Framework for policymaking on self-management of health by older adults using technologies.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, the use of information and communication technologies (ICTs) to support care management exponentially increased. Governments around the world adapted existing programs to meet the needs of patients. The reactivity of governments, however, led to changes that were inequitable, undermining groups such as older adults living with chronic diseases and disability. Policies that align with recent developments in ICTs can promote better health outcomes and innovation in care management. A framework for policymaking presents potential for overcoming barriers and gaps that exist in current policies. OBJECTIVE: The goal of this study was to examine how well a provisional framework for policymaking represented the interactions between various components of government policymaking on older adults' self-management of chronic disease and disability using ICTs. METHODS: Through an online survey, the study engaged policymakers from various ministries of the government of Ontario in the evaluation and revision of the framework. The data were analyzed using simple statistics and by interpreting written comments. RESULTS: Nine participants from three ministries in the government of Ontario responded to the questionnaire. Overall, participants described the framework as useful and identified areas for improvement and further clarification. A revised version of the framework is presented. CONCLUSIONS: Through the revision exercise, our study confirmed the relevance and usefulness for a policymaking framework on the self-management of disease and disability of older adults' using ICTs. Further inquiries should examine the application of the framework to jurisdictions other than Ontario considering the dissociated nature of Canadian provincial healthcare systems.

Effects of virtual reality guided meditation in older adults: the protocol of a pilot randomized controlled trial.

Background: Virtual reality (VR) based meditation has been shown to help increase relaxation and decrease anxiety and depression in younger adults. However, this has not been studied in Randomized Controlled Trials (RCT) in the older adult population. The aim of this RCT is to assess the feasibility and acceptability of a VR-guided meditation intervention for community-dwelling older adults and its effect on stress and mental health. Methods: We will recruit 30 participants aged ≥ 60 years, whose perceived stress score (PSS) is > 14 (moderate stress), and randomize them 1:1 to the intervention or control waitlist group. The intervention will involve exposure to eight 15-min VR-guided meditation sessions distributed twice weekly for 4-weeks. Two modalities will be offered: in-home and at the hospital. Data analysis: Baseline and post-intervention assessments will evaluate perceived stress, anxiety, depression, sleep quality, quality of life, and mindfulness skills. Analyses will employ mixed methods repeated ANOVA tests. Qualitative analyses through semi-structured interviews and participant observation will be used to assess participants' experiences. Study outcomes include: (A) feasibility and acceptability compared to a waitlist control (B) stress, using the Perceived Stress Scale (PSS); (C) anxiety, and depression, using the Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9); (D) insomnia, quality of life and mindfulness skills, using the Athens Insomnia Scale (AIS), Quality of Life Questionnaire (EQ-5D-5L) and Five Facets Mindfulness Questionnaire Short Forms (FFMQ-SF), respectively. We will also measure immersive tendencies, sickness and sense of presence using the Simulator Sickness Questionnaire (SSQ) and the Presence Questionnaire (PQ). Discussion: Virtual reality-guided meditation could be an acceptable, feasible, safe, and cost-effective novel alternative health intervention for improving older adults' mental health.Clinical trial registration: NCT05315609 at https://clinicaltrials.gov.

Policymaker perspectives on self-management of disease and disabilities using information and communication technologies.

BACKGROUND: Policies that support health self-management are malleable and highly dependent on various factors that influence governments. Within a world that is shifting toward digitalization due to pressures such as the COVID-19 pandemic and labor shortages, policymaking on older adults' self-management of chronic diseases and disability using information and communication technologies (ICTs) needs to be better understood. Using the province of Ontario, in Canada, as a case study, the research question was What is the environment that policymakers must navigate through in development and implementation of policies related to older adults' self-management of disease and disability using information and communication technologies (ICTs)? METHODS: This study used a qualitative approach where public servants from 4 ministries within the government of Ontario were invited to participate in a 1-h, one-on-one, semi-structured interview. The audio-recorded interviews were based on an adapted model of the policy triangle, where the researcher asked questions about the influences from the different sources identified in the model. The interviews were later transcribed and analyzed using a deductive-inductive coding approach. RESULTS: Ten participants across 4 different Ministries participated in the interviews. Participants shared insights on various aspects of context, process and actors that help shape the current content of policies. The analysis revealed that policies, in the form of programs, services, legislation and regulations, are the result of collaborations and dialogue between different actors and get developed and implemented via a set of complex government processes. In addition, policy actions come from a plethora of sectors which all get influenced by several predictable and unpredictable external pressures. CONCLUSIONS: The environment for policymaking in the government of Ontario regarding older adults' self-management of disease and disability using ICTs is one that is mostly reactive to external pressures, while organized within a set of complex processes and multi-sectoral collaborations. The present research helped us to understand the complexity of policymaking on the topic and highlights the need for increased foresight and proactive policymaking, regardless of which governments are in-place.

