Treatment Of Chronic Cardiovascular Diseases Research Articles

Enhanced Oral NO Delivery through Bioinorganic Engineering of Acid-Sensitive Prodrug into a Transformer-like DNIC@MOF Microrod.

Nitric oxide (NO) is an endogenous gasotransmitter regulating alternative physiological processes in the cardiovascular system. To achieve translational application of NO, continued efforts are made on the development of orally active NO prodrugs for long-term treatment of chronic cardiovascular diseases. Herein, immobilization of NO-delivery [Fe2(μ-SCH2CH2COOH)2(NO)4] (DNIC-2) onto MIL-88B, a metal-organic framework (MOF) consisting of biocompatible Fe3+ and 1,4-benzenedicarboxylate (BDC), was performed to prepare a DNIC@MOF microrod for enhanced oral delivery of NO. In simulated gastric fluid, protonation of the BDC linker in DNIC@MOF initiates its transformation into a DNIC@tMOF microrod, which consisted of DNIC-2 well dispersed and confined within the BDC-based framework. Moreover, subsequent deprotonation of the BDC-based framework in DNIC@tMOF under simulated intestinal conditions promotes the release of DNIC-2 and NO. Of importance, this discovery of transformer-like DNIC@MOF provides a parallel insight into its stepwise transformation into DNIC@tMOF in the stomach followed by subsequent conversion into molecular DNIC-2 in the small intestine and release of NO in the bloodstream of mice. In comparison with acid-sensitive DNIC-2, oral administration of DNIC@MOF results in a 2.2-fold increase in the oral bioavailability of NO to 65.7% in mice and an effective reduction of systolic blood pressure (SBP) to a ΔSBP of 60.9 ± 4.7 mmHg in spontaneously hypertensive rats for 12 h.

Moving toward genome-editing therapies for cardiovascular diseases.

The rapid invention of genome-editing technologies over the past decade, which has already been transformative for biomedical research, has raised the tantalizing prospect of an entirely new therapeutic modality. Whereas the treatment of chronic cardiovascular diseases has heretofore entailed the use of chronic therapies that typically must be taken repeatedly and frequently for the remainder of the lifetime, genome editing will enable the development of “one-and-done” therapies with durable effects. This Review summarizes the variety of available genome-editing approaches, including nuclease editing, base editing, epigenome editing, and prime editing; illustrates how these various approaches could be implemented as novel therapies for cardiovascular diseases; and outlines a path from technology development to preclinical studies to clinical trials. Although this Review focuses on PCSK9 as an instructive example of the various genome-editing approaches under active investigation, the lessons learned will be broadly applicable to the treatment of a variety of diseases.

Effects of long-term moderate-small intensity aerobic exercise on differential expression of proteome in left ventricular muscle of rats

Objective: To investigate the effects of long-term moderate-small intensity aerobic exercise on the differential expression of proteome in left ventricular muscle of rats, and to screen the target proteins sensitive to moderate-small intensity aerobic exercise stimulation. This study will enrich the basic theory of exercise and fitness and provide new ideas and experimental basis for the rehabilitation treatment of chronic cardiovascular disease. Methods: Twenty male SD rats were randomly divided into exercise group and control group (n=10). The treadmill training model of long-term moderate-small intensity aerobic exercise was established, and the whole protein samples of left ventricular muscle were extracted and separated by two-dimensional gel electrophoresis (2-DE). The two-dimensional gel electrophoresis map was analyzed by Bio PD quest image analysis software. The protein spots with differential expression more than 5 times or down-regulated over 80% after exercise were identified by tandem time-of-flight mass spectrometry (ULGRAFL-FLEX-TOF/TOF). Results: Compared with the group C, the heart weight index of the group E was increased by 32.0%, and the difference was significant (P＜0.05). Compared with the group C, there were 71 protein spots expression were up-regulated≥2 times or down-regulated≥50% in the group E. 4 protein spots expression were up-regulated≥5 times or down-regulated≥80% were identified by mass spectrometry, 3 proteins and 1 unknown protein were identified. Conclusion: After long-term moderate-small intensity aerobic exercise, the rats heart had a good adaptive change, and the proteome of left ventricular muscle changed significantly. Long-term moderate-small intensity aerobic exercise can effective enhance the ability of myocardial antioxidation.

