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Evaluation of the vasopressor responses of metformin and one analogue of metformin in insulin resistance rats
Author(s) -
GutierrezLara Erika J,
SanchezLopez Araceli,
NavarreteVazquez Gabriel,
Centurion David
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1270.5
Subject(s) - metformin , medicine , insulin resistance , methoxamine , endocrinology , insulin , isoflurane , diabetes mellitus , bolus (digestion) , blood pressure , anesthesia , agonist , receptor
Cardiovascular diseases and diabetes are the leading causes of mortality in the world; both of them are associated with insulin resistance. Metformin improves insulin sensitivity and it is associated with cardioprotection and vasculoprotection. In vitro studies have demonstrated that metformin improves vasorelaxation and normalization of endothelial function during diabetes. Thus, in this study the vasopressor responses induced by sympathetic stimulation or by i.v. bolus injections of the agonists noradrenaline (endogenous ligand), methoxamine (α 1 ) and UK 14,304 (α 2 ) were determined in rats with insulin resistance or control rats pretreated with: (1) metformin; (2) one analogue of metformin (N‐benzylimidodicarbonimidic diamide; EGL‐6M); or (3) its vehicle. For this purpose, rats were treated with fructose (solution 15%) or its vehicle (water; control) for four months. Next, both groups were divided into three subgroups which were administrated with: (i) metformin (50 mg Kg −1 day −1 ), (ii) EGL‐6M (50 mg Kg −1 day −1 ) or its (iii) vehicle (water; 1 mL Kg −1 day −1 ) during 28 days. Tolerance glucose curve (TGC) and insulin levels were determined after administration of glucose (1 g Kg −1 , p.o.) in the above subgroups. Animals treated with fructose showed hyperinsulinaemia during TGC, which were reverted by metformin or EGL‐6M. Then, under anesthesia with isoflurane, animals were pithed and prepared to measure blood pressure and heart rate. In animals with insulin resistance, the vasopressor responses to sympathetic stimulation were decreased, while responses to noradrenaline were increased and those induced by methoxamine and UK 14,304 were not modified. In control animals, metformin failed to modify the vasopressor responses induced by sympathetic stimulation or by noradrenaline, methoxamine and UK‐14,304. In contrast, EGL‐6M significantly increased the vasopressor responses to sympathetic stimulation; the same results were showed in the insulin resistance rats. In animals with insulin resistance, metformin decreased vasopressor response to noradrenaline but did not modify the sympathetic stimulation responses. These results suggest that insulin resistance modified the vasopressor responses by inhibiting sympathetic tone and probably as a compensatory mechanism it may increase α‐adrenoceptor expression. Moreover, during insulin resistance, the analogue, but not metformin, improved sympathetic neurotransmission in the systemic vasculature. Support or Funding Information The authors acknowledge to Conacyt for their financial support.