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Neurohormonal activation in patients with acute myocardial infarction or chronic congestive heart failure. With special reference to treatment with angiotensin converting enzyme inhibitors
Abstract
Neurohormonal activation may provide a pathophysiological link between acute myocardial infarction and chronic congestive heart failure, and modulation of neurohormonal activity may be an important therapeutic target in these conditions. Plasma neurohormones were studied in 55 patients with acute myocardial infarction. Angiotensin II, noradrenaline and ANP were elevated in the early phase but tended to normalize during the first week in patients without signs of heart failure. In patients with heart failure angiotensin II and noradrenaline remained elevated for 1 month and ANP for 4-6 months. During head-up tilt, angiotensin II and noradrenaline increased most in patients with heart failure. In patients with a first myocardial infarction there was a positive correlation between sustained neurohormonal activity and infarct size. Almost complete suppression of plasma ACE activity was achieved within 30 min in 48 patients treated with intravenous enalaprilat, initiated within 24 h from the onset of infarction. The drug was tolerated in dosages of 1.0-1.2 mg given over 1-2h. Patients with systolic blood pressure between 100 and 110 mmHg incurred a greater risk of hypotension than those with higher blood pressure at baseline. Tolerance was not worse among patients treated with intravenous diuretics, metoprolol or nitroglycerin. A total of 98 patients were randomized to treatment with enalapril or placebo, initiated within 24 h from onset of infarction and continued for 4-6 months. During treatment there were no significant differences in plasma levels of angiotensin II, aldosterone, ANP or catecholamines between groups. Echocardiographic recordings were performed in 28 patients. Among patients on placebo there was a positive correlation between plasma levels of noradrenaline at days 5-7 and the increase in left ventricular volumes during the study period, and an inverse correlation between plasma aldosterone at days 5-7 and the increase in left ventricular ejection fraction during the study. No such correlation was found among patients on enalapril. ANP levels at 1 month correlated inversely with the left ventricular ejection fraction at the same time. Plasma neurohormones were measured in 223 patients with mild or moderately severe chronic heart failure, randomized to treatment with ramipril or placebo for 3 months. There was wide variation in hormone levels. Noradrenaline and aldosterone correlated inversely with exercise duration at baseline. Noradrenaline correlated positively with the degree of symptoms. Aldosterone and ANP were reduced with ramipril compared with placebo. Noradrenaline was reduced among patients with baseline levels in the highest tertile. Plasma hormones were also measured at peak exercise in 54 patients. Hormonal levels at rest correlated strongly with those at peak exercise.(ABSTRACT TRUNCATED AT 400 WORDS)
... It is important to note that GRK-2 participates not only in desensitization of β-AR, but also in desensitization of other GPCRs in the cell, such are the adrenergic and muscarinic receptor family [23]. Role of G protein related kinase in coronary artery disease – evidence from animal studies Neurohormonal activation occurs early in the progression to HF, as reflected by increased catecholamine levels and adrenergic drive immedi ately after myocardial infarction (MI) and before progression to end-stage HF [24] . Therefore, sympathetic nervous activity has been investigated as a possible early trigger for increasing GRK activity in the failing myocardium. ...
... Therefore, sympathetic nervous activity has been investigated as a possible early trigger for increasing GRK activity in the failing myocardium. Excessive catecholamine stimulation modulates β-AR signaling and damps sympathetic signaling [24]. This is considered to be an adaptive mechanism to sympathetic overstimulation . ...
In coronary artery disease the G protein related kinases (GRKs) play a role in desensitization of β-adrenoreceptors (AR) after coronary occlusion. Targeted deletion and lowering of cardiac myocyte GRK-2 decreases the risk of post-ischemic heart failure (HF). Studies carried out in humans confirm the role of GRK-2 as a marker for the progression of HF after myocardial infarction (MI). The level of GRK-2 could be an indicator of β-AR blocker efficacy in patients with acute coronary syndrome. Elevated levels of GRK-2 are an early ubiquitous consequence of myocardial injury. In hypertension an increased level of GRK-2 was reported in both animal models and human studies. The role of GRKs in vagally mediated disorders such as vasovagal syncope and atrial fibrillation remains controversial. The role of GRKs in the pathogenesis of neurocardiological diseases provides an insight into the molecular pathogenesis process, opens potential therapeutic options and suggests new directins for scientific research.
... In humans, neurohormonal activation such as adrenergic overdrive has been observed in patients acutely after cardiac stress/injury including after a myocardial infarction (230). In addition, increased levels of GRK2 have also been reported in other human studies of disease states (reviewed in Refs. ...
