Role of peripheral 5-HT5A receptors in 5-HT-induced cardiac sympatho-inhibition in type 1 diabetic rats

Abstract

5-HT inhibits cardiac sympathetic neurotransmission in normoglycaemic rats, via 5-HT1B, 5-HT1D and 5-HT5A receptor activation. Since type 1 diabetes impairs the cardiac sympathetic innervation leading to cardiopathies, this study aimed to investigate whether the serotonergic influence on cardiac noradrenergic control is altered in type 1 diabetic rats. Diabetes was induced in male Wistar rats by streptozotocin (50 mg/kg, i.p.). Four weeks later, the rats were anaesthetized, pithed and prepared for producing tachycardic responses by electrical preganglionic stimulation (C7-T1) of the cardioaccelerator sympathetic outflow or i.v. noradrenaline bolus injections. Immunohistochemistry was performed to study 5-HT1B, 5-HT1D and 5-HT5A receptor expression in the stellate ganglion from normoglycaemic and diabetic rats. In the diabetic group, i) i.v. continuous infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT1/5A agonist 5-carboxamidotryptamine (without modifying noradrenaline-induced tachycardia), but not by the agonists indorenate (5-HT1A), CP 93,129 (5-HT1B), PNU 142633 (5-HT1D), or LY344864 (5-HT1F); ii) SB 699551 (5-HT5A antagonist; i.v.) completely reversed 5-CT-induced cardiac sympatho-inhibition; and iii) 5-HT5A receptors were more expressed in the stellate ganglion compared to normoglycaemic rats. These results show the prominent role of the peripheral 5-HT5A receptors prejunctionally inhibiting the cardiac sympathetic drive in type 1 diabetic rats.

Renal Sympathetic Hyperactivity in Diabetes Is Modulated by 5-HT1D Receptor Activation via NO Pathway

“…The serotonergic system acts as modulator, both potentiating and inhibiting noradrenergic or vagal outflow at cardiac and vascular levels in different experimental models [ 21 , 22 , 23 , 24 , 40 , 41 ]. Furthermore, our group has described the serotonergic inhibitory action of noradrenergic input at mesenteric and renal levels [ 18 , 19 , 39 ].…”

“…The 5-HT 1D receptor, at prejunctional locus, has already been described as sympatholytic at the renal level [ 18 ], and at cardiac and vascular levels, in pithed rats as well [ 21 , 40 ] in normoglycaemic animals. In any case, it is worthwhile to mention that short-term diabetic state modifies the serotonergic profile involved in the sympatho-modulation, unmasking peripheral prejunctional 5-HT 1A and 5-HT 5A at vascular and cardiac level, respectively, in pithed rats [ 22 , 41 ].…”

Serotonergic Modulation of Neurovascular Transmission: A Focus on Prejunctional 5-HT Receptors/Mechanisms

“…5-HT 1 receptors are widely expressed in perivascular and cardiac sympathetic nerve endings; their activation is linked to cardiovascular sympathetic inhibition [48][49][50][51]. Specifically, selective stimulation of 5-HT 1A , 5-HT 1B , and 5-HT 1D receptors produced inhibition of the sympathetic vasopressor outflow in pithed rats [38,52].…”

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

“…In pithed rats, 5-HT regulates sympathetic cardiac outflow [ 16 , 17 ] and also modulates vagal outflow to the heart via 5-HT 2 and 5-HT 3 receptor activation [ 18 ]. However, experimental T1DM, as well as pharmacological 5-HT modulation by the antagonism of 5-HT 2 receptor, modifies the serotonergic effect on both sympathetic and parasympathetic cardiac discharge [ 19 , 20 , 21 , 22 , 23 , 24 ]. Furthermore, our group has demonstrated that, in naïve animals, the chronic treatment with a SSRI (fluoxetine) modifies the serotonergic modulation of vagal bradycardia, exerting an inhibitory action of the vagal cardiac input due to activation of prejunctional 5-HT 1D receptors [ 25 ].…”