The Cardiorenal Effects of Piper amalago Are Mediated by the Nitric Oxide/Cyclic Guanosine Monophosphate Pathway and the Voltage-Dependent Potassium Channels Ethnopharmacological investigation of Piper amalago L

Authors: MONTEIRO, LUCIANE - State University Of Ponta Grossa; KLIDER, LISLAINE - State University Of Ponta Grossa; MARQUES, ALINE - Federal University Of Big Dourados (UFGD); FARAGO, PAULO - State University Of Ponta Grossa; EMILIANO, JANAÍNA - State University Of Mato Grosso Do Sul; SOUZA, ROOSEVELT - Federal University Of Big Dourados (UFGD); DOS SANTOS, ARIANY - Federal University Of Big Dourados (UFGD); DOS SANTOS, VERA - State University Of Ponta Grossa; Wang, Mei; CASSEMIRO, NADLA - State University Of Mato Grosso Do Sul; SILVA, DENISE - State University Of Mato Grosso Do Sul; KHAN, IKHLAS - University Of Mississippi; GASPAROTTO,JR, ARQUIMEDES - Federal University Of Big Dourados (UFGD); MANFRON, JANE - State University Of Ponta Grossa

Submitted to: Pharmaceuticals
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/14/2023
Publication Date: 11/20/2023
Citation: Monteiro, L.M., Klider, L.M., Marques, A.A., Farago, P.V., Emiliano, J., Souza, R.I., Dos Santos, A.C., Dos Santos, V.L., Wang, M., Cassemiro, N.S., Silva, D.B., Khan, I.A., Gasparotto,Jr, A., Manfron, J. 2023. The Cardiorenal Effects of Piper amalago Are Mediated by the Nitric Oxide/Cyclic Guanosine Monophosphate Pathway and the Voltage-Dependent Potassium Channels Ethnopharmacological investigation of Piper amalago L. Pharmaceuticals. 16:1-24. https://doi.org/10.3390/ph16111630.
DOI: https://doi.org/10.3390/ph16111630

Interpretive Summary: Piper amalago L., popularly known as ‘pariparoba’ and ‘falso-jaborandi’, has been widely used in traditional medicine as analgesic, anti-inflammatory, antihypertensive, and healing. To investigate the chemical composition and the possible toxicological, cardiovascular, and renal effects of essential oil (OEPA) and the aqueous (EAPA) and hydroalcoholic extract (EHPA) from P. amalago were studied. GC/MS analysis revealed that the main components of essential oil were bicyclogermacrene, spathulenol, ß-phellandrene and a-pinene. Glycosylated flavones, organic acids, amino acids and amides were found by LC/MS/MS in P. amalago leaves. The biological studies demonstrated that the EAPA, EHPA and OEPA can be considered safe after acute administration in rats. The EAPA, EHPA and OEPA showed diuretic activity after acute and prolonged administration. P. amalago hydroalcoholic extract induced a significant vasodilatory response in mesenteric vascular beds.

Technical Abstract: Piper amalago L., popularly known as ‘pariparoba’ and ‘falso-jaborandi’, has been widely used in traditional medicine as analgesic, anti-inflammatory, antihypertensive, and healing. To investigate the chemical composition and the possible toxicological, cardiovascular, and renal effects of essential oil (OEPA) and the aqueous (EAPA) and hydroalcoholic extract (EHPA) from P. amalago were studied in rats. Firstly, the samples OEPA, EAPA and EHPA aqueous and hydroalcoholic extract and the essential oil extracted from the leaves of P. amalago were prepared. The chemical composition from the essential oil OEPA was determined by GC-MS and the chemical profile from the extracts EAPA and EHPA were determined by LC-DAD- MS/MS. The acute oral toxicity studies were conducted in female Wistar rats. Finally, the electrocardiographic profile as well as the possible diuretic, hypotensive and vasodilator response in mesenteric vascular beds (MVBs) were evaluated in male Wistar rats. The chemical composition from OEPA revealed the main compounds bicyclogermacrene (11%), sphatulenol (9.21%), ß-felandrene (8.12%) and a-pinene (6.17%), while 47 compounds were annotated from EAPA and EHPA, including glycosylated flavones, organic acids, amino acids and amides such as methoxy-methylenedioxy cis-cinnamoyl pyrrolidine, methoxy-methylenedioxy trans-cinnamoyl pyrrolidine, and cyclobutene-2,4-bis (1,3-benzodioxol-5-methoxy-6-yl)-1,3-dicarboxapyrrolidide. Regarding toxicity, the EAPA, EHPA and OEPA can be considered safe after acute administration in rats, since they did not cause mortality or significant changes in behavior, body weight gain, feed, and water consumption, as well as significant changes in organ relative weight or in histopathological analyses. Regarding the efficacy, the data showed that a single administration of the EAPA and EHPA at doses of 30 and 300 mg/kg increased urinary volume and reduced renal solute excretion. In long-term treatment, solute excretion was increased for the OEPA (30 mg/kg), EAPA (300 mg/kg), and EHPA (300 mg/kg) groups on the 3rd-day of treatment. On the 7th day, the animals that received the EAPA (30 mg/kg) increased the excretion of urine and electrolytes, whereas the EHPA only increased the elimination of solutes. Rats treated with OEPA (30 and 300 mg/kg) showed increased urinary volume on the 7th day of treatment. None of the extracts were able to promote hypotension or changes in cardiac electrical activity. Only the EHPA (0.1, 1, and 3 mg) promoted significant vasodilatory effects in MVBs. The vasodilatory effects of EHPA were significantly reduced in the presence of L-NAME (a non-selective inhibitor of nitric oxide [NO] synthase), KCl (40 mM), or 4-aminopyridine (a voltage-dependent potassium channel blocker). In conclusion, the EAPA, EHPA and OEPA are safe and showed diuretic activity after acute and prolonged administration. Moreover, EHPA induced significant vasodilator response in MVBs by NO/cyclic GMP pathway and voltage-depend K+ channels activation.