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PubMed2001

Impaired renal vascular endothelial function in vitro in experimental hypercholesterolemia.

Hypercholesterolemia (HC) induces alterations in systemic vascular reactivity, which can manifest as an attenuated endothelium-dependent relaxation, partly consequent to an impairment in nitric oxide (NO) activity. To determine whether experimental HC has a similar effect on renal vascular function, renal artery segments obtained from pigs fed a HC (n=5) or normal (n=5) diet were studied in vitro. Endothelium-dependent relaxation was examined using increasing concentrations of acetylcholine (Ach), calcium ionophore A23187, and Ach following pre-incubation with N(G)-monomethyl-L-arginine or L-arginine (L-ARG). The NO-donor diethylamine (DEA) was used to examine smooth muscle relaxation response and cyclic GMP generation in endothelium-denuded vessels. The expression of endothelial NO synthase (eNOS) in the renal arteries was examined using Western blotting. Endothelium-dependent relaxation to Ach was significantly attenuated in the HC group compared to normal (53.3+/-9.1 vs. 98.8+/-3.7%, P<0.005), but normalized after pre-incubation with L-ARG (82.3+/-13.8%, P=0.21). Receptor-independent endothelium-dependent relaxation to A23187 was also significantly blunted in HC (75.2+/-10.5 vs. 115.5+/-4.2%, P<0. 017). Smooth muscle relaxation and cyclic GMP generation in response to DEA were greater in denuded HC vessels, while relaxation of intact vessels to nitroprusside was unaltered. In the HC vessels eNOS was almost undetectable. In conclusion, experimental HC attenuates in vitro endothelium-dependent relaxation of the porcine renal artery, possibly due to low bioavailability of NO. These vascular alterations in HC could play a role in the pathogenesis of renal disease or hypertension, supporting a role for HC as a risk factor for renovascular disease.

Animals↗

PubMed2005

Restoration of endothelial function via enhanced nitric oxide synthesis after long-term treatment of raloxifene in adult hypertensive rats.

Raloxifene (CAS 84449-90-1, RAL), a selective estrogen receptor modulator (SERM) effective for the prevention of post-menopausal osteoporosis, also has been shown to acutely stimulate nitric oxide (NO) synthesis associated with improved endothelium-dependent relaxation. The effect of a 3-month RAL treatment (10 mg/kg/d) on basal blood pressure, measured via the carotid artery, and its challenge with increasing doses of intravenous bradykinin (1, 3 and 10 nmol/kg) was investigated. Furthermore, aortic NO bioavailability and relaxation in 9-month-old male and female ovarectomized (OVX) spontaneously hypertensive rats (SHR) was tested. Calcium ionophore stimulated NO release from aortic endothelial cells and aortic superoxide (O2-) production was directly assessed by using electrochemical nanosensors. Relaxation studies were performed with acetylcholine (10(-8) to 10(-5) mol/L) following precontraction with phenylephrine (10(-7) mmol/L). Whereas basal blood pressure (BP) was not significantly decreased in RAL treated SHR, the dose-dependent challenge with bradykinin induced an enhanced BP reduction in either gender. In contrast to female animals, aortic segments from RAL treated male animals showed significantly improved relaxaSHR) to 360 +/- 15 nmol/L. Vice versa, O2- was decreased from 110 +/- 15 to 22 +/- 1 nmol/L. In female SHR, ovarectomy led to an increase/decrease of NO/O2- from 130 +/- 5 to 180 +/- 10 nmol/L and 82 +/- 7 to 68 +/- 3 nmol/L, respectively. These effects were significantly amplified by RAL treatment (NO: 370 +/- 10 and O2-: 25 +/- 2 nmol/L). The results show that long-term treatment with RAL has beneficial affects on the cardiovascular system in old male and female OVX SHR via an increased NO bioavailability.

Animals↗

PubMed2002

Effect of estrogen on endothelial function and angiogenesis.