Efficacy and safety of dapagliflozin in the treatment of chronic heart failure: A protocol for systematic review and meta-analysis.

Background:As the last link in the chain of cardiovascular events, chronic heart failure (CHF) has high morbidity, high mortality, and poor prognosis. It is one of the main causes of death and disability worldwide. As a new drug for the treatment of chronic cardiovascular disease, dapagliflozin, the efficacy, and safety issues are still the focus of attention. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of dapagliflozin in the treatment of CHF.Methods:According to the search strategy, regardless of publication date or language, randomized controlled trials (RCTs) of dapagliflozin for CHF will be retrieved from 8 databases. First of all, the literature was screened according to the eligibility criteria, and use the Cochrane Collaboration's tool to assess the quality of the included literature. Then, using Rev Man 5.3 and STATA 14.2 software for traditional meta-analysis. Finally, the evaluation of the quality of the evidence and the strength of the recommendations will adopt the Grading of Recommendations, Assessment, Development and Evaluation method.Results:This study will evaluate the efficacy and safety of dapagliflozin for CHF, thereby providing more evidence support for clinical decision-making in CHF.Conclusion:Our research will provide more references for the clinical medication of patients with CHF.Protocol registration number:INPLASY202150046

Изменения морфофункциональных параметров сердечно-сосудистой системы на фоне рациона питания с повышенной калорийностью у спонтанно гипертензивных крыс

Introduction. Hypertension with left ventricular hypertrophy (LVH) is a major independent risk factor for cardiovascular-related morbidity. Diet plays an essential role in the prevention and treatment of chronic cardiovascular disease. The aim of our study was to analyze the influence of 10-week diets consisting of different high fats and carbohydrates on the myocardium in spontaneously hypertensive rats (SHR). Materials and methods. The SHR (n=34) and WKY (n=34) were randomly divided into five groups (n=6 or 7 per group). For 10 weeks, the control group was fed the standard diet; the experimental groups were fed the standard chow diet with the different fats and sucrose (11% of the calorie intake). Systolic blood pressure (SBP) was measured before the experiment and 10 weeks after by the non-invasive tail-cuff method. After the experiment, the animals were humanely sacrificed. The heart specimens after routine processing were stained with hematoxylin and eosin. We determined the thickness of the left ventricle and the number of cardiomyocyte nuclei per unit area using morphometry. Results. An increase in SBP at the end of the experiment was found in SHR animals in groups receiving trans-fat and sucrose by 10.9 mm Hg and 13.4 mm Hg, respectively. Myocardial hypertrophy was observed in the SHR Butter group. Conclusion. We found that the increased content of trans-fats and sucrose in the diet leads to an increase in SBP in spontaneously hypertensive rats; saturated fatty acids – to myocardial hypertrophy in spontaneously hypertensive rats without aggravation of systolic hypertension. In normotensive animals, no negative effect of the high-fat diet on the cardiovascular system was observed. Keywords: myocardial hypertrophy, arterial hypertension, high fat diets, palm oil, carbohydrates

A wearable blood oxygen saturation monitoring system based on bluetooth low energy technology

