Detail of "4138-96-9"

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Spironolactone and its main metabolite canrenoic acid block hKv1

Spironolactone and its main metabolite canrenoic acid block hKv1.5, Kv4.3 and Kv7.1 + minK channels. Gomez, Ricardo; Nunez, Lucia; Caballero, Ricardo; Vaquero, Miguel; Tamargo, Juan; Delpon, Eva (Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 28040, Spain). British Journal of Pharmacology, 146(1), 146-161 (English) 2005 Nature Publishing Group. CODEN: BJPCBM. ISSN: 0007-1188. 4138-96-9 is just another one chemical used in this study. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Both spironolactone (SP) and its main metabolite, canrenoic acid (CA), prolong cardiac action potential duration and decrease the Kv11.1 (HERG) current. We examd. the effects of SP and CA on cardiac hKv1.5, Kv4.3 and Kv7.1 + minK channels that generate the human IKur, Ito1 and IKs, which contribute to the control of human cardiac action potential duration. Kv1.5 currents were recorded in stably transfected mouse fibroblasts and Kv4.3 and Kv7.1+minK in transiently transfected Chinese hamster ovary cells using the whole-cell patch clamp. SP (1 mM) and CA (1 nM) inhibited hKv1.5 currents by 23.2±3.2 and 18.9±2.7%, resp., shifted the midpoint of the activation curve to more neg. potentials and delayed the time course of tail deactivation. SP (1 mM) and CA (1 nM) inhibited the total charge crossing the membrane through Kv4.3 channels at +50 mV by 27.1±6.4 and 27.4±5.7%, resp., and accelerated the time course of current decay. CA, but not SP, shifted the inactivation curve to more hyperpolarized potentials (Vh-37.0±1.8 vs. -40.8±1.6 mV, n = 10, P < 0.05).SP (10 mM) and CA (1 nM) also inhibited Kv7.1 + minK currents by 38.6±2.3 and 22.1±1.4%, resp., without modifying the voltage dependence of channel activation. SP, but not CA, slowed the time course of tail current decay. CA (1 nM) inhibited the IKur (29.2±5.5%) and the Ito1 (16.1±3.9%) recorded in mouse ventricular myocytes and the IK (21.8±6.9%) recorded in guinea-pig ventricular myocytes. A math. model of human atrial action potentials demonstrated that K+ blocking effects of CA resulted in a lengthening of action potential duration, both in normal and atrial fibrillation simulated conditions. The results demonstrated that both SP and CA directly block hKv1.5, Kv4.3 and Kv7.1 + minK channels, CA being more potent for these effects. Since peak free plasma concns. of CA ranged between 3 and 16 nM, these results indicated that blockade of these human cardiac K+ channels can be obsd. after administration of therapeutic doses of SP. Blockade of these cardiac K+ currents, together with the antagonism of the aldosterone proarrhythmic effects produced by SP, might be highly desirable for the treatment of supraventricular arrhythmias. .