BACKGROUND. Cardiovascular disease occurs at lower incidence in premenopausal females compared with age-matched males. This variation may be linked to sex differences in inflammation. We prospectively investigated whether inflammation and components of the inflammatory response are altered in females compared with males.METHODS. We performed 2 clinical studies in healthy volunteers. In 12 men and 12 women, we assessed systemic inflammatory markers and vascular function using brachial artery flow-mediated dilation (FMD). In a further 8 volunteers of each sex, we assessed FMD response to glyceryl trinitrate (GTN) at baseline and at 8 hours and 32 hours after typhoid vaccine. In a separate study in 16 men and 16 women, we measured inflammatory exudate mediators and cellular recruitment in cantharidin-induced skin blisters at 24 and 72 hours.RESULTS. Typhoid vaccine induced mild systemic inflammation at 8 hours, reflected by increased white cell count in both sexes. Although neutrophil numbers at baseline and 8 hours were greater in females, the neutrophils were less activated. Systemic inflammation caused a decrease in FMD in males, but an increase in females, at 8 hours. In contrast, GTN response was not altered in either sex after vaccine. At 24 hours, cantharidin formed blisters of similar volume in both sexes; however, at 72 hours, blisters had only resolved in females. Monocyte and leukocyte counts were reduced, and the activation state of all major leukocytes was lower, in blisters of females. This was associated with enhanced levels of the resolving lipids, particularly D-resolvin.CONCLUSIONS. Our findings suggest that female sex protects against systemic inflammation-induced endothelial dysfunction. This effect is likely due to accelerated resolution of inflammation compared with males, specifically via neutrophils, mediated by an elevation of the D-resolvin pathway.TRIAL REGISTRATION. ClinicalTrials.gov NCT01582321 and NRES: City Road and Hampstead Ethics Committee: 11/LO/2038.FUNDING. The authors were funded by multiple sources, including the National Institute for Health Research, the British Heart Foundation, and the European Research Council.

A TP-sensitive potassium channels (K ATP ) are widely expressed in a range of tissues, including brain, heart, pancreas, and smooth muscle (SM), where they are involved in the regulation of biological processes such as insulin release, vascular tone, and adaptation to stresses such as ischemia and hypoxia. They are activated by either declining ATP or increasing ADP concentrations or both, thus coupling intracellular metabolism to membrane excitability. 1 K ATP channels are composed of 4 pore-forming Kir6.x subunits (Kir6.1 or Kir6.2) and 4 large regulatory sulphonylurea receptor subunits (SUR1, SUR2A or SUR2B) to form a functional hetero-octomeric complex.1 The vascular SM K ATP channel is thought to be composed of the Kir6.1 and SUR2B subunits.2,3 These SM K ATP channels have been implicated in the regulation of vascular tone through their proposed involvement in the actions of vasoconstrictors and vasodilators. [4][5][6][7] The integrative physiological role of these channels has been investigated in mice with global genetic deletion of either Kir6.1 or SUR2. 8,9 The mice were hypertensive and prone to sudden death, which was attributed to coronary artery vasospasm because of the absence of K ATP currents in the SM of the coronary arteries. However, when SUR2B was specifically expressed in SM in SUR2 global knockout mice resulting in reconstitution of the K ATP current, the lethal phenotype persisted.10 Furthermore, transgenic expression of SUR2A in cardiomyocytes in SUR2 null mice led to a dramatic reduction in the degree and frequency of episodes of ST elevation on the ECG measured using telemetry.11 The implication was that reconstitution of K ATP in cardiac myocytes led to a reduction of coronary artery SM spasm and it was proposed that K ATP channels outside the SM cell (SMC) are critical in driving the vascular phenotype in the global knockout mice and that the vascular SM K ATP channel contributes modestly to vascular control. 10 A global genetic deletion of Kir6.1 or SUR2 is not selective for the SM channel and potentially channels in the endothelium, nervous system, and heart might all be affected. Here, using a new mouse model, we show that Kir6.1 is indeed the pore-forming subunit of the K ATP channel in vascular SM and that it has a central role in the regulation of blood pressure (BP).Abstract-ATP-sensitive potassium channels (K ATP ) regulate a range of biological activities by coupling membrane excitability to the cellular metabolic state. In particular, it has been proposed that K ATP channels and specifically, the channel subunits Kir6.1 and SUR2B, play an important role in the regulation of vascular tone. However, recent experiments have suggested that K ATP channels outside the vascular smooth muscle compartment are the key determinant of the observed behavior. Thus, we address the importance of the vascular smooth muscle K ATP channel, using a novel murine model in which it is possible to conditionally delete the Kir6.1 subunit.

Nitric oxide (NO), a potent vasodilator critical in maintaining vascular homeostasis, can reduce blood pressure in vivo. Loss of constitutive NO generation, for example as a result of endothelial dysfunction, occurs in many pathological conditions, including hypertension, and contributes to disease pathology. Attempts to therapeutically deliver NO via organic nitrates (e.g. glyceryl trinitrate, GTN) to reduce blood pressure in hypertensives have been largely unsuccessful. However, in recent years inorganic (or ‘dietary’) nitrate has been identified as a potential solution for NO delivery through its sequential chemical reduction via the enterosalivary circuit. With dietary nitrate found in abundance in vegetables this review discusses epidemiological, pre-clinical and clinical data supporting the idea that dietary nitrate could represent a cheap and effective dietary intervention capable of reducing blood pressure and thereby improving cardiovascular health.