Dynamic monitoring of blood oxygen saturation value is an important method for the prevention and treatment of chronic cardiovascular disease. In order to meet the design requirements of wearable mobile medical, this paper uses the main controller to read, filter, and calculate pulse rate and blood oxygen value, and saturate the pulse signal and blood oxygen through the Bluetooth low-power module. The degree value and pulse rate value are transmitted to the Android smartphone, and the APP on the Android phone side manages the user’s physiological parameters and establishes a personal health file. Monitoring of blood oxygen saturation in a dynamic environment can be affected by severe motion disturbances. Aiming at this problem, this paper proposes a new adaptive cancellation algorithm based on adaptive filtering. Based on the interference analysis of the photoelectric volume pulse wave signal in a dynamic environment, this paper uses the envelope information of the PPG (Photoplethysmography) signal to extract the AC component of the photoelectric volume pulse wave signal, and construct interference-related signals as reference signals and perform adaptive filtering to suppress motion interference. The adaptive cancellation algorithm proposed in this paper performs digital signal processing on the collected original information and analyzes the calculation results. Comparing the calculated results with those of the DST (Discrete Saturation Transform) signal extraction technology, the effectiveness of the algorithm in eliminating motion interference is verified, and the anti-interference ability and time complexity of the algorithm under severe motion are verified.

The phospholipid fraction obtained from egg yolk reduces blood pressure increase induced by acute stress in spontaneously hypertensive rats.

Despite continuous research, an improved understanding of the pathophysiology of hypertension and the development of new antihypertensive therapies, hypertension is still the most prevalent chronic cardiovascular disease (CVD) among adults in Western societies. Stress is a common factor related to cardiovascular morbidity. An increase in blood pressure is one of the most common reactions to stress. Chronic and acute stress have also been related to cardiovascular disorders. Polyunsaturated fatty acids (PUFAs) have attracted considerable interest as potential complementary therapy for the treatment of CVD, including hypertension. Egg yolk, rich in PUFAs and phospholipids, might be a good source of phospholipids and PUFAs. The current study was aimed at investigating the potential effect of the phospholipid fraction of eggs on blood pressure changes in spontaneously hypertensive rats (SHRs) as a response to acute stress. Male, 7-week-old SHRs received dietary phospholipid fraction for 12 weeks. The control animals received standard feed. At the end of the treatment, they were exposed to 40 min of white noise in order to induce acute stress. Then, blood pressure measurements were carried out under normal conditions for 12 h before and during the acute stress procedure. Blood pressure was measured by telemetry. Diastolic, systolic and mean blood pressure were significantly lower in the SHRs treated with phospholipid fraction than in the control group. The acute stressor caused a significant increase in diastolic, systolic and mean blood pressure in both the treated and untreated animals, but the increase in blood pressure as a response to the stressor was significantly less pronounced in the rats treated with phospholipid fraction than in control rats. These results show that egg phospholipids can limit a stress-induced rise in blood pressure. The results of this research show that phospholipid fraction derived from egg yolk reduces stress-induced increases in blood pressure.

A novel integrated care concept (NICC) versus standard care in the treatment of chronic cardiovascular diseases: protocol for the randomized controlled trial CardioCare MV

BackgroundCardiovascular diseases are the major cause of death globally and represent a major economic burden on health care systems. Positive effects of disease management programs have been shown for patients with heart failure (HF). Remote monitoring and telemonitoring with active intervention are beneficial in atrial fibrillation (AF) and therapy-resistant hypertension (TRH), respectively. For these patients, we have developed a novel integrated care concept (NICC) which combines telemedicine with intensive support by a care center, including a call center, an integrated care network including inpatient and outpatient care providers and guideline therapy for patients.MethodsThe aim of the study is to demonstrate the superiority of NICC over guideline therapy alone. The trial is designed as open-label, bi-center, parallel-group design with two groups and a blinded observer. Patients will be included if they are either inpatients or if they are referred to the outpatient clinic of the hospitals by their treating physician. Randomization will be done individually with stratification by cardiovascular disease (AF, HF, TRH), center and admission type. Primary endpoints are based on the 1-year observation period after randomization. The first primary endpoint is the composite endpoint consisting of mortality, stroke and myocardial infarction. The number of hospitalizations form the second primary endpoint. The third primary endpoint is identical to the first primary endpoint plus cardiac decompensation. Adjustments for multiple testing are done using a fall-back strategy. Secondary endpoints include patient adherence, health care costs, quality of life, and safety. A sample size of 2930 gives 80% power at the two-sided 2.5% test level for the first primary endpoint. The power for the second primary endpoint is 99.8% at this sample size, and it is 80% with 1086 patients.DiscussionThis study will inform care providers whether quality of care can be improved by an integrated care concept providing telemedicine through a round-the-clock call center approach. We expect that cost of the NICC will be lower than standard care because of reduced hospitalizations. If the study has a positive result, NICC is planned to be immediately rolled out in the federal state of Mecklenburg-West Pomerania and other federal states in Germany. The trial will also guide additional research to disentangle the effects of this complex intervention.Trial registrationDRKS, ID: DRKS00013124. Registered on 5 October 2017;ClinicalTrials.gov, ID: NCT03317951. Registered on 17 October 2017.