Evolution of public health policy on healthcare self-management: the case of Ontario, Canada.

BACKGROUND: As people live longer, they are at increased risk for chronic diseases and disability. Self-management is a strategy to improve health outcomes and quality of life of those who engage in it. This study sought to gain a better understanding of the factors, including digital technology, that affect public health policy on self-management through an analysis of government policy in the most populous and multicultural province in Canada: Ontario. The overarching question guiding the study was: What factors have influenced the development of healthcare self-management policies over time? METHODS: Archival research methods, combining document review and evaluation, were used to collect data from policy documents published in Ontario. The documents were analyzed using the READ approach, evaluated using a data extraction table, and synthesized into themes using the model for health policy analysis. RESULTS: Between January 1, 1985, and May 5, 2022, 72 policy documents on self-management of health were retrieved from databases, archives, and grey literature. Their contents largely focussed on self-management of general chronic conditions, while 47% (n = 18/72) mention diabetes, and 3% (n = 2/72) focussed solely on older adults. Digital technologies were mentioned and were viewed as tools to support self-management in the context of healthcare delivery and enhancing healthcare infrastructure (i.e., telehealth or software in healthcare settings). The actors involved in the policy document creation included mostly Ontario government agencies and departments, and sometimes expert organizations, community groups and engaged stakeholders. The results suggest that several factors including pressures on the healthcare system, hybrid top-down and bottom-up policymaking, and political context have influenced the nature and implementation timing of self-management policy in Ontario. CONCLUSIONS: The policy documents on self-management of health reveal a positive evolution of the content discussed over time. The changes were shaped by an evolving context, both from a health and political perspective, within a dynamic system of interactions between actors. This research helps understand the factors that have shaped changes and suggests that a critical evidence-based approach on public health policy is needed in understanding processes involved in the development of healthcare self-management policies from the perspective of a democratic governing system.

Isolating together during COVID-19: Results from the Telehealth Intervention Program for older adults.

Background: A pressing challenge during the COVID-19 pandemic and beyond is to provide accessible and scalable mental health support to isolated older adults in the community. The Telehealth Intervention Program for Older Adults (TIP-OA) is a large-scale, volunteer-based, friendly telephone support program designed to address this unmet need. Methods: A prospective cohort study of 112 TIP-OA participants aged ≥60 years old was conducted in Quebec, Canada (October 2020-June 2021). The intervention consisted of weekly friendly phone calls from trained volunteers. The primary outcome measures included changes in scores of stress, depression, anxiety, and fear surrounding COVID-19, assessed at baseline, 4 and 8-weeks. Additional subgroup analyses were performed with participants with higher baseline scores. Results: The subgroup of participants with higher baseline depression scores (PHQ9 ≥10) had significant improvements in depression scores over the 8-week period measured [mean change score = -2.27 (±4.76), 95%CI (-3.719, -0.827), p = 0.003]. Similarly, participants with higher baseline anxiety scores (GAD7 ≥10) had an improvement over the same period, which, approached significance (p = 0.06). Moreover, despite peaks in the pandemic and related stressors, our study found no significant (p ≥ 0.09) increase in stress, depression, anxiety or fear of COVID-19 scores. Discussion: This scalable, volunteer-based, friendly telephone intervention program was associated with decreased scores of depression and anxiety in older adults who reported higher scores at baseline (PHQ 9 ≥10 and GAD7 ≥10).

Acute cardiovascular effects of inhaled ambient particulate matter: Chemical composition-related oxidative stress, endothelin-1, blood pressure, and ST-segment changes in Wistar rats.

