Although having no apparent effect on venous tone, apelin causes nitric oxide-dependent arterial vasodilation in vivo in man. The apelin-APJ system merits further clinical investigation to determine its role in cardiovascular homeostasis.

Background-Endothelin (ET) is implicated in the pathophysiology of chronic renal failure (CRF). We therefore studied the systemic and renal hemodynamic effects of ET receptor antagonists in CRF and examined differences between selective ETA, selective ETB, and combined ETA/B receptor blockade. Methods and Results-We conducted a randomized, placebo-controlled, double-blind, 4-way crossover study comparing selective ET receptor antagonists BQ-123 (ETA) and BQ-788 (ETB), given alone and in combination, in acute studies in 8 hypertensive CRF patients and 8 matched healthy controls. BQ-123, alone and in combination with BQ-788, reduced blood pressure in CRF, particularly with BQ-123 alone (mean arterial pressure: controls Ϫ4Ϯ2%, CRF Ϫ13Ϯ2%, PϽ0.01 versus placebo). In CRF, in the face of this fall in blood pressure, BQ-123 substantially increased renal blood flow (38.8Ϯ23.9%, PϽ0.01 versus placebo) and reduced renal vascular resistance (Ϫ44.5Ϯ11.3%, PϽ0.01 versus placebo) when given alone but not when combined with BQ-788. These changes were accompanied by a reduction in effective filtration fraction. BQ-123, alone or in combination with BQ-788, had minimal effects on the renal circulation in healthy controls, and BQ-788 alone produced both systemic and renal vasoconstriction in CRF and healthy controls. Conclusions-ETA receptor antagonism was highly effective in lowering blood pressure in CRF patients currently treated for hypertension. In addition, there were effects consistent with a renoprotective action. However, because the ETB receptor appears to play a key role in the maintenance of tonic renal vasodilation, combined ETA/B receptor antagonism, although it lowered blood pressure, did not confer these renal benefits.

2؉oscillations arising through activation of the metabotropic glutamate receptor mGluR5a expressed in Chinese hamster ovary cells and find that these oscillations are largely insensitive to agonist concentration. Using an inducible receptor expression system and a non-competitive antagonist, in conjunction with the translocation of eGFP-PH PLC␦ to monitor inositol 1,4,5-trisphosphate (InsP 3 ) oscillations in single cells, we show that mGluR5a density determines the frequency of these oscillations. The predominant underlying mechanism resulted from a negative feedback loop whereby protein kinase C (PKC) inhibited InsP 3 generation. Down-regulation of PKC by prolonged exposure to phorbol ester revealed a second form of Ca

Background-Apelin, the endogenous ligand for the novel G protein-coupled receptor APJ, has major cardiovascular effects in preclinical models. The study objectives were to establish the effects of acute apelin administration on peripheral, cardiac, and systemic hemodynamic variables in healthy volunteers and patients with heart failure. Methods and Results-Eighteen patients with New York Heart Association class II to III chronic heart failure, 6 patients undergoing diagnostic coronary angiography, and 26 healthy volunteers participated in a series of randomized, double-blind, placebo-controlled studies. Measurements of forearm blood flow, coronary blood flow, left ventricular pressure, and cardiac output were made by venous occlusion plethysmography, Doppler flow wire and quantitative coronary angiography, pressure wire, and thoracic bioimpedance, respectively. Intrabrachial infusions of (Pyr 1 )apelin-13, acetylcholine, and sodium nitroprusside caused forearm vasodilatation in patients and control subjects (all PϽ0.0001). Vasodilatation to acetylcholine (Pϭ0.01) but not apelin (Pϭ0.3) or sodium nitroprusside (Pϭ0.9) was attenuated in patients with heart failure. Intracoronary bolus of apelin-36 increased coronary blood flow and the maximum rate of rise in left ventricular pressure and reduced peak and end-diastolic left ventricular pressures (all PϽ0.05). Systemic infusions of (Pyr 1 )apelin-13 (30 to 300 nmol/min) increased cardiac index and lowered mean arterial pressure and peripheral vascular resistance in patients and healthy control subjects (all PϽ0.01) but increased heart rate only in control subjects (PϽ0.01). Conclusions-Acute apelin administration in humans causes peripheral and coronary vasodilatation and increases cardiac output. APJ agonism represents a novel potential therapeutic target for patients with heart failure. (Circulation.

