Flow Debt Repayment Research Articles

Fiber-rich diet with brown rice improves endothelial function in type 2 diabetes mellitus: A randomized controlled trial.

Background & AimsA fiber-rich diet has a cardioprotective effect, but the mechanism for this remains unclear. We hypothesized that a fiber-rich diet with brown rice improves endothelial function in patients with type 2 diabetes mellitus.MethodsTwenty-eight patients with type 2 diabetes mellitus at a single general hospital in Japan were randomly assigned to a brown rice (n = 14) or white rice (n = 14) diet and were followed for 8 weeks. The primary outcome was changes in endothelial function determined from flow debt repayment by reactive hyperemia using strain-gauge plethysmography in the fasting state. Secondary outcomes were changes in HbA1c, postprandial glucose excursions, and markers of oxidative stress and inflammation. The area under the curve for glucose after ingesting 250 kcal of assigned rice was compared between baseline (T0) and at the end of the intervention (T1) to estimate glucose excursions in each group.ResultsImprovement in endothelial function, assessed by fasting flow debt repayment (20.4% vs. −5.8%, p = 0.004), was significantly greater in the brown rice diet group than the white rice diet group, although the between-group difference in change of fiber intake was small (5.6 g/day vs. −1.2 g/day, p<0.0001). Changes in total, HDL-, and LDL-cholesterol, and urine 8-isoprostane levels did not differ between the two groups. The high-sensitivity C-reactive protein level tended to improve in the brown rice diet group compared with the white rice diet group (0.01 μg/L vs. −0.04 μg/L, p = 0.063). The area under the curve for glucose was subtly but consistently lower in the brown rice diet group (T0: 21.4 mmol/L*h vs. 24.0 mmol/L*h, p = 0.043, T1: 20.4 mmol/L*h vs. 23.3 mmol/L*h, p = 0.046) without changes in HbA1c.ConclusionsIntervention with a fiber-rich diet with brown rice effectively improved endothelial function, without changes in HbA1c levels, possibly through reducing glucose excursions.

A fish-based diet intervention improves endothelial function in postmenopausal women with type 2 diabetes mellitus: A randomized crossover trial

ObjectiveThe beneficial effects of fish and n-3 polyunsaturated fatty acids (PUFAs) consumption on atherosclerosis have been reported in numerous epidemiological studies. However, to the best of our knowledge, the effects of a fish-based diet intervention on endothelial function have not been investigated. Therefore, we studied these effects in postmenopausal women with type 2 diabetes mellitus (T2DM). Materials/MethodsTwenty-three postmenopausal women with T2DM were assigned to two four-week periods of either a fish-based diet (n-3 PUFAs≧3.0g/day) or a control diet in a randomized crossover design. Endothelial function was measured with reactive hyperemia using strain-gauge plethysmography and compared with the serum levels of fatty acids and their metabolites. Endothelial function was determined with peak forearm blood flow (Peak), duration of reactive hyperemia (Duration) and flow debt repayment (FDR). ResultsA fish-based dietary intervention improved Peak by 63.7%, Duration by 27.9% and FDR by 70.7%, compared to the control diet. Serum n-3 PUFA levels increased after the fish-based diet period and decreased after the control diet, compared with the baseline (1.49 vs. 0.97 vs. 1.19mmol/l, p<0.0001). There was no correlation between serum n-3 PUFA levels and endothelial function. An increased ratio of epoxyeicosatrienoic acid/dihydroxyeicosatrienoic acid was observed after a fish-based diet intervention, possibly due to the inhibition of the activity of soluble epoxide hydrolase. ConclusionsA fish-based dietary intervention improves endothelial function in postmenopausal women with T2DM. Dissociation between the serum n-3 PUFA concentration and endothelial function suggests that the other factors may contribute to this phenomenon.

A1 adenosine receptor negatively modulates coronary reactive hyperemia via counteracting A2A-mediated H2O2 production and KATP opening in isolated mouse hearts

