The Renin-Angiotensin System Modulates Inflammatory Processes in Atherosclerosis: Evidence from Basic Research and Clinical Studies

Recent evidence shows that the renin-angiotensin system is a crucial player in atherosclerotic processes. The regulation of arterial blood pressure was considered from its first description of the main mechanism involved. Vasoconstriction (mediated by angiotensin II) and salt and water retention (mainly due to aldosterone) were classically considered as pivotal proatherosclerotic activities. However, basic research and animal studies strongly support angiotensin II as a proinflammatory mediator, which directly induces atherosclerotic plaque development and heart remodeling. Furthermore, angiotensin II induces proatherosclerotic cytokine and chemokine secretion and increases endothelial dysfunction. Accordingly, the pharmacological inhibition of the renin-angiotensin system improves prognosis of patients with cardiovascular disease even in settings of normal baseline blood pressure. In the present review, we focused on angiotensin-convertingenzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and renin inhibitors to update the direct activities of the renin-angiotensin system in inflammatory processes governing atherosclerosis

Renin-Angiotensin System Hyperactivation Can Induce Inflammation and Retinal Neural Dysfunction

The renin-angiotensin system (RAS) is a hormone system that has been classically known as a blood pressure regulator but is becoming well recognized as a proinflammatory mediator. In many diverse tissues, RAS pathway elements are also produced intrinsically, making it possible for tissues to respond more dynamically to systemic or local cues. While RAS is important for controlling normal inflammatory responses, hyperactivation of the pathway can cause neural dysfunction by inducing accelerated degradation of some neuronal proteins such as synaptophysin and by activating pathological glial responses. Chronic inflammation and oxidative stress are risk factors for high incidence vision-threatening diseases such as diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma. In fact, increasing evidence suggests that RAS inhibition may actually prevent progression of various ocular diseases including uveitis, DR, AMD, and glaucoma. Therefore, RAS inhibition may be a promising therapeutic approach to fine-tune inflammatory responses and to prevent or treat certain ocular and neurodegenerative diseases

Characterisation of the pharmacological actions in humans of multiple vasoactive enzyme inhibitors with therapeutic potential in heart failure