Abstract-Proteinuria is associated with adverse cardiovascular and renal outcomes that are not prevented by current treatments.Endothelin 1 promotes the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism in proteinuric chronic kidney disease patients, assessing proteinuria, blood pressure (BP), and arterial stiffness, key independent, surrogate markers of chronic kidney disease progression and cardiovascular disease risk. In a randomized, double-blind, 3-way crossover study, 27 subjects on recommended renoprotective treatment received 6 weeks of placebo, 100 mg once daily of sitaxsentan, and 30 mg once daily of nifedipine long acting. Twenty-four-hour proteinuria, protein:creatinine ratio, 24-hour ambulatory BP, and pulse wave velocity (as a measure of arterial stiffness) were measured at baseline and week 6 of each treatment. In 13 subjects, renal blood flow and glomerular filtration rate were assessed at baseline and week 6 of each period.

Abstract-Endothelin-1 (ET-1) is an important mediator of vascular tone in humans, and a number of endothelin receptor antagonists are currently in clinical development as vasodilator agents. While the vasoconstrictor role of the ET A receptor is undisputed, the role of the ET B receptor remains unclear. Hemodynamic effects of systemic doses of the ET B -selective antagonist BQ-788 were investigated in 5 healthy male volunteers (age range, 33 to 48 years) in a placebo-controlled, four-way crossover study. After a 15-minute infusion of BQ-788 (3, 30, or 300 nmol/min) or placebo, plasma ET-1 and big ET-1, blood pressure, heart rate, cardiac index, and stroke index were measured. Total peripheral vascular resistance was calculated from cardiac index and mean arterial pressure. Hemodynamic data are expressed as maximum, placebo-corrected, percentage change from baseline following BQ-788 (300 nmol/min) and were examined by ANOVA. Plasma ET-1 increased by 3.7Ϯ1.2 pg/mL (maximum at 15 minutes, Pϭ0.02), whereas there was no significant change in plasma big ET-1. Although BQ-788 had no effect on mean arterial pressure, there was a reduction in heart rate (13Ϯ7% at 50 minutes; Pϭ0. Key Words: endothelin Ⅲ vasoconstriction Ⅲ blood pressure Ⅲ receptors, endothelin Ⅲ endothelin receptor antagonist T he importance of endothelin-1 (ET-1) as a mediator of basal vascular tone in vivo in humans has been demonstrated by local 1-3 and systemic 2 vasodilatation in response to endothelin receptor antagonism. The potent vasoconstrictor effects of ET-1, 4,5 combined with the increased plasma concentrations of ET-1 associated with cardiovascular diseases, including heart failure 6 and renal failure, 7 provide strong evidence to support a functional role for ET-1 in the development and maintenance of the increased peripheral vascular resistance associated with these conditions.The vascular effects of ET-1 are mediated by two distinct receptors: the ET-1-selective ET A receptor 8 and the nonisopeptide-selective ET B receptor. 9 The sustained vasoconstrictor effects of ET-1 are predominantly mediated by the ET A receptor, although vascular smooth muscle ET B receptors have also been described 10 and may, under some circumstances, contribute to ET-1-mediated vasoconstriction in animal models 11 and humans in vivo. 12 ET B receptors were first described on endothelial cells, where they act to modulate the vasoconstrictor effects of ET-1 through generation of nitric oxide 13 and prostacyclin. 14 The ET B receptor also has a role in the clearance of ET-1 from the circulation, 15 although the exact site of the clearance receptor remains to be confirmed. The contribution of the vascular ET B receptor to the recognized endogenous ET-1-mediated constrictor tone depends on the balance between the ET B receptor-mediated effects of vasodilatation, vasoconstriction, and ET-1 clearance.Local vasoconstriction to ET B receptor agonists has been described in healthy volunteers 12,16 and in patients with heart failure. 17 However, more recently, vasoconstri...