Animal studies evaluating gender difference, the effects of gonadectomy and estrogen replacement and clinical studies in post-menopausal women with and without estrogen replacement therapy (ERT) proved that estrogen exerts significant benefits on the cardiovascular system. Since effects on the plasma lipoprotein profile is responsible for only approximately 25-40% of the cardiovascular protection exerted by estrogens, it is postulated that direct effects of estrogen on the vascular wall must play an important role. Indeed, experimental and clinical evidence accumulated over the past decade, and reviewed briefly here, indicate that at least a part of cardiovascular benefits of 17 beta-estradiol can be attributed to the direct effect of the ovarian sex steroid hormone on vascular endothelial cells. Maintenance and upregulation of endothelial nitric oxide production and suppression of EDCF generation by 17 beta-estradiol may play an important role in preventing or reversing endothelial dysfunction, associated with atherosclerosis, hypertension and other cardiovascular diseases. Stimulation of angiogenesis (especially collateral vessel formation in ischemic tissues) by the ovarian steroid hormone could be beneficial in coronary artery disease, peripheral vascular disease, cerebral ischemia (stroke) and congestive heart failure. Despite these indisputable beneficial effects, several key questions remain to be answered in the future, including the better understanding of the apparently opposite effects of estrogen on prevention of cardiovascular disease vs. treatment of existing disease.

Animals↗

PubMed1996

Differential contribution of endothelial function to vascular reactivity in conduit and resistance arteries from deoxycorticosterone-salt hypertensive rats.

The purpose of these studies was to compare changes in conduit and resistance artery function in deoxycorticosterone-salt hypertensive rats. We hypothesized that if there was a common mechanism producing changes in vascular function in hypertension, then there would be similar alterations in reactivity of conduit and resistance arteries. Helically cut strips of common carotid artery were prepared for measurement of isometric force generation, and segments of small mesenteric arteries were pressurized for video dimension analysis. Sensitivity of arteries to phenylephrine and acetylcholine was determined. Carotid arteries from deoxycorticosterone-salt hypertensive rats were more sensitive to phenylephrine than arteries from control rats, whereas mesenteric resistance arteries from hypertensive rats were less sensitive to phenylephrine. In carotid arteries, endothelial denudation or incubation with N psi-nitro-L-arginine increased phenylephrine sensitivity in control rats to the level seen in deoxycorticosterone-salt rats. These manipulations had no effect on phenylephrine sensitivity in arteries from deoxycorticosterone-salt rats. In mesenteric resistance arteries, endothelium denudation normalized the depressed phenylephrine sensitivity in arteries from hypertensive rats but had no effect on arteries from normotensive rats. This depressed phenylephrine sensitivity in deoxycorticosterone-salt mesenteric arteries was not reversed by incubation with Npsi-nitro-L-arginine. Acetylcholine-induced relaxation was depressed in carotid arteries from deoxycorticosterone-salt hypertensive rats, and Npsi-nitro-L-arginine blocked these relaxations. In contrast, acetylcholine relaxation in the mesenteric arteries from normotensive and hypertensive rats did not differ. N psi-nitro-L-arginine slightly but significantly attenuated acetylcholine dilation only in mesenteric resistance arteries from the hypertensive rats. We conclude that qualitatively different changes in vasoconstrictor sensitivity to phenylephrine occur in carotid arteries and mesenteric resistance arteries of deoxycorticosterone-salt hypertensive rats. The increased phenylephrine sensitivity in carotid arteries in this model of hypertension is due to the loss of endothelium-derived nitric oxide production. In contrast, the decreased phenylephrine sensitivity in mesenteric resistance arteries from deoxy-corticosterone-salt rats is due to a non-nitric oxide-mediated influence of the endothelium that is absent in arteries from normotensive rats.

Acetylcholine↗

PubMed1998

Endothelial function in health and disease: new insights into the genesis of cardiovascular disease.

