Effect of sarpogrelate treatment on 5-HT modulation of vascular sympathetic innervation and platelet activity in diabetic rats

Juan Francisco Fernández-González; José Ángel García-Pedraza; Ana Marín-Quílez; José María Bastida; María Luisa Martín; Asunción Morán; Mónica García-Domingo

doi:10.1016/j.biopha.2022.113276

Effect of sarpogrelate treatment on 5-HT modulation of vascular sympathetic innervation and platelet activity in diabetic rats

Biomed Pharmacother. 2022 Sep:153:113276. doi: 10.1016/j.biopha.2022.113276. Epub 2022 Jun 16.

Authors

Juan Francisco Fernández-González¹, José Ángel García-Pedraza¹, Ana Marín-Quílez², José María Bastida², María Luisa Martín¹, Asunción Morán¹, Mónica García-Domingo³

Affiliations

¹ Laboratorio de Farmacología, Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo San Vicente 58-182, 37007 Salamanca, Spain.
² Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo San Vicente 58-182, 37007 Salamanca, Spain; Departamento de Hematología, Complejo Asistencial Universitario de Salamanca (CAUSA), 37007 Salamanca, Spain.
³ Laboratorio de Farmacología, Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo San Vicente 58-182, 37007 Salamanca, Spain. Electronic address: mgarciad@usal.es.

PMID: 35717784
DOI: 10.1016/j.biopha.2022.113276

Abstract

This study aimed to investigate whether the 5-HT₂ receptor blockade alters the 5-HT effect on vascular sympathetic neurotransmission and platelet activation in type 1 diabetes. 28-day diabetes was obtained by alloxan (150 mg/kg; s.c.) in male Wistar rats, administering sarpogrelate (5-HT₂ blocker; 30 mg/kg/day; p.o.) for 14 days. Blood glucose and body weight were monitored for 28 days. After 4 weeks of diabetes induction, food and drink intake, urine, plasma-platelet 5-HT, and platelet activation were determined in normoglycemic, non-treated diabetic and sarpogrelate-treated diabetic rats. Another set of diabetic rats were pithed to run the vascular sympathetic stimulation or exogenous noradrenaline administration, examining the induced vasoconstrictor responses. Sarpogrelate treatment significantly reduced drink intake and urine, whereas BW gain, hyperglycemia, and food intake were not modified in diabetic rats. The platelet activation and plasma 5-HT concentration were decreased (increasing the stored 5-HT platelet) by 5-HT₂ blockade in diabetic animals. The sympathetic-induced vasoconstrictions were higher in non-treated than in sarpogrelate-treated diabetic rats. 5-HT inhibited these vasopressor responses, reproduced exclusively by the 5-HT_1/5/7 receptor agonist, 5-CT. The 5-CT-produced inhibition was partly reversed by 5-HT_1D or 5-HT₇ antagonists (LY310762 or SB-258719, respectively), and totally annulled by the mixture of LY310762+SB-258719. Noradrenaline-caused vasoconstrictions were also decreased by 5-CT. In conclusion, our results reveal that 14-day sarpogrelate treatment improves polydipsia and polyuria, reduces platelet hyperactivation, plasma 5-HT and the vascular sympathetic tone, and changes 5-HT receptors inhibiting noradrenergic drive in diabetic rats: pre and/or postjunctional 5-HT_1D/7 are involved in the sympatho-inhibition.

Keywords: 5-HT; 5-HT(1D/7) receptors; 5-HT(2) antagonism; Diabetes; Platelet activation; Sympathetic neurotransmission.

MeSH terms

Animals
Diabetes Mellitus, Experimental* / drug therapy
Male
Norepinephrine / pharmacology
Rats
Rats, Wistar
Serotonin* / pharmacology
Succinates
Sympathetic Nervous System
Vasoconstrictor Agents / pharmacology

Substances

Succinates
Vasoconstrictor Agents
sarpogrelate
Serotonin
Norepinephrine