Therapeutic effects of Qishen Yiqi Dropping Pill on myocardial injury induced by chronic hypoxia in rats

The present study was designed to determine the effects of a traditional Chinese medicine, called Qishen Yiqi Dropping Pill on chronic hypoxia-induced myocardial injury. To establish a rat chronic hypoxia model to be used in the evaluation of the therapeutic effects of the Qishen Yiqi Dropping Pill, Sprague-Dawley (SD) rats were randomly divided into three groups: the control, model, and treatment groups (n = 10 per group). The animals were housed in a plexiglass container. The control animals were under normal oxygen concentration and the model and treatment groups were exposed to air and nitrogen for 5 weeks. The rats in the treatment group were orally administered the Qishen Yiqi Dropping pill (35 mg·kg−1·d−1) for 5 weeks. After the treatment, the cardiac function and morphology were analyzed, and the expression levels of hypoxia-inducible factor 1α (HIF-1α) were determined using Western blotting. Our results indicated that the cardiac function was impaired, cell apoptosis was enhanced, and HIF-1α expression was up-regulated in the model group, compared to the control group. These changes were ameliorated by the treatment with the Qishen Yiqi Dropping Pill. In conclusion, Qishen Yiqi Dropping pill can ameliorate myocardial injury induced by chronic hypoxia, improve cardiac function, and decrease myocardial cell apoptosis, which may provide a basis for its clinical use for the treatment of chronic cardiovascular diseases

US Cardiologist Workforce From 1995 To 2007: Modest Growth, Lasting Geographic Maldistribution Especially In Rural Areas

A sufficient cardiology workforce is necessary to ensure access to cardiovascular care. Specifically, access to cardiologists is important in the management and treatment of chronic cardiovascular disease. Given this, we examined the supply and distribution of the cardiologist workforce. In doing so, we mapped the ratios of cardiologists, primary care physicians, and total physicians to the population age sixty-five or older within different Hospital Referral Regions from the years 1995 and 2007. We found that within the twelve-year span of our study, the cardiology workforce grew modestly compared with the primary care physician and total physician workforces. Also, despite increases in the number of cardiologists, there was a persistent geographic maldistribution of the workforce. For example, approximately 60 percent of the elderly population had access to only 38 percent of the cardiologists. Our results suggest that large segments of the US population, specifically in rural and socioeconomically disadvantaged areas, continue to have a lower concentration of cardiologists. This maldistribution could be addressed through a variety of strategies, including the use of telemedicine and economic incentives.

Kardioprotektion

The demographic change is associated with an increasing number of elderly patients with serious comorbidities. The prevalence of coronary heart disease in particular increases with age and raises the risk of perioperative myocardial ischemia. In the last few years various interventions have been evaluated to lower the perioperative risk for serious cardiovascular events. This includes cardioprotective medical interventions, for example with β-receptor blockers and statins. Current guidelines recommend that patients who are on β-receptor blockers or statins for chronic treatment of cardiovascular diseases should continue this medication throughout the perioperative period. Myocardial conditioning has been assessed to be effective under numerous experimental conditions and clinical trials have also provided evidence for myocardial protection by conditioning. Besides ischemic and anesthetic-induced preconditioning the noninvasive technique of remote preconditioning offers interesting possibilities, especially for patients with serious comorbidities; however, large scale randomized clinical multicentre trials are still needed. Regarding cardioprotective effectiveness, the clinical data for regional anesthesia are very heterogeneous; nevertheless regional anesthesia is very effective in postoperative pain therapy. Therefore regional anesthesia should be used as a part of multimodal therapy concepts to lower the risk of perioperative cardiovascular events.

