Plasma levels of IL-6 correlate with high blood pressure under many circumstances, and ANG II has been shown to stimulate IL-6 production from various cell types. This study tested the role of IL-6 in mediating the hypertension caused by high-dose ANG II and a high-salt diet. Male C57BL6 and IL-6 knockout (IL-6 KO) mice were implanted with biotelemetry devices and placed in metabolic cages to measure mean arterial pressure (MAP), heart rate (HR), sodium balance, and urinary albumin excretion. Baseline MAP during the control period averaged 114 +/- 1 and 109 +/- 1 mmHg for wild-type (WT) and IL-6 KO mice, respectively, and did not change significantly when the mice were placed on a high-salt diet (HS; 4% NaCl). ANG II (90 ng/min sc) caused a rapid increase in MAP in both groups, to 141 +/- 9 and 141 +/- 4 in WT and KO mice, respectively, on day 2. MAP plateaued at this level in KO mice (134 +/- 2 mmHg on day 14 of ANG II) but began to increase further in WT mice by day 4, reaching an average of 160 +/- 4 mmHg from days 10 to 14 of ANG II. Urinary albumin excretion on day 4 of ANG II was not different between groups (9.18 +/- 4.34 and 8.53 +/- 2.85 microg/2 days for WT and KO mice). By day 14, albumin excretion was nearly fourfold greater in WT mice, but MAP dropped rapidly back to control levels in both groups when the ANG II was stopped after 14 days. Thus the approximately 30 mmHg greater ANG II hypertension in the WT mice suggests that IL-6 contributes significantly to ANG II-salt hypertension. In addition, the early separation in MAP, the albumin excretion data, and the rapid, post-ANG II recovery of MAP suggest an IL-6-dependent mechanism that is independent of renal injury.

Chronic angiotensin II (AngII) infusion stimulates IL-6 release, and we and others have shown that preventing the increase in IL-6 significantly attenuates AngII hypertension. This study measured renal blood flow (RBF) chronically, using Transonic flow probes in wildtype (WT) and IL-6 knockout (KO) mice, to determine the role of renal blood flow regulation in that response. AngII infusion at 200, 800, and 3600 ng/kg/min caused a dose-dependent decrease in renal blood flow in WT mice, and the response at 800 ng/kg/min was compared between WT and IL-6 KO mice. AngII infusion increased plasma IL-6 concentration in WT mice and increased MAP (19 hrs/day; DSI telemetry) from 113±4 to 149±4 mmHg (Δ 36 mmHg) over the 7-day infusion period, and that effect was blocked in IL-6 KO mice (119±7 to 126±7 mmHg). RBF decreased to an average of 61±8% of control over the 7-day period (control = 0.86±0.02 ml/min) in the WT mice; however, the average decrease to 72±6% of control (control = 0.88±0.02 ml/min) in the KO mice was not significantly different. There also was no difference in afferent arteriolar constriction by AngII in blood-perfused juxtamedullary nephrons in WT vs. KO mice. Phosphorylation of JAK2 and STAT3 in renal cortex homogenates increased significantly in AngII-infused WT mice, and that effect was prevented completely in AngII-infused IL-6 KO mice. These data suggest that IL-6-dependent activation of the renal JAK2/STAT3 pathway plays a role in AngII hypertension, but not by mediating the effect of AngII to decrease total renal blood flow.

Purpose of review Erectile dysfunction (ED) is recognized as a quality of life disorder that needs to be treated. Currently, it is estimated to affect as many as 30 million American men. Thirty percent of hypertensive patients complain of ED. The understanding of common mechanisms involved in the etiology of ED associated with hypertension, and the investigation of antihypertensive drugs that impact ED, will provide important tools toward indentifying new therapeutic targets that will improve the quality of life for patients in these conditions. Recent findings Hypertension and ED are closely intertwined diseases which have endothelium dysfunction as a common base. During hypertension and/or ED, disturbance of endothelium derived factors can lead to an increase in vascular smooth muscle (VSM) contraction. Hypertension can also lead to ED as a consequence of high blood pressure (BP) or due to antihypertensive treatment. However, growing evidence suggests ED as an early sign for hypertension. Also, some PDE-5 inhibitors used to treat ED can improve BP, but the link between these conditions has not been totally understood. Summary This review will discuss the interplay between hypertension and ED, exploring newest insights regarding hypertension-associated ED, as well as the effect of antihypertensive drugs in ED patients.