We previously demonstrated that A2A, but not A2B, adenosine receptors (ARs) mediate coronary reactive hyperemia (RH), possibly by producing H2O2 and, subsequently, opening ATP-dependent K(+) (KATP) channels in coronary smooth muscle cells. In this study, A1 AR knockout (KO), A3 AR KO, and A1 and A3 AR double-KO (A1/A3 DKO) mice were used to investigate the roles and mechanisms of A1 and A3 ARs in modulation of coronary RH. Coronary flow of isolated hearts was measured using the Langendorff system. A1 KO and A1/A3 DKO, but not A3 KO, mice showed a higher flow debt repayment [~30% more than wild-type (WT) mice, P < 0.05] following a 15-s occlusion. SCH-58261 (a selective A2A AR antagonist, 1 μM) eliminated the augmented RH, suggesting the involvement of enhanced A2A AR-mediated signaling in A1 KO mice. In isolated coronary arteries, immunohistochemistry showed an upregulation of A2A AR (1.6 ± 0.2 times that of WT mice, P < 0.05) and a higher magnitude of adenosine-induced H2O2 production in A1 KO mice (1.8 ± 0.3 times that of WT mice, P < 0.05), which was blocked by SCH-58261. Catalase (2,500 U/ml) and glibenclamide (a KATP channel blocker, 5 μM), but not N(G)-nitro-l-arginine methyl ester, also abolished the enhanced RH in A1 KO mice. Our data suggest that A1, but not A3, AR counteracts the A2A AR-mediated CF increase and that deletion of A1 AR results in upregulation of A2A AR and/or removal of the negative modulatory effect of A1 AR, thus leading to an enhanced A2A AR-mediated H2O2 production, KATP channel opening, and coronary vasodilation during RH. This is the first report implying that A1 AR has a role in coronary RH.

Interactions between A2A adenosine receptors, hydrogen peroxide, and KATP channels in coronary reactive hyperemia

Myocardial metabolites such as adenosine mediate reactive hyperemia, in part, by activating ATP-dependent K(+) (K(ATP)) channels in coronary smooth muscle. In this study, we investigated the role of adenosine A(2A) and A(2B) receptors and their signaling mechanisms in reactive hyperemia. We hypothesized that coronary reactive hyperemia involves A(2A) receptors, hydrogen peroxide (H(2)O(2)), and KATP channels. We used A(2A) and A(2B) knockout (KO) and A(2A/2B) double KO (DKO) mouse hearts for Langendorff experiments. Flow debt for a 15-s occlusion was repaid 128 ± 8% in hearts from wild-type (WT) mice; this was reduced in hearts from A(2A) KO and A(2A)/(2B) DKO mice (98 ± 9 and 105 ± 6%; P < 0.05), but not A(2B) KO mice (123 ± 13%). Patch-clamp experiments demonstrated that adenosine activated glibenclamide-sensitive KATP current in smooth muscle cells from WT and A(2B) KO mice (90 ± 23% of WT) but not A(2A) KO or A(2A)/A(2B) DKO mice (30 ± 4 and 35 ± 8% of WT; P < 0.05). Additionally, H(2)O(2) activated KATP current in smooth muscle cells (358 ± 99%; P < 0.05). Catalase, an enzyme that breaks down H(2)O(2), attenuated adenosine-induced coronary vasodilation, reducing the percent increase in flow from 284 ± 53 to 89 ± 13% (P < 0.05). Catalase reduced the repayment of flow debt in hearts from WT mice (84 ± 9%; P < 0.05) but had no effect on the already diminished repayment in hearts from A(2A) KO mice (98 ± 7%). Our findings suggest that adenosine A(2A) receptors are coupled to smooth muscle KATP channels in reactive hyperemia via the production of H(2)O(2) as a signaling intermediate.

Fenofibrate improves endothelial function in the brachial artery and forearm resistance arterioles of statin-treated Type 2 diabetic patients

Dyslipidaemia contributes to endothelial dysfunction and CVD (cardiovascular disease) in Type 2 diabetes mellitus. While statin therapy reduces CVD in these patients, residual risk remains high. Fenofibrate corrects atherogenic dyslipidaemia, but it is unclear whether adding fenofibrate to statin therapy lowers CVD risk. We investigated whether fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. In a cross-over study, 15 statin-treated Type 2 diabetic patients, with LDL (low-density lipoprotein)-cholesterol <2.6 mmol/l and endothelial dysfunction [brachial artery FMD (flow-mediated dilatation) <6.0%] were randomized, double-blind, to fenofibrate 145 mg/day or matching placebo for 12 weeks, with 4 weeks washout between treatment periods. Brachial artery FMD and endothelium-independent NMD (nitrate-mediated dilatation) were measured by ultrasonography at the start and end of each treatment period. PIFBF (post-ischaemic forearm blood flow), a measure of microcirculatory endothelial function, and serum lipids, lipoproteins and apo (apolipoprotein) concentrations were also measured. Compared with placebo, fenofibrate increased FMD (mean absolute 2.1+/-0.6 compared with -0.3+/-0.6%, P=0.04), but did not alter NMD (P=0.75). Fenofibrate also increased maximal PIFBF {median 3.5 [IQR (interquartile range) 5.8] compared with 0.3 (2.1) ml/100 ml/min, P=0.001} and flow debt repayment [median 1.0 (IQR 3.5) compared with -1.5 (3.0) ml/100 ml, P=0.01]. Fenofibrate lowered serum cholesterol, triacylgycerols (triglycerides), LDL-cholesterol, apoB-100 and apoC-III (P < or = 0.03), but did not alter HDL (high-density lipoprotein)-cholesterol or apoA-I. Improvement in FMD was inversely associated with on-treatment LDL-cholesterol (r=-0.61, P=0.02) and apoB-100 (r=-0.54, P=0.04) concentrations. Fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. This may relate partly to enhanced reduction in LDL-cholesterol and apoB-100 concentrations.

