Increased superoxide is thought to play a major role in vascular dysfunction in a variety of disease states. Superoxide dismutase (SOD) limits increases in superoxide; however, the functional significance of selected isoforms of SOD within the vessel wall are unknown. We tested the hypothesis that selective loss of CuZnSOD results in increased superoxide and altered vascular responsiveness in CuZnSOD-deficient (CuZnSOD ^−/− ) mice compared with wild-type (CuZnSOD ^+/+ ) littermates. Total SOD activity was reduced ( P <0.05) by approximately 60% and CuZnSOD protein was absent in aorta from CuZnSOD ^−/− as compared with wild-type mice. Vascular superoxide levels, measured using lucigenin (5 μmol/L)-enhanced chemiluminescence and hydroethidine (2 μmol/L)-based confocal microscopy, were increased (approximately 2-fold; P <0.05) in CuZnSOD ^−/− mice as compared with wild-type mice. Relaxation of the carotid artery in response to acetylcholine and authentic nitric oxide was impaired ( P <0.05) in CuZnSOD ^−/− mice. For example, maximal relaxation to acetylcholine (100 μmol/L) was 50±6% and 69±5% in CuZnSOD ^−/− and wild-type mice, respectively. Contractile responses of the carotid artery were enhanced ( P <0.05) in CuZnSOD ^−/− mice in response to phenylephrine and serotonin, but not to potassium chloride or U46619. In vivo, dilatation of cerebral arterioles (baseline diameter=31±1 μm) to acetylcholine was reduced by approximately 50% in CuZnSOD ^−/− mice as compared with wild-type mice ( P <0.05). These findings provide the first direct insight into the functional importance of CuZnSOD in blood vessels and indicate that this specific isoform of SOD limits increases in superoxide under basal conditions. CuZnSOD-deficiency results in altered responsiveness in both large arteries and microvessels.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a unique class of oral anti-hyperglycaemic medications that act to reduce glucose reabsorption in the renal proximal tubules, thereby enhancing urinary glucose excretion. Large randomized placebo-controlled trials in people with diabetes at high cardiovascular risk have demonstrated that SGLT2 inhibitors reduce heart failure hospitalization within months of commencing therapy. These findings are of considerable interest, as diabetes is associated with an increased risk of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. In addition, left ventricular (LV) hypertrophy and impaired diastolic function is thought to be more prevalent in people with diabetes. Although many hypotheses have been proposed, the underlying mechanisms through which SGLT2 inhibitors reduce the risk of heart failure in people with diabetes are not fully understood. Given the rapid reduction in heart failure hospitalization, it is conceivable that the benefits of SGLT2 inhibitors are due to favourable haemodynamic and metabolic effects on LV function. Several clinical studies have been conducted to investigate the effect of SGLT2 inhibitors on LV structure and function and have found that LV mass index and diastolic function improve following SGLT2 inhibitor therapy in people with type 2 diabetes. If these findings are confirmed in future studies utilizing novel cardiac imaging modalities and large randomized controlled trials, then this will bring new hope for the prevention and management of heart failure with preserved ejection fraction, for which no current treatments have been shown to reduce mortality. At the present time, SGLT2 inhibitors are indicated for the treatment of type 2 diabetes; however, the results of ongoing trials in participants with heart failure but without diabetes are eagerly awaited. The purpose of this review is to summarize current knowledge regarding the effects of SGLT2 inhibitors on LV function, particularly the findings from clinical studies, proposed biological mechanisms, and future directions.

Objective: Hypoglycaemia poses a significant management challenge in patients with unresectable functional malignant insulinoma. Novel agents such as mammalian target of rapamycin (mTOR) inhibitors and radiolabelled peptides may be effective where there is failure of conventional therapy.Design: We present the cases of two men diagnosed with inoperable malignant insulinoma and hepatic metastases who developed severe symptomatic hypoglycaemia, and review potential therapies for glycaemic support.Method: Despite treatment with diazoxide, frequent oral carbohydrate, prednisolone and somatostatin analogue therapy, both men required hospital admission for treatment with continuous i.v. dextrose. Both were treated with Lutetium-177 octreotate. One man was also treated with everolimus, a mTOR inhibitor.Result: Use of Lutetium-177 octreotate, and in one case everolimus, successfully achieved normoglycaemia, facilitating safe discharge from hospital. Both men also had regression in the size and number of hepatic metastases.Conclusion: Lutetium-177 octreotate and everolimus are options for managing hypoglycaemia due to unresectable malignant insulinoma when refractory to conventional supportive therapies.

We tested the hypothesis that the mitochondrial form of superoxide dismutase [manganese superoxide dismutase (Mn-SOD)] protects the cerebral vasculature. Basilar arteries (baseline diameter ∼140 μm) from mice were isolated, cannulated, and pressurized to measure vessel diameter. In arteries from C57BL/6 mice preconstricted with U-46619, acetylcholine (ACh; an endothelium-dependent vasodilator) produced dilation that was similar in male and female mice and abolished by an inhibitor of nitric oxide synthase. Vasodilation to ACh was not altered in heterozygous male or female Mn-SOD-deficient (Mn-SOD^+/−) mice compared with wild-type littermate controls (Mn-SOD^+/+). Constriction of the basilar artery to arginine vasopressin, but not KCl or U-46619, was increased in Mn-SOD^+/− mice ( P < 0.05), and this effect was prevented by tempol, a scavenger of superoxide. We also examined responses of cerebral (pial) arterioles (branches of the middle cerebral artery, control diameter ∼30 μm) to ACh in anesthetized mice using a cranial window. Responses to ACh, but not nitroprusside (an endothelium-independent agonist), were reduced ( P < 0.05) in cerebral arterioles in Mn-SOD^+/− mice, and this effect was prevented by tempol. Thus these are the first data on the role of Mn-SOD in cerebral circulation. In the basilar artery, ACh produced nitric oxide-mediated dilation that was similar in male and female mice. Under normal conditions in cerebral arteries, responses to ACh were not altered but constrictor responses were selectively enhanced in Mn-SOD^+/− mice. In the cerebral microcirculation, there was superoxide-mediated impairment of responses to ACh.