Metabolic syndrome (MetS) is a group of cardio-metabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia; these are also a combination of independent coronary artery disease (CAD) risk factors. Alarmingly, the prevalence of MetS risk factors are increasing and a leading cause for mortality. In the vasculature, complications from MetS and type 2 diabetes (T2D) can be divided into microvascular (retinopathy and nephropathy) and macrovascular (cardiovascular diseases and erectile dysfunction). In addition to vascular and endothelial dysfunction, vascular remodeling and stiffness are also hallmarks of cardiovascular disease (CVD), and well-characterized vascular changes that are observed in the early stages of hypertension, T2D, and obesity (1-3). In the heart, the link between obstructive atherosclerosis of coronary macrovessels and myocardial ischemia (MI) is well established. However, recent studies show that abnormalities in the coronary microcirculation are associated with functional and structural changes in coronary microvessels (classically defined as being <150-200 μm internal diameter), which may cause or contribute to MI even in the absence of obstractive CAD. This suggests a prognostic value of an abnormal coronary microcirculation as an early sub-clinical culprit in the pathogenesis and progression of heart disease in T2D and MetS. The aim of this review is to summarize recent studies investigating the coronary microvascular remodeling in an early pre-atherosclerotic phase of MetS and T2D, and to explore potential mechanisms associated with the timing of coronary microvascular remodeling relative to that of the macrovasculature.

Introduction Increased angiotensin II (AngII) levels cause hypertension, which is a major risk factor for erectile dysfunction (ED). Studies have demonstrated that increased AngII levels in penile tissue are associated with ED. A recent study showed that metformin treatment restored nitric oxide synthase (NOS) protein expression in penile tissue in obese rats; however, whether metformin treatment can be beneficial and restore erectile function in a model of ED has not yet been established. Aim The goal of this study was to test the hypothesis that AngII induces ED by means of increased corpus cavernosum contraction, and that metformin treatment will reverse ED in AngII-treated rats. Methods Male Sprague-Dawley rats were implanted with mini-osmotic pumps containing saline or AngII (70 ng/min, 28 days). Animals were then treated with metformin or vehicle during the last week of AngII infusion. Main Outcome Measures Intracavernosal pressure (ICP); corpus cavernosum contraction and relaxation; nNOS protein expression; extracellular signal-regulated kinase (ERK1/2), AMP-activated protein kinase (AMPK) and eNOS protein expression and phosphorylation. Results AngII induced ED was accompanied with an increase in corpus cavernusom contractility, decreased nitrergic relaxation and increased ERK1/2 phosphorylation. Metformin treatment improved erectile function in the AngII-treated rats by reversing the increased contraction and decreased relaxation. Metformin treatment also resulted in an increase in eNOS phosphorylation at ser1177. Conclusions Metformin treatment increased eNOS phosphorylation and improved erectile function in AngII hypertensive rats by re-establishing normal cavernosal smooth muscle tone.

Adenosine increases coronary flow mainly through the activation of A 2A and A 2B adenosine receptors (ARs). However, the mechanisms for the regulation of coronary flow are not fully understood. We previously demonstrated that adenosine-induced increase in coronary flow is in part through NADPH oxidase (Nox) activation, which is independent of activation of either A 1 or A 3 ARs. In this study, we hypothesize that adenosine-mediated increase in coronary flow through Nox activation depends on A 2A but not A 2B ARs. Functional studies were conducted using isolated Langendorff-perfused mouse hearts. Hydrogen peroxide (H 2 O 2 ) production was measured in isolated coronary arteries from WT, A 2A AR k n o c k o u t ( K O ) , a n d A 2 B A R K O m i c e u s i n g dichlorofluorescein immunofluorescence. Adenosineinduced concentration-dependent increase in coronary flow was attenuated by the specific Nox2 inhibitor gp91 ds-tat or reactive oxygen species (ROS) scavenger EUK134 in both WT and A 2B but not A 2A AR KO isolated hearts. Similarly, the A 2A AR selective agonist CGS-21680-induced increase in coronary flow was significantly blunted by Nox2 inhibition in both WT and A 2B AR KO, while the A 2B AR selective agonist BAY 60-6583-induced increase in coronary flow was not affected by Nox2 inhibition in WT. In intact isolated coronary arteries, adenosine-induced (10 μM) increase in H 2 O 2 formation in both WT and A 2B AR KO mice was attenuated by Nox2 inhibition, whereas adenosine failed to increase H 2 O 2 production in A 2A AR KO mice. In conclusion, adenosine-induced increase in coronary flow is partially mediated by Nox2-derived H 2 O 2 , which critically depends upon the presence of A 2A AR.