Metabolic syndrome reduces the contribution of K+ channels to ischemic coronary vasodilation

This investigation tested the hypothesis that metabolic syndrome decreases the relative contribution of specific K(+) channels to coronary reactive hyperemia. Ca(2+)-activated (BK(Ca)), voltage-activated (K(V)), and ATP-dependent (K(ATP)) K(+) channels were investigated. Studies were conducted in anesthetized miniature Ossabaw swine fed a normal maintenance diet (11% kcal from fat) or an excess calorie atherogenic diet (43% kcal from fat, 2% cholesterol, 20% kcal from fructose) for 20 wk. The latter diet induces metabolic syndrome, increasing body weight, fasting glucose, total cholesterol, and triglyceride levels. Ischemic vasodilation was determined by the coronary flow response to a 15-s occlusion before and after cumulative administration of antagonists for BK(Ca) (penitrem A; 10 microg/kg iv), K(V) (4-aminopyridine; 0.3 mg/kg iv) and K(ATP) (glibenclamide; 1 mg/kg iv) channels. Coronary reactive hyperemia was diminished by metabolic syndrome as the repayment of flow debt was reduced approximately 30% compared with lean swine. Inhibition of BK(Ca) channels had no effect on reactive hyperemia in either lean or metabolic syndrome swine. Subsequent inhibition of K(V) channels significantly reduced the repayment of flow debt ( approximately 25%) in both lean and metabolic syndrome swine. Additional blockade of K(ATP) channels further diminished ( approximately 45%) the repayment of flow debt in lean but not metabolic syndrome swine. These data indicate that the metabolic syndrome impairs coronary vasodilation in response to cardiac ischemia via reductions in the contribution of K(+) channels to reactive hyperemia.

Relationship between endogenous concentrations of vasoactive substances and measures of peripheral vasodilator function in patients with coronary artery disease

1. The aim of the present study was to determine the relationship between plasma concentrations of nitrite/nitrate (NO(x)) and endothelin (ET)-1 and non-invasive measures of peripheral vasodilator function in patients with coronary artery disease (CAD). 2. Twenty-two patients with angiographic CAD underwent non-invasive measurement of peripheral vasodilator function in the brachial conduit artery (flow-mediated dilation (FMD) testing via ultrasound) and in the forearm resistance arteries (via venous occlusion plethysmography) during reactive hyperaemia after 5 min ischaemia. In addition, plasma NO(x) and ET-1 concentrations were determined. 3. The plasma concentration of NO(x) was related to the peak brachial FMD response when expressed as either the relative (%) or absolute (mm) change in diameter (r = 0.73, P < 0.001; and r = 0.64, P < 0.01, respectively). Moreover, plasma concentrations of NO(x) demonstrated a relationship with forearm vasodilation estimated by total forearm blood flow following 5 min ischaemia (r = 0.63, P < 0.01) and the flow debt repayment of the forearm (r = 0.54, P < 0.01). Finally, ET-1 concentrations were inversely related to FMD% (r = -0.45, P < 0.05). 4. The findings of the present study demonstrate a relationship between the plasma concentrations of NO(x) and measures of vascular reactivity in conduit and resistance arteries in patients with CAD. Therefore, measurement of plasma NO(x) may serve as a reliable marker for peripheral vasodilator dysfunction in patients with CAD.

Effects of the prototype serotonin 5-HT 1B/1D receptor agonist sumatriptan and the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP 8–37 on myocardial reactive hyperemic response in conscious dogs