Dietary polyphenols, such as those from grape products, may exert beneficial effects on cardiovascular health, including anti-hypertensive effects. We investigated the effect of a specific grape seed extract (GSE) rich in low-molecular-weight polyphenolic compounds on ambulatory blood pressure (ABP) in untreated subjects with pre-and stage I hypertension. In addition, potential mechanisms that could underlie the hypothesised effect of GSE on blood pressure (BP), and platelet aggregation, were explored. The study was designed as a doubleblind, placebo-controlled, randomised, parallel-group intervention study including seventy healthy subjects with systolic BP between 120 and 159 mmHg. A 1-week run-in period was followed by an 8-week intervention period, during which subjects consumed capsules containing either 300 mg/d of GSE or a placebo (microcrystalline cellulose). Before and after the intervention, daytime ABP readings, 24 h urine samples and fasting and non-fasting blood samples were taken. The mean baseline systolic BP was 135·8 (SE 1·3) mmHg and diastolic BP was 81·5 (SE 0·9) mmHg. BP values were modestly, but not significantly, affected by the polyphenol-rich GSE treatment v. placebo with an effect of 23·0 mmHg for systolic BP (95 % CI 26·5, 0·5) and 2 1·4 mmHg for diastolic BP (95 % CI 2 3·5, 0·6). Vasoactive markers including endothelin-1, NO metabolites and asymmetric dimethylarginine, plasma renin activity and platelet aggregation were not affected by the GSE intervention. Our findings show that consumption of polyphenol-rich GSE does not significantly lower ABP in untreated subjects with pre-and stage I hypertension.

Abstract-Endothelin 1 is implicated in the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism with BQ-123 on key independent surrogate markers of cardiovascular risk (blood pressure, proteinuria and renal hemodynamics, arterial stiffness, and endothelial function) in patients with nondiabetic chronic kidney disease. In a double-blind, randomized crossover study, 22 subjects with proteinuric chronic kidney disease received, on 2 separate occasions, placebo or BQ-123. Ten of these subjects also received nifedipine (10 mg) as an active control for the antihypertensive effect of BQ-123. Blood pressure, pulse wave velocity, flow-mediated dilation, renal blood flow, and glomerular filtration rate were monitored after drug dosing. Key Words: endothelin Ⅲ blood pressure Ⅲ arterial stiffness Ⅲ proteinuria Ⅲ chronic kidney disease C hronic kidney disease (CKD) is common, affecting 6% to 11% of the population in the developed world. 1 Hypertension is a frequent finding in patients with CKD, 2 and its prevalence increases as CKD progresses. 3 Despite treatment with multiple antihypertensive agents, the majority of CKD patients fail to reach target blood pressure (BP). 4 Proteinuria is a common feature of CKD and is independently associated with an adverse renal outcome. 5 Current treatments for proteinuria focus on BP reduction, 5 ideally using angiotensin-converting enzyme (ACE) inhibitors 6 and angiotensin receptor blockers, 7 both of which are thought to reduce proteinuria to a greater extent than accounted for by BPlowering alone. 5 Nevertheless, many CKD patients have significant residual proteinuria despite optimal treatment. 8 CKD is also strongly associated with incident cardiovascular disease (CVD). 9 Hypertension 10 and proteinuria 11 make an important contribution to CVD risk in CKD, as do arterial stiffness 12 and endothelial dysfunction. 13 Thus, there remains an unmet need for newer treatments in CKD that will not only lower BP and proteinuria beyond the levels achieved with standard therapies but will also have favorable effects on arterial stiffness and endothelial dysfunction and so offer longer term cardiovascular and renal protection.Endothelin (ET) 1 is the most potent endogenous vasoconstrictor produced within the vasculature. It is implicated in both the development and progression of CKD. 14 The effects of ET-1 are mediated via 2 receptors, the ET A and ET B receptors, with the major pathological effects in CKD being ET A receptor mediated. 14 However, there are currently few human studies. 15,16 ET-1 also contributes to arterial stiffness 17 and endothelial dysfunction 18 in patients with CVD; however, there are no similar studies in CKD patients.Our group has shown previously that selective ET A receptor antagonism, but not mixed ET A/B antagonism, reduces BP, increases renal blood flow, and reduces the effective filtration fraction in patients with CKD. 15 However, this was a s...