Antiarrhythmic properties of triamterene derivatives in the coronary artery ligated rat model

Büsch, Andreas; Ullrich, Frank; Mutschler, E.

doi:10.1002/ardp.2503241114

Cited by 3 publications

(5 citation statements)

References 11 publications

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“…Therefore, a parameter ApH was introduced, to allow for a systematic deviation of the local pH at the outer membrane surface from the pH of the bulk solution. Using: pH10 ,1 = pHeulk + ApH, (2) introduced into the expression for B (in Eq. 1), the data were fitted to Eq.…”

Section: Resultsmentioning

confidence: 99%

“…For several triamterene derivatives, distinct effects on the excretion of Na t , K + and Mgt were observed in vivo [13,19]. In addition, certain triamterene derivatives exerted antiarrhythmic effects in the heart in both in vivo and in vitro studies [1,2]. In the present study, we were therefore interested in the sensitivity of rENaC to triamterene and several triamterene derivatives with distinct antikaliuretic profiles [13].…”

Section: Introductionmentioning

confidence: 99%

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Blockade of epithelial Na+ channels by triamterenes — Underlying mechanisms and molecular basis

Büsch

Suessbrich

Kunzelmann

et al. 1996

Pflugers Arch - Eur J Physiol

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The three subunits (alpha, beta, gamma) encoding for the rat epithelial Na+ channel (rENaC) were expressed in Xenopus oocytes, and the induced Na+ conductance was tested for its sensitivity to various triamterene derivatives. Triamterene blocked rENaC in a voltage-dependent manner, and was 100-fold less potent than amiloride at pH 7.5. At -90 mV and -40 mV, the IC50 values were 5 microM and 10 microM, respectively. The blockage by triamterene, which is a weak base with a pKa of 6.2, was dependent on the extracellular pH. The IC50 was 1 microM at pH 6.5 and only 17 microM at pH 8.5, suggesting that the protonated compound is more potent than the unprotonated one. According to a simple kinetic analysis, the apparent inhibition constants at -90 mV were 0.74 microM for the charged and 100.6 microM for the uncharged triamterene. The main metabolite of triamterene, p-hydroxytriamterene sulfuric acid ester, inhibited rENaC with an approximately twofold lower affinity. Derivatives of triamterene, in which the p-position of the phenylmoiety was substituted by acidic or basic residues, inhibited rENaC with IC50 values in the range of 0.1-20 microM. Acidic and basic triamterenes produced a rENaC blockade with a similar voltage and pH dependence as the parent compound, suggesting that the pteridinemoiety of triamterene is responsible for that characteristic. Expression of the rENaC alpha-subunit-deletion mutant, Delta278-283, which lacks a putative amiloride-binding site, induced a Na+ channel with a greatly reduced affinity for both triamterene and amiloride. In summary, rENaC is a molecular target for triamterene that binds to its binding site within the electrical field, preferably as a positively charged molecule in a voltage- and pH-dependent fashion. We propose that amiloride and triamterene bind to rENaC using very similar mechanisms.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blockade of epithelial Na+ channels by triamterenes — Underlying mechanisms and molecular basis

Büsch

Suessbrich

Kunzelmann

et al. 1996

Pflugers Arch - Eur J Physiol

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“…23 Triamterene can also reduce the incidence and duration of arrhythmias induced by either cardiac glycoside toxicity25 or reperfusion of ligated rat coronary artery. 26 Moreover, it has been reported that triamterene can increase the QT interval independently of plasma potassium concentration in humans. 27 The mechanisms by which triamterene exhibits cardiac electrophysiological effects are unknown.…”

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Triamterene inhibits the delayed rectifier potassium current (IK) in guinea pig ventricular myocytes.

Daleau¹,

Turgeon²

1994

Circulation Research

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In humans, proarrhythmia during therapy with action potential-prolonging drugs can be associated with hypokalemia often provoked by concomitant administration of diuretic agents. Consequently, therapy with class III antiarrhythmics and K'-sparing diuretics, such as triamterene, may be indicated. Triamterene, along with its K'-sparing properties, exhibits other pharmacological effects. In the heart, it can increase action potential duration (guinea pig atria and papillary muscles), protect against reperfusion-induced arrhythmias (rat), and increase the QT interval (humans the slow component of IK (IE) was decreased 36±6% (n=6) and 51±8% (n=6) by triamterene 10-5 and 10`mol/L, respectively. After low-voltage short pulses (-20 mV; 250 milliseconds), tail current amplitude corresponding essentially to the rapid component of IK ('Kr) was decreased only 14±11% (n=9) and 19+10% (n=10) by triamterene 10-5 and 10-4 mol/L, respectively. These results were confirmed under conditions of pure IKS (block of IK, by E-4031) and pure IKr (block of Isi with nisoldipine, extracellular Ca 2+ decreased to virtually 0 mmol/L, and 250-millisecond depolarizing pulse to -20 mV). In contrast, triamterene had no effects on time-independent currents. Thus, data obtained indicate that triamterene, at clinically relevant concentrations, inhibits IKS in a selective manner, although both components of IK (IKr and IKS) were decreased. This block of 'K may explain triamterene-related prolongation of cardiac repolarization and warn about potential drug interaction with action potential-prolonging agents.

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“…To further evaluate the antiarrhythmic properties of pteridine derivatives, selected compounds were tested in the coronary artery ligated and reperfused rat (CAL-R) (BUSCH 1989;BUSCH et al 1991a;NETZER 1991). Some compounds such as 4-benzyltriamterene could not be investigated following i.v.…”

Section: B) In Vivo Studiesmentioning

confidence: 99%

“…(0), triamterene (ill), and two benzyltriamterene derivatives [RPH 3007 (t? BUSCH (1989) performed electrophysiologic studies with 4-(amethylpiperazinobenzyl)triamterene using calf Purkinje and ventricular muscle fibers. (NETZER et al 1992c) prolong action potential duration (+26%) in guinea pig papillary muscle with only minor effects on V max (-4%), which is indicative of a class-III antiarrhythmic mechanism of action (U.…”

Section: B) In Vivo Studiesmentioning

confidence: 99%

Diuretics

1995

Handbook of Experimental Pharmacology

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Antiarrhythmic properties of triamterene derivatives in the coronary artery ligated rat model

Cited by 3 publications

References 11 publications

Blockade of epithelial Na+ channels by triamterenes — Underlying mechanisms and molecular basis

Blockade of epithelial Na+ channels by triamterenes — Underlying mechanisms and molecular basis

Triamterene inhibits the delayed rectifier potassium current (IK) in guinea pig ventricular myocytes.

Diuretics

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