The triptans, serotonin 5-HT 1B/1D receptor agonists exemplified by sumatriptan, are a mainstay migraine therapy but have class labeling contraindicating their use in patients with coronary artery disease. Triptans constrict human coronary artery in vitro, and there are case reports of myocardial infarction in patients using sumatriptan. However, preclinical studies with sumatriptan in normal dogs have failed to demonstrate effects on resting coronary flow. Calcitonin gene-related peptide (CGRP) receptor antagonism, exemplified by the prototype CGRP receptor antagonist peptide CGRP 8–37, is a new antimigraine mechanism which also has been reported to have no effect on coronary flow in normal, non-stressed animals. The goal of the present studies was to compare the effects of sumatriptan (10 μg/kg/min i.v.) and CGRP 8–37 (30 μg/kg/min i.v.) on systemic and coronary hemodynamics in conscious dogs under resting conditions and during myocardial reactive hyperemia following a brief 15 s of coronary artery occlusion. Neither CGRP 8–37 nor sumatriptan affected resting coronary flow. However, whereas CGRP 8–37 had no effect on myocardial reactive hyperemic response, sumatriptan reduced peak reactive hyperemic coronary artery blood flow (baseline vs treatment: 75.4 ± 12.7 vs 60.0 ± 10.3 ml/min, P < 0.05), reactive hyperemic flow (16.7 ± 5.2 vs 11.6 ± 3.3 ml, P < 0.05) and the repayment of coronary blood flow debt following coronary artery occlusion (484 ± 76 vs 369 ± 57%, P < 0.05), indicating an impairment in coronary blood flow reserve. The positive control nitric oxide synthase inhibitor L-NNA (30 mg/kg/30 min i.v.) likewise significantly attenuated myocardial reactive hyperemic response. These findings provide evidence for a differentiation between CGRP receptor antagonism and triptan effects on coronary vascular function.

Effects of Fuscoporia obliqua on Postprandial Glucose Excursion and Endothelial Dysfunction in Type 2 Diabetic Patients

Postprandial hyperglycemia has been reported to elicit endothelial dysfunction and provoke future cardiovascular complications. A reduction of postprandial blood glucose levels by the glucosidase inhibitor Fuscoporia obliqua was associated with a risk reduction of cardiovascular complications, but the effects of Fuscoporia obliqua on endothelial function have never been elucidated. This study is aimed to assess the efficacy of Fuscoporia obliqua on postprandial metabolic parameters and endothelial function in type 2 diabetic patients. Postprandial peak glucose (14.47 +/- 1.27 vs. 8.50 +/- 0.53 mmol/liter), plasma glucose excursion (PPGE), and change in the area under the curve (AUC) glucose after a single loading of test meal (total 450 kcal; protein 15.3%; fat 32.3%; carbohydrate 51.4%) were significantly higher in the diet-treated type 2 diabetic patients (n=14) than the age- and sex-matched controls (n=12). The peak forearm blood flow response and total reactive hyperemic flow (flow debt repayment) during reactive hyperemia, indices of resistance artery endothelial function on strain-gauge plethysmography, were unchanged before and after meal loading in the controls. But those of the diabetics were significantly decreased 120 and 240 min after the test meal. A prior administration of Fuscoporia obliqua decreased postprandial peak glucose, PPGE, and AUC glucose. The peak forearm blood flow and flow debt repayment were inversely well correlated with peak glucose, PPGE, and AUC glucose, but not with AUC insulin or the other lipid parameters. Even a single loading of the test meal was shown to impair the endothelial function in type 2 diabetic patients, and the postprandial endothelial dysfunction was improved by a prior use of Fuscoporia obliqua. Fuscoporia obliqua might reduce macrovascular complication by avoiding endothelial injury in postprandial hyperglycemic status.

Short-term Low-dosage Pioglitazone Treatment Improves Vascular Dysfunction in Patients with Type 2 Diabetes

Endothelial dysfunction is an early marker of atherosclerosis. Pioglitazone is commonly used in the treatment of type 2 diabetes and has vascular protective effects beyond its hypoglycemic ones. We investigated the vascular effects of short-term, low-dosage pioglitazone in patients with type 2 diabetes. The study included 15 subjects with type 2 diabetes with normoalbuminuria (age, 60.7 +/- 11.9 years; body mass index [BMI], 23.9 +/- 3.3 kg/m2). The patients received pioglitazone at 15 mg daily for 4 weeks. BMI, systolic and diastolic blood pressure, laboratory parameters (fasting plasma glucose, insulin, lipid profile, high-sensitive C-reactive protein [hsCRP], and adiponectin) were assessed at baseline and after treatment. The forearm blood flow (FBF) was measured during reactive hyperemia by strain-gauge plethysmography. Short-term, low-dosage pioglitazone did not improve glycemic control or insulin sensitivity. However, the peak FBF and flow debt repayment (FDR) were markedly improved. There was no correlation of the improvement of peak FBF and FDR with the observed changes of metabolic parameters. However, the increment of adiponectin and decrement of hsCRP were well correlated with the improvement of peak FBF. These results indicate that short-term low-dosage pioglitazone may improve vascular function via increasing adiponectin expression and decreasing low-grade inflammation in type 2 diabetic patients.