G protein-coupled receptors (GPCRs) are important regulators of various cellular functions via activation of intracellular signaling events. Active GPCR signaling is shut down by GPCR kinases (GRKs) and subsequent β-arrestin-mediated mechanisms including phosphorylation, internalization, and either receptor degradation or resensitization. The seven-member GRK family varies in their structural composition, cellular localization, function, and mechanism of action (see sect. II). Here, we focus our attention on GRKs in particular canonical and novel roles of the GRKs found in the cardiovascular system (see sects. III and IV). Paramount to overall cardiac function is GPCR-mediated signaling provided by the adrenergic system. Overstimulation of the adrenergic system has been highly implicated in various etiologies of cardiovascular disease including hypertension and heart failure. GRKs acting downstream of heightened adrenergic signaling appear to be key players in cardiac homeostasis and disease progression, and herein we review the current data on GRKs related to cardiac disease and discuss their potential in the development of novel therapeutic strategies in cardiac diseases including heart failure.
Copyright © 2015 the American Physiological Society.
... A prominent hypothesis is that the underlying mechanism involves an increase in the activity of GRK2, which phosphorylates and desensitizes the βAR as well as other GPCRs (Rockman et al., 2002;Hata and Koch, 2003). During progression to heart failure, sustained elevation of catecholamine levels leads to prolonged stimulation of βAR resulting in chronic desensitization of the receptor by GRK2 (Sigurdsson, 1995;Rundqvist et al., 1997;Hata and Koch, 2003). Gβγ recruits GRK2 to the receptor (Pitcher et al., 1992). ...
... The most pronounced activation was observed in the group of patients with impaired systolic cardiac function at discharge. This observation is in accordance with studies describing that activation in this system is related to infarct size and to indices of ventricular function [18]. ...
The study was designed to assess (1) the time course of catecholaminergic activation in acute myocardial infarction (AMI) as estimated by adrenaline (ADR) and noradrenaline (NOR) concentrations, and (2) to relate activation of these hormones to predict the outcome of cardiac performance.
Eighteen patients with first AMI were studied. Blood samples were drawn within the first 4-18 h, after 18-24 h, on day 2, day 3 and on day 6 as well as after 1 year. Radionuclide ventriculography was performed on the day of discharge and after 1 year to determine left-ventricular ejection fraction (LVEF).
In the study group as a whole, the concentrations of ADR decreased from (mean +/- SEM) 0.80 +/- 0.12 nmol/l on admission to 0.33 +/- 0.03 nmol/l at discharge (p < 0.05). NOR decreased from 4.19 +/- 0.78 to 2.44 +/- 0.33 nmol/l (p < 0.05). Initial peak concentrations of both ADR and NOR on admission were correlated to LVEF at discharge (r = -0.56, p < 0.05 and r = -0.72, p < 0.05, respectively). If NOR was normal (<3 nmol/l) at admission, the LVEF was normal or almost normal (= 0.46) at discharge. The mean plasma level of ADR and NOR after 1 year follow-up was 0.34 +/- 0.04 and 1.95 +/- 0.25 nmol/l, respectively. The values after 1 year were unchanged compared to values at discharge, at day 6 (n.s.). Mean LVEF was 0.50 +/- 0.03 (range: 0.23-0.69) at discharge and unchanged 0.46 +/- 0.05 (range: 0.18-0.72) at 1 year follow-up (n.s.). During hospitalisation, the group with LVEF <0.50 had an 86% higher initial ADR and an 82% higher initial NOR concentration compared to values in patients with LVEF >0.50 (p < 0.05).
(1) Catecholaminergic activation, as measured by plasma ADR and NOR in AMI, is acute and restricted to the first 5 days. Thereafter, the hormone levels are normal and stable. (2) The magnitude of the early catecholaminergic activation correlates with left ventricular systolic performance. (3) Normal NOR values at admittance predicts normal or almost normal LVEF at discharge.
Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality globally, posing significant challenges in cardiology and internal medicine. AMI is characterized by the sudden interruption of blood flow to a portion of the myocardium, resulting in ischemic injury and myocardial necrosis. This condition presents a wide range of clinical manifestations, from asymptomatic cases to severe complications. Advances in treatment underscore the need for a comprehensive understanding of AMI's path physiology and prognostic indicators to improve patient outcomes. One crucial aspect of myocardial function impacted by AMI is left ventricular diastolic function (LVDF), which involves the heart's ability to relax and fill with blood during diastole. Impaired LVDF can be an early sign of myocardial injury and is a significant determinant of clinical outcomes post-AMI. Ischemic damage to the myocardium can lead to changes in LVDF, affecting relaxation, ventricular filling, and myocardial stiffness, thereby influencing the overall prognosis. Research links LV diastolic dysfunction (LVDD) with various adverse clinical outcomes in AMI patients, including exacerbated heart failure symptoms, adverse ventricular remodeling, and increased risk of chronic heart failure and cardiovascular mortality. Echocardiography, particularly Doppler imaging, is vital for assessing LVDF, with the E/A and E/e' ratios serving as key parameters. An abnormal E/A ratio suggests impaired LV relaxation or increased stiffness, while an elevated E/e' ratio indicates increased LV filling pressures (LVFP) and is associated with worse outcomes. Studies have shown that elevated E/e' ratios predict higher left atrial pressures and increased heart failure risk, correlating with prolonged hospitalization and higher mortality in AMI patients. Conversely, normalization of diastolic parameters can indicate a positive response to therapy and improved recovery. In conclusion, assessing LVDF through echocardiographic parameters like the E/A and E/e' ratios is essential in managing AMI patients. These measures provide valuable insights into LVFP and LVDF, crucial for understanding AMI's clinical course and optimizing patient care. Ongoing research and clinical application of these parameters are vital for enhancing prognostic accuracy and treatment strategies for AMI.
Cardiovascular diseases (CVDs) represent the leading cause of death globally. Despite major advances in the field of pharmacological CVD treatments, particularly in the field of heart failure (HF) research, case numbers and overall mortality remain high and have trended upwards over the last few years. Thus, identifying novel molecular targets for developing HF therapeutics remains a key research focus. G protein-coupled receptors (GPCRs) are critical myocardial signal transducers which regulate cardiac contractility, growth, adaptation and metabolism. Additionally, GPCR dysregulation underlies multiple models of cardiac pathology, and most pharmacological therapeutics currently used in HF target these receptors. Currently-approved treatments have improved patient outcomes, but therapies to stop or reverse HF are lacking. A recent focus on GPCR intracellular-regulating proteins such as GPCR kinases (GRKs) has uncovered GRK2 as a promising target for combating HF. Current literature strongly establishes increased levels and activity of GRK2 in multiple models of CVD. Additionally, the GRK2 interactome includes numerous proteins which interact with differential domains of GRK2 to modulate both beneficial and deleterious signaling pathways in the heart, indicating that these domains can be targeted with a high level of specificity unique to various cardiac pathologies. These data support the premise that GRK2 should be at the forefront of a novel investigative drug search. This perspective reviews cardiac GPCRs, describes the structure and functions of GRK2 in cardiac function and maladaptive pathology, and summarizes the ongoing and future research for targeting this critical kinase across cellular, animal and human models of cardiac dysfunction and HF.
Ischemia–reperfusion (I/R) injury is the main reason why infarct size continues to progress during the process of restoring myocardial perfusion, and it significantly increases the risk of death. At present, the therapeutic effects of clinically used drugs are limited. Therefore, it is particularly necessary to explore myocardial-protective agents that effectively prevent I/R injury. Lycium barbarum polysaccharide (LBP) is a water-soluble polysaccharide extracted from wolfberry fruit. In this study, we found that LBP limited myocardial infarct size, improved adverse remodeling, and reduced cell death and oxidative stress. GRK2 is a key molecule involved in myocardial I/R injury. In vivo and in vivo experiments showed that LBP inhibited the upregulation of GRK2 expression induced by I/R injury, which was related to the antiapoptotic effect of LBP. In addition, we found that LBP partially restored I/R-induced mitochondrial fission/fusion imbalance, as well as levels of p-AKT and p-eNOS, and this restorative effect could be attenuated by overexpression of GRK2. Overall, our findings suggest that LBP antagonizes cardiomyocyte apoptosis by inhibiting the upregulation of GRK2 induced by I/R injury and saves mitochondrial fission/fusion imbalance and AKT/eNOS signaling. This study may provide new ideas for the study of I/R injury and the rational application of the herbal medicine LBP.