The vascular endothelium secretes factors that not only modulate blood vessel tone, but also participate in the development and progression of atherosclerosis through their effects on platelet adhesion and aggregation, thrombogenicity, and cell proliferation. Altered activities of these substances in patients with risk factors for cardiovascular disease (e.g., hypercholesterolemia, hypertension, diabetes, aging, postmenopausal status, smoking, and infections) appear to underlie the atherosclerotic process. There is increasing evidence from both preclinical studies and clinical trials that nitric oxide (NO) plays a pivotal role in the pathophysiology of arteriosclerosis. This review describes the role of NO in human health and disease and summarizes strategies currently being used to measure and improve endothelial dysfunction.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1999

Prothrombotic factors, endothelial function and left ventricular hypertrophy in isolated systolic hypertension compared with systolic-diastolic hypertension.

BACKGROUND: Individuals with systolic-diastolic hypertension (SDH, systolic blood pressure (SBP) >160 mm Hg and diastolic blood pressure (DBP) >90 mm Hg) are at increased risk of thrombotic complications, such as stroke and heart attacks, which may be related to a hypercoagulable state. Individuals with only isolated systolic hypertension (ISH; i.e. SBP >160 mm Hg but DBP <90 mm Hg) are also at significant cardiovascular risk. We hypothesized that patients with ISH would exhibit a prothrombotic state similar to that seen in SDH. A secondary hypothesis was that individuals with ISH had similar echocardiographic parameters to those seen in SDH. METHODS: We measured indices of haemorheology, endothelial dysfunction, thrombogenesis and platelet activation in 23 individuals with ISH (mean blood pressure 193/82 mm Hg), who were compared with 51 matched patients with SDH (mean blood pressure 198/112 mm Hg) and 34 age- and sex- matched normotensive healthy control individuals (mean blood pressure 130/78 mm Hg). Echocardiographic parameters in patients with ISH were compared to those from patients with SDH. RESULTS: Mean plasma viscosity (an index of blood rheology, ANOVA, P = 0.001), von Willebrand factor (an index of endothelial damage, P = 0.013), plasminogen activator inhibitor-1 and lipoprotein (a) (both markers of thrombogenesis; Kruskal-Wallis test, both P<0.001) were all significantly raised in ISH and SDH relative to controls. Individuals with SDH also had high mean plasma fibrinogen (P = 0.018) and haematocrit (P = 0.010) levels compared with control individuals. There were no significant differences in levels of fibrin D-dimer or the platelet activation marker soluble P-selectin in the hypertensive patients (i.e. ISH and SDH) compared with control individuals. Patients with ISH had similar M-mode and Doppler echocardiographic parameters compared to patients with SDH. CONCLUSIONS: We conclude that individuals with ISH have abnormalities in plasma prothrombotic factors and markers of endothelial dysfunction, and echocardiographic parameters, broadly similar to that seen in SDH. This is consistent with the increased risk of thrombotic events (strokes and heart attacks) in patients with ISH.

Aged↗

PubMed2003

Vascular endothelial function and blood pressure homeostasis in mice overexpressing IGF binding protein-1.

IGFs and their binding proteins (IGFBPs) play a significant role in metabolic regulation, and there is growing evidence that they also exert important vascular effects. IGFBP-1 contributes to glucose counterregulation, and observational studies demonstrate an inverse association between circulating IGFBP-1 levels and cardiovascular risk factors. Furthermore, IGFBP-1 levels are lower in subjects with overt macrovascular disease. We therefore hypothesized that IGFBP-1 exerts potentially beneficial effects, either directly or indirectly, on blood pressure regulation and vascular function. We tested this hypothesis using a unique transgenic mouse, which overexpresses human IGFBP-1, and explored the effect of this protein on metabolic, blood pressure, and vascular homeostasis. IGFBP-1-overexpressing mice exhibited postprandial hyperinsulinemia with preservation of glucocompetence and insulin sensitivity. Blood pressure was unchanged in the fasting state but was significantly lower in transgenic mice after a carbohydrate load. Aortic rings from IGFBP-1-overexpressing mice were hypocontractile in response to vasoconstrictors, and relaxation responses were unimpaired. Basal nitric oxide production was increased and endothelial nitric oxide synthase mRNA expression upregulated in aortae of these mice. Our data suggest that IGFBP-1 plays an important and potentially beneficial role in regulating metabolic and vascular homeostasis.

