Suppression of store overload-induced calcium release by hydroxylated metabolites of carvedilol
Thomas Malig1, Zhichao Xiao2, S R Wayne Chen2
1Department of Chemistry, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
Insights
Carvedilol metabolites were studied for their effect on store overload-induced calcium release (SOICR). The 3- and 4'-hydroxy metabolites showed enhanced inhibition of SOICR, suggesting metabolic deactivation is insignificant.
Area of Science:
- Pharmacology
- Cardiovascular Research
- Molecular Biology
Background:
- Carvedilol is a key drug for heart failure and arrhythmias.
- Carvedilol uniquely suppresses store overload-induced calcium release (SOICR) via the cardiac ryanodine receptor (RyR2).
- SOICR can precipitate dangerous ventricular arrhythmias.
Purpose of the Study:
- To investigate the impact of carvedilol metabolites on SOICR.
- To determine if metabolic hydroxylation affects carvedilol's SOICR-inhibiting properties.
Main Methods:
- Synthesized three hydroxylated carvedilol metabolites (3-, 4 omino-, and 5 omino-).
- Assayed metabolite activity using a mutant HEK 293 cell line expressing RyR2 R4496C, which is prone to SOICR.
- Measured calcium release using a calcium-sensitive fluorescent dye.
Main Results:
- The 3- and 4 omino-hydroxy carvedilol derivatives demonstrated slightly enhanced inhibition of SOICR compared to carvedilol.
- The 5 omino-hydroxy analog exhibited slightly reduced activity in suppressing SOICR.
- These findings indicate that hydroxylation does not significantly deactivate carvedilol's SOICR-inhibiting function.
Conclusions:
- Metabolic hydroxylation of carvedilol at the 3-, 4 omino-, and 5 omino-positions does not lead to significant deactivation of its SOICR-inhibiting properties.
- The observed enhanced activity of certain metabolites suggests potential for similar or improved therapeutic efficacy.
- These results are crucial for understanding carvedilol's overall pharmacological profile and its metabolites' roles in cardiovascular health.
Abstract:
Carvedilol is a drug widely used in the treatment of heart failure and associated cardiac arrhythmias. A unique action of carvedilol is its suppression of store overload-induced calcium release (SOICR) through the cardiac ryanodine receptor (RyR2), which can trigger ventricular arrhythmias. Since the effects of carvedilol metabolites on SOICR have not yet been investigated, three carvedilol metabolites hydroxylated at the 3-, 4' and 5'-positions were synthesized and assayed for SOICR inhibition in mutant HEK 293 cells expressing the RyR2 mutant R4496C. This cell line is especially prone to SOICR and calcium release through the defective RyR2 channel was measured with a calcium-sensitive fluorescent dye. These results revealed that the 3- and 4'-hydroxy derivatives are slightly more effective than carvedilol in suppressing SOICR, while the 5'-analog proved slightly less active. Metabolic deactivation of carvedilol via these hydroxylation pathways is therefore insignificant.
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