21 research outputs found
Endothelin-1: The yin and yang on vascular function
Abstract: Endothelin-1 (ET-1) is a vasoconstrictor secreted by endothelial cells, which acts as the natural
counterpart of the vasodilator nitric oxide (NO). ET-1 contributes to vascular tone and regulates cell
proliferation through activation of ETA and ETB receptors. Physical factors such as shear stress, or stimuli
including thrombin, epinephrine, angiotensin II, growth factors, cytokines and free radicals enhance secretion
of ET-1. By contrast, mediators like nitric oxide (NO), cyclic GMP, atrial natriuretic peptide, and prostacyclin
reduce the release of endogenous ET-1. Thus, under normal conditions, the effects of the ET-1 are carefully
regulated through inhibition or stimulation of ET-1 release from endothelium.
Endothelial dysfunction is one of the earliest landmarks of vascular abnormalities. Altered function of
endothelium may result from absolute decrease in bioavailability of NO as well as from relative augment in ET-
1 synthesis, release or activity. Imbalance in the production of vasodilator and vasoconstrictor agents may
contribute to the onset of hemodynamic disorders.
Since dysregulation of the endothelin system is important in the pathogenesis of several cardiovascular
diseases, the ETA and ETB receptors are attractive therapeutic targets for disorders associated with elevated ET-
1 levels. ET receptor antagonists may be regarded as disease-modifying agents thanks to their ability to
preserve endothelial integrity when the endothelin system is overactive.
This review summarizes the current knowledge on the role of ET-1 in experimental hypertension and describes
recent findings on the involvement of MAPK signalling pathways in ET-1 release in hypertension associated
with insulin resistance.
Moreover, therapeutic applications of ET-1 receptor blockers are also discussed
INCREASED P22PHOX EXPRESSION AND REDUCED SOD ACTIVITY ARE INVOLVED IN EARLY IMPAIRMENT OF INSULIN-INDUCED VASODILATION ON RESISTANCE VESSELS OF SPONTANEOUSLY HYPERTENSIVE RATS (SHR)
Rosiglitazone improves hypertension in spontaneously hypertensive rats (SHR) by decreasing endothelial MAP kinase signaling and endothelin-1 (ET-1) secretion RID B-1970-2008
MOLECULAR MECHANISMS INVOLVED IN ACUTE AND CHRONIC EFFECTS OF EPIGALLOCATECHIN GALLATE (EGCG), A GREEN TEA POLYPHENOL, ON VASCULAR FUNCTION OF SPONTANEOUSLY HYPERTENSIVE RATS (SHR)
Treatment of spontaneously hypertensive rats with rosiglitazone and/or enalapril restores balance between vasodilator and vasoconstrictor actions of insulin with simultaneous improvement in hypertension and insulin resistance RID B-1970-2008
Spontaneously hypertensive rats (SHRs) exhibit endothelial
dysfunction and insulin resistance. Reciprocal relationships
between endothelial dysfunction and insulin
resistance may contribute to hypertension by causing imbalanced
regulation of endothelial-derived vasodilators
(e.g., nitric oxide) and vasoconstrictors (e.g., endothelin-1
[ET-1]). Treatment of SHRs with rosiglitazone (insulin
sensitizer) and/or enalapril (ACE inhibitor) may simultaneously
improve hypertension, insulin resistance, and endothelial
dysfunction by rebalancing insulin-stimulated
production of vasoactive mediators. When compared with
WKY control rats, 12-week-old vehicle-treated SHRs were
hypertensive, overweight, and insulin resistant, with elevated
fasting levels of insulin and ET-1 and reduced serum
adiponectin levels. In mesenteric vascular beds (MVBs)
isolated from vehicle-treated SHRs and preconstricted
with norepinephrine (NE) ex vivo, vasodilator responses