Introduction The work described in this thesis looks particularly but not exclusively at two recently developed molecules which have dual enzyme inhibitor activity. Omapatrilat, a molecule which inhibits both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), and SLV 306 (active metabolite KC12615) a compound with both NEP and endothelin converting enzyme (ECE) inhibiting properties. Neurohumoral activation characterises the complex chronic heart failure syndrome. Clearly there is value in antagonizing neurohumoral systems likely to have detrimental effects in patients with heart failure, while simultaneously augmenting potentially desirable neurohumoral mediators. However enzyme inhibitors which act on multiple vasoactive mediators with complex interactions have unpredictable effects. Omapatrilat has received much attention following demonstration of a powerful hypotensive effect but a higher than expected incidence of angioedema in patients with hypertension or heart failure. GW660511X is another dual ACE/NEP inhibitor at an earlier stage in development. The pharmacodynamic profile of neither the ACE inhibitor activity nor the NEP inhibitor activity of GW 660511X has been fully described in humans. SLV 306 is the first orally available molecule of its kind and its NEP and ECE inhibitory properties have not previously been demonstrated in humans either in vitro or in vivo. The intention of this thesis is further characterisation of these molecules and their therapeutic potential while utilising their inhibitory properties in further investigation of the human neurohumoral system. I specifically consider the possible mediators of the impressive hypotensive effects of these molecules and of the unexpected and potentially life threatening side effects associated with them. Having demonstrated the complex neurohumoral substrate of these molecules I go on to report, for the first time in heart failure patients, the benefits of a more specific approach to neurohumoral manipulation using a recently developed renin inhibitor, aliskiren. Aliskiren has been shown to offer haemodynamic benefit in patients with hypertension but has not previously been given to patients with chronic heart failure. Methods 1) Small resistance arteries from patients (n=89) with coronary artery disease but normal left ventricular function were studied using wire myography. The vasopressor response to various neurohormones in the presence of omapatrilat, KC12615 (the active metabolite of SLV 306) and other vasoactive enzyme inhibitors is reported. 2) Following pilot studies of the pressor response to intravenous infusion of big ET-1 (n=6) and pharmacokinetic modeling of orally dosed SLV 306 in healthy volunteers (n=29), the effect of 3 doses of SLV 306 and placebo given at four separate visits one week apart, on the pressor and neurohumoral response to intravenous infusion of big endothelin-1 in healthy volunteers (n=15) is compared. 3) The effect of 2 oral doses of GW660511X and a single dose of the ACE inhibitor ramipril, given on three separate visits one week apart, on the pressor and neurohumoral response to an intravenous infusion of angiotensin I in healthy volunteers (n=16) is compared. 4) Finally, the neurohumoral and blood pressure response to aliskiren an orally active, long acting renin inhibitor is compared with placebo for one week and the ACE inhibitor ramipril for 6 weeks, in patients with left ventricular systolic dysfunction (n=27). Results 1) In patients with coronary artery disease but normal left ventricular systolic dysfunction; the vasodilator response to bradykinin was augmented by omapatrilat, KC 12615, phosphoramidon (NEP/ECE inhibitor), captopril (ACE inhibitor), and thiorphan (NEP inhibitor). Of note the augmentation is no greater with omapatrilat than captopril and in arteries taken from patients prescribed ACE inhibitor, KC 12615 does not augment the response. The vasodilator response to adrenomedullin was augmented by omapatrilat, KC 12615 and phosphoramidon. The vasoconstrictor response to angiotensin I was inhibited by omapatrilat and captopril and the vasoconstrictor response to endothelin-1 was inhibited by KC 12615 and phosphoramidon. 2) In healthy volunteers, SLV 306 caused a dose dependent attenuation of the hypertensive and reflex bradycardia response to big ET-1. There was also a dose dependent increase in ANP, big ET-1 and the ratio big ET-1: ET-1 but no increase in ET-1 following big ET-1 infusion. 3) In healthy volunteers, there was no notable change in blood pressure (pre angiotensin I infusion) and no significant inhibition of pressor response to angiotensin I following administration of GW660511X. Ramipril 10mg was associated with a reduction in blood pressure (pre angiotensin I infusion) and inhibition of the response to angiotensin I. There was significantly greater reduction in ACE activity with ramipril than GW660511X. GW660511X but not ramipril led to a dose dependent increase in plasma ANP concentration. 4) In patients with chronic heart failure, aliskiren suppressed plasma renin activity and reduced plasma angiotensin II. Ramipril in comparison caused an increase in renin activity and no change in angiotensin II. There were no significant changes in blood pressure with either treatment. Conclusion I have demonstrated the ACE and NEP inhibitory properties of omapatrilat and for the first time in humans, the ECE and NEP inhibitory properties of SLV 306, in vitro in patients with coronary artery disease but normal left ventricular dysfunction. I found no additional augmentation of bradykinin by omapatrilat or SLV 306 over and above that offered by ACE inhibition but significant augmentation by both dual inhibitors of adrenomedullin. This contradicts the suggestion that bradykinin has a role in the incidence of angioedema offers adrenomedullin as an alternative mediator. Adrenomedullin augmentation may also contribute significantly to the hypotensive effects of these molecules. I have demonstrated for the first time in humans the ECE and NEP inhibitory properties of SLV 306 in vivo. GW660511X is shown to inhibit NEP but to a much lesser extent ACE. Of note the comparison made is with full dose of a powerful pure ACE inhibitor. Any inhibition of ACE activity in contrast to the study of pure NEP inhibitors is consistent with the belief that dual inhibition offers additional benefit. Finally I have demonstrated for the first time in patients with chronic heart failure the renin inhibitor activity of aliskiren, confirming attenuation of the renin angiotensin aldosterone pathway consistently from its origin and in contrast the rise in renin activity seen with ACE inhibitors

Potential for deep geological sequestration of CO2 in Switzerland: a first appraisal

Possibilities to sequester anthropogenic CO2 in deep geological formations are being investigated worldwide, but the potential within Switzerland has not yet been evaluated. This study presents a first-order appraisal based solely on geological criteria collated from the literature. The Swiss Molasse Basin (SMB) and the adjacent Folded Jura are the only realms of the country where CO2 could conceivably be stored in saline aquifers. Evaluation of geological criteria at the basin-wide scale shows that the SMB-Jura has moderate potential (score of 0.6 on a scale from 0 to 1) when compared to basins elsewhere. At the intrabasinal scale, inspection of the stratigraphy reveals four regional candidate aquifers that are sealed by suitable caprocks: top Basement plus basal Mesozoic sandstones, all sealed by the Anhydrite Group; Upper Muschelkalk sealed by the Gipskeuper; Hauptrogenstein sealed by the Effinger Member, and Upper Malm plus Lower Cretaceous sealed by the Lower Freshwater Molasse. Nine geological criteria are defined to evaluate the storage potential of these and other smaller scale candidates. A numerical scoring and weighting scheme allows the criteria to be assessed simultaneously, permitting the storage potential to be depicted using the 0-1 scale in contoured maps. Approximately 5,000km2 of the central SMB exhibits potentials between 0.6 and 0.96. The Fribourg-Olten-Luzern area is the most favoured owing to the presence of several sealed aquifers within the preferred 800-2,500m depth interval, and to its low seismicity, low geothermal gradient, low fault density, and long groundwater residence times. Smaller areas with good potential lie between Zürich and St. Gallen. In contrast, western Switzerland, the Jura and the southern SMB have markedly poorer potential. Considering only the portions of the aquifers with potential above 0.6, the theoretical, effective storage capacity of the basin is estimated to be 2,680 million tonnes of CO

