Impaired regulation of heart rate and sinoatrial node function by the parasympathetic nervous system in type 2 diabetic mice

Abstract Heart rate (HR) and sinoatrial node (SAN) function are modulated by the autonomic nervous system. HR regulation by the parasympathetic nervous system (PNS) is impaired in diabetes mellitus (DM), which is denoted cardiovascular autonomic neuropathy. Whether blunted PNS effects on HR in type 2 DM are related to impaired responsiveness of the SAN to PNS agonists is unknown. This was investigated in type 2 diabetic db/db mice in vivo and in isolated SAN myocytes. The PNS agonist carbachol (CCh) had a smaller inhibitory effect on HR, while HR recovery time after CCh removal was accelerated in db/db mice. In isolated SAN myocytes CCh reduced spontaneous action potential firing frequency but this effect was reduced in db/db mice due to blunted effects on diastolic depolarization slope and maximum diastolic potential. Impaired effects of CCh occurred due to enhanced desensitization of the acetylcholine-activated K+ current (IKACh) and faster IKACh deactivation. IKACh alterations were reversed by inhibition of regulator of G-protein signaling 4 (RGS4) and by the phospholipid PIP3. SAN expression of RGS4 was increased in db/db mice. Impaired PNS regulation of HR in db/db mice occurs due to reduced responsiveness of SAN myocytes to PNS agonists in association with enhanced RGS4 activity

The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis

Aims/hypothesis Angiotensin II is well-recognised to be a key mediator in driving the pathological events of diabetes-associated atherosclerosis via signalling through its angiotensin II type 1 receptor (AT(1)R) subtype. However, its actions via the angiotensin II type 2 receptor (AT(2)R) subtype are still poorly understood. This study is the first to investigate the role of the novel selective AT(2)R agonist, Compound 21 (C21) in an experimental model of diabetes-associated atherosclerosis (DAA). Methods Streptozotocin-induced diabetic Apoe-knockout mice were treated with vehicle (0.1 mol/l citrate buffer), C21 (1 mg/kg per day), candesartan cilexetil (4 mg/kg per day) or C21 + candesartan cilexetil over a 20 week period. In vitro models of DAA using human aortic endothelial cells and monocyte cultures treated with C21 were also performed. At the end of the experiments, assessment of plaque content and markers of oxidative stress, inflammation and fibrosis were conducted. Results C21 treatment significantly attenuated aortic plaque deposition in a mouse model of DAA in vivo, in association with a decreased infiltration of macrophages and mediators of inflammation, oxidative stress and fibrosis. On the other hand, combination therapy with C21 and candesartan (AT(1)R antagonist) appeared to have a limited additive effect in attenuating the pathology of DAA when compared with either treatment alone. Similarly, C21 was found to confer profound anti-atherosclerotic actions at the in vitro level, particularly in the setting of hyperglycaemia. Strikingly, these atheroprotective actions of C21 were completely blocked by the AT(2)R antagonist PD123319. Conclusions/interpretation Taken together, these findings provide novel mechanistic and potential therapeutic insights into C21 as a monotherapy agent against DAA

The Road to India’s Renewable Energy Transition Must Pass through Crowded Lands

The significance of renewable energy in achieving necessary reductions in emissions to limit global warming to 1.5 degrees Celsius is widely acknowledged. However, there is growing concern over the allocation of land for constructing the required new infrastructure. Nowhere is this conflict more apparent than in India, where renewable energy targets are ambitious and land use conflicts are already significant. India intends to increase renewable energy to 500 GW by 2030. This would require an additional 42 GW of renewable energy to be installed every year. Although renewable energy can provide the solution to both India’s growing need for cheap energy and climate change mitigation, the sustainable future of renewable energy deployment is far from simple due to its associated land use impacts and socio-ecological risk. While others have highlighted challenges to India’s renewable energy targets, here we focus on the land use change issues that will need to be addressed for India to meet its targets. We introduce a series of recommendations and highlight how these could contribute to mainstreaming land values and facilitate the implementation of India’s 2030 renewable energy targets. These recommendations include suggested planning approaches that would guide the development of standard siting guidelines, identification of preferential “go-to” areas for renewable energy, and the development of tools that allow access to data and information to site renewable right. Policy recommendations highlight utilizing converted lands and existing built infrastructure for renewable energy development, and adapting existing policies so they address land use impacts