Short-term increases in particulate matter (PM) are associated with heightened morbidity and mortality from cardiovascular causes. Inhalation of PM is known to increase endothelin (ET)-1 levels. Yet, less is known about particle composition-related changes at the molecular level including the endothelinergic system and relationship with cardiovascular function changes. In this work, adult Wistar male rats were exposed for 4 h by nose-only inhalation to clean air, Ottawa urban particles (EHC-93, 48 mg/m3) and water-leached (EHC-93L, 49 mg/m3) particles, to examine the effect of particle compositional changes on oxidative stress, circulating ETs, blood pressure, and heart electrophysiology. Particle deposition in the respiratory compartment was estimated at 85 µg (25 ng/cm2). Lung cell proliferation was low in both treatment groups, indicating absence of acute injury. Inhalation of EHC-93 caused statistically significant elevations (p < 0.05) of oxidative stress markers, ET-1, ET-3, blood pressure, and a decrease of ST-segment duration in the ECG at 1.5 days post-exposure. Leached particles (EHC-93L) caused rapid but transient elevation (p < 0.05) of oxidative stress, ET-1, ET-2, and ET-3 at earlier time points, with no changes in blood pressure or ST-segment. These results demonstrate that inhalation of urban particles at an internal dose inadequate to cause acute lung injury can induce oxidative stress, enhance vasoactive endothelins, leading to vasopressor response, affecting cardiac electrophysiology in Wistar rats, consistent with the cardiovascular impacts of ambient particles in human populations. Change in particle potency after removal of soluble species, notably cadmium, zinc and polar organics suggests that the toxicodynamics of cardiovascular effects can be modified by physicochemical properties of particles.

Towards triple vasopeptidase inhibitors for the treatment of cardiovascular diseases.

Cardiovascular diseases (CDs) are among the most encountered pathologies in western countries; with obesity reaching pandemic proportions, they are soon to become a worldwide problem. High blood pressure is the main risk factor for CDs, and its tight control is an imperative for the treatment of complications such as renal diseases, heart failure, and atherosclerosis. Blood homeostasis and vascular tone are regulated through at least 3 major closely interrelated pathways in which zinc metallopeptidases modulate the concentration of vasoactive mediators. Those extensively studied vasopeptidases were therefore rapidly targeted with specific inhibitors in order to control the levels of vasoconstrictors [angiotensin II (AII) and endothelin-1 (ET-1)] and vasodilators [bradykinin (BK) and atrial natriuretic peptide (ANP)], thereby controlling blood pressure. The first class of inhibitors to be developed were against angiotensin-converting enzyme (ACE), recently followed by dual inhibitors of ACE/neprylisin (NEP), NEP/endothelin-converting enzyme (ECE), and finally triple ACE/NEP/ECE inhibitors. The dual and triple inhibitors are defined as vasopeptidase inhibitors (VPI). In addition to their ability to effectively lower blood pressure in hypertensive patients, drugs targeting these enzymes also displayed antiinflammatory and antifibrotic activities. The major point emerging from recent studies undertaken to improve the management of CDs is that the combined action of different therapeutic strategies (ie, simultaneous modulation of several neurohumoral mediators) shows better results than conservative therapeutic approaches. In this review, we historically present the advances made in the comprehension of the different mechanisms of blood pressure regulation and some of the drugs that arose from this understanding.

Inhibition of basal and stimulated release of endothelin-1 from guinea pig tracheal epithelial cells in culture by beta 2-adrenoceptor agonists and cyclic AMP enhancers.

