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Many patients undergoing surgical procedures have a history of hypertension, diabetes mellitus, heart failure, or a combination. Often, these conditions involve the chronic use of a renin–angiotensin system inhibitor, including angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). Observational studies have suggested that continuing ACEIs/ARBs before major noncardiac surgery can increase the risk of intraoperative hypotension, which might drive postoperative complications such as acute kidney injury, myocardial injury, or stroke. Strong recommendations on how to manage ACEIs/ARBs before surgery are, however, lacking owing to insufficient evidence, mostly limited to data from observational studies. Recently, the SPACE trial investigated the impact of preoperative management of ACEIs/ARBs on postoperative myocardial injury. Myocardial injury occurred in 48.3% patients randomised to discontinue and 41.3% patients randomised to continue ACEI/ARB (odds ratio for continuing: 0.77, 95% confidence interval 0.45–1.31). Patients randomised to the 'Stop' group experienced more postoperative hypertension. In a post hoc analysis, patients randomised to the 'Continue' group with low preoperative NT-proBNP concentrations (<100 pg ml−1) experienced less myocardial injury after surgery than the 'Stop' group, whereas no significant difference was observed in patients with elevated preoperative NT-proBNP concentrations. The SPACE trial provides important and new reassuring data on the safety of continuing ACEIs/ARBs before major surgery, challenging previous beliefs. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) patients with pre-existing cardiovascular disease (CVD) or with cardiovascular complications have a higher risk of mortality. The main cardiovascular complications of COVID-19 include acute cardiac injury, acute myocardial infarction (AMI), myocarditis, arrhythmia, heart failure, shock, and venous thromboembolism (VTE)/pulmonary embolism (PE). COVID-19 can cause cardiovascular complications or deterioration of coexisting CVD through direct or indirect mechanisms, including viral toxicity, dysregulation of the renin–angiotensin–aldosterone system (RAAS), endothelial cell damage and thromboinflammation, cytokine storm, and oxygen supply–demand mismatch. We systematically review cardiovascular manifestations, histopathology, and mechanisms of COVID-19, to help to formulate future research goals and facilitate the development of therapeutic management strategies. [ABSTRACT FROM AUTHOR]

Oleanolic acid is known to possess beneficial effects on the regulation of the cardiovascular homeostasis. However, the exact nature of the role of oleanolic acid on the regulation of body fluid balance and blood pressure homeostasis and its mechanisms involved are not well defined. Experiments were performed to identify the effects of oleanolic acid on the renin-angiotensin system and cardiac natriuretic hormone (ANP) system, and also renal function and blood pressure in normotensive and renovascular hypertensive rats. The change in the plasma levels of hormones and the expressions of renin, angiotensin II receptors, ANP, natriuretic peptide receptor-C, M 2 muscarinic receptor and GIRK4 were determined in the kidney, heart and aorta. Oleanolic acid was administered orally for 1 or 3 weeks. Here, we found that oleanolic acid suppressed plasma levels of renin activity and aldosterone and intrarenal levels of renin and angiotensin II type 1 receptor expression and increased angiotensin II type 2 receptor in normotensive and hypertensive rats. Also, oleanolic acid increased plasma levels of ANP. Further, oleanolic acid suppressed angiotensin II type 1 receptor and natriuretic peptide receptor-C expression and increased angiotensin II type 2 receptor and ANP expression in the heart and aorta. Along with these changes, oleanolic acid accentuated urinary volume, electrolyte excretion and glomerular filtration rate in normotensive rats and suppressed arterial blood pressure in hypertensive rats. These findings suggest that beneficial effects of oleanolic acid on the cardiorenal system are closely associated with its roles on the renin-angiotensin system and cardiac natriuretic hormone system. [ABSTRACT FROM AUTHOR]