Animals↗

PubMed2002

Bezafibrate-induced improvement in glucose uptake and endothelial function in protease inhibitor-associated insulin resistance.

Protease inhibitors used as therapy for HIV-1 infection have been associated with metabolic side-effects such as peripheral fat wasting, central adiposity, hyperlipidaemia and insulin resistance. This metabolic disorder is known as the lipodystrophy syndrome. This syndrome can be recognized by the early appearance of an increase in serum triglyceride, cholesterol and plasma-free fatty acid levels. Here, we describe an HIV-1 positive patient with the lipodystrophy syndrome in whom a decline in serum triglycerides was seen along with a significant improvement in glucose uptake following treatment with bezafibrate for 3 months. This improvement may be a consequence of the Randle effect, i.e. increased availability of plasma-free fatty acids is negatively correlated to glucose uptake. We also noted a significant improvement in endothelial-dependent flow-mediated dilatation after treatment with bezafibrate. This effect could result from the increased glucose uptake observed and a decrease in insulin resistance secondary to the lowered triglyceride levels by bezafibrate. We conclude that bezafibrate may be of clinical utility in the lipodystrophy syndrome, through its beneficial effects on insulin resistance, glucose uptake and endothelial dysfunction.

Adult↗

PubMed2006

A novel endothelial-specific heat shock protein HspA12B is required in both zebrafish development and endothelial functions in vitro.

A zebrafish transcript dubbed GA2692 was initially identified via a whole-mount in situ hybridization screen for vessel specific transcripts. Its mRNA expression during embryonic development was detected in ventral hematopoietic and vasculogenic mesoderm and later throughout the vasculature up to 48 hours post fertilization. Morpholino-mediated knockdown of GA2692 in embryos resulted in multiple defects in vasculature, particularly, at sites undergoing active capillary sprouting: the intersegmental vessels, sub-intestinal vessels and the capillary sprouts of the pectoral fin vessel. During the course of these studies, a homology search indicated that GA2692 is the zebrafish orthologue of mammalian HspA12B, a distant member of the heat shock protein 70 (Hsp70) family. By a combination of northern blot and real-time PCR analysis, we showed that HspA12B is highly expressed in human endothelial cells in vitro. Knockdown of HspA12B by small interfering RNAs (siRNAs) in human umbilical vein endothelial cells blocked wound healing, migration and tube formation, whereas overexpression of HspA12B enhanced migration and accelerated wound healing - data that are consistent with the in vivo fish phenotype obtained in the morpholino-knockdown studies. Phosphorylation of Akt was consistently reduced by siRNAs against HspA12B. Overexpression of a constitutively active form of Akt rescued the inhibitory effects of knockdown of HspA12B on migration of human umbilical vein endothelial cells. Collectively, our data suggests that HspA12B is a highly endothelial-cell-specific distant member of the Hsp70 family and plays a significant role in endothelial cells during development and angiogenesis in vitro, partially attributable to modulation of Akt phosphorylation.

Alkaline Phosphatase↗

PubMed2001

Endothelial function and myogenic reactivity in small mesenteric arteries of hyperlipidemic pregnant rats.

