Nitric oxide synthase Puns

High doses of simvastatin upregulate dopamine D1 and D2 receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase

>This study aims to investigate whether or not long-term statin treatment causes upregulation of D1 and D2 receptor gene expression with concomitant increase in endothelial nitric oxide synthase (eNOS) expression in Sprague-Dawley rats. Serum triglyceride levels were dose dependently reduced in the simvastatin-treated rats reaching statistical significance at the highest dose (49% reduction), while pravastatin caused similar effects (52%) at the same dose. Cholesterol levels remained unchanged in both groups at all doses. Simvastatin, 10 or 30 mg kg(-1) day(-1), increased D1 and D2 receptor expressions in the prefrontal cortex. Similar upregulation was observed neither with simvastatin in the striatum nor with pravastatin in both brain regions. Simvastatin (10 mg kg(-1) day(-1)) also increased eNOS expression in the prefrontal cortex but not neuronal NOS or inducible NOS. D1 receptor activation by chloro-APB (5 microM) increased cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin-treated rats by 88 and 285%, respectively. This effect was markedly attenuated by the selective D1 antagonist SCH-23390 (25 microM). D2 receptor activation by quinpirole (5 microM) had no effect on the basal cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin-treated rats, while the same concentration of quinpirole completely abolished the D1 receptor-mediated increase. These results suggest that lipophilic statins can alter dopaminergic functions in the prefrontal cortex possibly via a central mechanism. The possibility of a nitric oxide mechanism involving eNOS requires further investigation.

https://pubmed.ncbi.nlm.nih.gov/15711596/

https://diabetes.diabetesjournals.org/content/55/8/2301

Abstract

In metabolic syndrome, a systemic deregulation of the insulin pathway leads to a combined deregulation of insulin-regulated metabolism and cardiovascular functions. Free fatty acids (FFAs), which are increased in metabolic syndrome, inhibit insulin signaling and induce metabolic insulin resistance. This study was designed to examine FFAs’ effects on vascular insulin signaling and endothelial nitric oxide (NO) synthase (eNOS) activation in endothelial cells. We showed that FFAs inhibited insulin signaling and eNOS activation through different mechanisms. While linoleic acid inhibited Akt-mediated eNOS phosphorylation, palmitic acid appeared to affect the upstream signaling. Upregulation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) activity and transcription by palmitic acid mediated the inhibitory effects on insulin signaling. We further found that activated stress signaling p38, but not Jun NH2-terminal kinase, was involved in PTEN upregulation. The p38 target transcriptional factor activating transcription factor (ATF)-2 bound to the PTEN promoter, which was increased by palmitic acid treatment.

In summary

Both palmitic acid and linoleic acid exert inhibitory effect on insulin signaling and eNOS activation in endothelial cells. Palmitic acid inhibits insulin signaling by promoting PTEN activity and its transcription through p38 and its downstream transcription factor ATF-2. Our findings suggest that FFA-mediated inhibition of vascular insulin signaling and eNOS activation may contribute to cardiovascular diseases in metabolic syndrome.

Proton pump inhibitors like Prilosec and Protonix are said to potentially increase the risk for cardiovascular events when taken long-term. This scares me since I use them daily for severe GERD. Here's a summary of how they cause cardio problems:

"PPIs elevated asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. The impairment is in the endothelial nitric oxide synthase system, which leads to reduced nitric oxide levels. Low nitric oxide in turn is associated with increased vascular resistance and the promotion of inflammation and thrombosis."

I've read that agmatine sulfate has a beneficial effect on nitric oxide in the body. Would it be beneficial for PPI-induced nitric oxide problems? Or potentially harmful? I don't understand enough about agmatine's mechanism of action to determine whether it would be a help or a hindrance. Thought I'd check here before I start taking it since I can't find anything elsewhere.

So Ive read this is a substantial function of agmatine but is that a good or bad thing? I know the benefits of NO but completely inhibiting seem contradictory since alot of weight lifters use it.

Any insights

Can anyone point me in the direction of a list of known NOS inducers? Particularly eNOS. A list of NOS coenzymes or allosteric modulators would also be helpful.

Anyone know much about these type of drugs? I was doing some searching online and found an article discussing them and some positive results from trials. How would I find a trial for something like this?

Anyone done a drug trial to treat their migraine or headache? I have a chronic daily tension headache.

Watts J, Whitton PS, Pearce B Pharmacology 2005;74:163-168 (DOI: 10.1159/000085774)

Bredt DS, Glatt CE, Hwang PM, Fotuhi M, Dawson TM, Snyder SH. Neuron. 1991 Oct;7(4):615-24.