Comprehensive evaluation of clinical care in patients with cardiac implanted electronic devices and arrhythmias: action towards improved workflow and outcomes

Heart rhythm disorders contribute a great burden to modern healthcare, but new opportunities for optimal usage of resources and improved standards of care are available due to progress in technology. In particular, the diagnosis, treatment and follow-up of heart rhythm disorders is evolving with emergence of game-changing technologies. To maximise impact of these technological advances, appropriate identification of opportunities and integration into care delivery is needed. This thesis aims to address the following three specific areas in the field of heart rhythm disorders. First, to explore challenges for follow-up care of patients with a Cardiac Implantable Electronic Device (CIED). Second, to determine optimal CIED selection for patients requiring continuous heart rhythm monitoring. Last, to define the utility of modern digital technology for heart rhythm assessment with a focus on atrial fibrillation (AF) screening. Chapter 1 provides a review of the current literature surrounding these topics. Chapter 2 and 3 each present research studies investigating in-hospital services for CIED checks in the Emergency Department and in the pre- and post-scan setting of Magnetic Resonance Imaging. These studies provide granular, patient-level details of current healthcare service utilisation that can be used to identify opportunities for improved care delivery. Acknowledging the growing burden of healthcare utilisation for follow-up and analysis of CIEDs, Chapter 4 pivots towards understanding the role of optimal implant technology to maximize efficiency of resources. Research presented in this chapter assesses current generation implant devices to demonstrate differences in the electrograms that are obtained by insertable cardiac monitors (ICM) with different sensing vector length. Chapter 5 then explores the utility of a longer sensing vector, by proxy of surface electrocardiogram (ECG) tracings simulating ICM rhythm strips, for obtaining optimal electrogram sensing. This has implications for ICM selection in varying patients to optimise efficiency of continuous cardiac monitoring. The recent growth in personal ownership of digital devices, such as smartphones and watches, that are capable of heart rhythm monitoring has provided a feasible alternate option for arrhythmia detection. However, in comparison to implantable devices, these technologies broadly vary in their mechanism of rhythm detection, complexity and fidelity of data acquisition. The increasing accessibility of such wearable or portable digital technology presents a clinical conundrum for its appropriate utility in healthcare settings. Chapter 6 investigates the utility of portable digital technology, specifically that which can obtain single-lead ECG tracings and apply automated algorithms for arrhythmia detection, to screen for the most common heart rhythm disorder of atrial fibrillation (AF). Chapter 7 assesses the ability of such personal digital devices to identify AF even in low-resource communities. This body of work identifies opportunities where integration of emerging technologies in the management of heart rhythm disorders can guide strategic investment of expenditure and resource allocation to provide more efficient healthcare service that may improve patient outcomes.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 202

Nitric Oxide Releasing Multitarget Drugs

In the last few years, the “one-drug-one-target” paradigm has been shelved and numerous multi-target drugs have been projected and synthesised. Such compounds share two (or more) desired pharmacodynamic properties ensured by the presence of overlapping or conjugation of pharmacophores. This strategy has led to the development of important multi-target drugs consisting of pharmacodynamic hybrids obtained by combining a “native” drug with a molecular moiety able to release nitric oxide (NO), with the aim to reduce possible side-effects or improve the therapeutic impact. My PhD work was focused on the design, characterisation and pharmacological evaluation of two main classes of cardiovascular new “hybrid-drug”: the nitrooxy-derivatives of anti-hypertensive drugs such as sartans and the nitrooxy-derivatives of a hypoglycaemic drug such as glibenclamide. The new class of NO-sartans was represented by several dual compounds in which the native drug Losartan or its active metabolite EXP 3174 are linked to a nitric ester by a series of different spacers conveniently designed in order to modulate the NO-release. These drugs underwent a deep pharmacological characterisation on animal models, through an in vitro evaluation of their vasorelaxing, AT1-antagonist, cardioprotective, anti-hypertrophic and anti-platelet properties. Moreover also an in vivo experimental protocol was carried out in order to compare the NO-sartan effect on blood pressure with those of well-known anti-hypertensive drugs. The two nitrooxy-derivatives of the active metabolite of glibenclamide, the 4-trans-hydroxy derivative, underwent an in vitro pharmacological study on animal models focused to demonstrate an additional vasorelaxing NO-mediated effect conferred through the NO-donor moiety. At the same time, these new hybrid molecules were evaluated by an other in vitro experimental protocol on human islets aimed to verify the maintenance of the hypoglycaemic property through the evaluation of the insulinotropic response

Bulletin der deutschen Slavistik 22.2016

Bulletin der deutschen Slavistik 22, 201