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Antihypertensive Drug Classes
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
Engi Abdel-Hady Algharably, Reinhold Kreutz
Loop diuretics exert their effects at the thick ascending limb of the loop of Henle, where they inhibit Na+/K+/2Cl—cotransporter (NKCC). Loop diuretics are more potent diuretics than thiazides, but they are shorter acting, causing reflex stimulation of the RAS, which attenuates their BP-lowering efficacy (10). Because of their pharmacodynamics and kinetic profile, they have no place in the routine management of hypertension in patients with normal renal function. They should replace thiazides, however, if eGFR is >30 mL/min/1.73 m2 or their use is required to control volume status of patients; e.g. with severe oedema (2).
Atrial Natriuretic Peptide, Sodium Transport Systems, and Essential Hypertension
Published in Antonio Coca, Ricardo P. Garay, Ionic Transport in Hypertension: New Perspectives, 2019
Josep Closas, Jean R. Cusson, Pierre Larochelle
More conflicting results were reported regarding the effect of ANP on Na+,K+,Cl− cotransport in bovine endothelial cells. While Fujita et al.71 reported that ANP selectively activates the Na+, K+, Cl− cotransporter in the aforementioned cells, the findings of O’Donnell72 indicated that ANP reduces this cotransporter. One possible explanation for this difference may be the distinct transporter inhibitor used in the experiments.
The Cell Membrane in the Steady State
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
A cotransporter is a transmembrane protein that couples the transport of substances, against electrochemical potential gradients, to the transport of other substances down electrochemical potential gradients, again without directly involving ATP hydrolysis. If the substances are moved in the same direction, the cotransporter is a symporter. If the substances are moved in opposite directions, the cotransporter is an antiporter. If the substances moved by an antiporter are ions, the antiporter is an ion exchanger. An example of a symporter is the K+-Cl– symporter that moves one K+ and one Cl– outward. K+ are moved down their electrochemical potential gradient, which provides the energy for driving Cl– outward and establishing an electrochemical potential gradient for Cl– that can drive them passively inward. This electrochemical potential gradient is essential for the action of some inhibitory synapses (Section 6.2.2). Note that the driving electrochemical potential of K+ is established in the first place by active transport that utilizes ATP hydrolysis. The K+-Cl– symporter is also known as a KCC2 (potassium chloride cotransporter 2). In some cases, a Na+-K+-2Cl– symporter (also known as NKCC) transports Cl– ions inward from the extracellular medium and establishes an electrochemical potential gradient for Cl– that can drive them passively outward, as in presynaptic inhibition (Section 6.4). The energy for driving the NKCC symporter is the electrochemical potential for Na+, which again is established by active transport that utilizes ATP hydrolysis. Because of this, the action of cotransporters is often referred to as secondary active transport. Both the K+-Cl– and the Na+-K+-2Cl– symporters are electrically neutral, as no net transfer of charge occurs, because equal quantities of positive charge and negative charge are moved in the same direction.
Emerging drug targets for sickle cell disease: shedding light on new knowledge and advances at the molecular level
Published in Expert Opinion on Therapeutic Targets, 2023
KCl cotransport inhibitors: The third potential target for specific transport pathway inhibitors is KCC. Like PIEZO1 and the Gárdos channel, KCC is found in red cells from normal individuals and also in other tissues, notably transporting epithelia [56]. KCC is also homologous to the Na+-linked cotransporter, NKCC, which is present in two isoforms, a housekeeping NKCC1 present in many tissues and a renal-specific NKCC2, the target of the loop diuretics. A major problem, again, therefore is one of specificity. Nevertheless, its significance as one of the three main dehydration pathways of sickle cells warrants attention. A number of bumetanide/furosemide analogues were synthesized by Hoechst in the 1980s [223]. One of these, H74, was shown to be effective in inhibiting KCC in human red cells, with good specificity over NKCC1 but no further developments have been reported. KCC is also notable in its regulation by protein phosphorylation [68–70], and the potential for this as a target is discussed in the next section.
The prognostic value of the furosemide stress test in predicting delayed graft function following deceased donor kidney transplantation
Published in Biomarkers, 2018
Blaithin A. McMahon, Jay L. Koyner, Tessa Novick, Steve Menez, Robert A. Moran, Bonnie E. Lonze, Niraj Desai, Sami Alasfar, Marvin Borja, William T. Merritt, Promise Ariyo, Lakhmir S. Chawla, Edward Kraus
Via inhibition of the Na-K-Cl cotransporter (NKCC) in the thick ascending limb of the loop of Henle, loop diuretics inhibit sodium reabsorption, giving rise to natriuresis and an increase in urine flow (Dirks and Seely 1970, Burg et al.1973, Brater et al.1979). Based on these properties, furosemide-stimulated increases in urine output (UO) may represent a useful technique to assess the integrity of renal tubular function in the setting of AKI. In preliminary studies, Chawla et al. have standardized this methodology which has been coined the furosemide stress test (FST) (Chawla et al.2013). Increased UO after the intravenous administration of furosemide (1.0 or 1.5 mg/kg) predicted the progression of early AKI in this study (Chawla et al.2013). The area under the receiver-operating characteristic curve (AUC) for UO at 2 h post FST to predict progression from AKI network (AKIN) stage 1 to AKIN stage 3 AKI in 77 patients was 0.87 (p = 0.001). The ideal cut-off for predicting progression of AKI during the first 2 h was a urine volume of 200 mL (100 mL/hr.) with a sensitivity and specificity of 87.1% and 84.1%, respectively (Chawla et al.2013).
A resurging boom in new drugs for epilepsy and brain disorders
Published in Expert Review of Clinical Pharmacology, 2018
Iyan Younus, Doodipala Samba Reddy
Bumetanide is rapidly and completely absorbed from the gastrointestinal tract. The half-life of the drug is 0.8–1.5 h and can range from 6 to 15 h in infants [47]. Bumetanide is tightly bound to plasma proteins and nearly completely ionized at physiologic pH, hampering its ability to cross the blood–brain barrier. The major adverse effects of bumetanide stem from its diuretic action at the level of the nephron NKCC, leading to excessive fluid loss, electrolyte depletion, hypokalemia, dehydration, hypotension, and possibility of thrombus and emboli. Furthermore, bumetanide has been reported to lead to hearing loss in adults and infants after high doses. The underlying mechanism behind ototoxicity is thought to be due to inhibition of NKCC located in the inner ear, blocking the endocochlear potential required for amplification [48]. Future strategies for the development of bumetanide derivatives aim to improve specificity while decreasing major side effects by increasing brain penetration while decreasing diuresis and ototoxicity.