The Cyclooxygenase and Nitric Oxide Synthesis/Pathways Mediate the Inhibitory Serotonergic Response to the Pressor Effect Elicited by Sympathetic Stimulation in Long-Term Diabetic Pithed Rats

Abstract

We investigated the mechanisms involved in the 5-hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in long-term-diabetic pithed rats. Diabetes was induced in rats by alloxan administration. Eight weeks later, the animals were anaesthetized and pithed. The action and mechanisms of 5-HT were analysed based on the pressor responses induced by sympathostimulation. In 8-week-diabetic animals, 5-HT (20 µg/kg/min) inhibits the pressor effect of sympathostimulation which is reproduced by two selective 5-HT_1A and 5-HT₂ receptor agonists: 8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT, 5 µg/kg/min) and α-methyl-5-HT (5 µg/kg/min). A bolus injection of 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, 10 µg/kg), or L-arginine HCl, N^ω-L-arginine methyl ester hydrochloride (L-NAME, 10 mg/kg), an inhibitor of NO production, prior to the infusion of 8-OH-DPAT (5 µg/kg/min) reversed the inhibitory effect of 8-OH-DPAT. The inhibitory effect of infusion of α-methyl 5-HT (5 µg/kg/min) was abolished in the presence of indomethacin (2 mg/kg), a non-selective cyclooxygenase (COX) inhibitor, or FR 122047 (1.5 mg/kg) or nimesulide (1.5 mg/kg), two selective COX-1 and COX-2 inhibitors, respectively, in long-term-diabetic pithed rats. Our results indicate that 5-HT inhibition of the pressor responses induced by electrical stimulation is mediated both by the NO and COX pathways in long-term-diabetic rats.

Pharmacological evidence that 5‐HT1D activation induces renal vasodilation by NO pathway in rats

“…Furthermore, pretreatment with l ‐arginine (NOS substrate) reversed the renal vasodilator effect induced by L‐694,247 in the presence of L‐NAME. In agreement with this suggestion there are many studies (both in different experimental models and vascular beds) linking vasorelaxant actions by activation of 5‐HT 1 receptors with the NO pathway; moreover, the current research group has already demonstrated involvement of NO in 5‐HT inhibitory actions of total sympathetic outflow in pithed rats . Additionally, Hou et al .…”

“…In agreement with this suggestion there are many studies (both in different experimental models and vascular beds) linking vasorelaxant actions by activation of 5-HT 1 receptors with the NO pathway; [42][43][44] moreover, the current research group has already demonstrated involvement of NO in 5-HT inhibitory actions of total sympathetic outflow in pithed rats. 45,46 Additionally, Hou et al 47 demonstrated the co-localization of the 5-HT 1D receptor with NOS in human trigeminal ganglia. On the other hand, some studies have related 5-HT 1D activation with inhibition of vasodilator agents.…”

5-HT1D receptor inhibits renal sympathetic neurotransmission by nitric oxide pathway in anesthetized rats

“…(ii) The vasorelaxant actions by activation of 5-HT 1 receptors have been linked with the NO pathway [50][51][52][53][54]. iii) We have already demonstrated the NO involvement in inhibitory actions of total sympathetic outflow in pithed rats [48,55]. iv) Hou et al [56] established the co-localization of 5-HT 1D receptor with NOS in human trigeminal ganglia.…”

“…In this line, the COX pathway modulates autonomic transmission in the peripheral circulation [42]; nitrergic nerves inhibit sympathetic neurotransmission [43] and EDHF contributes to the endotheliumdependent relaxation, which is crucial for the regulation of organ blood flow, peripheral vascular resistance and blood pressure [44]. Consequently, we decided to investigate the effects of glibenclamide (a blocker of ATP-sensitive K + channels), indomethacin (a COX 1/2 inhibitor) and L-NAME (a NO synthase inhibitor) [23,24,26,[45][46][47][48].…”

Blocking 5-HT2 receptor restores cardiovascular disorders in type 1 experimental diabetes

“…Therefore, depth knowledge in the mechanisms of cardiovascular diseases and novel approaches to treat cardio and vasculopathies is extremely crucial 4 5 6 . In this sense, the serotonergic system stands out for its relevance in the diabetic pathophysiology, since: (i) 5-HT concentrations are altered in diabetes 7 8 ; (ii) 5-HT inhibits the peripheral sympathetic neurotransmission in type 1 diabetic rats 9 10 ; (iii) it has been described an increase in serotonergic peripheral actions, mainly by 5-HT 2 receptor activation (increasing platelet aggregation or contractile responses) 11 12 13 14 15 and (iv) 5-HT 2 receptor activation is involved in an enhanced serotonergic vasoconstriction in the type 1 diabetic rat kidney 16 . Taking into consideration the above-mentioned evidence, 5-HT 2 receptor seems to trigger harmful actions at cardiovascular level (whose actions are amplified in T1D).…”