Erectile dysfunction predicts generalised cardiovascular disease: Evidence from a case–control study

Aims To determine whether idiopathic erectile dysfunction, in the absence of overt cardiovascular disease or cardiovascular risk factors, is associated with vascular or autonomic dysfunction. Methods We studied 49 men with ED (without known cardiovascular risk factors or disease) and 50 age-matched controls, aged 40–70 years. Macrovascular endothelial function was examined by brachial artery ultrasonography and microvascular function by venous occlusion plethysmography. Blood pressure measurement and electrocardiography were performed lying and standing, and the 30:15 RR ratio calculated. Results Body mass index, testosterone, fasting lipids and glucose did not differ significantly between groups. Standing pulse pressure was higher (50 ± 1 mm Hg versus 43 ± 2 mm Hg, p < 0.004) and 30:15 RR ratio lower (0.97 ± 0.01 versus 1.01 ± 0.01, p < 0.02) in the ED group. Flow-mediated dilatation of the brachial artery was not significantly different between groups. Flow debt repayment during forearm reactive hyperaemia was lower in the ED group (7.2 ± 0.7 ml versus 9.5 ± 0.8 ml per 100 ml, p < 0.02) than in controls. Conclusions Men with idiopathic ED have evidence of endothelial dysfunction in forearm resistance vessels, increased pulse pressure and impaired heart rate variability. This supports the concept that erectile dysfunction is a predictor of cardiovascular dysfunction and a precursor of clinical cardiovascular disease.

Comparison of the antioxidant and vascular effects of gliclazide and glibenclamide in Type 2 diabetic patients: A randomized crossover study

The aim of the present study is to compare the short-term effects of gliclazide and glibenclamide on the oxidative state and vascular endothelium function of Type 2 diabetic patients in an observer-blinded, randomized crossover study. Thirteen Type 2 diabetic patients were enrolled: one group of seven patients took daily 160 mg of gliclazide for the first 4 weeks and then daily 5 mg of glibenclamide for the next 4 weeks; another group of six patients took daily 5 mg of glibenclamide for the first 4 weeks and 160 mg of gliclazide for the next 4 weeks. Forearm blood flow (FBF) measurement for endothelial function and biochemical analyses were conducted before and after each crossover treatment. Four weeks of treatment with either sulfonylurea showed the similar antihyperglycemic effects and enhancement of the peak FBF and total reactive hyperemic flow (flow debt repayment: FDR) during reactive hyperemia. Treatment with gliclazide resulted in the significant reduction to about 60% of baseline in urinary 8- iso-prostaglandin F 2α (8iPGF 2α) excretion while no such change was detected in the glibenclamide period. The increases in peak FBF and FDR were in parallel with its anti-hyperglycemic effect, but not with antioxidant state. Results suggest that gliclazide and glibenclamide can protect vascular endothelium from hyperglycemia-induced injury in Type 2 diabetic patients.

Effects of a Single Administration of Acarbose on Postprandial Glucose Excursion and Endothelial Dysfunction in Type 2 Diabetic Patients: A Randomized Crossover Study

Postprandial hyperglycemia has been reported to elicit endothelial dysfunction and provoke future cardiovascular complications. A reduction of postprandial blood glucose levels by the alpha-glucosidase inhibitor acarbose was associated with a risk reduction of cardiovascular complications, but effects of acarbose on endothelial function have never been elucidated. This study was aimed to assess the efficacy of acarbose on postprandial metabolic parameters and endothelial function in type 2 diabetic patients. Postprandial peakglucose (14.47 +/- 1.27 vs. 8.50 +/- 0.53 mmol/liter), plasma glucose excursion (PPGE), and change in the area under the curve (DeltaAUC)glucose after a single loading of test meal (total 450 kcal; protein 15.3%; fat 33.3%; carbohydrate 51.4%) were significantly higher in diet-treated type 2 diabetic patients (n = 14) than age- and sex-matched controls (n = 12). The peak forearm blood flow response and total reactive hyperemic flow (flow debt repayment) during reactive hyperemia, indices of resistance artery endothelial function on strain-gauge plethysmography, were unchanged before and after meal loading in controls. But those of diabetics were significantly decreased 120 and 240 min after the test meal. A prior administration of acarbose decreased postprandial peakglucose, PPGE, and DeltaAUCglucose. The peak forearm blood flow and flow debt repayment were inversely well correlated with peakglucose, PPGE, and DeltaAUCglucose but not with DeltaAUCinsulin or the other lipid parameters. Even a single loading of test meal was shown to impair endothelial function in type 2 diabetic patients, and the postprandial endothelial dysfunction was improved by a prior use of acarbose. Acarbose might reduce macrovascular complication by avoiding endothelial injury in postprandial hyperglycemic status.