The effects of cyclic AMP-related compounds and beta adrenoceptor agonists on the basal and lipopolysaccharide (LPS)-stimulated release of endothelin-1 (ET-1) from guinea-pig tracheal epithelial cells (GPTEpCs) in culture were studied. Forskolin (a potent activator of adenylyl cyclase), 8-bromo-cyclic AMP (a cyclic AMP analogue), salbutamol and salmeterol (two beta 2-adrenoceptor agonists), were used to increase cyclic AMP levels. Cultured GPTEpCs released ET-1 continuously over a 24 h incubation period. The values reached 1,938 +/- 122 pg/mg of total cell proteins after 24 h. LPS (10 microg/ml) significantly stimulated the release of ET-1 by 1.6- to 1.8-fold, up to 1,262 +/- 56 pg/mg total cell proteins after an 8 h incubation period. Compound 8-bromo-cyclic AMP (10(-5), 10(-4) and 10(-3) M) reduced the basal release of ET-1 from GPTEpCs by up to 31% (P < 0.01) and the LPS stimulated release by up to 42% (P < 0.05), after an 8 h incubation period. Forskolin (10(-6), 10(-5) and 10(-4) M) also inhibited the basal release of ET-1 by up to 28% (P < 0.05) and LPS-stimulated release of ET-1 by up to 50% (P < 0.05), after an 8 h incubation period. At the concentration of 10(-5) M, forskolin increased cyclic AMP levels in GPTEpCs by 17-fold (P < 0.001) in the medium, 15 min after the beginning of the incubation. Salbutamol (10(-8) to 10(-6) M) had no effect on the basal production and release of ET-1 after 8 h. Conversely, this short acting beta 2-adrenoceptor agonist significantly reduced LPS-mediated increase of ET-1 production by up to 55% (P < 0.05) after an 8 h incubation period. Salmeterol (10(-9) M to 10(-5) M) inhibited basal and LPS-stimulated production and release of ET-1 after an 8 h incubation period (between 44 and 51%, P < 0.01). Both salbutamol and salmeterol (10(-6) M) increase cyclic AMP levels by five- and twofold, respectively (P < 0.05). In summary, these observations indicate that beta 2-adrenoceptor agonists or cyclic AMP enhancers can modulate both basal and more markedly, the enhanced production of ET-1 from LPS-activated guinea pig airway EpCs. In addition, these compounds increase cyclic AMP levels in the cells. It is suggested that there is a correlation between cyclic AMP increase and inhibition of ET-1 release by guinea pig airway EpCs. Since ET-1 production was shown to be elevated in asthmatic subjects and in patients suffering from other inflammatory lung disorders, the inhibition of its production by beta adrenoceptor agonists, such as salbutamol and salmeterol, could be added to their therapeutical benefits.

Profile of past and current clinical trials involving endothelin receptor antagonists: the novel "-sentan" class of drug.

Since its initial characterization in 1988, over 18,236 papers, including 2,485 reviews, have been published in the endothelin (ET) field. Over this period, several generations of selective and mixed (dual) ET receptor antagonists (ERAs), from peptidic backbones to orally active potent (subnanomolar) small molecular compounds, have been developed. These agents have been studied in many experimental animal models of various pathological conditions (cardiovascular, respiratory, and neuro-immunological). Continued basic research has led to a better understanding of the complex interactions between the ET axis and other biologic systems in human pathophysiology. The first clinical trial involved patients with idiopathic pulmonary arterial hypertension and led to approval of bosentan (Tracleer) for use in the United States and Europe in 2002. Since then, bosentan, the only currently approved dual (mixed) ERA, has been used in numerous other clinical trials. In addition, more selective ET(A) receptor antagonists (ambrisentan, atrasentan, avosentan, clazosentan, darusentan, and sitaxsentan) are undergoing clinical trials. Here we outline the ERAs undergoing development and summarize the standing of completed and ongoing trials at the time of the Ninth International Conference on Endothelin and even thereafter. This review is intended to provide a useful reference for those interested in the current state of clinical trials involving ERAs, and to identify lessons that might apply to the design of future trials.

The kinin system mediates hyperalgesia through the inducible bradykinin B1 receptor subtype: evidence in various experimental animal models of type 1 and type 2 diabetic neuropathy.

Both insulin-dependent (type 1) and insulin-independent (type 2) diabetes are complex disorders characterized by symptomatic glucose intolerance due to either defective insulin secretion, insulin action or both. Unchecked hyperglycemia leads to a series of complications among which is painful diabetic neuropathy, for which the kinin system has been implicated. Here, we review and compare the profile of several experimental models of type 1 and 2 diabetes (chemically induced versus gene-prone) and the incidence of diabetic neuropathy upon aging. We discuss the efficacy of selective antagonists of the inducible bradykinin B1 receptor (BKB1-R) subtype against hyperalgesia assessed by various nociceptive tests. In either gene-prone models of type 1 and 2 diabetes, the incidence of hyperalgesia mostly precedes the development of hyperglycemia. The administration of insulin, achieving euglycemia, does not reverse hyperalgesia. Treatment with a selective BKB1-R antagonist does not affect basal nociception in most normal control rats, whereas it induces a significant time- and dose-dependent attenuation of hyperalgesia, or even restores nociceptive responses, in experimental diabetic neuropathy models. Diabetic hyperalgesia is absent in streptozotocin-induced type 1 diabetic BKB1-R knockout mice. Thus, selective antagonism of the inducible BKB1-R subtype may constitute a novel and potential therapeutic approach for the treatment of painful diabetic neuropathy.