Supraphysiological increases in serum triglycerides and cholesterol often occur during pregnancy, but their effects on vascular function are poorly understood. Intraperitoneal injection of the nontoxic surfactant poloxamer 407 (P-407) results in sustained elevation of triglycerides and cholesterol. We asked if P-407-induced hyperlipidemia during late pregnancy adversely affects mesenteric resistance artery vasodilator function. On days 13-15 of pregnancy, rats were given a single intraperitoneal injection of P-407, sterile water vehicle, or non-lipid-altering pluronic F-88 (P-88). Four days postinjection, serum triglycerides, cholesterol, free fatty acids, and the lipid peroxidation product malondialdehyde were significantly increased in P-407-treated rats. Mesenteric arteries from P-407-treated rats displayed significant increases in myogenic reactivity (constrictor responses to step increases in intraluminal pressure). The nitric oxide (NO) blocker N(alpha)-methyl-L-arginine increased the myogenic response in control but not in P-407 arteries, normalizing group differences. Endothelial removal increased myogenic reactivity beyond that of prior NO synthase inhibition in controls and potentiated myogenic reactivity in P-407 arteries such that responses again converged. Relaxation responses to the endothelium-dependent vasodilator methacholine did not differ. We conclude that that P-407-induced hyperlipidemia during pregnancy increases myogenic reactivity due to selective attenuation of an NO-mediated vasodilator component of the myogenic response.

Animals↗

PubMed1997

Coronary endothelial function in health and disease.

The endothelium participates in the control of coronary vascular tone and growth through the release of vasodilating and growth-inhibiting factors such as nitric oxide (NO) and C-type natriuretic peptide (CNP), and vasoconstricting and growth-promoting substances such as endothelin-1 (ET-1). Abnormalities in NO and/or CNP generation or actions have been demonstrated in various cardiovascular pathophysiological states, specifically atherosclerosis, congestive heart failure, hypertension and hypercholesterolaemia. Moreover, an increase in plasma ET-1 levels has also been reported in these disease states. When these observations are considered together, these states may be characterised by an attenuated release or action of NO and/or CNP, together with an augmented release of ET-1. Thus, an imbalance between these opposing factors may contribute to the alteration in vascular tone and the vascular remodelling characteristics of cardiovascular disease. The following article summarises the present knowledge of endothelial control of the coronary circulation and derangements associated with coronary endothelial dysfunction.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2002

The effect of insufficiency of tetrahydrobiopterin on endothelial function and vasoactivity.

OBJECTIVE: It has recently been defined that levels of tetrahydrobiopterin, a cofactor of nitric oxide synthase, decreases under some disease conditions including atherosclerosis, hypercholesterolemia, diabetes, and ischemia-reperfusion. The present study was designed to investigate whether or not a deficiency in tetrahydrobiopterin affected vasoactivation in vivo and in vitro. SUBJECTS AND METHODS: Male Sprague-Dawley rats were divided into two groups, and given either 2, 4-diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of tetrahydrobiopterin production, or a vehicle (10% polyethylene glycol 400 in 5% glucose, 20 ml/kg), intraperitoneally at 24 hr prior to examination. Responses to several vasodilating agents were examined in both pretreatment groups in vivo and in vitro. Furthermore, the isolated heart was perfused with a 37 degrees C Krebs-Henseleit solution for 30 min. The effects of insufficient tetrahydrobiopterin on the left ventricular function were examined. Moreover, nitrite plus nitrate (NOx) in the coronary effluent was examined in both groups. RESULTS: Depressor and vasodilatation responses to an endothelium-dependent vasodilator were significantly attenuated in the DAHP Group in comparison with those in the vehicle Control Group, while the endothelium-independent vasodilator caused equivalent depressor and vasodilatation responses between the two groups. The NOx levels in the coronary effluent were lower in the DAHP Group than in the Control Group (p < 0.05). The cardiovascular parameters were also lower in the DAHP Group than in the Control Group. CONCLUSIONS: We concluded from these findings that a deficiency in tetrahydrobiopterin aggravated endothelial dysfunction and the left ventricular dysfunction. These findings were consistent with the hypothesis that decreased levels of tetrahydrobiopterin may cause cardiac and vascular dysfunction.

Animals↗

PubMed1995

The nonpeptide endothelin receptor antagonist bosentan enhances myocardial recovery and endothelial function during reperfusion of the ischemic rat heart.

