Effect of Short-term Polyphenol Treatment on Endothelial Dysfunction and Thromboxane A&lt;sub&gt;2&lt;/sub&gt; Levels in Streptozotocin-Induced Diabetic Mice

Ando

et al. 2016

Self Cite

An accumulating body of evidence suggests that males and females differ in vascular function in arteries under pathophysiological states. In this study, we tested whether there was a sex difference associated with serotonin (5-hydroxytryptamine, 5-HT)-mediated contraction in the carotid arteries of long-term streptozotocin (STZ)-induced diabetic rats [viz. 23 or 24 weeks after STZ (65 mg/kg, intravenously (i.v.)) injection starting at 8 weeks old of rats]. In the control group, the 5-HT-and high-K -induced contractions were greater in females than in males. In both sexes, treatment with STZ led to a decrease of 5-HT-induced contraction in carotid arteries compared to controls. In STZ-induced diabetic rats, the carotid arterial 5-HTinduced contraction was greater in female rats than in diabetic male rats. The high-K -induced contraction was greater in diabetic female rats than in either age-matched female controls or diabetic male rats. Expression of the 5-HT 2A receptor, which is the main receptor for 5-HT-induced contraction in rat carotid arteries, was similar among the four groups. These results suggest that decreased 5-HT-induced carotid arterial contraction is seen in both sexes under long-term STZ-induced diabetic conditions. Further, this reduction seems to be weaker in females than in males. This alteration of 5-HT-induced contraction may be partly associated with increased voltage-dependent Ca 2 channel activity.Key words carotid artery; contraction; serotonin; sex difference; streptozotocin Although women generally develop cardiovascular diseases several years later than men, this benefit may be diminished in diabetic individuals. The results of numerous epidemiological studies investigating the relationship between sex and the development of cardiovascular disease in diabetics have been inconsistent.1,2) Alterations in the responsiveness of blood vessels to various hormones and/or neurotransmitters in patients of both sexes with diabetes mellitus are well established. [3][4][5][6] However, there is confounding evidence of vascular function between diabetics of both male and females.The neurotransmitter serotonin [5-hydroxytriptamine (5-HT)] is an important factor that is involved in the regulation of several vascular functions, including blood flow, blood pressure, and vascular tone, in pathophysiological states. 7-9)Several reports by our research team [10][11][12] and others 3,[13][14][15] have found that alterations in vasocontraction induced by 5-HT were observed in patients with cardiovascular diseases as well as in those with diabetes. An accumulating body of evidence suggests that 5-HT plays a role in the development of diabetic complications. For example, sarpogrelate, an antagonist of the 5-HT 2A receptor, has beneficial effects against diabetic nephropathy, neuropathy, and diabetes-associated vascular dysfunction, including arterial stiffness and arteriosclerosis, in diabetic patients and animal models. [16][17][18][19] This relevant evidence suggests that the manipulation of 5-HT function c...

Section: Measurement Of Blood Parameters and Blood Pressurementioning

confidence: 99%

Effect of Long-Term Diabetes on Serotonin-Mediated Contraction in Carotid Arteries from Streptozotocin-Induced Diabetic Male and Female Rats

Watanabe

Ando

et al. 2016

Self Cite

“…8) We then studied the effects of RV using aortic ring preparations from controls. We performed 2 sequential experiments to construct the concentration-response curves (1st experiment: control, 2nd experiment: RV pretreatment).…”

Section: Body Weight and Blood Glucosementioning

confidence: 99%

“…[5][6][7] We previously reported that RV increased nitric oxide (NO) production in diabetic mice. 8) However, the underlying mechanisms are complicated and remain unclear.…”

mentioning

confidence: 99%

Resveratrol Ameliorates Clonidine-Induced Endothelium-Dependent Relaxation Involving Akt and Endothelial Nitric Oxide Synthase Regulation in Type 2 Diabetic Mice