Integrated in vivo pharmacology using an instrumented, unrestrained and conscious rat platform: application to rat models of diabetes.

INTRODUCTION: We define the technical and methodological aspects that led to a practical and reproducible biological in vivo platform allowing the measurement of more than 65 physiobiochemical parameters on a daily basis in freely moving conscious animals. Such a platform presents the ability to unleash incremental information in the hands of modern-day pharmacologists and physiologists. METHODS: To validate this platform, we fully characterized three rat models of Type 1 and Type 2 diabetes and their respective controls. Control, streptozotocin- and alloxan-diabetic Wistar rats in addition to ZDF-Lean and ZDF-Fatty rats were chronically implanted with an arterial catheter and kept in metabolic cages. The catheter was connected to a minipump infusing saline at a constant rate to maintain patency and used to collect blood and measure hemodynamic parameters on a daily basis. RESULTS: Catheter implantation was successful in over 95% of animals and catheter patency was successfully maintained for 30 days in about 75% of animals. The three diabetic rat strains showed elevations in food and water consumption, urinary output, plasma glucose, blood urea nitrogen, triglycerides and cholesterol. The two Type I models also showed a depressed body weight and hemodynamic function. The STZ model differed from the alloxan-model by elevations in liver enzyme activities (AST, ALT, and bilirubin) and a more severe dyslipidemia (triglycerides and total cholesterol). The ZDF-Fatty rats distinguished themselves by higher body weight and elevated white blood cell counts. DISCUSSION: This integrated platform represents a significant improvement in standard in vivo evaluations and could greatly improve the pace of development of potential new drugs.

Triple vasopeptidase inhibition normalizes blood pressure in conscious, unrestrained, and spontaneously hypertensive rats.

BACKGROUND: CGS 35601 is a potent triple vasopeptidase inhibitor (VPI) of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP), and endothelin-converting enzyme (ECE). The aim of the study was to determine the effects of this VPI on the hemodynamic profile of conscious, instrumented, unrestrained spontaneously hypertensive rats (SHR), in comparison to selective inhibitors of ACE and ACE + NEP, than +ECE combined. Circulating plasma concentrations of vasoactive mediators and reactive oxygen species were measured. METHODS: Old SHR male were instrumented (arterial catheter) and placed in a metabolic cage for daily hemodynamic measurements and blood samplings. Seven days after surgery, SHR received 1) saline vehicle; 2) increasing doses of the triple CGS 35601 (0.01, 0.1, 1, and 5 mg/kg/d, intra-arterially (i.a.) infusion for 5 d/dose) followed by a 5-day washout period; 3) benazepril (ACE inhibitor), ACE inhibitor + CGS 24592 (NEP inhibitor) and ACE inhibitor + NEP inhibitor + CGS 35066 (ECE inhibitor) (1 or 5 mg/kg/d i.a. infusion for 5 d/combination) followed by a 5-day washout period. RESULTS: The lowest dose of CGS 35601 had no effect. Doses at 0.1, 1, and 5 mg/kg/d reduced mean arterial blood pressure by 10%, 22%, and 40%, respectively. Heart rate was unaffected in all groups. CGS 35601 decreased concentrations of angiotensin II (Ang II), endothelin-1 (ET-1), and pro-atrial natriuretic peptide (proANP), and increased those of big ET-1, atrial natriuretic peptide (ANP), bradykinin (BK), and hydrogen peroxide (H2O2) dose dependently. CONCLUSIONS: The blood pressure-lowering effect of this triple VPI was superior to that of the other VPI in this preclinical rat model of hypertension. Further experiments are needed to assess triple VPI to other combinations in other models with regard to efficacy and angioedema. Only then it may constitute a first-in-class approach for the treatment of hypertension and other cardiovascular disorders.

Inhibition of type 1 diabetic hyperalgesia in streptozotocin-induced Wistar versus spontaneous gene-prone BB/Worchester rats: efficacy of a selective bradykinin B1 receptor antagonist.