We investigated the effects of bosentan, a nonpeptide endothelin (ET) receptor antagonist, on ET-induced changes in coronary flow and myocardial ischemic and reperfusion injury in the isolated rat heart. Bosentan (10(-5) M ) attenuated coronary constriction induced by ET-1 and dilatation induced by the ETB agonist IRL 1620. In hearts subjected to 30 min of global ischemia followed by 30 min of reperfusion, bosentan (10(-5) M) significantly improved the recoveries of the left ventricular developed pressure, dP/dtmax, and coronary flow at the end of reperfusion, compared to vehicle-treated controls. During reperfusion, left ventricular end-diastolic pressure was significantly lower in the bosentan group than in the vehicle group. Acetylcholine-induced, endothelium-dependent vasodilatation was significantly attenuated at the end of reperfusion in controls but not in bosentan-treated hearts. We conclude that bosentan reduces myocardial and endothelial injury after ischemia/reperfusion in the isolated rat heart, indicating a pathophysiologic role of endogenous ET.

Animals↗

PubMed1989

Angiographic assessment of human coronary artery endothelial function by measurement of endothelium-dependent vasodilation.

In isolated atherosclerotic human coronary arteries endothelium-dependent vascular relaxation is abolished with acetylcholine whereas another EDRF-dependent vasodilator, substance P, still produces significant relaxation. To study further these in vitro findings, graded doses of acetylcholine and substance P, which produced no systemic effects, were infused into the left anterior descending artery of patients with angiographically moderate coronary artery disease. The effects of acetylcholine and substance P on LAD diameter were analysed by quantitative angiography. Generally, acetylcholine caused no relaxation but concentration-dependent contraction from 1.67 +/- 0.06 mm to 1.45 +/- 0.09 mm (P less than 0.01), whereas substance P dilated the arteries to 1.89 +/- 0.10 mm (P less than 0.01). In contrast, both drugs caused a marked increase in great cardiac vein oxygen saturation, indicating an increase of coronary flow. The results suggest that the failure of the atherosclerotic epicardial human coronary artery to vasodilate in response to acetylcholine represents a muscarinic endothelial defect. The preserved vasodilation with substance P in the presence of a refractoriness to acetylcholine suggests that atherosclerotic human coronary endothelial cells exposed to appropriate non-muscarinic stimuli are still capable to release EDRF and that atherosclerotic smooth muscle retains a responsive receptor mechanism for EDRF.

Acetylcholine↗

PubMed2000

Improvement of endothelial function by chronic angiotensin-converting enzyme inhibition in heart failure : role of nitric oxide, prostanoids, oxidant stress, and bradykinin.

BACKGROUND-Chronic heart failure (CHF) impairs the endothelium-dependent, flow-mediated dilation (FMD) of small arteries. However, whether chronic angiotensin-converting enzyme (ACE) inhibition affects the impairment of FMD in CHF is unknown. We investigated the effects of long-term ACE inhibition on the FMD of peripheral arteries in rats with CHF and the mechanism(s) involved. METHODS AND RESULTS-FMD was assessed in isolated, perfused gracilis muscle arteries from sham-operated, and untreated or ACE inhibitor-treated (perindopril 2 mg. kg(-1). day(-1) for 10 weeks) rats with CHF (coronary artery ligation). The role of nitric oxide (NO), prostaglandins, and free radicals was assessed by pretreating the vessels with the NO synthase inhibitor N(W)-nitro-L-arginine, the cyclooxygenase inhibitor diclofenac, or the free radical scavenger N-2-mercaptopropionyl-glycine (MPG). Endothelial NO synthase mRNA expression was determined by reverse transcriptase polymerase chain reaction. In animals with hemodynamic and echographic signs of CHF, FMD was converted into vasoconstriction, and this was prevented by ACE inhibition. FMD of arteries from sham-operated or ACE inhibitor-treated CHF rats was abolished by N(W)-nitro-L-arginine. In untreated CHF rats, FMD was increased by diclofenac and MPG. In contrast, in arteries from ACE inhibitor-treated rats, neither diclofenac nor MPG affected FMD. In parallel, ACE inhibition prevented the reduction of endothelial NO synthase mRNA by CHF. CONCLUSIONS-In CHF, ACE inhibition normalized NO-dependent dilatation and suppressed the production of vasoconstrictor prostanoid(s), resulting in improved FMD. The improvement of FMD might contribute to the beneficial effects of ACE inhibition during CHF.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

The coagulo-lytic system and endothelial function in cyclosporine-treated kidney allograft recipients.