The objective of this study was to determine whether the magnitude of adrenergic activation, as measured by plasma norepinephrine concentration (PNE) in the acute phase of myocardial infarction, may be useful as an independent predictor of long-term morbidity and mortality following acute myocardial infarction (AMI). Plasma norepinephrine was obtained within 3 days of admission to the cardiac intensive care unit in 146 randomly selected patients presenting with their first AMI. We analysed the relationship between the initial PNE and the clinical outcomes of death, reinfarction, and congestive heart failure during the subsequent 18 months. Patients with initial PNE over 565 pg/ml (n = 54) were found to have a significantly higher likelihood of cardiac death within the following 18 months (RR = 4.22; p = 0.04), as compared with patients with a lower PNE (n = 98). Even adjustment for variables significant on the univariate level, the difference in mortality remained significant (RR = 4.67; p = 0.03). No correlation was found between PNE and subsequent incidence of reinfarction and congestive heart failure in these patients (RR = 0.087; p = 0.80 and RR = 1.00; p = 0.09, respectively). Our observations support the hypothesis that PNE obtained early in the course of myocardial infarction can be a useful independent prognostic tool for post-AMI mortality.
G proteins mediate the action of G protein coupled receptors (GPCRs), a major target of current pharmaceuticals and a major target of interest in future drug development. Most pharmaceutical interest has been in the development of selective GPCR agonists and antagonists that activate or inhibit specific GPCRs. Some recent thinking has focused on the idea that some pathologies are the result of the actions of an array of GPCRs suggesting that targeting single receptors may have limited efficacy. Thus, targeting pathways common to multiple GPCRs that control critical pathways involved in disease has potential therapeutic relevance. G protein βγ subunits released from some GPCRs upon receptor activation regulate a variety of downstream pathways to control various aspects of mammalian physiology. There is evidence from cell- based and animal models that excess Gβγ signaling can be detrimental and blocking Gβγ signaling has salutary effects in a number of pathological models. Gβγ regulates downstream pathways through modulation of enzymes that produce cellular second messengers or through regulation of ion channels by direct protein-protein interactions. Thus, blocking Gβγ functions requires development of small molecule agents that disrupt Gβγ protein interactions with downstream partners. Here we discuss evidence that small molecule targeting Gβγ could be of therapeutic value. The concept of disruption of protein-protein interactions by targeting a "hot spot" on Gβγ is delineated and the biochemical and virtual screening strategies for identification of small molecules that selectively target Gβγ functions are outlined. Evaluation of the effectiveness of virtual screening indicates that computational screening enhanced identification of true Gβγ binding molecules. However, further refinement of the approach could significantly improve the yield of Gβγ binding molecules from this screen that could result in multiple candidate leads for future drug development.
Die neuroendokrine Aktivierung spielt bei der Entwicklung und Progression der chronischen Herzinsuffizienz sowohl im Rahmen der Pathophysiologie als auch als Ansatzpunkt einer möglichen medikamentösen Intervention eine bedeutende Rolle. In der Therapie der chronischen Herzinsuffizienz konnte durch den Einsatz von ACE-Hemmern nicht nur eine Verbesserung der Symptomatik, sondern auch eine Verringerung der Mortalität erreicht werden. Ziel der hier vorgelegten klinischen Studie war es, den Einfluss des ACE-Hemmers Perindopril auf die neurohumoralen Parameter Renin, Aldosteron, Atrialer Natriuretischer Faktor (ANF), zyklisches Guanosinmonophosphat (cGMP), Endothelin-1, sowie Vasopressin bei Patienten mit chronischer Herzinsuffizienz zu untersuchen. Die gewonnen Daten wurden zudem mit den im Rahmen einer parallel laufenden Untersuchung erfassten hämodynamischen Messwerten korreliert, um nähere Aufschlüsse über den Zusammenhang zwischen hämodynamischen Verhältnissen und dem dabei vorliegenden Grad der neurohumoralen Aktivierung zu erhalten. Weiterhin sollten durch die Ermittlung der Korrelationen zwischen den einzelnen neurohumoralen Parametern weitere Aufschlüsse über die bestehenden Zusammenhänge zwischen den neurohumoralen Systemen erhalten werden. Die Erhebung der Daten erfolgte im Rahmen einer doppelblinden placebokontrollierten Studie über 24 Wochen, an 25 Patienten mit chronischer Herzinsuffizienz im Stadium NYHA