Insulin-dependent type 1 diabetes (T1D) is linked to a series of complications, including painful diabetic neuropathy (PDN). Several neurovascular systems are activated in T1D, including the inducible bradykinin (BK) B1 receptor (BKB1-R) subtype. We assessed and compared the efficacy profile of a selective BKB1-R antagonist on hyperalgesia in 2 models of T1D: streptozotocin (STZ) chemically induced diabetic Wistar rats and spontaneous BioBreeding/Worchester diabetic-prone (BB/Wor-DP) rats. Nociception was measured using the hot plate test to determine thermal hyperalgesia. STZ diabetic rats developed maximal hyperalgesia (35% decrease in their hot plate reaction time) within a week and remained in such condition and degree for up to 4 weeks postinjection. BB/Wor-DP rats also developed hyperalgesia over time that preceded hyperglycemia, starting at the age of 6 weeks (9% decrease in the hot plate reaction time) and stabilizing over the age of 16 to 24 weeks to a maximum (60% decrease in the hot plate reaction time). Single, acute subcutaneous administration of the selective BKB1-R antagonist induced significant time- and dose-dependent attenuation of hyperalgesia in both STZ diabetic and BB/Wor-DP rats. Thus, selective antagonism of the inducible BKB1-R subtype may constitute a novel and potential therapeutic approach for the treatment of PDN.

Modulating effect of a selective endothelin A receptor antagonist on pulmonary endothelin system protein expression in experimental diaphragmatic hernia.

BACKGROUND/PURPOSE: Previously, we reported that perinatal administration of atrasentan, a selective endothelin A receptor (ETA) antagonist, provided a beneficial effect on the cardiopulmonary profile under short-term conditions in newborn lambs with surgically induced congenital diaphragmatic hernia (CDH). We hypothesized that changes in the hemodynamic profile that we observed at birth in treated animals could be influenced by pulmonary modulation of the endothelin (ET) system. METHODS: The effect of atrasentan on protein expression levels of ETs and ET receptors (ETA and ETB receptor) was investigated by immunohistochemistry in lung tissues of untreated control (n = 3), treated control (n = 6), untreated CDH (n = 6), and treated CDH newborn lambs (n = 8). RESULTS: Right lung tissue of treated control lambs showed significantly higher ETA protein expression levels in both vascular adventitia and airway epithelia when compared with that of untreated control lambs (P < .05). In contrast, protein expression levels of ETA and ETB receptor were significantly lower in the vascular smooth muscle cells among other tissue subcompartments of the right lung of treated CDH newborn lambs vs CDH lambs (P < .02 and P = .005, respectively). CONCLUSIONS: We speculate that rapid pulmonary modulation of ET system protein expression levels by atrasentan results from an indirect effect possibly dependent on ventilation and/or perfusion. In CDH groups, this could contribute to the beneficial effect of the treatment.

Effects of a selective bradykinin B1 receptor antagonist on increased plasma extravasation in streptozotocin-induced diabetic rats: distinct vasculopathic profile of major key organs.

Diffuse vasculopathy is a common feature of the morbidity and increased mortality associated with insulino-dependent type 1 diabetes. Increased vascular permeability leading to plasma extravasation occurs in surrounding tissues following endothelial dysfunction. Such micro- and macro-vascular complications develop over time and lead to oedema, hypertension, cardiomyopathy, renal failure (nephropathy) and other complications (neuropathy, retinopathy). In the present investigation, we studied the effect of a selective bradykinin B(1) receptor antagonist, R-954, on the enhanced vascular permeability in streptozotocin (STZ)-induced diabetic Wistar rats compared with age-matched controls. Plasma extravasation was determined using Evans blue dye in selected target tissues (left and right heart atria, ventricles, lung, abdominal and thoracic aortas, liver, spleen, renal cortex and medulla), at 1 and 4 weeks following STZ administration. The vascular permeability was significantly increased in the aortas, cortex, medulla, and spleen in 1-week STZ rats and remained elevated at 4 weeks of diabetes. Both atria showed an increased vascular permeability only after 4-week STZ-administration. R-954 (2 mg/kg, bolus, s.c.), given 2 h prior to Evans blue dye, to 1- and 4-week diabetic rats significantly inhibited (by 48-100%) plasma leakage in most tested tissues affected by diabetes with no effect in healthy rats. These results showed that the inducible bradykinin B(1) receptor subtype participates in the modulation of the vascular permeability in diabetic rats and suggest that selective bradykinin B(1) receptor antagonism could have a beneficial role in reducing diabetic vascular complications.