Intramyocardial injection of autologous bone marrow mononuclear cells for patients with chronic ischemic heart disease and left ventricular dysfunction ( First M ononuclear Cells injected in the US [FOCUS]): Rationale and design

The increasing worldwide prevalence of coronary artery disease (CAD) continues to challenge the medical community. Management options include medical and revascularization therapy. Despite advances in these methods, CAD is a leading cause of recurrent ischemia and heart failure, posing significant morbidity and mortality risks along with increasing health costs in a large patient population worldwide. The Cardiovascular Cell Therapy Research Network (CCTRN) was established by the National Institutes of Health to investigate the role of cell therapy in the treatment of chronic cardiovascular disease. FOCUS is a CCTRN-designed randomized, phase II, placebo-controlled clinical trial that will assess the effect of autologous bone marrow mononuclear cells delivered transendocardially to patients with left ventricular (LV) dysfunction and symptomatic heart failure or angina. All patients need to have limiting ischemia by reversible ischemia on single-photon emission computed tomography assessment. After thoughtful consideration of both statistical and clinical principles, we will recruit 87 patients (58 cell treated and 29 placebo) to receive either bone marrow-derived stem cells or placebo. Myocardial perfusion, LV contractile performance, and maximal oxygen consumption are the primary outcome measures. The designed clinical trial will provide a sound assessment of the effect of autologous bone marrow mononuclear cells in improving blood flow and contractile function of the heart. The target population is patients with CAD and LV dysfunction with limiting angina or symptomatic heat failure. Patient safety is a central concern of the CCTRN, and patients will be followed for at least 5 years.

Perioperative Organprotektion – Beta-Blocker und Statine

The number of patients with limited organ function is steadily increasing due to the aging of the population. Consequently, a growing number of patients needing surgery is accompanied by serious comorbidities. These patients are at high risk of perioperative organ dysfunction. In this context cardiac events (e.g. cardiac arrhythmias, angina or myocardial infarction) play a major role with significant impact on postoperative care, long term outcome and economic sequelae. Thus, anaesthesiologists must prevent such events in the perioperative period. Besides general measures such as adequate analgesia, protection from stressful events and sufficient volume replacement, medical intervention with beta-blockers or HMG-CoA-reductase-inhibitors (statins) are necessary to reduce the incidence of perioperative cardiac events. Both beta-blockers and HMG-CoA-reductase-inhibitors are known to exhibit pleiotropic effects (defined as additional cardioprotective effects) besides the primary blockade of the beta-adrenergic receptor or the inhibition of the synthesis of serum cholesterol, respectively. Both groups of drugs improve cardiac function, decrease inflammatory response, decrease activation of blood coagulation and stabilize endothelial plaques. Based on the current literature the following recommendations are published concerning the perioperative administration of beta-blockers: (i) Patients who are on beta-blockers on a regular basis following guidelines concerning chronic treatment of cardiovascular diseases should continue this medication throughout the perioperative period; (ii) a sufficient indicator of an adequate therapy is the baseline heart rate. It should not exceed 60-70bpm at rest; (iii) the Revised Cardiac Risk Index (RCRI) is a widely accepted score to estimate the patient's perioperative cardiac risk; (iv) patients with a RCRI > or =3 should not be scheduled for routine surgery without sufficient beta-adrenergic-receptor blockade; (v) in patients at high cardiac risk based on the RCRI who are scheduled for emergency surgery beta-blocker-therapy should not be initiated de novo perioperatively. However, for perioperative treatment of tachycardia or hypertension beta-blockers are the drug of first choice. Concerning perioperative statin-therapy the following recommendations are suggested: (i) chronic statin-therapy should be continued throughout surgery and the perioperative period; (ii) in patients without chronic statin-therapy scheduled for vascular surgery this treatment should be started perioperativly; (iii) no data is available concerning other patient populations; (iv) if statin-therapy is indicated it should be started independently from baseline serum LDL-C-concentration; (v) side effects of statin-therapy are rare and usually not live threatening, thus treatment is considered to be without serious risks to the patient.

