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May 20, 2022International Journal of Molecular SciencesOpen Access

Fluoxetine Treatment Decreases Cardiac Vagal Input and Alters the Serotonergic Modulation of the Parasympathetic Outflow in Diabetic Rats

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Why the study?

Comorbid diabetes and depression worsens cardiovascular diseases, but the role of fluoxetine on cardiac diabetic complications remains unknown.

Does fluoxetine modify cardiac vagal input and its serotonergic modulation in male Wistar diabetic rats?

Key Points

To determine whether fluoxetine modifies cardiac vagal input and its serotonergic modulation in alloxan-induced diabetic male Wistar rats.
Diabetes was induced in male Wistar rats using alloxan for 28 days, with oral fluoxetine administered at 10 mg/kg/day during the final 14 days.
Bradycardia was induced via electrical vagal stimulation at 3, 6, and 9 Hz, as well as intravenous acetylcholine administration at 1, 5, and 10 μg/kg.
Pharmacological challenges with 5-HT, 5-HT1/7 agonist 5-CT, 5-HT1D agonist L-694,247, 5-HT1D antagonist LY310762, and 5-HT7 antagonist SB269970 were evaluated.
Oral fluoxetine significantly reduced vagally-induced bradycardia without altering bradycardic responses provoked by exogenous acetylcholine.
5-HT and 5-CT exerted dose-dependent dual actions on bradycardia, enhancing vagal responses at low doses via prejunctional 5-HT7 receptors and decreasing responses at high doses via prejunctional 5-HT1D receptors.
High-dose inhibitory effects on vagally-induced bradycardia were mimicked by L-694,247 and reversed by LY310762, while low-dose enhancements by 5-CT were abolished by SB269970.

Structured PICO

Does fluoxetine modify cardiac vagal input and its serotonergic modulation in male Wistar diabetic rats?

Population

Male Wistar diabetic rats (diabetes induced by alloxan and maintained for 28 days)

Intervention

Fluoxetine 10 mg/kg/day oral (p.o.) administered for the last 14 days

Outcome

Cardiac vagal input and its serotonergic modulation (assessed via bradycardia induced by vagal stimulation at 3, 6, and 9 Hz or i.v. acetylcholine administrations at 1, 5, and 10 μg/kg)surrogate

Fluoxetine decreases cardiac cholinergic activity and alters serotonergic modulation of parasympathetic outflow in diabetic rats, highlighting potential autonomic cardiovascular effects of this antidepressant in the setting of diabetes.

Implication

Should not yet inform fluoxetine use in diabetic patients; leaves open serotonergic vagal effects in diabetes models.

Abstract

Comorbid diabetes and depression constitutes a major health problem, worsening associated cardiovascular diseases. Fluoxetine’s (antidepressant) role on cardiac diabetic complications remains unknown. We determined whether fluoxetine modifies cardiac vagal input and its serotonergic modulation in male Wistar diabetic rats. Diabetes was induced by alloxan and maintained for 28 days. Fluoxetine was administered the last 14 days (10 mg/kg/day; p.o). Bradycardia was obtained by vagal stimulation (3, 6 and 9 Hz) or i.v. acetylcholine administrations (1, 5 and 10 μg/kg). Fluoxetine treatment diminished vagally-induced bradycardia. Administration of 5-HT originated a dual action on the bradycardia, augmenting it at low doses and diminishing it at high doses, reproduced by 5-CT (5-HT1/7 agonist). 5-CT did not alter the bradycardia induced by exogenous acetylcholine. Decrease of the vagally-induced bradycardia evoked by high doses of 5-HT and 5-CT was reproduced by L-694,247 (5-HT1D agonist) and blocked by prior administration of LY310762 (5-HT1D antagonist). Enhancement of the electrical-induced bradycardia by 5-CT (10 μg/kg) was abolished by pretreatment with SB269970 (5-HT7 receptor antagonist). Thus, oral fluoxetine treatment originates a decrease in cardiac cholinergic activity and changes 5-HT modulation of bradycardic responses in diabetes: prejunctional 5-HT7 receptors augment cholinergic-evoked bradycardic responses, whereas prejunctional 5-HT1D receptors inhibit vagally-induced bradycardia.