Enhanced dermal and retinal vascular permeability in streptozotocin-induced type 1 diabetes in Wistar rats: blockade with a selective bradykinin B1 receptor antagonist.

The vascular complications associated with type 1 diabetes are to some extent related to the dysfunction of the endothelium leading to an increased vascular permeability and plasma extravasation in the surrounding tissues. The various micro- and macro-vascular complications of diabetes develop over time, leading to nephropathy, retinopathy and neuropathy and cardiomyopathy. In the present study, the effect of a novel selective bradykinin B1 receptor (BKB1-R) antagonist, R-954, was investigated on the changes of vascular permeability in the skin and retina of streptozotocin (STZ)-induced type 1 diabetic rats. Plasma extravasation increased in the skin and retina of STZ-diabetic rats after 1 week and persisted over 4 weeks following STZ injection. Acute treatment with R-954 (2 mg/kg, bolus s.c.) highly reduced the elevated vascular permeability in both 1- and 4-week STZ-diabetic rats. These results showed that the inducible BKB1-R subtype modulates the vascular permeability of the skin and retina of type 1 diabetic rats and suggests that BKB1-R antagonists could have a beneficial role in diabetic neuropathy and retinopathy.

CGS 35601, a triple inhibitor of angiotensin converting enzyme, neutral endopeptidase and endothelin converting enzyme.

CGS 35601 (L-tryptophan, N-[[1-[[(2S)-2-mercapto-4-methyl-1-oxopentyl]amino]-cyclopentyl]carbonyl]) is one of a few single molecules capable of inhibiting the activities of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP) and endothelin converting enzyme (ECE) simultaneously, with IC(50) values of 22, 2, and 55 nM, respectively. Through the inhibition of ACE and ECE, it blocks the conversion of angiotensin I (AI) and big endothelin-1 (big ET-1) into the two most potent peptidic vasoconstrictors, angiotensin II (AII) and ET-1, respectively. By inhibiting NEP, CGS 35601 also prevents the degradation of peptidic vasodilators such as bradykinin (BK), natriuretic peptides (NPs) and adrenomedullin (ADM) and, hence, modulates the secondary release of other vasoactive mediators such as nitric oxide (NO) and prostaglandins. In chronic (30 days) experiments, CGS 35601 is well tolerated with a very good safety profile in healthy normotensive, hypertensive and type 2 diabetic rats. The antihypertensive efficacy of CGS 35601 was demonstrated in chronically instrumented, unrestrained and conscious rat models of hypertension (SHR and DSS) and type 2 diabetes (ZDF-fatty). It lowered blood pressure effectively as well as modulated plasma concentrations of a number of circulating vasoactive peptidic mediators that are keys to the regulation of the vascular tone. These data suggest that CGS 35601, a triple vasopeptidase inhibitor (VPI), may represent a novel class of antihypertensive drugs and may have the potential to reduce morbidity and mortality from cardiovascular disorders, diabetes and subsequent renal complications. Similar in vivo ACE, NEP, and ECE inhibitory activities were also observed with the orally active prodrug, CGS 37808 (L-tryptophan, N-[[1-[[(2S)-2-(acetylthio)-4-methyl-1-oxopentyl]amino]cyclopentyl]-carbonyl]-, methyl ester.

Early endothelial dysfunction in cholesterol-fed rabbits: a non-invasive in vivo ultrasound study.

BACKGROUND: Endothelial function in hypercholesterolemic rabbits is usually evaluated ex vivo on isolated aortic rings. In vivo evaluation requires invasive imaging procedures that cannot be repeated serially. AIM: We evaluated a non-invasive ultrasound technique to assess early endothelial function in rabbits and compare data with ex vivo measurements. METHODS: Twenty-four rabbits (fed with a cholesterol diet (0.5%) for 2 to 8 weeks) were given progressive infusions of acetylcholine (0.05-0.5 microg/kg/min) and their endothelial function was assessed in vivo by transcutaneous vascular ultrasound of the abdominal aorta. Ex vivo endothelial function was evaluated on isolated aortic rings and compared to in vivo data. RESULTS: Significant endothelial dysfunction was demonstrated in hypercholesterolemic animals as early as 2 weeks after beginning the cholesterol diet (aortic cross-sectional area variation: -2.9% vs. +4% for controls, p < 0.05). Unexpectedly, response to acetylcholine at 8 weeks was more variable. Endothelial function improved in 5 rabbits while 2 rabbits regained a normal endothelial function. These data corroborated well with ex vivo results. CONCLUSION: Endothelial function can be evaluated non-invasively in vivo by transcutaneous vascular ultrasound of the abdominal aorta in the rabbit and results correlate well with ex vivo data.