Weaning preeclamptic (PE) rats exhibit exaggerated endotoxic signs of hypotension and cardiac autonomic neuropathy. Considering the role of renin-angiotensin system (RAS) in maternal programming during PE, we investigated the hypothesis that gestational modulation of offensive (Angiotensin II, Ang II) and defensive (Ang 1–7) components of RAS alleviates cardiovascular hyperresponsiveness of weaning PE mothers to postpartum endotoxemia. PE was induced by treating pregnant rats with the nitric oxide synthase inhibitor L-NAME (50 mg/kg/day) for 7 consecutive days starting from gestational day 14. The PE-associated elevations in gestational systolic blood pressure and proteinuria were reduced after gestational treatment with Ang 1–7 (Ang II-derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (RAS modulator), or combined losartan/pioglitazone, with the latter therapy being the most effective. In weaning PE rats, the potentiated falls in mean arterial pressure and spectral index of cardiac sympathovagal balance (low frequency/high frequency ratio) caused by i.v. Lipopolysaccharides (LPS, 5 mg/kg) were attenuated by all therapies. Pioglitazone and Ang 1–7 were more effective in reversing increases and decreases in left ventricular contractility and isovolumic relaxation time constant, respectively, seen in endotoxic PE mothers. Immunohistochemically, cardiac Toll-like receptor 4 (TLR-4) expression was increased in endotoxic PE rats, and this effect was abrogated by Ang 1–7 or losartan/pioglitazone. The same treatments blunted the increased cardiac angiotensin converting enzyme (ACE) expression whereas ACE2 expression was altered by none of the intervening therapies. Overall, the mitigation of Ang II/ACE imbalances alleviates the sensitized cardiovascular and inflammatory actions of endotoxemia in weaning PE mothers. • Prenatal losartan/pioglitazone regimen reduces PE hypertension and proteinuria. • Endotoxic hypotension in PE rats is attenuated by Ang1-7 and RAS inhibitions. • Ang1-7 or RAS inhibition blunts endotoxic cardiac parasympathetic dominance. • Ang 1–7 normalizes PE/LPS-evoked tachycardia and diastolic dysfunction. • Cardiac TLR-4/ACE protein expressions are abrogated by Ang1-7 or RAS inhibition. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme-2, or ACE2, is primarily a zinc-dependent peptidase and ectoenzyme expressed in numerous cell types and functioning as a counterbalance to ACE in the renin-angiotensin system. It was discovered 21 years ago more than 40 years after the discovery of ACE itself. Its primary physiological activity is believed to be in the conversion of angiotensin II to the vasodilatory angiotensin-(1−7) acting through the Mas receptor. As such it has been implicated in numerous pathological conditions, largely in a protective mode which has led to the search for ACE2 activatory mechanisms. ACE2 has a diverse substrate specificity allowing its participation in multiple peptide pathways. It also regulates aspects of amino acid transport through its homology with a membrane protein, collectrin. It also serves as a viral receptor for the SARS virus, and subsequently SARS-CoV2, driving the current COVID-19 pandemic. ACE2 therefore provides a therapeutic target for the treatment of COVID and understanding the biological events following viral binding can provide insight into the multiple pathologies caused by the virus, particularly inflammatory and vascular. In part this may relate to the ability of ACE2, like ACE, to be shed from the cell membrane. The shed form of ACE2 (sACE2) may be a factor in determining susceptibility to certain COVID pathologies. Hence, for just over 20 years, ACE2 has provided numerous surprises in the field of vasoactive peptides with, no doubt, more to come but it is its central role in COVID pathology that is producing the current intense interest in its biology. [Display omitted] • ACE2 is a multi-functional enzyme primarily metabolising regulatory peptides. • ACE2 counterbalances the actions of ACE through conversion of Ang II to Ang-(1−7). • ACE2 participates in intestinal amino acid transport. • ACE2 is the receptor for some coronaviruses, especially SARS-CoV-2. • ACE2 provides a key therapeutic target in the prevention and treatment of COVID-19. [ABSTRACT FROM AUTHOR]

The renin–angiotensin system (RAS) is a major component of cardiovascular and renal homeostasis, maintaining blood pressure and water and electrolyte balance in health and disease. Whilst knowledge regarding the RAS in adult organisms has substantially increased over the last three decades, physiological effects and levels of functioning of the system during the perinatal period are poorly understood. It has been shown, however, that the RAS is subject to remarkable developmental changes that involve all system components, including the main active biologic peptide, angiotensin II (Ang II) and the receptors through which these effects are mediated, type 1 receptors (AT1Rs) and type 2 receptors (AT2Rs). The pattern of developmental changes suggests a relevant physiological role for the RAS in the critical cardio-renal adaptations to life after birth. In adulthood, the majority of the physiological functions of Ang II are mediated by activation of AT1Rs, whilst the roles for AT2Rs are less clear. Although the integrity of the AT1R signalling pathway is a pre-requisite for normal renal development, the physiological effects mediated by A1TRs during ontogeny are not well characterized. Much less is known regarding the roles that AT2Rs may play in regulating cardio-renal homeostasis in the newborn, despite the fact that the RAS appears to be a major player in fetal programming of disease. This article reviews current knowledge regarding the temporal and spatial expression pattern of ATRs during ontogeny, the cardiovascular and renal effects mediated by the ATRs early in life, as well as the clinical relevance for ATRs in the newborn period. [ABSTRACT FROM AUTHOR]