II-III aufgrund von dilatativer Kardiomyopathie oder koronarer Herzerkrankung. Die tägliche Dosierung von Perindopril betrug dabei zu Studienbeginn 2 mg und wurde bei Verträglichkeit auf 4 mg erhöht. Es wurden die Plasmaspiegel der untersuchten Neurohormone wie auch die hämodynamischen Parameter Belastungstoleranz, Herzfrequenz, sowie systolischer und diastolischer Blutdruck bei Untersuchungsbeginn, sowie nach 4, 12 und 24 Wochen erfasst. Die Bestimmung der linksventrikulären Auswurffraktion erfolgte zu Studienbeginn sowie nach 12 und 24 Wochen, die des kardiothorakalen Quotienten zu Beginn und am Ende der Studie. Perindopril führte zu einem Anstieg des mittleren Renin-Plasmaspiegels, der zu allen Untersuchungszeitpunkten das Signifikanzniveau sowohl im Vergleich zum Untersuchungsbeginn als auch im Vergleich zur Placebogruppe erreichte. Der Plasmaspiegel von Aldosteron lag zu allen Untersuchungszeitpunkten in der Verumgruppe unterhalb des Ausgangsniveaus, ein signifikanter Unterschied im Vergleich mit dem Untersuchungsbeginn konnte jedoch nicht erreicht werden. Nur zum Zeitpunkt 12 Wochen bestand ein signifikanter Unterschied im Vergleich zur Placebogruppe. Diese Ergebnisse weisen auf eine langanhaltende Hemmung des Angiotensin-Converting-Enzyms während des gesamten Untersuchungsverlaufes durch Perindopril hin. Ob eine Dosiserhöhung zu einer stärkeren Suppression des Aldosteronspiegels führt, sollte durch weitere Untersuchungen geklärt werden. Perindopril führte zu keiner signifikanten Änderung des ANF-Plasmaspiegels während des gesamten Untersuchungsverlaufes. Der Plasmaspiegel von cGMP wurde durch Perindopril gesenkt, ein Signifikanzniveau konnte aber nur zum Zeitpunkt 4 Wochen im Vergleich zum Studienbeginn erreicht werden. Auch hier sollte geprüft werden, ob eine Dosiserhöhung von Perindopril zu einem stärkeren Einfluss auf diese Parameter führen kann. Überraschenderweise kam es in der Verumgruppe zu einem Anstieg des Plasmaspiegels von Endothelin-1, der das Signifikanzniveau zu den Zeitpunkten 12 und 24 Wochen im Vergleich zum Studienbeginn erreichte. Durch weitere Untersuchungen sollte geklärt werden, ob es sich hier um eine substanzspezifische Wirkung von Perindopril handelt. Eine Beeinflussung des Vasopressin-Plasmaspiegels durch Perindopril konnte nicht gezeigt werden. Eine signifikante lineare Korrelation innerhalb der neurohumoralen Parameter ergab sich nur für ANF und cGMP sowie in schwächerer Form für cGMP und Vasopressin. Zwischen hämodynamischen und neurohumoralen Messgrößen ergaben sich für ANF und cGMP signifikante positive lineare Korrelationen mit der linksventrikulären Auswurffraktion sowie negative Korrelationen mit dem kardiothorakalen Quotienten. Für Vasopressin konnte eine schwache positive lineare Korrelation mit dem diastolischen Blutdruck und der Herzfrequenz nachgewiesen werden. Auffallend war eine starke Streuung der Einzelwerte sämtlicher gemessener Plasmaspiegel. Die Ergebnisse zeigen, dass die Aktivierung der einzelnen neurohumoralen Systeme nicht parallel, sondern interindividuell verschieden und komplex verläuft. Nur für cGMP als second messenger konnte eine Koinzidenz mit ANF nachgewiesen werden. Ansonsten ist der Rückschluss von der Aktivierung eines neurohumoralen Systems auf ein anderes bei Patienten mit Herzinsuffizienz im Stadium NYHA II-III nicht möglich. Von den gemessenen neurohumoralen Parametern haben nur die Plasmaspiegel von ANF und vor allem cGMP eine verwertbare Aussagekraft als humorale Marker für die linksventrikuläre Funktion bei Patienten mit chronischer Herzinsuffizienz im Stadium NYHA II-III.
Ischaemic heart disease is a major cause of chronic heart failure in Western societies. Despite some progress in the treatment of heart failure, it is still a disabling disorder with both high mortality and high morbidity. The incidence of chronic heart failure has increased over the past decade, probably as a result of the recent success in the management of patients with acute myocardial infarction. The importance of measures with potential capacity to prevent the development of symptomatic heart failure may be best illustrated by the fact that, among patients with left ventricular dysfunction, the prognosis is much worse in those with symptomatic failure than in those who are asymptomatic. Recently, the efficacy of angiotensin converting enzyme (ACE) inhibitors after myocardial infarction has been studied in a number of large placebo-controlled trials. These studies indicate that patients with symptomatic or asymptomatic left ventricular dysfunction after an acute myocardial infarction should receive long-term treatment with an ACE inhibitor and that such treatment may improve survival, reduce the incidence of overt heart failure and reduce the risk of reinfarction.