Triple vasopeptidase inhibition of angiotensin-converting enzyme/neutral endopeptidase/endothelin-converting enzyme activities on the hemodynamic profile of chronically instrumented unrestrained conscious spontaneously hypertensive rats.

Inhibition of the renin-angiotensin system with an angiotensin-converting enzyme inhibitor (ACEi) is an effective therapy in hypertension. Vasopeptidase inhibition was initially proposed with compounds inhibiting both angiotensin-converting enzyme and neutral endopeptidase (omapatrilat), but clinical trials revealed that reducing angiotensin II while blocking the degradation of vasodilatory peptides was not without concerns. We have previously investigated the combination of an ACEi with an endothelin-converting enzyme inhibitor (ECEi); now we add a neutral endopeptidase inhibitor (NEPi) toward triple vasopeptidase inhibition. Male spontaneously hypertensive rats were surgically implanted with a vascular catheter and treated with an ACEi (benazepril), a NEPi (CGS 24592) and an ECEi (CGS 35066) (continuous intra-arterial infusion at 1 or 5 mg/kg/day x 5 days each). After 15 days, drugs administration was stopped for 3 days. ACEi (1 mg/kg per day) reduced the mean arterial blood pressure by 8.4%. The addition of a NEPi and an ECEi at the same dose did not shown any added benefit. The mean arterial blood pressure came back to baseline upon cessation of treatment. ACEi (5 mg/kg per day) reduced the mean arterial blood pressure by 28%. The mean arterial blood pressure remained attenuated by 21% and 19% with the addition of the NEPi and the ECEi. Again, the mean arterial blood pressure rose back to 148 +/- 4 mmHg following cessation of treatment. Daily biochemical and hematological analysis of plasma did not reveal any signs of toxicity, except for a rapid elevation in K (40%) after 1 day of ACEi. Thus, angiotensin II inhibition plays a primary role in controlling the blood pressure of spontaneously hypertensive whereas additional NEPi and ECEi did not provide further benefits under the present dose combinations. The normalizing effect of the higher dose of ACEi by itself made it impossible to discriminate the role of neutral endopeptidase and endothelin-converting enzyme-modulated peptides and to further define the paradigm of triple vasopeptidase inhibition toward better control of vascular hemodynamics. Additional studies are underway.

Profile of endothelin isopeptides and markers of oxidative stress alongside the onset of streptozotocin-type I diabetes in rats.

Type I diabetes is associated with vascular endothelial abnormalities. Vasoactive mediators such as endothelins and reactive oxygen species are modulated in diabetic patients. We studied the hemodynamic profile and the release of mediators alongside the onset of streptozotocin-induced type I diabetes in rats. Arterial plasma samples were collected from chronically instrumented, unrestrained and conscious normotensive versus streptozotocin-diabetic rats. Streptozotocin-diabetic rats developed severe hypoinsulinemia and subsequent hyperglycemia within 5 days. Mean arterial blood pressure and heart rate decreased from 107 to 87 mmHg (19%) and from 386 to 282 beats per minute (bpm) (27%), respectively over 21 days. On day 20 post-streptozotocin administration, markers of oxidative stress (reactive oxygen species: hydrogen peroxide, total peroxides) and related vasodilatory nitric oxide metabolites, increased. Plasma concentrations of atrial natriuretic peptide were not affected, while vasocontractile endothelin-1 and big endothelin-1 increased in streptozotocindiabetic rats versus chronically instrumented, unrestrained and conscious normotensive rats. In addition, the ratios of endothelin-1 : big endothelin-1 and nitric oxide : endothelin-1 were increased. The depressed hemodynamic profile may result from an imbalance between vasocontracting and relaxing factors. Their interactions with reactive oxygen species may affect vascular tone and lead to vascular complications prevalent in this pathological condition. Defining the complex regulation and roles of these factors merits further investigations, especially in the later endstages of vascular complications, because the development of these complications is linked to the duration of the diabetic state.