Taguchi

Hida

et al. 2015

Self Cite

Diabetic vascular complication is one of the manifestations of endothelial dysfunction. Resveratrol (RV)is considered to be beneficial in protecting endothelial function. However, the exact protective effect and mechanisms involved have not been fully clarified. In this study, we investigated the relationship between Akt/endothelial nitric oxide synthase (eNOS) activation and RV in diabetes-induced endothelial dysfunction. Aortas were dissected and placed in organ chambers, and nitric oxide (NO) production in response to acetylcholine (ACh) and RV was measured. ACh-induced endothelium-dependent relaxation was markedly increased in controls by RV pretreatment. Furthermore, RV caused NO-dependent relaxation via the Akt signaling pathway, which was weaker in the aortas of diabetic mice than age-matched controls. To further examine the underlying mechanisms, we measured the phosphorylation of Akt and eNOS by Western blotting. RV caused the phosphorylation of Akt and eNOS in aortas, which was decreased in diabetic mice. However, RV augmented the impaired clonidine-induced relaxation in diabetic mice. Interestingly, the phosphorylation of Akt and eNOS was increased under stimulation with RV and clonidine only in diabetic mice. Thus, either RV or clonidine causes Akt-dependent NO-mediated relaxation, which is weaker in diabetic mice than controls. However, additional exposure to RV and clonidine has an augmenting effect on the Akt/eNOS signaling pathway under diabetic conditions. RV-induced Akt/eNOS activity may be a common link involved in the clonidine-induced Akt/eNOS activity, so RV and clonidine may have a synergistic effect. Key words resveratrol (RV); endothelial dysfunction; nitric oxide (NO); AktType 2 diabetes (DM) is associated with several complications, especially vascular complications (e.g., coronary insufficiency, cerebrovascular and peripheral vascular disease), which are the main etiologies leading to morbidity and mortality.1) Patients with DM exhibit complex vascular changes, such as an accelerated atherosclerosis process and hypercoagulability.2) Atherosclerosis is a major factor that accelerates diabetic vascular complications, and vascular endothelial dysfunction is considered to be the earliest detectable abnormality in the process of atherosclerosis.3) Thus, improving vascular endothelial dysfunction plays an important role in diabetic treatment.Resveratrol (RV; 3,5,4′-trihydroxystilbene) is a naturally occurring polyphenolic phytoalexin found in many plants, and it has been shown to prolong the lifespan of lower organisms. 4)Foods and drinks rich in RV, such as Mediterranean diets and French wine, are associated with a reduced risk of cardiovascular mortality in humans, and evidence has confirmed that RV has antiapoptotic, anti-inflammatory, anti-aging, and anticancer effects as well as a cardiovascular protective effect. 5-7)We previously reported that RV increased nitric oxide (NO) production in diabetic mice. 8) However, the underlying mechanisms are complicated and remain unclear.Endotheli...

“…22,25,[32][33][34] Functional Studies Vascular isometric force was essentially recorded as described in our previous studies. 13,17,22,25,26,28,[32][33][34] Concentration-response curves to ATP (10 for 20 min prior to PE application. To investigate the effect of endothelium on relaxations, we analyzed concentrationresponse curves in the presence/absence of endothelium of superior mesenteric arteries from Wistar rat at 17 weeks of age.…”

Section: 18)mentioning

confidence: 99%

A Comparative Study of Vasorelaxant Effects of ATP, ADP, and Adenosine on the Superior Mesenteric Artery of SHR

Watanabe

Ando

et al. 2016

Self Cite

We investigated superior mesenteric arteries from spontaneously hypertensive rats (SHR) to determine the relaxation responses induced by ATP, ADP, and adenosine and the relationship between the relaxant effects of these compounds and nitric oxide (NO) or cyclooxygenase (COX)-derived prostanoids. In rat superior mesenteric artery, relaxation induced by ATP and ADP but not by adenosine was completely eliminated by endothelial denudation. In the superior mesenteric arteries isolated from SHR [vs. age-matched control Wistar Kyoto rats (WKY)], a) ATP-and ADP-induced relaxations were weaker, whereas adenosine-induced relaxation was similar in both groups, b) ATP-and ADP-induced relaxations were substantially and partly reduced by N G -nitro-L-arginine [a NO synthase (NOS) inhibitor], respectively, c) indomethacin, an inhibitor of COX, increased ATP-and ADP-induced relaxations, d) ADP-induced relaxation was weaker under combined inhibition by NOS and COX, and e) adenosine-induced relaxation was not altered by treatment with these inhibitors. These data indicate that levels of responsiveness to these nucleotides/adenosine vary in the superior mesenteric arteries from SHR and WKY and are differentially modulated by NO and COX-derived prostanoids.Key words adenosine; ADP; ATP; relaxation; spontaneously hypertensive rat Extracellular nucleotides and their metabolites including ATP, ADP, and adenosine play pivotal roles in (patho)-physiological processes, including immune responses, inflammation, cardiac fibrosis, atherosclerosis, hypertension, and diabetes.1-10) They also exert a variety of effects on the vasculature, such as platelet activation and alteration in smooth muscle contraction and relaxation, by activating plasmalemmal receptors (e.g., purinoceptors). 1,2,8,11,12) Purinoceptors are classified into two subtypes, namely P1 and P2, based on their pharmacological properties and molecular cloning characteristics.11,12) Adenosine and its phosphates ATP and ADP are endogenous ligands for P1 and P2 receptors, respectively. Several studies have suggested that the expression and signaling responses of these receptors is altered under disease conditions. 4,11,[13][14][15][16][17] Moreover, these receptors can mediate a variety of responses to several nucleotides, resulting in the existence of multiple receptors with overlapping ligand preferences. 11,18)Therefore, it is difficult to understand the effect of nucleotides on vascular function under pathophysiological conditions. Hypertension is a leading risk factor for cardiovascularassociated morbidity and mortality. An important and contributory element in sustained hypertension is an increase in vascular tone, potentially resulting from concurrently reduced relaxation and augmented contraction induced by various endogenous ligands. [19][20][21][22][23][24][25][26] Hypertension-associated vascular dysfunction is partly regulated by endothelium-derived factors. [21][22][23][24] There is a fine balance between endothelium-derived relaxing and contracting factors, a disturba...