Abstract: Cardiovascular function is affected by many mechanisms, including the autonomic system, the kallikrein–kinin system (KKS), the renin–angiotensin system (RAS) and the endothelin system. The function of these systems seems to be fairly well preserved throughout the vertebrate scale, but evolution required several adaptations. Snakes are particularly interesting for studies related to the cardiovascular function because of their elongated shape, their wide variation in size and length, and because they had to adapt to extremely different habitats and gravitational influences. To keep the normal cardiovascular control the snakes developed anatomical and functional adaptations and interesting structural peculiarities are found in their autonomic, KKS, RAS and endothelin systems. Our laboratory has characterized some biochemical, pharmacological and physiological properties of these systems in South American snakes. This review compares the components and function of these systems in snakes and other vertebrates, and focuses on differences found in snakes, related with receptor or ligand structure and/or function in autonomic system, RAS and KKS, absence of components in KKS and the intriguing identity between a venom and a plasma component in the endothelin system. [Copyright &y& Elsevier]

Angiotensin II (ANG II) is part of the renin-angiotensin system (RAS) in vertebrates and exert vasoconstriction in all species studied. The present study examines the vasopressor effect of ANG II in the ball python (Python regius), and examines whether ANG II exert its effect through direct angiotensin receptors or through an activation of α-adrenergic receptors. The studies were conducted in snakes with chronic arterial catheters that had recovered from anesthesia. In addition to demonstrating a clear and pronounced dose-dependent rise in arterial blood pressure upon repeated injections of boluses with ANG II (0.001–1 μg/kg), we demonstrate that the pressor response persisted following α-adrenergic blockade using the α-adrenergic antagonist phentolamine (2.5 mg/kg). Unfortunately, it proved impossible to block the ANG receptors using losartan (1, 3 or even 10 mg/kg). The pressor response to ANG II was associated with a significant rise in heart rate at the higher dosages, pointing to a resetting of the barostatic mechanism for heart rate regulation. The responses were similar in fasting and digesting pythons despite the expected rise in baseline values for blood pressure and heart rate of the digesting snakes. Image 1 • Angiotensin II exerts a pronounced vasopressor action in ball pythons (Python regius) with small effects on heart rate. • The effects of angiotensin II (ANG II) are not altered by blockade of the α-adrenergic receptors. • Angiotensin II (ANG II) elicited similar in responses in fasting and digesting snakes. • Losartan could not block the cardiovascular responses to ANG II in Python regius. [ABSTRACT FROM AUTHOR]

Genetic mapping of modifier loci affecting malignant hypertension in TGRm Ren2 rats. Background. Genetic background has a major influence on the manifestation of multifactorial diseases such as hypertension in which severe complications may be caused through an interaction with additional factors, which may be genetically determined. We have previously described a genetic model of malignant hypertension (MH) in rats carrying the mouse Ren2 gene (TGRmRen2 -27), in which the phenotype is dependent on the genetic background. Methods. Using a single homozygous TGRmRen2 -27 male as transgene donor, we produced two F1 populations with (a ) 100% penetrance of MH in progeny heterozygous for the Fischer F344 genetic background and (b ) 58.5% penetrance in progeny heterozygous for the Lewis genetic background. To identify the modifier loci affecting the phenotype, a cohort of 252 males was produced by breeding the same single male with Fischer-Lewis F1 females. The progeny were phenotyped for clinical and pathological features of MH. Results. Genome-wide screening and quantitative trait loci (QTL) analysis identified two loci, on chromosome 10 (LOD 4.4) and on chromosome 17 (LOD 3.9) close to the Ace and At1 genes, respectively, which contribute to the lethal MH phenotype. Their influence on mortality was consistent with a multiplicative effect of the two loci. In addition, we found higher plasma angiotensin-converting enzyme activity in progeny receiving the Fischer allele than in progeny receiving the Lewis allele (123.5 ± 9.5 vs. 91.8 ± 4.9 U/liter, P < 0.01), suggesting the association of angiotensin-converting enzyme and MH. Conclusions. Our study demonstrates the application of a transgene as a “major gene” to facilitate the identification of modifier loci, which can affect the phenotype of MH, and reveals Ace and At1 as candidate genes involved in the manifestation of the MH phenotype. [ABSTRACT FROM AUTHOR]