrel for 14 days (n = 50, cilostazol group) or ozagrel alone for 14 days (n = 50, control group). The primary end point was the proportion of favorable outcomes 30 days after randomization as defined by a modified Rankin Scale (mRS) score of 0–2. Secondary end points included the incidence of neurological deterioration (an increase of ≥2 on the National Institutes of Health Stroke Scale within 7 days). Results: Favorable outcomes (mRS scores 0–2) were similar in both groups (81.3 and 82.0% in the cilostazol and control groups, respectively). The incidence of neurological deterioration was lower in the cilostazol group than the control group (12.5 and 16.0%, respectively) with a 21.9% relative risk reduction, although the difference was not statistically significant. Conclusions: Cilostazol did not prevent the neurological deterioration of perforating artery infarction.

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Cilostazol improves endothelial dysfunction by increasing endothelium-derived hyperpolarizing factor response in mesenteric arteries from Type 2 diabetic rats

Cited by 22 publications

References 47 publications

Alterations of voltage‐dependent K⁺ channels in the mesenteric artery during the early and chronic phases of diabetes

Alterations of voltage‐dependent K⁺ channels in the mesenteric artery during the early and chronic phases of diabetes

Intrinsic sex-specific differences in microvascular endothelial cell phosphodiesterases

Effect of Cilostazol in the Treatment of Acute Ischemic Stroke in the Lenticulostriate Artery Territory

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Cilostazol improves endothelial dysfunction by increasing endothelium-derived hyperpolarizing factor response in mesenteric arteries from Type 2 diabetic rats

Cited by 22 publications

References 47 publications

Alterations of voltage‐dependent K+ channels in the mesenteric artery during the early and chronic phases of diabetes

Alterations of voltage‐dependent K+ channels in the mesenteric artery during the early and chronic phases of diabetes

Intrinsic sex-specific differences in microvascular endothelial cell phosphodiesterases

Effect of Cilostazol in the Treatment of Acute Ischemic Stroke in the Lenticulostriate Artery Territory

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Alterations of voltage‐dependent K⁺ channels in the mesenteric artery during the early and chronic phases of diabetes

Alterations of voltage‐dependent K⁺ channels in the mesenteric artery during the early and chronic phases of diabetes