Forearm reactive hyperemia and mortality in end-stage renal disease

Reports on the general population indicated that decreased endothelial-mediated vasodilation has a prognostic impact on cardiovascular (CV) morbidity and mortality. Flow-dependent vasodilation of conduit arteries and ischemia-induced forearm reactive hyperemia are impaired in end-stage renal disease (ESRD). Whether deterioration of vasodilator function in ESRD patients has a prognostic impact has not been documented. The aim of this study was to determine whether the impaired forearm postischemic vasodilation is an independent predictor of mortality in ESRD patients, independently from CV end-organ damages, which are usually associated with decreased vasodilatory response. Common carotid artery intima-media thickness (CCA-IMT), aortic stiffness (pulse wave velocity-PWV), and LV mass (LVM) were determined for 78 stable ESRD patients on hemodialysis. Forearm postischemic vasodilation [flow debt repayment (FDR)] was measured by venous plethysmography. All-cause mortality served as the outcome variable over a median follow-up of 60 +/- 27 months. Twenty-four deaths occurred (16 of CV origin). According to Cox regression adjusted for age, CCA-IMT, LVM, and PWV, all-cause mortality was independently associated with decreased FDR (RR 0.69 for every 10% increase; 95% CI 0.56-0.85; P= 0.0006) and increased aortic PWV (RR 1.16 for 1 m/s increase; 95% CI 1.04-1.29; P= 0.0091). Our data indicate that lower postischemic forearm reactive hyperemia is associated with all-cause mortality of ESRD patients, independently of the presence of end-organ damage such as LVH or arteriosclerosis.

Vascular function of the peripheral circulation in patients with nephrosis

Nephrotic syndrome is associated with abnormal lipoprotein metabolism and increased risk of coronary heart disease. Endothelial dysfunction, an early phase of atherogenesis that manifests as impaired flow-mediated dilation (FMD) of the peripheral circulation, may link these associations. We examined endothelial function of the brachial artery and forearm resistance arteries in 15 patients with nephrosis (NP), 15 patients with primary hyperlipidemia (HL) alone, and 15 normolipidemic, nonproteinuric subjects (NC) matched for age, sex, and weight. The NP and HL groups had similar serum cholesterol and triglyceride concentrations. Post-ischemic FMD (endothelium-dependent) and glyceryl trinitrate-mediated dilation (GTNMD; endothelium-independent) of the brachial artery were studied using ultrasonography and computerized edge detection software. Postischemic forearm blood flow was also measured using plethysmography. Postischemic FMD of the brachial artery was significantly lower in the NP and HL groups compared with NC group (mean +/- SE): NP 4.91 +/- 0.8%, HL 4.53 +/- 0.6%, NC 8.45 +/- 0.5% (P < 0.001). There were no significant differences among the groups in baseline diameter and GTNMD of the brachial artery, nor in maximal forearm blood flow and flow debt repayment of the forearm microcirculation. Significant differences in FMD among the groups were principally related to differences in serum low-density lipoprotein cholesterol. Patients with NP have abnormal endothelium-dependent but preserved endothelium-independent dilation of the brachial artery following an ischemic stimulus. Postischemic forearm microcirculatory function is unimpaired. Dyslipoproteinemia is probably the principal cause of endothelial dysfunction of conduit arteries in patients with NP and the basis for their increased risk of cardiovascular disease.

Investigation of mechanisms that mediate reactive hyperaemia in guinea-pig hearts: role of K(ATP) channels, adenosine, nitric oxide and prostaglandins.

1. Reactive hyperaemia is a transient vasodilatation following a brief ischaemic period. ATP-dependent K(+) (K(ATP)) channels may be important in mediating this response, however it is unclear whether mitochondrial K(ATP) channels contribute to this in the heart. 2. We examined the involvement of K(ATP) channels and the relative role of mitochondrial channels as mediators of coronary reactive hyperaemia and compared them to mechanisms involving NO, prostaglandins and adenosine in the guinea-pig isolated heart. 3. Reactive hyperaemic vasodilatation (peak vasodilator response and flow debt repayment) were assessed after global zero-flow ischaemia (5 -- 120 s) in the presence of nitro-L-arginine methyl ester (L-NAME, 10(-5) M, n=9), 8-phenyltheophylline (8-PT, 10(-6) M, n=12) and indomethacin (10(-5) M, n=12). 4. Glibenclamide (10(-6) M, n=12) a non-selective K(ATP) channel inhibitor and 5-hydroxy-decanoic acid (5-HD, 10(-4) M, n=10) a selective mitochondrial K(ATP) channel inhibitor were also used. The specificity of the effects of glibenclamide and 5-HD (n=6 each) were confirmed using pinacidil (38 nmol -- 10 micromol) and diazoxide (42 nmol -- 2 micromol). Glibenclamide was most effective in blocking the hyperaemic response (by 87%, P<0.001) although 5-HD and 8-PT also had a marked effect (40% inhibition, P<0.001 and 32%, P<0.001, respectively). L-NAME and indomethacin had little effect. 5. Perfusion with L-NAME and glibenclamide significantly reduced baseline coronary flow (22%, P<0.01 and 33%, P<0.01) while 8-PT, indomethacin and 5-HD had no effect. 6. K(ATP) channels are the major mediators of the coronary reactive hyperaemic response in the guinea-pig. Although mitochondrial K(ATP) channels contribute, they appear less important than sarcolemmal channels.

