Activation of renal vascular smooth muscle TRPV4 channels by 5-hydroxytryptamine impairs kidney function in neonatal pigs.

Control of microvascular reactivity by 5-hydroxytryptamine (5-HT; serotonin) is complex and may depend on vascular bed type and 5-HT receptors. 5-HT receptors consist of seven families (5-HT1-5-HT7), with 5-HT2 predominantly mediating renal vasoconstriction. Cyclooxygenase (COX) and smooth muscle intracellular Ca2+ levels ([Ca2+]i) have been implicated in 5-HT-induced vascular reactivity. Although 5-HT receptor expression and circulating 5-HT levels are known to be dependent on postnatal age, control of neonatal renal microvascular function by 5-HT is unclear. In the present study, we demonstrate that 5-HT stimulated human TRPV4 transiently expressed in Chinese hamster ovary cells. 5-HT2A is the predominant 5-HT2 receptor subtype in freshly isolated neonatal pig renal microvascular smooth muscle cells (SMCs). HC-067047 (HC), a selective TRPV4 blocker, attenuated cation currents induced by 5-HT in the SMCs. HC also inhibited the 5-HT-induced increase in renal microvascular [Ca2+]i and constriction. Intrarenal artery infusion of 5-HT had minimal effects on systemic hemodynamics but reduced renal blood flow (RBF) and increased renal vascular resistance (RVR) in the pigs. Transdermal measurement of glomerular filtration rate (GFR) indicated that kidney infusion of 5-HT reduced GFR. HC and 5-HT2 receptor antagonist ritanserin attenuated 5-HT effects on RBF, RVR, and GFR. Moreover, the serum and urinary COX-1 and COX-2 levels in 5-HT-treated piglets were unchanged compared with the control. These data suggest that activation of renal microvascular SMC TRPV4 channels by 5-HT impairs kidney function in neonatal pigs independently of COX production.

Transdermal Measurement of Glomerular Filtration Rate in Mechanically Ventilated Piglets.

Transdermal measurement of glomerular filtration rate (GFR) has been used to evaluate kidney function in conscious animals. This technique is well established in rodents to study acute kidney injury and chronic kidney disease. However, GFR measurement using the transdermal system has not been validated in pigs, a species with a similar renal system to humans. Hence, we investigated the effect of sepsis on transdermal GFR in anesthetized and mechanically ventilated neonatal pigs. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP). The transdermal GFR measurement system consisting of a miniaturized fluorescence sensor was attached to the pig's shaved skin to determine the clearance of fluorescein-isothiocyanate (FITC) conjugated sinistrin, an intravenously injected GFR tracer. Our results show that at 12 h post-CLP, serum creatinine increased with a decrease in GFR. This study demonstrates, for the first time, the utility of the transdermal GFR approach in determining renal function in mechanically ventilated, neonatal pigs.

Antihypertensive effect of Phragmanthera incana (Schum) Balle on NG-nitro-L-Arginine methyl ester (L-NAME) induced hypertensive rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Phragmanthera incana (Schum) Balle is a member of the African mistletoes that has been reported to be used in ethnomedicine for the treatment of hypertension. AIM: The aim of this study was to investigate the antihypertensive effect of Phragmanthera incana leaf ethanol extract (PILEE) in NG-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. MATERIALS AND METHODS: Phytochemical analysis of PILEE was determined using the Gas chromatography - Mass spectrophotometry (GC-MS) method. Antihypertensive activity was investigated in rats that received PILEE (50, 100 and 200 mg/kg) or captopril (40 mg/kg) daily for 28 days together with oral administration of L-NAME (40 mg/kg). Blood pressure parameters were measured on day 7, 14, 21 and 28. Blood was obtained for determination of serum nitrite, interleukin-6 (IL-6) and tumor necrosis factor, TNF-α. The heart, liver and kidneys were used to determine oxidative stress indices (malondialdehyde, reduced glutathione and catalase). The cardiac tissue was processed for histopathological changes. RESULTS: The GC-MS profiling of PILEE identified 20 compounds namely fatty acid esters. Administration of PILEE (50, 100 and 200 mg/kg) dose dependently and significantly reduced systolic blood pressure and mean arterial pressure in hypertensive rats. PILEE administration significantly (p < 0.05) reversed elevated IL-6 and TNF-α in hypertensive rats. PILEE demonstrated antioxidant activity by attenuating L-NAME-induced elevated malondialdehyde and depletion of reduced glutathione and catalase activity in rat tissues. PILEE treatment demonstrated cardioprotective effect in L-NAME-induced cardiac hyperplasia and necrosis in rats. CONCLUSION: It can be concluded that Phragmanthera incana leaf ethanol extract possess antihypertensive, antioxidant and anti-inflammatory properties, suggesting a protective role in cardiovascular diseases.

Clofibrate, a PPAR-α agonist, abrogates sodium fluoride-induced neuroinflammation, oxidative stress, and motor incoordination via modulation of GFAP/Iba-1/anti-calbindin signaling pathways.

Fluoride is an environmental contaminant that is ubiquitously present in air, water, and soil. It is commonly added in minute quantity to drinking water, toothpaste, and mouth rinses to prevent tooth decay. Epidemiological findings have demonstrated that exposure to fluoride induced neurodevelopmental toxicity, developmental neurotoxicity, and motor disorders. The neuroprotective effect of clofibrate, a peroxisome proliferator-activated receptor alpha agonist, was investigated in the present study. Forty male Wistar rats were used for this study and randomly grouped into 10 rats per group as control, sodium fluoride (NaF) alone (300 ppm), NaF plus clofibrate (250 mg/kg), and NaF plus lisinopril (10 mg/kg), respectively, for 7 days. NaF was administered in drinking water while clofibrate and lisinopril were administered by oral gavage. Markers of neuronal inflammation and oxidative stress, acetylcholinesterase activity, and neurobehavioral (hanging wire and open field) tests were performed. Immunohistochemistry was performed on brain tissues, and they were probed with glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, and cerebellar Ca2+ -binding protein calbindin-D28k. The results showed that NaF significantly increased of oxidative stress and neuroinflammation and inhibited AChE activity. Immunostaining showed reactive astrocytes, microgliosis, loss of dendritic spines, and arborization in Purkinje cells in rats administered only NaF. Neurobehavioral results showed that cotreatment of NaF with clofibrate improved muscular strength and locomotion, reduced anxiety, and significantly reduced astrocytic count. Overall, cotreatment of NaF with either clofibrate or lisinopril showed neuroprotective effects by mitigating neuronal inflammation and oxidative and motor incoordination. Hence, clofibrate could be seen as a novel drug candidate against neurodegeneration and motor disorders.