Altered function of the GH/IGF-I axis in patients with dilated cardiomyopathy (DCM) has been reported. In fact, DCM patients show reduction of IGF-I levels, which could reflect slight peripheral GH resistance or, alternatively, reduced somatotroph secretion. Spontaneous GH secretion has been reported to be altered by some but not by other authors, whereas the GH response to GHRH, but not that to GH-releasing peptides, seems reduced in DCM patients. On the other hand, it is well known that the GH response to GHRH in humans is markedly potentiated by arginine (ARG), which probably acts via inhibition of hypothalamic somatostatin release; in fact the GHRH+ARG test is known as one of the most reliable to evaluate the maximal secretory capacity of somatotroph cells.
In order to further clarify the somatotroph function in DCM, in well-nourished patients with DCM (34 male, 4 female; age (mean+/-s.e. m.) 57.8+/-1.1 years; body mass index (BMI) 24.6+/-0.6kg/m(2); left ventricular ejection fraction 23.2+/-1.6%; New York Heart Association classification I/1, II/17, III/18, IV/2) we studied the GH response to GHRH (1.0 microgram/kg i.v.) alone or combined with ARG (0.5g/kg i.v.). The results in DCM patients were compared with those in age-matched control subjects (CS) (39 male, 7 female; age 58.9+/-1.0 years; BMI 23.2+/-0.3kg/m(2)).
Mean IGF-I levels in DCM patients were lower than in CS (144.3+/-6.9 vs 175.1+/-8. 4 microgram/l, P<0.05) whereas basal GH levels were similar in both groups (1.7+/-0.3 vs 1.7+/-0.3 microgram/l). The GH response to GHRH in DCM patients was lower (P<0.05) than that in CS (GH peak 6.5+/-1.2 vs 10.7+/-2.1 microgram/l). In both groups the GH response to GHRH+ARG was higher (P<0.001) than that to GHRH alone. However, the GH response to GHRH+ARG in DCM patients remained clearly lower (P<0.01) than that in CS (18.3+/-3.2 vs 34.1+/-4.6 microgram/l). The GH response to GHRH alone and combined with ARG was not associated with the severity of the disease.
DCM patients show blunted GH responses to GHRH both alone and combined with ARG. Evidence that ARG does not restore the GH response to GHRH in DCM patients makes it unlikely that the somatotroph hyporesponsiveness to the neurohormone reflects hyperactivity of hypothalamic somatostatinergic neurons.
Angiotensin-converting enzyme inhibitors improve long-term survival in patients with left ventricular dysfunction after a myocardial infarction, but their mechanism of action is not entirely clear. The neurohormonal effects may be important in this respect, as well as an early hemodynamic unloading induced by these drugs. The primary objective was to assess the effect of trandolapril on plasma levels of atrial natriuretic peptide. A secondary objective was to assess the effects of trandolapril on selected neurohormones, vasoactive peptides and enzymes, which may be important in the development of left ventricular remodeling and heart failure following an acute myocardial infarction. A total of 119 patients with an acute myocardial infarction and a wall motion index < or =1.2 (16-segment echocardiographic model) were randomized to double blind treatment with trandolapril or placebo within 3-7 days after the onset of infarction. Blind treatment was discontinued 21 days after the index infarction. Venous blood samples were collected at rest, before randomization and on the day after treatment was discontinued. At the end of the study, there were no differences in plasma levels of atrial natriuretic peptide between the two treatment groups. Angiotensin-converting enzyme activity was suppressed and plasma renin activity was higher in the trandolapril group. No differences in plasma levels of N-terminal pro-atrial natriuretic peptide, brain natriuretic peptide, aldosterone, noradrenaline, adrenaline, vasopressin, big endothelin-1 and neuropeptide Y were found between the two treatment groups. There were positive correlations between several markers of neurohormonal activation at baseline and variables expressing left ventricular dysfunction and clinical heart failure. Neurohormonal activation is related to left ventricular dysfunction. The effects of 2-3 weeks of angiotensin-converting enzyme inhibition on neurohormonal activation does not predict the already established beneficial long-term effects after myocardial infarction. Thus, early modulation of circulatory neurohormone levels may not be a major mechanism for the efficacy of angiotensin-converting enzyme inhibitors in these patients. Selected plasma hormone markers may still be used to identify patients who might get the greatest benefit from treatment.
Our purpose was to study the changes in vasoconstrictive neurohormones, N-terminal proatrial natriuretic peptide (Nt-proANP), and brain natriuretic peptide (BNP) and their relationship with left ventricular (LV) remodeling soon after anterior myocardial infarction (MI).
