Diabetes‐induced Changes in 5‐hydroxytryptamine Modulation of Vagally Induced Bradycardia in Rat Heart

Abstract

1. In the present study, we investigated how alloxan-induced diabetes affects the ability of 5-hydroxytryptamine (5-HT) to modulate bradycardia induced in vivo by electrical stimulation of the vagus nerve in pithed rats. We also analysed the type and/or subtype of 5-HT receptors involved. 2. Diabetes was induced in male Wistar rats with a single injection of alloxan (150 mg/kg, s.c.). Four weeks later, rats were anaesthetized, pretreated with atenolol and pithed. Electrical stimulation (3, 6 and 9 Hz) of the vagus nerve resulted in frequency dependent decreases in heart rate (HR). 3. In diabetic rats, intravenous bolus administration of high doses of 5-HT (100 and 200 microg/kg) increased the bradycardia induced by vagal electrical stimulation. Similarly, low doses (10 microg/kg) of the 5-HT(1/7) receptor agonist 5-carboxamidotryptamine (5-CT), increased vagally induced bradycardia. However, at high doses (50, 100 and 150 microg/kg), 5-CT reduced the bradycardia. Attenuation of the vagally induced bradycardia evoked by the higher doses of 5-CT was reproduced by L-694,247 (50 microg/kg), a selective agonist for the non-rodent 5-HT(1B) and 5-HT(1D) receptors. Enhancement of the vagally induced bradycardia elicited by low doses of 5-CT was reproduced by the selective 5-HT(1A) receptor agonist 8-hydroxydipropylaminotretalin hydrobromide (8-OH-DPAT; 50 microg/kg). These stimulatory and inhibitory actions on vagal stimulation-induced bradycardia in diabetic rats were also observed after administration of exogenous acetylcholine. 4. Vagally induced bradycardia in diabetic rats was not affected by administration of the selective 5-HT(2) receptor agonist alpha-methyl-5-HT (150 microg/kg), the selective 5-HT(3) receptor agonist 1-phenylbiguanide (150 microg/kg) or the selective 5-HT(1B) receptor agonist CGS-12066B (50 microg/kg). 5. Enhancement of the electrical stimulation-induced bradycardia in diabetic rats caused by 5-CT (10 microg/kg) or 8-OH-DPAT (50 microg/kg) was abolished by the selective 5-HT(2/7) receptor antagonist mesulergine (1 mg/kg) and the selective 5-HT(1A) receptor antagonist WAY-100,635 (100 microg/kg), respectively. Similarly, pretreatment with the non-selective 5-HT(1) receptor antagonist methiothepin (0.1 mg/kg) blocked the inhibitory effect of 5-CT (50 microg/kg) on the bradycardia induced by vagal electrical stimulation in diabetic rats. BRL-15572 (2 microg/kg), a selective 5-HT(1D) receptor antagonist, inhibited the action of L-694,247 (50 microg/kg), a selective agonist for the non-rodent 5-HT(1B) and 5-HT(1D) receptors, on the vagally induced bradycardia. 6. In conclusion, in the present study, experimental diabetes evoked changes in both the nature and 5-HT receptor types/subtypes involved in vagally induced bradycardia.

Peripheral 5-HT1Aand 5-HT7Serotonergic Receptors Modulate Parasympathetic Neurotransmission in Long-Term Diabetic Rats

“…Alloxan is a diabetogenic agent which induces a syndrome in animals resembling type 1 diabetes mellitus characterized by hyperglycemia, hypercholesterolemia, glycosuria, and raised levels of glycosylated hemoglobin in erythrocytes [12, 17, 21–24]. This agent, in our experiments, did not modify heart rate, as previously indicated by Lee et al [25], Zola et al [26], and Howarth et al [27].…”

“…The first group of experiments was conducted in normoglycaemic (kept in parallel during eight weeks) and four-week diabetic rats to confirm previous data from our research team [11, 12]. Each group was subdivided in two.…”

“…We have also shown that experimental diabetes elicits changes in the nature and 5-HT receptor type/subtype involved in vagal bradycardia stimulated by electrical means [12]. …”

“…Such parasympathetic dysfunction in the diabetic heart may lead to an autonomic imbalance that may predispose the heart to ventricular arrhythmias and sudden death [13]. Long-term diabetes reduces the body's ability to finely regulate heart rate (HR); this is attributed to profound disturbances in autonomic function [14] which are probably due to parasympathetic dysfunction [12, 15]. Several studies conducted under different conditions have supported the theory that, during the development of diabetes, there are impaired myocardial responses to muscarinic activation by acetylcholine.…”

Chlorpheniramine exerts anxiolytic-like effects and activates prefrontal 5-HT systems in mice

“…Further studies will be important to clarify the involvement of central DA and NA systems in the chlorpheniramine-induced, anxiolyticlike, and antidepressant-like effect. Moreover, methiothepin was reported to have non-selective affinity for 5-HT1/7 (Abe et al 2009;García et al 2007), 5-HT2A (Campiani et al 2002), and 5-HT6 receptors (Schoeffter and Waeber 1994). Deletion of gene and pharmacological blockade of 5-HT7 receptors have been reported to reduce the depressiveand anxiety-like behaviors (Guscott et al 2005;Wesołowska et al 2006).…”