Peptidomimetics - antagonists of the fibrinogen receptors: molecular design, structures, properties and therapeutic applications.

The platelet aggregation is a crucial step in a pathophisiology of thromboses, leading to development of cardio-vascular diseases (myocardial infarction, transient ischemic attacks, strokes, etc.). The final step in the aggregation is the binding of fibrinogen to receptor - glycoprotein IIb/IIIa (GP IIb/IIIa) on the surface of activated platelets. In recent years the increasing attention is paid to the role of fibrinogen antagonists in the prevention of thrombosis. The search for these compounds is based on the molecular design of structures mimicking some fragment of RGD (Arg-Gly-Asp) sequence, responsible for the binding of fibrinogen to GP IIb/IIIa. Up to now, a large number of potent and selective GP IIb/IIIa antagonists, including non-peptide inhibitors are identified (derivatives of benzodiazepines, aminobenzamidinosuccinyles, isoxazolines, isoquinolines). The modification of natural peptide structures for obtaining of more active and selective fibrinogen receptor antagonists is realized in several ways: substitution of main pharmacophores of RGD sequence; cyclization of RGD-containing peptides; design of conformationally constrained peptidomimetics. For the treatment of chronic cardio-vascular diseases, the clinic needs high orally active RGD-peptidomimetics. This task is realized by obtaining of prodrugs on the base of the most potent RGD-mimetics. In our laboratory the molecular design and synthesis of non-peptide fibrinogen receptor antagonists were carried out. The series of RGD-mimetics on the basis of 4-oxo-(piperazine-1-yl)butyric acid as Arg-mimetic and beta-aryl-beta-alanines as Asp-Phe-mimetics were synthesized. Obtained RGD-mimetics showed a high antiaggregatory activity in vitro experiments with IC(50)values of 10(-7) - 10(-9) M.

Short-term administration of insulin-like growth factor I (IGF-1) does not induce myocardial IGF-1 resistance.

The advent of recombinant technology has revealed attractive therapeutic profile of insulin-like growth factor I (IGF-1) in the treatment of chronic cardiovascular diseases such as diabetes and heart failure. However, the safety and potential adverse effect of IGF-1 have not been well defined. This study was designed to evaluate the impact of short-term IGF-1 administration on myocardial contractile function. Adult rats were given recombinant human IGF-1 (3mg/kg/d, s.c.) for 8 weeks. Mechanical properties were evaluated in left-ventricular papillary muscles using a force-transducer. Myocardial contractile properties analyzed included peak tension development (PTD), time-to-peak tension (TPT), time-to-90% relaxation (RT(90)), and maximal velocity of tension development/decline (+/-VT). Short-term IGF-1 treatment enhanced the plasma IGF-1 level but had no effect on body and organ weights. The myocardium from IGF-1-treated rats exhibited enhanced PTD associated with similar TPT, RT(90), and +/-VT compared to the control group. IGF-1-treated myocardium exhibits an enhanced PTD-Ca(2+) response and a better intracellular Ca(2+) replenishing ability at the low stimulus frequencies. Acute application of IGF-1 (1-500 ng/ml) elicited a comparable concentration-dependent increase in PTD in myocardium from both control and the IGF-1-treated groups. Acute IGF-1 application had no effect on +/-VT, TPT, and RT(90) in either group tested. Pretreatment with the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester blunted the IGF-1-induced positive response in myocardium from both control and IGF-1-treated groups. These results suggest that short-term IGF-1 treatment is unlikely to induce IGF-1 resistance in myocardial contractile function.