Since thromboembolic complications in transplanted patients are generally attributed to combined abnormalities in platelets and coagulo-lytic system, some hemostatic parameters tPA (tissue plasmogin activator):Ag and activity, its inhibitor-PAIAg and activity, tPA/PAI, thrombin-antithrombin (TAT) and plasmin-antiplasmin complexes (PAP), urokinase-uPA, euglobulin clot lysis time-ECLT, fibrinogen, plasminogen, protein C activity, D-dimer, prothrombin fragments1+2 (F1+2), fibrin monomers, fibronectin, lipoprotein-a, and von Willebrand factor(vWF), were evaluated using commercially available kits. The studies were performed on kidney transplant recipients treated with CsA, azathioprine and prednisone (n=21), and healthy volunteers (n=21). ECLT was significantly prolonged in kidney transplant recipients together with a rise in F1+2,lipoprotein-a, fibrinogen, fibronectin, and vWF when compared with controls. The TPA level was lower, whereas the PAI level was higher in kidney transplant recipients when compared with controls. In conclusion, CsA-treated kidney transplant recipients show evidence of pronounced impairment in fibrinolysis and endothelial damage in comparison with healthy volunteers.

Adult↗

PubMed2004

Vasopeptidase inhibition improves insulin sensitivity and endothelial function in the JCR:LA-cp rat.

The insulin-resistant, hyperinsulinemic, normoglycemic, and obese JCR:LA-cp rat was used to study the effects of ramipril (an ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidases) on insulin sensitivity and vascular function. Both compounds reduced the surge of plasma insulin in a meal tolerance test by approximately 50%. Ramipril had no effect on acetylcholine-induced relaxation but increased the sensitivity to sodium nitroprus-side at low concentrations. AVE7688 significantly reduced the EC50 for acetylcholine to relax phenylephrine-contracted aortic rings. None of the compounds affected the baseline coronary flow and reactive hyperemia. Coronary flow response to bradykinin in AVE7688- and ramipril-treated rat hearts showed a significantly lower EC50 than in control rats. Maximum flow rate was not different between groups. In summary, both ramipril and AVE7688 had significant hypoinsulinemic and insulin-sensitizing effects. Whereas ramipril had limited vascular effects, AVE7688 had more marked beneficial vascular effects, probably of endothelial origin and possibly related to lowered insulin levels.

Acetylcholine↗

PubMed2006

Gender differences in endothelial function and inflammatory markers along the occurrence of pathological events in stroke-prone rats.

Spontaneously hypertensive stroke-prone rats (SHRSP) feature an established model for human cerebrovascular disease. SHRSP, kept on a high-salt permissive diet (JPD), develop hypertension, renal and brain damage. In this report we compared the behavior of female and male SHRSP regarding the main aspects of their pathological condition. Brain abnormalities, detected by magnetic resonance imaging, developed spontaneously in males after 42+/-3 days, in females after 114+/-14 days from the start of JPD. Survival was >3-fold longer for females than for males. The development of brain damage was preceded, in both genders, by an inflammatory condition characterized by the accumulation in serum and urine of acute-phase proteins. The increase in thiostatin level was significantly lower and delayed in female in comparison to male SHRSP. During JPD female and male SHRSP developed massive proteinuria, its worsening being significantly slower in females. The alterations of vasculature-bound barriers in kidney and brain were connected with endothelial dysfunction and relative deficiency in nitric oxide (NO). In thoracic aortic rings, basal release of NO was significantly higher in female than in male SHRSP, both if receiving and if not receiving JPD. The gender differences in SHRSP thus appear to be connected to a more efficient control in females of inflammation and of endothelial dysfunction.

Acute-Phase Proteins↗