The acute cardiorespiratory effects of centrally injected arachidonic acid; the mediation of prostaglandin E, D and F 2α

Key pointsr Linoleic acid consumption is increasing in Western populations. r We investigated whether elevated linoleic acid in pregnancy was deleterious to mothers or offspring.r Maternal and fetal body and organ weights were not affected by elevated linoleic acid consumption.r Maternal lipids and leptin were altered following elevated linoleic acid consumption. r Male offspring numbers were reduced following elevated linoleic acid consumption.Abstract Dietary intakes of linoleic acid (LA) have increased dramatically in Western populations, including in women of reproductive age. Pro-inflammatory effects of LA may have detrimental effects on maternal and offspring outcomes. We aimed to investigate whether consumption of a maternal diet with elevated LA altered maternal inflammatory or metabolic markers during pregnancy, fetal growth and/or the sex ratio of the offspring. Female Wistar Kyoto rats consumed a diet high in LA (HLA) (6.21% of energy) or a diet low in LA (LLA) (1.44% of energy) for 10 weeks prior to mating and during pregnancy. Pregnant rats were killed at embryonic day 20 (E20). There were no differences in maternal or fetal body weights or organ weights in the HLA group compared to the LLA group. There was no difference in maternal circulating cytokine concentrations between dietary groups. In the maternal liver, IL-1α concentrations were significantly lower, and TNF-α and IL-7 significantly higher in the HLA group. Total plasma Nirajan Shrestha is currently studying for his PhD in School of Medical Sciences at Griffith University, Australia. He completed his MS in biomedical science at Chonbuk National University, South Korea and a BS in medical biochemistry at Pokhara University, Nepal. His current research focuses on the effect of maternal diet in offspring's metabolic health. He is also interested in fatty acid metabolism, endocannabinoid system and metabolic diseases. He has published five peer-reviewed journal articles and presented his research at different national and international conferences. 3350N. Shrestha and others J Physiol 597.13 cholesterol, LDL-cholesterol, HDL cholesterol and the total:HDL cholesterol ratio were lower in dams fed the HLA diet. mRNA expression of sterol regulatory element binding transcription factor 1 (SREBF-1) and leptin in maternal adipose tissue was lower in the HLA group, as were circulating leptin concentrations. The proportion of male fetuses was lower and circulating prostaglandin E metabolite concentrations were increased in the HLA group. In conclusion, consumption of a maternal diet high in linoleic acid alters cholesterol metabolism and prostaglandin E metabolite concentrations, which may contribute to the reduced proportion of male offspring.

show abstract

“…Previous study in rats demonstrated that arachidonic acid, a PUFA, increases

P_{{normalO}_{2}}

, suggesting a role for fatty acids in respiratory control (Erkan et al . ).…”

Section: Discussionmentioning

confidence: 97%

Elevated maternal linoleic acid reduces circulating leptin concentrations, cholesterol levels and male fetal survival in a rat model

Shrestha

Cuffe

Holland

et al. 2019

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…Some of the concentration-QTcF models for parent OBE002 (models both and OBE022; Table 2) tended to indicate a nonsignificant negative slope. An effect on cardiac function of exposure to the FP antagonists OBE002 or its parent OBE022 could be excluded despite the reported action of FP agonists on cardiac function in vitro 8,9,11,[30][31][32] and reports of blood pressure elevation in response to topical application of FP agonists. 33 This is consistent with previous clinical studies of allosteric FP antagonists that showed no QTc prolongation attributable to drug administration.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo studies have also demonstrated the relevance of FP modulation for cardiac function. Genetic deletion of FP protects against inflammatory tachycardia in mice, and PGF 2α antagonism partly blocks centrally administered arachidonic acid–evoked pressor responses . A clinical study of an FP allosteric inhibitory modulator recorded isolated QT‐interval prolongations that were probably not related to the investigational medical product …”

mentioning

confidence: 99%

“…Genetic deletion of FP protects against inflammatory tachycardia in mice, 9 and PGF 2α antagonism partly blocks centrally administered arachidonic acid-evoked pressor responses. 11 A clinical study of an FP allosteric inhibitory modulator recorded isolated QT-interval prolongations that were probably not related to the investigational medical product. 12 The electrophysiological effects of OBE022 and OBE002 on the human hERG potassium channel have been evaluated in vitro in patch clamp studies using HEK293 and CHO cell lines transfected with hERG (ObsEva, data on file).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Confirmation of the Cardiac Safety of PGF_2αReceptor Antagonist OBE022 in a First‐in‐Human Study in Healthy Subjects, Using Intensive ECG Assessments