Eplerenone: a selective aldosterone receptor antagonist (SARA).

Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 (AT(1)) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels--a phenomenon termed "aldosterone synthesis escape." Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenone--the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs)--is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24-h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding of selective aldosterone receptor antagonism in the treatment of chronic cardiovascular disease.

Endothelin-1 and Endothelin Receptor Antagonists in Cardiovascular Remodeling

Endothelins build a peptide family composed of three isoforms, each of them containing 21 amino acids. Endothelin-1 is the isoform mainly responsible for any cardiovascular action and therefore the sole scope of this review. Endothelin-1 is the most potent endogenous vasoconstrictor known; in addition it acts as a potent (co)mitogen. There is a substantial body of experimental evidence that endothelin-1 may contribute not only to sustained vasoconstriction, but also to remodeling within the cardiovascular system. Thus, with the help of endothelin receptor antagonists (available for a few years) the involvement of mainly ETA receptors in structural diseases such as heart failure, pulmonary hypertension, atherosclerosis, restenosis, systemic hypertension, and chronic renal failure has been shown. These data make endothelin receptor antagonists, and especially those selective for the ETA receptor, promising agents for the treatment of chronic cardiovascular diseases associated with remodeling. Currently several chemically distinct, orally available members of this novel class of therapeutic agents are under clinical investigation.

Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling.

Endothelins build a peptide family composed of three isoforms, each of them containing 21 amino acids. Endothelin-1 is the isoform mainly responsible for any cardiovascular action and therefore the sole scope of this review. Endothelin-1 is the most potent endogenous vasoconstrictor known; in addition it acts as a potent (co)mitogen. There is a substantial body of experimental evidence that endothelin-1 may contribute not only to sustained vasoconstriction, but also to remodeling within the cardiovascular system. Thus, with the help of endothelin receptor antagonists (available for a few years) the involvement of mainly ETA receptors in structural diseases such as heart failure, pulmonary hypertension, atherosclerosis, restenosis, systemic hypertension, and chronic renal failure has been shown. These data make endothelin receptor antagonists, and especially those selective for the ETA receptor, promising agents for the treatment of chronic cardiovascular diseases associated with remodeling. Currently several chemically distinct, orally available members of this novel class of therapeutic agents are under clinical investigation.

ChemInform Abstract: Synthesis of a Series of Compounds Related to Betaxolol, a New β1‐Adrenoceptor Antagonist with a Pharmacological and Pharmacokinetic Profile Optimized for the Treatment of Chronic Cardiovascular Diseases.

AbstractEtherification of the phenol (I) with epichlorohydrin (II) and subsequent amination reaction of (III) with isopropylamine (IV) produce betaxolol (V).

Synthesis of a series of compounds related to betaxolol, a new .beta.1-adrenoceptor antagonist with a pharmacological and pharmacokinetic profile optimized for the treatment of chronic cardiovascular diseases

A series of para-substituted phenoxypropanolamines has been synthesized and tested for beta-adrenoceptor blocking activity. Some derivatives (8, 11, 12, 20, 21) exhibited greater in vitro potency than the reference drugs metoprolol and propranolol. This series, in contrast to propranolol but similar to metoprolol, possesses cardioselectivity. The 3-[p-[(cycloalkylmethoxy)ethyl]phenoxy]-1-substituted-amino-2-prop anol derivatives 8 (cyclopropylmethoxyethyl: betaxolol) and 11 (cyclobutylmethoxyethyl) produced antihypertensive effects in spontaneously hypertensive rats. Betaxolol (Kerlon, 8) was found to exhibit an appropriate preclinical pharmacological and human pharmacokinetic profile (elevated oral bioavailability and prolonged plasma half-life) for the treatment of chronic cardiovascular diseases such as hypertension and angina.