Platelet glycoprotein IIb/IIIa receptor inhibitor preserves coronary flow reserve during progressive coronary arteriostenosis in swine.

Thrombosis resulting from blood platelet aggregation via glycoprotein (GP) IIb/IIIa receptor activation triggers the local release of vasoactive substances. Therefore, inhibition of these receptors could affect coronary vasoactive function during thrombotic coronary arteriostenosis. Twenty pigs were instrumented with an aortic catheter and with hydraulic occluders and flow probes on both the left anterior descending (LAD) and the left circumflex (LCx) coronary arteries. One of these 2 coronary arteries was repeatedly injured by external clamping for 15-second periods at 30-minute intervals while the pigs were given either a GP IIb/IIIa receptor inhibitor (L-739,758) (n=5), heparin (n=5), aspirin (n=3), or saline (n=7). There were no baseline differences between the 4 groups in mean arterial pressure, resting coronary blood flow (CBF), or reactive hyperemic response (RHR), which was induced by brief coronary artery occlusion and expressed as flow debt repayment. After multiple injuries, resting CBF had decreased by 95+/-2% (ie, nearly complete coronary artery occlusion) at 15+/-4 minutes in the control group, whereas in the heparin-, aspirin-, and GP IIb/IIIa inhibitor-treated groups, resting CBF had decreased by only 21+/-7% at 18+/-3 minutes, 15+/-3% at 18+/-5 minutes, and 15+/-7% at 21+/-4 minutes, respectively, suggesting that heparin, aspirin, and the GP IIb/IIIa inhibitor each prevented injury-induced coronary artery occlusion. After the initial injury, the RHR was progressively reduced in the control and heparin- and aspirin-treated groups but not in the GP IIb/IIIa inhibitor-treated group. At a comparable level of resting CBF ( approximately 15% below baseline), the RHR was reduced more in the control (-56+/-9%), heparin-treated (-49+/-9%), and aspirin-treated (-61+/-12) groups (P:<0.05) than in the GP IIb/IIIa inhibitor-treated group (-26+/-6%). When the resting CBF had decreased by approximately 35%, the RHR still was reduced significantly more (P<0.01) in the heparin-treated group (-64+/-9%) than in the GP IIb/IIIa inhibitor-treated group (-21+/-6%). In a separate group of control pigs (n=4) subjected to 2 injuries, coronary perfusion pressure distal to the injury site was reduced by 14+/-1 mm Hg from the arterial pressure, and the RHR was 20+/-6%. When the distal coronary perfusion pressure was reduced similarly (-14+/-1 mm Hg) in a separate group of GP IIb/IIIa inhibitor-treated pigs (n=4) by 2 injuries and the use of a hydraulic occluder, the RHR was 130+/-16% (P<0.01 versus control). Our data demonstrate for the first time that a platelet GP IIb/IIIa receptor inhibitor can preserve the distal coronary vasodilatory response during progressive coronary arteriostenosis.

Calf and forearm blood flow in hypercholesterolemic patients.

Patients with hypercholesterolemia without vascular disease have an impaired endothelium-dependent (nitric oxide-mediated) vasodilation in coronary and peripheral vascular beds. This study was designed to establish whether hypercholesterolemia (and its reduction) affects also the microcirculation vasomotion during postischemic hyperemia in both calf and forearm. Thirteen male patients, aged 36.2+/-8.5 years, mean +/-SD, with heterozygous familial hypercholesterolemia and 10 male control subjects, aged 32.2+/-3.6 years free from vascular lesions were studied. Plasma lipids, hematologic parameters, and limb vasoreactivity were evaluated while the patients were treated only with diet and during therapy with simvastatin. Calf and forearm blood flows were determined by venous occlusion strain gauge plethysmography at rest, during reactive hyperemia, and after sublingual isosorbide dinitrate administration. Calf resting flow rate of the hypercholesterolemic patients during and without treatment was similar to that of the controls. Calf resting vascular resistance was greater in the untreated hypercholesterolemic subjects than in the normal controls, but during treatment this difference was abolished. Peak flow during reactive hyperemia and flow debt repayment were lower in the untreated hypercholesterolemic subjects as compared to the controls, but they were normalized following hypocholesterolemic therapy. No differences were observed in forearm blood flow measurements between hypercholesterolemic subjects (without and during therapy) and control subjects. The blood flow and vascular resistance after isosorbide dinitrate were modified in a similar manner in the hypercholesterolemic (without and during therapy) and control subjects at both calf and forearm. Hypercholesterolemia does not affect vasodilation in the forearm as determined by postocclusive reactive hyperemia, while in the calf hypercholesterolemia is associated with higher resting vascular resistance, lower peak flow during reactive hyperemia, and lower flow debt repayment. These abnormalities are corrected by the hypocholesterolemic treatment.