Täubel

Lorch²,

Coates³

et al. 2018

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

OBE022, a new orally active prostaglandin F2α receptor antagonist (OBE022) with myometrial selectivity is being developed to reduce uterine contractions during preterm labor. This first‐in‐human study evaluated the effect of OBE022 following multiple doses on the QT interval in 23 healthy postmenopausal women, using the effect of a meal on QTc to demonstrate assay sensitivity. We report the cardiac safety outcome performed during the multiple ascending part of this trial. OBE022 was administered after a standardized breakfast on day 1 and in the fasted state from day 3 to day 9 wth a standardized lunch 4 hours after administration. Concentration–effect modeling was used to assess the effect of prodrug OBE022 and parent OBE002 on QTc after a single dose (days 1 and 3) and multiple doses (day 9). The concentration–response analysis showed the absence of QTc prolongation at all doses tested. Two‐sided 90% confidence intervals of the geometric mean Cmax for estimated QTc effects of OBE022 and OBE002 of all dose groups were consistently below the threshold of regulatory concern. The sensitivity of this study to detect small changes in the QTc was confirmed by a significant shortening of the QTc on days 1, 3, and 9 after standardized meals. This study establishes that neither prodrug OBE022 nor parent OBE002 prolong the QTc interval. The observed food effect on the QT interval validated the assay on all assessment days. Both the change from predose, premeal and the change from premeal, postdose demonstrated the specificity of the method.

show abstract

“…20 It also modulates ion channels and regulates the activity of many enzymes, including protein kinase A, protein kinase C, and NADPH oxidase. 21 Recently we reported that intracerebroventricularly (ICV) administered AA, by activating the central COX pathway, leads to pressor cardiovascular effects in normotensive [22][23][24] and hemorrhaged hypotensive rats, 25,26 had a hyperventilation effect on respiratory system, 27,28 and stimulation of male hypothalamic-pituitary-gonadal axis. 29 We also reported that inhibition of central COX enzyme completely and blockage of central thromboxane A2 synthesis (TXA2) partially prevented AA-evoked pressor, [22][23][24][25][26] hyperventilation 27,28, and neuroendocrine effects.…”

Section: Introductionmentioning

confidence: 99%

Effect of Long-Term Centrally Injected Histamine and Its Receptors Antagonist on The Hypothalamic Cyclooxygenase and Lipoxygenase Enzymes in Rats

Yalçın

Baş

Guvenc-Bayram

et al. 2019

Journal of Research in Veterinary Medicine

View full text Add to dashboard Cite

The current study was designed to determine the effect of centrally chronic-administrated histamine and histaminergic receptors antagonist on the level of hypothalamic cyclooxygenase (COX) and lipoxygenase (LOX) enzymes.Studies were performed in male Sprague-Dawley rats. Histamine (100 nmol), histaminergic H1 receptor antagonist chlorpheniramine (100 nmol), histaminergic H2 receptor antagonist ranitidine (100 nmol) or histaminergic H3/H4 receptor antagonist thioperamide (100 nmol) was injected intracerebroventricularly for 7 days. Central chronic histamine treatment caused increases in the levels of all three enzymes in the hypothalamus. Central chronic treatments with all three histaminergic receptors antagonists reduced the hypothalamic COX-1 levels and raised the hypothalamic COX-2 and LOX levels.In conclusion, our findings show that the central histamine has a possible role to affect the central COX and LOX pathways. This could be interpreted as that central histaminergic system might have a potential to activate central COX and LOX pathways to regulate central nervous system functions.

show abstract

The acute cardiorespiratory effects of centrally injected arachidonic acid; the mediation of prostaglandin E, D and F 2α

Cited by 14 publications

References 36 publications

Elevated maternal linoleic acid reduces circulating leptin concentrations, cholesterol levels and male fetal survival in a rat model

Elevated maternal linoleic acid reduces circulating leptin concentrations, cholesterol levels and male fetal survival in a rat model

Confirmation of the Cardiac Safety of PGF_2αReceptor Antagonist OBE022 in a First‐in‐Human Study in Healthy Subjects, Using Intensive ECG Assessments

Effect of Long-Term Centrally Injected Histamine and Its Receptors Antagonist on The Hypothalamic Cyclooxygenase and Lipoxygenase Enzymes in Rats

Contact Info

Product

Resources

About

The acute cardiorespiratory effects of centrally injected arachidonic acid; the mediation of prostaglandin E, D and F 2α

Cited by 14 publications

References 36 publications

Elevated maternal linoleic acid reduces circulating leptin concentrations, cholesterol levels and male fetal survival in a rat model

Elevated maternal linoleic acid reduces circulating leptin concentrations, cholesterol levels and male fetal survival in a rat model

Confirmation of the Cardiac Safety of PGF2αReceptor Antagonist OBE022 in a First‐in‐Human Study in Healthy Subjects, Using Intensive ECG Assessments

Effect of Long-Term Centrally Injected Histamine and Its Receptors Antagonist on The Hypothalamic Cyclooxygenase and Lipoxygenase Enzymes in Rats

Contact Info

Product

Resources

About

Confirmation of the Cardiac Safety of PGF_2αReceptor Antagonist OBE022 in a First‐in‐Human Study in Healthy Subjects, Using Intensive ECG Assessments