to insulin were significantly impaired, whereas the ability
of insulin to oppose vasoconstrictor actions of NE was
absent (versus WKY controls). Three-week treatment of
SHRs with rosiglitazone and/or enalapril significantly reduced
blood pressure, insulin resistance, fasting insulin,
and ET-1 levels and increased adiponectin levels to values
comparable with those observed in vehicle-treated WKY
controls. By restoring phosphatidylinositol 3-kinase–dependent
effects, rosiglitazone and/or enalapril therapy of
SHRs also significantly improved vasodilator responses to
insulin in MVB preconstricted with NE ex vivo. Taken
together, our data provide strong support for the existence
of reciprocal relationships between endothelial dysfunction
and insulin resistance that may be relevant for developing
novel therapeutic strategies for the metabolic
syndrom
Pharmacological treatment with rosiglitazone restores insulin-mediated ET-1 release via MAPK-dependent pathway and ameliorates hypertension in SHR rats
Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production RID B-1970-2008
Insulin stimulates production of NO in vascular endothelium via activation of phosphatidylinositol (PI) 3-kinase, Akt, and endothelial NO synthase. We hypothesized that insulin resistance may cause imbalance between endothelial vasodilators and vasoconstrictors (e.g., NO and ET-1), leading to hypertension. Twelve-week-old male spontaneously hypertensive rats (SHR) were hypertensive and insulin resistant compared with control Wistar-Kyoto (WKY) rats (systolic blood pressure 202 +/- 11 vs. 132 +/- 10 mmHg; fasting plasma insulin 5 +/- 1 vs. 0.9 +/- 0.1 ng/ml; P < 0.001). In WKY rats, insulin stimulated dose-dependent relaxation of mesenteric arteries precontracted with norepinephrine (NE) ex vivo. This depended on intact endothelium and was blocked by genistein, wortmannin, or N(omega)-nitro-l-arginine methyl ester (inhibitors of tyrosine kinase, PI3-kinase, and NO synthases, respectively). Vasodilation in response to insulin (but not ACh) was impaired by 20% in SHR (vs. WKY, P < 0.005). Preincubation of arteries with insulin significantly reduced the contractile effect of NE by 20% in WKY but not SHR rats. In SHR, the effect of insulin to reduce NE-mediated vasoconstriction became evident when insulin pretreatment was accompanied by ET-1 receptor blockade (BQ-123, BQ-788). Similar results were observed during treatment with the MEK inhibitor PD-98059. In addition, insulin-stimulated secretion of ET-1 from primary endothelial cells was significantly reduced by pretreatment of cells with PD-98059 (but not wortmannin). We conclude that insulin resistance in SHR is accompanied by endothelial dysfunction in mesenteric vessels with impaired PI3-kinase-dependent NO production and enhanced MAPK-dependent ET-1 secretion. These results may reflect pathophysiology in other vascular beds that directly contribute to elevated peripheral vascular resistance and hypertension
Epigallocatechin gallate, a green tea polyphenol, mediates NO-dependent vasodilation using signaling pathways in vascular endothelium requiring reactive oxygen species and Fyn RID B-1970-2008
Green tea consumption is associated with reduced cardiovascular
mortality in some epidemiological studies. Epigallocatechin
gallate (EGCG), a bioactive polyphenol in green tea, mimics
metabolic actions of insulin to inhibit gluconeogenesis in
hepatocytes. Because signaling pathways regulating metabolic
and vasodilator actions of insulin are shared in common, we
hypothesized that EGCG may also have vasodilator actions to
stimulate production of nitric oxide (NO) from endothelial cells.