Postischemic vasodilation, endothelial activation, and cardiovascular remodeling in end-stage renal disease

Cardiovascular complications are the major cause of death in end-stage renal disease (ESRD) patients. These complications are associated with concomitant cardiac and vascular remodeling, including left ventricular (LV) hypertrophy and hypertrophy of arterial walls. The endothelium influences the process of arterial remodeling. ESRD patients are characterized by the development of both cardiovascular remodeling and endothelial dysfunction. Common carotid artery (CCA) intima-media thickness (IMT), CCA diameter, CCA distensibility, LV mass, and function were determined in 60 stable ESRD patients on hemodialysis and 34 age-, sex-, and blood pressure (BP)-matched controls, and their relationships with endothelial alterations were estimated by forearm postischemic vasodilation [flow debt repayment (FDR)] measured by venous plethysmography. We also evaluated the relationships between FDR and several cardiovascular risk factors or markers of inflammatory response or endothelial activation, for example, duration of dialysis, BP, smoking habits, cholesterol, parathormone (PTH), serum albumin, plasma fibrinogen, C-reactive protein (CRP), plasma homocysteine, plasminogen activator inhibitor (PAI-1), and von Willebrand factor (vWF). ESRD patients had increased LV mass, CCA diameter and CCA IMT, and had decreased CCA distensibility (P < 0.05). While the postischemic peak flow was comparable in controls and ESRD patients (29.2 +/- 9.1 vs. 27.9 +/- 0.2 mL/100 mL/min), FDR was lower in ESRD patients (116 +/- 31 vs. 88 +/- 32%, P < 0.001) because of the shorter duration of vasodilation (127 +/- 36 vs. 96 +/- 32 s, P < 0.001). The time to complete FDR was longer in ESRD patients (110 +/- 54 vs. 162 +/- 72 s, P < 0.001). ESRD patients had lower high-density lipoprotein cholesterol and serum albumin (P < 0.01) and higher triglycerides, fibrinogen, plasma homocysteine, vWF (P < 0.01), and PAI-1 (P < 0.05). For ESRD patients, significant negative age- and pressure-independent correlations were established between FDR and CCA diameter, duration of dialysis, and PAI-1. FDR was positively correlated with serum albumin. FDR and time to FDR were negatively correlated with CCA IMT and LV mass. CCA distensibility was positively associated with FDR (P < 0.001) and negatively with time to FDR (P < 0.001). The PAI-1 concentration was positively correlated with CCA IMT (P < 0.01) and negatively with CCA distensibility (P < 0.001). Our data provide the first evidence that cardiac and arterial remodeling in ESRD patients are inversely related to forearm reactive hyperemia. The diminished hyperemic response is due to the shorter duration of hyperemia and is associated with higher concentrations of serum markers of endothelial activation, suggesting that, in ESRD patients, endothelial dysfunction may be a factor influencing cardiovascular changes.

Preconditioning with Ischaemia Reduces Both Myocardial Oxygen Consumption and Infarct Size in a Graded Pattern

We tested the hypothesis that ischaemic preconditioning reduces pre-ischaemic energy demand and thereby reduces the energy supply–demand mismatch imposed by coronary artery occlusion. Experiments were performed in 52 open chest pigs anaesthetised with sodium pentobarbital. One or two cycles, each of 10 min LAD occlusion followed by 30 min reperfusion, served as the preconditioning stimuli. The degree of protection was evaluated by measuring infarct size (tetrazolium stain) as percentage of area at risk (fluorescent particles) after 45 min LAD occlusion followed by 2 h reperfusion. One preconditioning cycle reduced regional myocardial oxygen consumption (MVO2) by 15±3% (P<0.05), whereas two cycles of preconditioning reduced MVO2by 25±3% (P<0.05vone cycle). This reduction was probably due to reduced energy demand, as both coronary blood flow and arteriovenous oxygen differences decreased, without lactate release or reduction in peak hyperaemic flow response. Energy requirements were most likely also reduced during ischaemia since repayment of flow debt after the second ischaemic period was 33±7% less than after the first ischaemic period (P<0.001). One preconditioning cycle reduced infarct size from 58±3% of area at risk to 40±5% (P<0.05), whereas two cycles of preconditioning reduced infarct size to 15±4% of area at risk (P<0.05vone cycle). We conclude that preconditioning with ischaemia reduces energy consumption in a graded pattern. This effect may contribute to the graded protective effect of ischaemic preconditioning.