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Hydrogen sulfide (H2S) is a novel gasotransmitter synthetized from L‐Cysteine by three enzymatic pathways. In blood vessels, cystathionine‐gamma‐lyase (CSE) is mainly expressed and regulates vascular function. This enzyme may be affected by insulin resistance. Insulin resistance leads to vascular dysfunction and is the major mechanism underlying type 2 Diabetes Mellitus. The aim of this study was to determine the effect of chronic administration of sodium hydrosulfide (NaHS; inorganic H2S donor), L‐Cysteine (L‐Cys; substrate of H2S producing enzymes) and DL‐Propargylglycine (DL‐PAG; CSE inhibitor) on the vascular dysfunction induced by insulin resistance in male Wistar rat thoracic aorta. For that purpose, animals were divided into two main sets that received for 20 weeks: (1) tap water (control group; n=6); and (2) 15% p/v fructose in drinking water (insulin resistance group; n=30). Then, the insulin resistance group were divided into 5 subgroups (n=6 each) which received daily i.p. injections during 4 weeks of: (1) nothing (without pharmacological administration); (2) vehicle (phosphate buffer saline; PBS, 1 ml/kg); (3) NaHS (5.6 mg/kg); (4) L‐Cys (300 mg/kg); and (5) DL‐PAG (10 mg/kg). After 20 weeks, metabolic (oral glucose tolerance test, plasma insulin levels, and Matsuda‐index) and hemodynamics variables by tail‐cuff method as well as vascular function by in vitro experiments were determined. Fructose‐induced insulin resistance leads to: (1) hypertension (without affecting heart rate); (2) hyperinsulinemia; (3) a decrease in Matsuda‐index; and (4) a decrease in carbachol‐induced vasorelaxant responses with no effect on the contractile responses to noradrenaline. Interestingly, after 4 weeks of treatment, NaHS decreased blood pressure and restored vasorelaxant responses to carbachol with no effect on metabolic variables while L‐Cys improved the contractile and vasorelaxant responses to noradrenaline and carbachol, respectively, when compared to vehicle (PBS). On the other hand, DL‐PAG induced a slightly increase in systolic and median blood pressure with no effect on the contractile response to noradrenaline or relaxant responses to carbachol as well as metabolic variables compared to vehicle. Taken together, these results suggest that chronic treatment with NaHS and L‐Cys improved vascular dysfunction and hypertension induced by insulin resistance and may have a potential therapeutic application.Support or Funding InformationThe authors acknowledge to Conacyt (Grant No. 252702) for its financial support.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Several lines of evidence have shown the potential role of hydrogen sulfide (H2S) in insulin resistance. However, up to date, the effect of H2S has not been evaluated in the cardiovascular alterations by fructose‐induced insulin resistance. Thus, the aim of this study was to determine the effect of NaHS (sodium hydrosulfide; H2S donor), DL‐propargylglicine (DL‐PPG; cystathionine‐Ɣ‐lyase inhibitor) and hydroxylamine (HA; cystathionine‐β‐synthase inhibitor) on the vasopressor responses induced by sympathetic stimulation (0.03–3 Hz) or by bolus injections of the noradrenaline agonists (α1/2; 0.003–3 μg/kg), methoxamine (α1; 3–100 μg/kg) and UK‐14304 (α2; 0.03–30 μg/kg) in rats with fructose‐induced insulin resistance. For this purpose, 36 rats were divided in two groups. The first group (n=30) was treated with fructose (15% in drinking water) during 20 weeks, while the second group (control; n=6) received tap water. 16 weeks after the treatment with fructose, the first group was divided in 5 subgroups (n=6 each), which received daily i.p. administration during 4 weeks with: (1) nothing; (2) phosphate buffer saline (PBS; 1 mL/g); (3) NaHS (5.6 mg/kg); (4) DL‐PPG (10 mg/kg); and (5) HA (10 mg/g). Next, oral glucose tolerance test (OGTT) and insulin levels were determined before and after administration of glucose (2 g/kg, p.o.). Finally, under anesthesia with isoflurane, animals were pithed and prepared to determine the vasopressor responses induced by stimulation of the sympathetic nervous system. Animals treated with fructose showed hyperinsulinemia, insulin resistance and hypertension. Interestingly, these parameters were reverted by HA but not by PBS. NaHS decreased blood pressure while DL‐PPG increased blood pressure and diminished HOMA‐index. In animals with insulin resistance, the vasopressor responses to sympathetic stimulation were decreased (1 and 3 Hz) while those induced by noradrenaline, methoxamine and UK 14,304 remained unchanged when they were compared with control. PBS and DL‐PPG failed to modify the vasopressor responses aforementioned. On the other hand, NaHS increased the vasopressor responses to sympathetic stimulation (3 Hz), noradrenaline (1 μg/kg) and methoxamine (30 μg/kg), but the responses to UK‐14304 was no modify. HA decreased the vasopressor responses to sympathetic stimulation (1 and 3 Hz), noradrenaline (0.1–3 μg/kg), methoxamine (30 and 100 μg/kg) and UK‐14304 (3–30 μg/kg). These results suggest that chronic treatment with NaHS, but not DL‐PPG, was able to revert the cardiovascular alterations induced by fructose‐induced insulin resistance suggesting a beneficial effect of H2S in the cardiovascular system. In contrast, HA produced: (1) a marked decreased on sympathetic function which may explain its anti‐hypertensive effect; and (2) a significant reduction on insulin resistance. These data may suggest that H2S could be implicated in the pathophysiology of the insulin resistance.Support or Funding InformationThe authors acknowledge to Conacyt (Grant No. 252702) for its financial support.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.