Peripheral 5-HT_1Aand 5-HT₇Serotonergic Receptors Modulate Parasympathetic Neurotransmission in Long-Term Diabetic Rats

Abstract

We analyzed the modulation of serotonin on the bradycardia induced in vivo by vagal electrical stimulation in alloxan-induced long-term diabetic rats. Bolus intravenous administration of serotonin had a dual effect on the bradycardia induced either by vagal stimulation or exogenous Ach, increasing it at low doses and decreasing it at high doses of 5-hydroxytryptamine (5-HT), effect reproduced by 5-carboxamidotryptamine maleate (5-CT), a 5-HT1/7 agonist. The enhancement of the bradycardia at low doses of 5-CT was reproduced by 5-HT1A agonist 8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT) and abolished by WAY-100,635, 5-HT1A antagonist. Pretreatment with 5-HT1 antagonist methiothepin blocked the stimulatory and inhibitory effect of 5-CT, whereas pimozide, 5-HT7 antagonist, only abolished 5-CT inhibitory action. In conclusion, long-term diabetes elicits changes in the subtype of the 5-HT receptor involved in modulation of vagally induced bradycardia. Activation of the 5-HT1A receptors induces enhancement, whereas attenuation is due to 5-HT7 receptor activation. This 5-HT dual effect occurs at pre- and postjunctional levels.

Pharmacological Evidence that Histamine H3 Receptors Mediate Histamine‐Induced Inhibition of the Vagal Bradycardic Out‐flow in Pithed Rats

“…The frequency‐dependent decreases in heart rate produced by electrical vagal stimulation was a selective procedure as diastolic blood pressure was unchanged (fig. ), as previously reported by our group . Moreover, i.v.…”

“…In all cases, these bradycardic responses were due to cardiac vagal selective stimulation, as only negligible effects in diastolic blood pressure were observed (fig. ), as previously shown . Similarly, i.v.…”

“…Under these conditions, the responses to histamine and methimepip were considered to be vago-inhibitory as both compounds were capable of inhibiting the bradycardic responses to electrical vagal stimulation, but not those to exogenous ACh. These findings highlight the role of histamine H 3 receptors in the modulation of vagal ACh release at cardiac level, as previously shown for serotonin 5-HT 1 receptors [2,4,5]; hence, these receptors may be a therapeutic target in cardiac problems [3,[28][29][30].…”

“…As continuous vagal stimulation increases the size of cardiac infarct by sympathetic co-activation [3], the activation of modulatory mechanisms on vagal acetylcholine release may be a therapeutic target in cardiac problems. In this respect, our group has already shown that activation serotonin 5-HT 1 receptors inhibit the vagal bradycardic out-flow in normoglycaemic and diabetic pithed rats [2,4,5].…”

Serotonin and sensory nerves: Meeting in the cardiovascular system

“…5-HT acts as an inhibitory hormone in the nervous system through presynaptic inhibition of neurotransmitter release (reviewed in Feuerstein, 2008; Restrepo et al, 2010). This includes both the sympathetic and parasympathetic branches of the autonomic nervous system and, of current interest, the sensory nervous system.…”