Acute intra-arterial administration of EGCG to mesenteric vascular
beds isolated ex vivo from WKY rats caused dose-dependent
vasorelaxation. This was inhibitable by L-NAME (NO synthase
inhibitor), wortmannin (phosphatidylinositol 3-kinase
inhibitor), or PP2 (Src family kinase inhibitor). Treatment of
bovine aortic endothelial cells (BAEC) with EGCG (50 M)
acutely stimulated production ofNO(assessed with NO-specific
fluorescent dye DAF-2) that was inhibitable by L-NAME, wortmannin,
or PP2. Stimulation of BAEC with EGCG also resulted
in dose- and time-dependent phosphorylation of eNOS that was
inhibitable by wortmannin or PP2 (but not by MEK inhibitor
PD98059). Specific knockdown of Fyn (but not Src) with small
interfering RNA inhibited both EGCG-stimulated phosphorylation
of Akt and eNOS as well as production ofNOin BAEC. Treatment
of BAEC with EGCG generated intracellular H2O2 (assessed
with H2O2-specific fluorescent dye CM-H2DCF-DA), whereas
treatment withN-acetylcysteine inhibited EGCG-stimulated phosphorylation
of Fyn, Akt, and eNOS. We conclude that EGCG has
endothelial-dependent vasodilator actions mediated by intracellular
signaling pathways requiring reactive oxygen species and Fyn
that lead to activation of phosphatidylinositol 3-kinase, Akt, and
eNOS. This mechanism may explain, in part, beneficial vascular
and metabolic health effects of green tea consumption
Endothelial COX-1 and -2 differentially affect reactivity of MVB in portal hypertensive rats
Expression of constitutive and inducible cyclooxygenase (COX-1 and COX-2, respectively) and the role of prostanoids were investigated in the aorta and mesenteric vascular bed (MVB) from the portal vein-ligated rat (PVL) as a model of portal hypertension. Functional experiments were carried out in MVB from PVL and sham-operated rats in the absence or presence of the nonselective COX inhibitor indomethacin or the selective inhibitors of COX-1 (SC-560) or COX-2 (NS-398). Western blots of COX-1 and COX-2 proteins were evaluated in aorta and MVB, and PGI(2) production by enzyme immunoassay of 6-keto-PGF(1alpha) was evaluated in the aorta. In the presence of functional endothelium, decreased contraction to norepinephrine (NE) and increased vasodilatation to ACh were observed in MVB from PVL. Exposure of MVB to indomethacin, SC-560, or NS-398 reversed the hyporeactivity to NE and the increased endothelial vasodilatation to ACh in PVL, with NS-398 being more potent than the other two inhibitors. Upregulation of COX-1 and COX-2 expressions was detected in aorta and MVB from PVL portal hypertensive rats, and increased production of 6-keto-PGF(1alpha) was observed in aorta from portal hypertensive rats. These results suggest that generation of endothelial vasodilator prostanoids, from COX-1 and COX-2 isoforms, accounts for the increased mesenteric blood flow in portal hypertension
EGCG, a green tea polyphenol, improves endothelial function and insulin sensitivity, reduces blood pressure, and protects against myocardial I/R injury in SHR RID B-1970-2008
Epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea, may augment metabolic and vascular actions of insulin. Therefore, we investigated effects of EGCG treatment to simultaneously improve cardiovascular and metabolic function in spontaneously hypertensive rats (SHR; model of metabolic syndrome with hypertension, insulin resistance, and overweight). In acute studies, EGCG (1-100 microM) elicited dose-dependent vasodilation in mesenteric vascular beds (MVB) isolated from SHR ex vivo that was inhibitable by N(omega)-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthase antagonist) or wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor]. In chronic studies, 9-wk-old SHR were treated by gavage for 3 wk with EGCG (200 mg.kg(-1).day(-1)), enalapril (30 mg.kg(-1).day(-1)), or vehicle. A separate group of SHR receiving L-NAME (80 mg/l in drinking water) was treated for 3 wk with either EGCG or vehicle. Vasodilator actions of insulin were significantly improved in MVB from EGCG- or enalapril-treated SHR (when compared with vehicle-treated SHR). Both EGCG and enalapril therapy significantly lowered systolic blood pressure (SBP) in SHR. EGCG therapy of SHR significantly reduced infarct size and improved cardiac function in Langendorff-perfused hearts exposed to ischemia-reperfusion (I/R) injury. In SHR given L-NAME, beneficial effects of EGCG on SBP and I/R were not observed. Both enalapril and EGCG treatment of SHR improved insulin sensitivity and raised plasma adiponectin levels. We conclude that acute actions of EGCG to stimulate production of nitric oxide from endothelium using PI 3-kinase-dependent pathways may explain, in part, beneficial effects of EGCG therapy to simultaneously improve metabolic and cardiovascular pathophysiology in SHR. These findings may be relevant to understanding potential benefits of green tea consumption in patients with the metabolic syndrome