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Advanced Therapeutic Options in Acute Heart Failure
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Tiffany Dong, Aditi Nayak, Alanna Morris
Novel vasodilators include serelaxin and ularitide. Serelaxin is a recombinant form of relaxin, which releases nitric oxide allowing for cardiovascular and renal adaptations during pregnancy. In the RELAX-AHF trial, which enrolled 1,161 patients with ADHF, the serelaxin arm attained the primary endpoint of relief of dyspnea by day five but not day one.12 A follow-up study with 6,800 patients with ADHF (RELAX-AHF-2), failed to show cardiovascular mortality benefit or improvement in heart failure by day 5.13 Ularitide is a synthetic form of urodilatin, which is spliced into atrial natriuretic peptide, thus promoting natriuresis by the distal tubules and the collecting duct.14 In the SIRIUS II trial, patients who were randomized to a 24-h infusion of ularitide had dose-dependent reductions in pulmonary capillary wedge pressure (PCWP) and in dyspnea score at six hours. Patients on higher doses also had lower systemic vascular resistance and increased cardiac index that persisted 24 hours after starting ularitide.15 Despite these promising results, ularitide failed to improve cardiovascular mortality and clinical outcomes after 48-hours in a study of 2,157 patients.16
Hypertensive Emergencies and Urgencies
Published in Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei, Manual of Hypertension of the European Society of Hypertension, 2019
Maria Lorenza Muiesan, Anna Paini, Claudia Agabiti Rosei, Fabio Bertacchini, Massimo Salvetti
Clevidipine is a third-generation calcium antagonist inhibiting selectively extracellular calcium influx through the L-type channel, relaxing smooth muscle of small arteries and reducing peripheral vascular resistance. The advantages of clevidipine are the blood metabolism, the very short (1-minute) half-life and the rapid titration (42,47) with minimal effects on stroke volume, cardiac output or heart rate. In the PRONTO study (48) clevidipine reduced SBP and improved dyspnoea more effectively than standard treatment did, with a reduction in the need of additional IV antihypertensive drugs and in the total dose of furosemide. In AHF, several other promising drugs including ularitide, an analogue of urodilatin, and serelaxin, a recombinant version of human relaxin-2, are currently under investigation (18).
Physical activity and kidney function in health and disease
Published in Roy J. Shephard, Physical Activity and the Abdominal Viscera, 2017
Physical activity usually has a marked anti-diuretic effect, as the pituitary gland attempts to maintain plasma volume in the face of fluid losses in sweat by increasing plasma concentrations of anti-diuretic hormone. However, this compen satory mechanism is not always sustained during prolonged heavy exercise.[20, 30] There is also an increased secretion of the hormone aldosterone; this facilitates the reabsorption of sodium ions in the glomerular tubules, counteracting increases in the secretion of atrial natriuretic peptides that would otherwise have increased glomerular flow rate and sodium excretion.[58, 68] Other factors limiting the action of atrial natriuretic peptides during heavy exercise likely include greater renal sympathetic nerve activity, and increased blood levels of angiotensin II and catecholamines.[57] Urodilatin is a hormone similar to the atrial natriuretic peptides and it causes diuresis by augmenting renal blood flow. The kidneys increase the output of this substance during physical activity.[69] Further research is needed to clarify the respective contributions of urodilatin and atrial natriuretic peptides to the exercise response.
Urinary peptidomics in kidney disease and drug research
Published in Expert Opinion on Drug Discovery, 2018
Magdalena Krochmal, Joost P Schanstra, Harald Mischak
About 30 years ago, the concept of investigating urinary peptides for biological activity and consequently, potential drug candidates was presented by the group of Forssmann and colleagues [19]. One of the first drug candidates that was identified through these efforts was urodilatin [20]. Based on this peptide, a drug candidate, ularitide, was developed and, after several smaller studies in kidney and heart diseases, tested for its ability to impact the short- and long-term clinical course of patients with acute heart failure [21]. Unfortunately, the trial to date could not demonstrate a significant improvement in outcome [22]. Another pioneering discovery in the field of bioactive peptides was the cyclic arginine-glycine-aspartic acid (RGD). Following the induction of ischemic acute renal failure in rats, administration of RGD peptide showed efficacy in improving in the renal function [23].
Relevance of the assessment of natriuretic peptide plasma concentrations in hypertensive pregnant women
Published in Biomarkers, 2020
Agata Gondek, Aleksandra Jagodzińska, Bronisława Pietrzak, Artur Mamcarz, Agnieszka Cudnoch-Jędrzejewska
ANP is released from the cardiomyocyte granules as a result of atrial wall stretch or under the effect of vasoactive peptides, i.e. endothelin 1 or angiotensin II (Wiese et al.2000, Iwanaga et al.2006). After release from the granules, the inactive N-terminal peptide (NT-proANP) is cleaved from proANP, resulting in the biologically active form of ANP. Within NT-proANP, amino acids from 53 to 90 are called the mid-regional proANP (MR-proANP). The enzyme involved in this process is the cardiac serine protease – corin, which is found in large amounts on the outer surface of the atrial cardiomyocytes. In turn, urodilatin, which regulates the excretion of water and sodium ions, is formed from proANP in the kidneys as a result of a different protease activity.
Neprilysin, the kidney brush border neutral proteinase: a possible potential target for ischemic renal injury
Published in Toxicology Mechanisms and Methods, 2020
Runali Sankhe, Manas Kinra, Jayesh Mudgal, Devinder Arora, Madhavan Nampoothiri
NPs are a family of genetically different but structurally related paracrine factor or hormones, having targeted role in the protection of cardiovascular system in condition like volume overload (Malek and Gaikwad 2017). NPs include ANP, BNP, and CNP (Lee and Burnett 2007). All the NPs possess common 17-amino acid ring in their structure (Chopra et al. 2013). In the body, NPs are degraded by two mechanisms, first is the internalization by NP receptor-C followed by lysosomal degradation. The second mechanism is NEP mediated enzymatic degradation (Ushijima et al. 2017). NPs contribute to the homeostasis of blood pressure by exerting a direct vasodilatory effect and indirectly through suppression of vasoconstrictors such as Ang II, ET-1, and reducing the sympathetic tone (Gervasini and Robles 2017). NPs act as endogenous hormones released in response to stretching and overloading effect from the heart (Lee and Burnett 2007; Gervasini and Robles 2017). In the kidney, ANP, BNP, and CNP are thought to mediate their effect by cyclic guanosine monophosphate (cGMP) signaling. Most of the beneficial influence of NPs including natriuresis, diuresis, vasodilation, inhibition of sympathetic tone and antiproliferative effects are mediated by the cGMP – protein kinase G (PKG) pathway (Ushijima et al. 2017). In acute renal failure, the levels of NPs including, ANP and BNP are elevated significantly (Vesely 2003). In distal tubular cells, post-translational processing of ANP pro-hormone leads to the generation of urodilatin (Malek and Gaikwad 2017). Urodilatin helps ANP, by inhibiting aldosterone-mediated sodium, water reabsorption and antidiuretic hormone (Malek and Gaikwad 2017). In renal injury, ANP and urodilatin have shown to reduce renal tissue injury and normalize the glomerular filtration rate (Zhao et al. 2015). ANP inhibits renin activity, Ang II production, aldosterone levels, apical sodium channel, and dopamine-induced sodium absorption in the proximal tubule (Lieberthal et al. 1990).