Potential Role Of Angiotensin Research Articles

Protective effects of dapagliflozin on vascular remodeling in the carotid artery following balloon injury – potential role of angiotensin and purinergic signaling

Abstract Introduction Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. The possibility that SGLT2 inhibitors improve endothelial regeneration and vascular restenosis is unknown. Purpose To examine whether dapagliflozin, a selective SGLT2 inhibitor, could prevent neointima thickening induced by balloon injury and, if so, to determine the underlying mechanisms. The effect of dapagliflozin was compared to that of losartan, an angiotensin type 1 receptor (AT1R) antagonist. Methods Saline, dapagliflozin (1.5 mg/kg/day), or losartan (30 mg/kg/day) were administered orally for 5 weeks to male Wistar rats. Balloon injury of the left carotid artery was performed 1 week after starting the treatment and sacrificed 4 weeks later. Vascular reactivity was assessed on left (injured) and right (healthy) carotid artery rings. The extent of neointima was assessed by histomorphometric analysis, changes of target factors by immunofluorescence, RT-qPCR and histochemistry. Results Dapagliflozin and losartan treatments reduced neointima thickening by 32% and 27%, respectively. Blunted contractile responses to phenylephrine and relaxations to acetylcholine and down-regulation of eNOS were observed in the injured artery. These effects were not modified by the dapagliflozin or the losartan treatments. RT-qPCR investigations indicated an increased in gene expression of inflammatory (IL-1beta, ITGAM, VCAM-1), oxidative (p47phox, p22phox) and fibrotic (TGF-beta1) markers and a decreased of eNOS in the injured carotid. However, these changes were not affected by the pharmacological treatments. By contrast, significant increased levels of AT1R angiotensin receptor and NTPDase1 (CD39) ectonucleotidase were observed in the restenotic carotid artery of the dapagliflozin group. Histochemical analysis evidenced important NTPDase1 activity in the neointima. Conclusions Dapagliflozin effectively reduced neointimal thickening. As the contribution of AT1R and P2Y2 ATP receptor in smooth muscle cell proliferation and neointima formation has been reported in the literature, the present data suggest that dapagliflozin prevents restenosis through interfering with angiotensin and/or extracellular nucleotides signaling. SGLT2 transporter represent potential new target for limiting vascular restenosis. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This work was supported by AstraZeneca

Potential role of angiotensin‐(1–7) in the improvement of vascular insulin sensitivity after a bout of exercise

What is the central question of this study? What is the mechanism by which a bout of exercise increases subsequent insulin-stimulated vasodilatation? What is the main finding and its importance? Angiotensin-(1-7) through the Mas receptor participates in enhanced insulin-induced vasorelaxation after a bout of exercise in healthy rats. This new potential role of angiotensin-(1-7) could help in understanding how physical activity improves vascular insulin sensitivity in normal and insulin-resistant states. Exercise increases insulin-stimulated vasodilatation, but the mechanisms involved are unclear. This study was performed to investigate the possible involvement of angiotensin-(1-7) (Ang-(1-7)), a vasoactive peptide of the renin-angiotensin system (RAS), in enhanced vascular insulin sensitivity after a bout of exercise. Male Wistar rats were subjected to swimming for 2.5 h. After exercise, carbachol- or insulin-induced relaxation in aorta was assessed. Prior exercise improved insulin-stimulated vasorelaxation; however, this insulin-sensitizing effect was prevented by the selective Mas receptor (MasR; an Ang-(1-7) receptor) antagonist A779. Carbachol-mediated vascular relaxation was not modified by exercise. These results suggest that Ang-(1-7) acting through MasR participates in the enhancement of vascular insulin sensitivity after an exercise session. This new potential role of Ang-(1-7) could help in understanding how exercise improves vascular insulin sensitivity in normal and insulin-resistant states.

Nitric oxide and angiotensin II regulate cardiovascular homeostasis and the arterial baroreflex control of heart rate in conscious lambs

To investigate the potential role of angiotensin II (Ang II) type 1 receptors (AT(1)Rs) as well as endogenously produced nitric oxide (NO) in regulating cardiovascular homeostasis during ontogeny, experiments were carried out in conscious lambs aged approximately 1 week (N = 9) and 6 weeks (N = 11). The arterial baroreflex control of heart rate (HR) was assessed before and after intravenous (IV) infusion of the selective AT(1)R antagonist, ZD 7155, before and after IV administration of the L-arginine analogue, N(G)-nitro-L-arginine methyl ester (L-NAME). In both groups, after ZD 7155 alone, mean arterial pressure decreased then increased after L-NAME. At 1 but not 6 weeks, HR decreased after ZD 7155 as well as after L-NAME. At 1 but not 6 weeks, there was a decrease in the HR range after ZD 7155 and after ZD 7155 + L-NAME, as compared to control. There was also a decrease in minimum HR after ZD 7155 + L-NAME at 1 week. These data provide new evidence that, together, Ang II and NO regulate cardiovascular homeostasis as well as the arterial baroreflex of HR early in life which may help to explain the activation of these two systems early in life.