The Healing and Afterload Reducing Therapy (HEART) trial has shown that early use of ramipril improves left ventricular ejection fraction (LVEF) and attenuates LV remodeling when initiated soon after MI. This neurohumoral substudy of HEART investigates the changes in vasoconstrictive and natriuretic peptides and their relationship with LV remodeling.
One hundred twenty-two patients had blood drawn for the measurement of catecholamines, endothelin-I, angiotensin II, Nt-proANP and BNP, and prostacyclins within 24 hours of an MI, and at 3, 14, and 90 days after the MI. Quantitative echocardiograms were performed at baseline and at 14 days.
All neurohormones except angiotensin II (P =.12) and prostaglandins were significantly elevated at baseline. Vasoconstrictive neurohormones decreased significantly over time but remained elevated at 14 days. Both Nt-proANP and BNP were elevated within the first 14 days. BNP decreased significantly by 90 days, whereas Nt-proANP exhibited no change between 14 and 90 days. Ramipril decreased plasma levels of angiotensin II at 3 days but had no effect on the other neurohormones.
Neurohumoral activation occurs and persists in patients with anterior MI and overall preserved LV function. Ramipril had only a modest impact on neurohormones despite its significant benefits on LV remodeling soon after MI.
Is heart failure an endocrine disease? Historically, congestive heart failure (CHF) has often been regarded as a mechanical and haemodynamic condition. However, there is now strong evidence that the activation of neuroendocrine systems, like the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, as well as the activation of natriuretic peptides, endothelin and vasopressin, play key roles in the progression of CHF. In this context, agents targeting neurohormones offer a highly rational approach to CHF management, with ACE inhibitors, aldosterone antagonists and beta-adrenergic blockade improving the prognosis for many patients. Although relevant improvements in clinical status and survival can be achieved with these drug classes, mortality rates for patients with CHF are still very high. Moreover, most patients do not receive these proven life-prolonging drugs, partially due to fear of adverse events, such as hypotension (with ACE inhibitors), gynaecomastia (with spironolactone) and fatigue (with beta-blockers). New agents that combine efficacy with better tolerability are therefore needed. The angiotensin II type 1 (AT(1))-receptor blockers have the potential to fulfil both these requirements, by blocking the deleterious cardiovascular and haemodynamic effects of angiotensin II while offering placebo-like tolerability. As shown with candesartan, AT(1)-receptor blockers also modulate the levels of other neurohormones, including aldosterone and atrial natriuretic peptide (ANP). Combined with its tight, long-lasting binding to AT(1)-receptors, this characteristic gives candesartan the potential for complete blockade of the RAAS-neurohormonal axis, along with the great potential to improve clinical outcomes.
GRKs critically regulate betaAR signaling via receptor phosphorylation and the triggering of desensitization. In the heart, betaARs control the chronotropic, lusitropic, and inotropic responses to the catecholamine neurotransmitters, norepinephrine and epinephrine. Signaling through cardiac betaARs is significantly impaired in many cardiovascular disorders, including congestive heart failure. betaARK1 (also known as GRK2) is the most abundant GRK in the heart, and it is increased in several cardiovascular diseases associated with impaired cardiac signaling and function, suggesting that this molecule could have pathophysiological relevance in the setting of heart failure. The ability to manipulate the mouse genome has provided a powerful tool to study the physiological implications of altering GRK activity and expression in the heart. Recent studies in several different mouse models have demonstrated that betaARK1 plays a key role not only in the regulation of myocardial signaling, but also in cardiac function and development. Moreover, studies have shown that targeting the activity of GRKs, especially betaARK1, appears to be a novel therapeutic strategy for the treatment of the failing heart. Gene therapy technology makes it possible, beyond what is possible in the mouse, to directly test in larger animals whether betaARK1 inhibition in the setting of disease will improve the function of the compromised heart, and this methodology has also lead to compelling results. These genetic approaches or the development of small molecule inhibitors of betaARK1 and GRK activity may advance therapeutic options for heart disease.