Hypertension is a disorder affecting millions worldwide, and is a leading cause of death and debilitation in the United States. It is widely accepted that during hypertension and other cardiovascular diseases the vasculature exhibits endothelial dysfunction; a deficit in the relaxatory ability of the vessel, attributed to a lack of nitric oxide (NO) bioavailability. Recently, the one electron redox variant of NO, nitroxyl anion (NO−) has emerged as an endothelium-derived relaxing factor (EDRF) and a candidate for endothelium-derived hyperpolarizing factor (EDRF). NO− is thought to exist protonated (HNO) in vivo, which would make this species more resistant to scavenging. However, no studies have investigated the role of this redox species during hypertension, and whether the vasculature loses the ability to relax to HNO. Thus, we hypothesize that aorta from angiotensin II (AngII)-hypertensive mice will exhibit a preserved relaxation response to Angeli’s Salt, an HNO donor. Male C57Bl6 mice, aged 12–14 weeks were implanted with mini-osmotic pumps containing AngII (90ng/min, 14 days plus high salt chow) or sham surgery. Aorta were excised, cleaned and used to perform functional studies in a myograph. We found that aorta from AngII-hypertensive mice exhibited a significant endothelial dysfunction as demonstrated by a decrease in acetylcholine (ACh)-mediated relaxation. However, vessels from hypertensive mice exhibited a preserved response to Angeli’s Salt (AS), the HNO donor. To confirm that relaxation responses to HNO were maintained, concentration response curves (CRCs) to ACh were performed in the presence of scavengers to both NO and HNO (carboxy-PTIO and L-cys, resp.). We found that ACh-mediated relaxation responses were significantly decreased in aorta from sham and almost completely abolished in aorta from AngII-treated mice. Vessels incubated with L-cys exhibited a modest decrease in ACh-mediated relaxations responses. These data demonstrate that aorta from AngII-treated hypertensive mice exhibit a preserved relaxation response to AS, an HNO donor, regardless of a significant endothelial dysfunction.

Uridine adenosine tetraphosphate (Up4A) exerts potent relaxation in porcine coronary arteries that is reduced following myocardial infarction, suggesting a crucial role for Up4A in the regulation of coronary flow (CF) in cardiovascular disorders. We evaluated the vasoactive effects of Up4A on CF in atherosclerosis using ApoE knockout (KO) mice ex vivo and in vivo. Functional studies were conducted in isolated mouse hearts using the Langendorff technique. Immunofluorescence was performed to assess purinergic P2X1 receptor (P2X1R) expression in isolated mouse coronary arteries. In vivo effects of Up4A on coronary blood flow (CBF) were assessed using ultrasound. Infusion of Up4A (10−9–10−5 M) into isolated mouse hearts resulted in a concentration-dependent reduction in CF in WT and ApoE KO mice to a similar extent; this effect was exacerbated in ApoE KO mice fed a high-fat diet (HFD). The P2X1R antagonist MRS2159 restored Up4A-mediated decreases in CF more so in ApoE KO + HFD than ApoE KO mice. The smooth muscle to endothelial cell ratio of coronary P2X1R expression was greater in ApoE KO + HFD than ApoE KO or WT mice, suggesting a net vasoconstrictor potential of P2X1R in ApoE KO + HFD mice. In contrast, Up4A (1.6 mg/kg) increased CBF to a similar extent among the three groups. In conclusion, Up4A decreases CF more in ApoE KO + HFD mice, likely through a net upregulation of vasoconstrictor P2X1R. In contrast, Up4A increases CBF in vivo regardless of the atherosclerotic model.