The Association of Angiotensin Converting Enzyme (ACE) Polymorphisms with Sleep Apnea and Hypertension

To identify the role of polymorphisms in the angiotensin-converting enzyme (ACE) gene in modulating susceptibility to hypertension in sleep apnea. Observational cross-sectional study. Nine hundred seventy-two participants of the Cleveland Family Study who underwent home sleep studies, blood pressure assessments, and genotyping. After controlling for age, sex, race, and obesity, hypertension risk was reduced in participants who possess the ACE deletion (D) polymorphism with an odds ratio = 0.63 (95% confidence interval: 0.41-0.96) comparing those with 2 versus no D alleles. In analyses stratified by apnea severity, the protective effect of the D allele was most evident in those with severe apnea. Among subjects with severe apnea, the odds ratios for hypertension were 0.47 (0.22-1.00) for 1 D allele and 0.57 (0.26-1.24) for 2 D alleles. The ACE deletion allele may protect against hypertension in the setting of obstructive sleep apnea. Further research into the potential role of angiotensin in modulating the hypertensive effect of sleep apnea is needed.

Downregulation of bradykinin B2 receptor mRNA expression in rat heart after the aortic coarctation: A potential role of angiotensin II

Downregulation of bradykinin B2 receptor mRNA expression in rat heart after the aortic coarctation: A potential role of angiotensin II

Depression of efferent parasympathetic control of heart rate in rats with myocardial infarction: effect of losartan.

Heart failure is associated with attenuation of parasympathetic nervous function and enhanced renin-angiotensin activity. We tested whether there was a dysfunction in the efferent cholinergic neurotransmission in the heart of rats with chronic myocardial infarction (MI) and the potential role of angiotensin II (Ang II) receptors in such changes. Rats with MI and sham-operation were anesthetized, and heart rate (HR) reduction in response to vagal nerve stimulation was measured before and after losartan administration (10 mg/kg, i.v.) in the presence or absence of physostigmine to inhibit acetylcholinesterase. Infarcted rats had an average infarct size (IS) of 38% of the left ventricle (LV), depressed LV dP/dtmax, elevated LVEDP, and cardiac hypertrophy. Nerve stimulation (1-16 Hz) reduced HR in a frequency-dependent manner. The bradycardiac responses were significantly attenuated in infarcted versus control rats (p < 0.01), indicating an impaired efferent vagal tone. In contrast, the bradycardic response to exogenous acetylcholine was similar in both groups, implying an unchanged muscarinic receptor responsiveness in hearts with MI. HR response to nerve stimulation was potentiated by losartan in infarcted rats by 21 +/- 4 versus 4 +/- 2 beats/min (p < 0.01) but was unaffected in control rats. This effect of losartan was inversely related to the extent of attenuation of vagally mediated HR reduction. IS was correlated with both the extent of attenuation in vagally mediated bradycardia and the effect of losartan. In conclusion, the efferent vagal control of HR is attenuated in rats with MI and heart failure. This attenuation may be partly due to a presynaptic inhibition of acetylcholine release through the tonic activation, by Ang II, of neuronal AT1 receptors.

Vascular Effects of Perindopril

Vascular remodeling is central to the pathophysiology of hypertension and atherosclerosis. The effects of antihypertensive drugs on this process are important to consider from a mechanistic and a pathogenetic point of view in relation to vascular complications of hypertension, e.g., decrease in vascular reserves, shift in cerebral blood flow autoregulation and atherosclerosis development. There is now evidence that, in addition to several other growth factors, vasoactive peptides such as angiotensin II may act as vascular smooth muscle growth promoting substances. Based on these data, the effects of perindopril, a potent and long-lasting angiotensin-converting enzyme (ACE) inhibitor, on structural and mechanical properties of the arterial wall, have been studied in animal models of hypertension as well as in humans. Perindopril completely reversed aortic medial hypertrophy and arterial stiffening observed in renovascular hypertensive rats. Similar benefits were reported in mesenteric resistance vessels of spontaneously hypertensive rats. The effect of perindopril was totally in keeping with potent inhibition of vascular ACE and emphasized the potential role of angiotensin II as a vascular growth modulator. Clinical studies confirmed animal experiments; both suggest that increases in arterial compliance and distensibility following perindopril is likely to be related to drug-induced modification of the arterial wall, at least partially independently of blood pressure reduction. The increase in arterial compliance was associated with a selective decrease in pulse pressure, a finding that is important, not only for the arterial wall, but also for the structure and function of the hypertensive heart.