Heart failure (HF) represents one of the leading causes of morbidity and mortality in developed nations today. Although this disease process represents a final common endpoint for several entities, including hypertension, coronary artery disease, and cardiomyopathy, a predominant characteristic of end-stage HF is an altered beta-adrenergic receptor signaling cascade. In the heart, beta-adrenergic receptors (beta ARs), members of the superfamily of G-protein-coupled receptors (GPCRs), modulate cardiac function by controlling chronotropic, inotropic, and lusitropic responses to catecholamines of the sympathetic nervous system. In HF, beta ARs are desensitized and downregulated in a maladaptive response to chronic stimulation. This process is largely mediated by G-protein-coupled receptor kinases (GRKs), which phosphorylate GPCRs leading to functional uncoupling. The most abundant cardiac GRK, known as GRK2 or beta AR kinase 1 (beta ARK1), is increased in human HF, and has been implicated in the pathogenesis of dysfunctional cardiac beta AR signaling. The association of beta ARs and GRKs with impaired cardiac function has been extensively studied using transgenic mouse models, which have demonstrated that beta ARK1 plays a vital role in the regulation of myocardial beta AR signaling. These findings have caused beta ARs and GRKs to be regarded as potential therapeutic targets, and gene therapy strategies have been used to manipulate the beta AR signaling pathway in myocardium, leading to improved function in the compromised heart. Ultimately, these genetic modifications of the heart may represent new potential therapies for human HF.
The actions of G-protein coupled receptor kinases (GRKs) critically regulate beta-adrenergic receptor (betaAR) signalling. In the cardiovascular system, the betaAR signalling pathway controls important responses of the heart such as the ability to contract (inotropy), the ability to contract faster (chronotropy) and the ability to relax (lusotropy). The observation that the betaAR kinase (betaARK1, also known as GRK2), the most abundant GRK in the heart, is increased in cardiovascular disease associated with impaired cardiac function, suggests that this molecule could have pathophysiological relevance in the setting of heart failure. Technological advances in the genetic engineering of mice have provided a powerful tool to study the physiological implications of altering GRK activity and expression in the heart. Recent studies have demonstrated that betaARK1 plays a key role in not only the regulation of myocardial signalling, but also in cardiac function and development. Importantly, targeting the activity of GRKs, and betaARK1 in particular, appears to represent a novel therapeutic strategy for the treatment of the failing heart. At present, gene therapy modalities are being tested which inhibit the activity of betaARK1 in the heart. This technology makes it possible to test directly whether betaARK1 inhibition in the setting of heart disease will improve the function of the compromised heart. Thus, these genetic approaches or the development of small molecule inhibitors of GRK activity, may lead to novel therapeutic approaches for cardiovascular disease.
In the heart, beta -adrenergic receptors (beta ARs), members of the superfamily of G protein-coupled receptors (GPCRs), modulate cardiac responses to catecholamines. beta AR signaling, which is compromised in many cardiac diseases (e.g., congestive heart failure), is regulated by GPCR kinases (GRKs). Levels of the most abundant cardiac GRK, known as GRK2 or beta AR kinase 1 (beta ARK1), are increased in both animal and human heart failure. Transgenic mouse models have demonstrated that beta ARK1 plays a vital role in cardiac function and development, as well as in the regulation of myocardial signaling, and pharmacological studies have further implicated GRKs in the impairment of cardiac GPCR signaling. Gene therapy, along with the development of small-molecule modulators of GRK activity, has indicated in multiple animal models that the manipulation of GRK activity may elicit therapeutic benefits in many forms of cardiac disease.
G proteins mediate the action of G protein coupled receptors (GPCRs), a major target of current pharmaceuticals and a major target of interest in future drug development. Most pharmaceutical interest has been in the development of selective GPCR agonists and antagonists that activate or inhibit specific GPCRs. Some recent thinking has focused on the idea that some pathologies are the result of the actions of an array of GPCRs suggesting that targeting single receptors may have limited efficacy. Thus, targeting pathways common to multiple GPCRs that control critical pathways involved in disease has potential therapeutic relevance. G protein betagamma subunits released from some GPCRs upon receptor activation regulate a variety of downstream pathways to control various aspects of mammalian physiology. There is evidence from cell- based and animal models that excess Gbetagamma signaling can be detrimental and blocking Gbetagamma signaling has salutary effects in a number of pathological models. Gbetagamma regulates downstream pathways through modulation of enzymes that produce cellular second messengers or through regulation of ion channels by direct protein-protein interactions. Thus, blocking Gbetagamma functions requires development of small molecule agents that disrupt Gbetagamma protein interactions with downstream partners. Here we discuss evidence that small molecule targeting Gbetagamma could be of therapeutic value. The concept of disruption of protein-protein interactions by targeting a "hot spot" on Gbetagamma is delineated and the biochemical and virtual screening strategies for identification of small molecules that selectively target Gbetagamma functions are outlined. Evaluation of the effectiveness of virtual screening indicates that computational screening enhanced identification of true Gbetagamma binding molecules. However, further refinement of the approach could significantly improve the yield of Gbetagamma binding molecules from this screen that could result in multiple candidate leads for future drug development.
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