P15: Myocardial necrosis related to hydrochlorothiazide-induced hypokalemia in cynomolgus monkeys

Takeuchi, Ayano; Shirakawa, Takafumi; Toyoda, Yuuji; Tabata, Hajime; Izumisawa, Nobuyuki; Watanabe, Kouji

doi:10.1016/j.etp.2009.02.052

Cited by 2 publications

(2 citation statements)

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“…The arrhythmic susceptibility in chronic hypokalemia is influenced not only by direct effects of low K + on cardiac electrophysiology but also by indirect effects caused by concomitant changes of systemic hemodynamics [44], cardiac systolic dysfunction [44–46], and sympathoadrenal activation [47]. Furthermore, severe chronic hypokalemia may cause ultrastructural changes in cardiac myocytes, especially at the junction of sarcoplasmic reticulum with the T‐tubule system [48], as well as gross histopathological changes such as focal myocardial necrosis [49].…”

Section: Experimental Models Of Hypokalemia and The Mechanisms Of Arrmentioning

confidence: 99%

Mechanisms of hypokalemia‐induced ventricular arrhythmogenicity

Osadchii

2010

Fundamemntal Clinical Pharma

127

106

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Hypokalemia is a common biochemical finding in cardiac patients and may represent a side effect of diuretic therapy or result from endogenous activation of renin–angiotensin system and high adrenergic tone. Hypokalemia is independent risk factor contributing to reduced survival of cardiac patients and increased incidence of arrhythmic death. Animal studies demonstrate that hypokalemia‐induced arrhythmogenicity is attributed to prolonged ventricular repolarization, slowed conduction, and abnormal pacemaker activity. The prolongation of ventricular repolarization in hypokalemic setting is caused by inhibition of outward potassium currents and often associated with increased propensity for early afterdepolarizations. Slowed conduction is attributed to membrane hyperpolarization and increased excitation threshold. Abnormal pacemaker activity is attributed to increased slope of diastolic depolarization in Purkinje fibers, as well as delayed afterdepolarizations caused by Ca2+ overload secondary to inhibition of Na+–K+ pump and stimulation of the reverse mode of the Na+–Ca2+ exchange. Hypokalemia effect on repolarization is not uniform at distinct ventricular sites thereby contributing to amplified spatial repolarization gradients which promote unidirectional conduction block. In hypokalemic heart preparations, the prolongation of action potential may be associated with shortening of effective refractory period, thus increasing the propensity for ventricular re‐excitation over late phase of repolarization. Shortened refractoriness and slowed conduction contribute to reduced excitation wavelength thereby facilitating re‐entry. The interplay of triggering factors (early and delayed afterdepolarizations, oscillatory prepotentials in Purkinje fibers) and a favorable electrophysiological substrate (unidirectional conduction block, reduced excitation wavelength, increased critical interval for ventricular re‐excitation) may account for the mechanism of life‐threatening tachyarrhythmias in hypokalemic patients.

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Section: Experimental Models Of Hypokalemia and The Mechanisms Of Arrmentioning

confidence: 99%

Mechanisms of hypokalemia‐induced ventricular arrhythmogenicity

Osadchii

2010

Fundamemntal Clinical Pharma

127

106

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“…In 2012, cTnI was qualified by the FDA as a marker of cardiac necrosis in rats and dogs for use in preclinical studies (Woodcock 2012). At the time the qualification document was submitted in late 2008, there were limited published studies demonstrating the use of this biomarker in nonhuman primates (NHP) studies, although more recently, additional publications have become available (Dunn et al 2012; Minomo et al 2009; Schultze et al 2015; Takeuchi et al 2008; Zabka, Irwin, and Albassam 2009). Based on the paucity of published information on the use of this biomarker in NHP at the time of submission, cTnI was not officially qualified for use in NHP.…”

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confidence: 99%

Assessment of Cardiac Troponin I Responses in Nonhuman Primates during Restraint, Blood Collection, and Dosing in Preclinical Safety Studies

et al. 2016

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Limited information has been published on the use of cardiac troponin I (cTnI) as a biomarker of cardiac injury in monkeys. The purpose of these studies was to characterize the cTnI response seen in cynomolgus macaques during routine dosing and blood collection procedures typically used in preclinical safety studies and to better understand the pathogenesis of this response. We measured cTnI using two different methods, the Siemens Immulite cTnI assay and the more sensitive Siemens Troponin I-Ultra assay. We were able to demonstrate that after oral, subcutaneous, or intravenous dosing of common vehicles, as well as serial chair restraint for venipuncture blood collection, that minimal to mild transient increases in cTnI could be detected in monkeys with both assays. cTnI values typically peaked at 2, 3, 4, or 6 hr after sham dosing and returned to baseline at 22 or 24 hr. In addition, marked increases in heart rate (HR) and blood pressure (BP) occurred in monkeys during the restraint procedures, which likely initiated the cTnI release in these animals. Monkeys that were very well acclimated to the chairing procedures and had vascular access ports for blood sampling did not have marked increases in HRs and BP or increases in cTnI.

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P15: Myocardial necrosis related to hydrochlorothiazide-induced hypokalemia in cynomolgus monkeys

Cited by 2 publications

References 0 publications

Mechanisms of hypokalemia‐induced ventricular arrhythmogenicity

Mechanisms of hypokalemia‐induced ventricular arrhythmogenicity

Assessment of Cardiac Troponin I Responses in Nonhuman Primates during Restraint, Blood Collection, and Dosing in Preclinical Safety Studies

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