For the developing fetal brain RAS, MLPD leads to significant alterations in the mRNA and protein expression, with changes in DNA methylation and miRNA, key regulators of hypertension in adults.

The normal murine placenta possesses several components of RAS, and in response to AMH several of these elements undergo important changes. In addition, differential expression of RAS mRNA, miRNA and protein, indicate post-transcriptional regulatory mechanisms involved with hypoxic stress, and necessitate further investigation.

This review evaluates the mechanism of volatile anesthetics as cardioprotective agents in both clinical and laboratory research and furthermore assesses possible cardiac side effects upon usage. Cardiac as well as non-cardiac surgery may evoke perioperative adverse events including: ischemia, diverse arrhythmias and reperfusion injury. As volatile anesthetics have cardiovascular effects that can lead to hypotension, clinicians may choose to administer alternative anesthetics to patients with coronary artery disease, particularly if the patient has severe preoperative ischemia or cardiovascular instability. Increasing preclinical evidence demonstrated that administration of inhaled anesthetics - before and during surgery - reduces the degree of ischemia and reperfusion injury to the heart. Recently, this preclinical data has been implemented clinically, and beneficial effects have been found in some studies of patients undergoing coronary artery bypass graft surgery. Administration of volatile anesthetic gases was protective for patients undergoing cardiac surgery through manipulation of the potassium ATP (KATP) channel, mitochondrial permeability transition pore (mPTP), reactive oxygen species (ROS) production, as well as through cytoprotective Akt and extracellular-signal kinases (ERK) pathways. However, as not all studies have demonstrated improved outcomes, the risks for undesirable hemodynamic effects must be weighed against the possible benefits of using volatile anesthetics as a means to provide cardiac protection in patients with coronary artery disease who are undergoing surgery.

Antenatal maternal hypoxia (AMH) can lead to intrauterine growth restriction (IUGR), as well as idiopathic pulmonary hypertension of newborn and adult, the latter of which may be a consequence of alterations in the local pulmonary renin-angiotensin system (RAS). Little is known of these adaptations, however. Thus, we tested the hypothesis that antenatal maternal hypoxia is associated with alterations in gene and protein expression of the pulmonary renin-angiotensin system, which may play an important role in pulmonary disorders in the offspring. In FVB/NJ mice, we studied messenger RNA (mRNA) and protein expression, as well as promoter DNA methylation and microRNA (miRNA) levels in response to 48 hours hypoxia (10.5% O(2)) at 15.5 day post coitum (DPC). In response to AMH, the pulmonary mRNA levels of angiotensin-converting enzyme (ACE) 1.2, ACE-2, and angiotensin II type 1b (AT-1b) receptors were increased significantly, as compared to controls (N = 4). In response to antenatal hypoxia, pulmonary protein levels of renin and ACE-2 also were increased significantly, whereas ACE-1 protein expression was reduced. In fetal lungs, we also observed reduced expression of the miRNAs: mmu-mir -199b, -27b, -200b, and -468 that putatively increase the translation of renin, ACE-1, ACE-2, and AT-1 receptors, respectively. In response to AMH, promoter methylation of ACE was unchanged. We conclude that AMH leads to changes in expression of pulmonary RAS of fetal mice. The possible implications of these changes for the regulation of pulmonary vascular contractility in later life remain to be explored.

Background and Purpose This study investigated whether isoflurane ameliorates neurological sequelae after germinal matrix hemorrhage (GMH) through activation of the cytoprotective sphingosine kinase/sphingosine-1-phosphate receptor/Akt pathway. Methods GMH was induced in P7 rat pups by intraparenchymal infusion of bacterial collagenase (0.3U) into the right hemispheric germinal matrix. GMH animals received 2% isoflurane either once 1 hour after surgery, or every 12 hours for 3 days. Isoflurane treatment was then combined with sphingosine-1-phoshate receptor-1/2 antagonist VPC23019 or sphingosine kinase 1/2 antagonist N,N-dimethylsphingosine. Results Brain protein expression of sphingosine kinase-1 and phosphorylated Akt were significantly increased after isoflurane post-treatment, and cleaved capase-3 was decreased at 24 hours after surgery; which was reversed by the antagonists. Isoflurane significantly reduced post-hemorrhagic ventricular dilation and improved motor, but not cognitive, functions in GMH animals 3 weeks after surgery; no improvements were observed following VPC23019 administration. Conclusion Isoflurane post-treatment improved the neurological sequelae after GMH possibly by activation of the sphingosine kinase/Akt pathway.

Antenatal maternal hypoxia (AMH) can lead to intra‐uterine growth restriction (IUGR), as well as idiopathic pulmonary hypertension of newborn and adult. This may be a consequence of alterations in the local pulmonary renin‐angiotensin system (RAS). Little is known of these adaptations, however. Thus, we tested the hypothesis that antenatal maternal hypoxia is associated with fetal programming of the pulmonary renin‐angiotensin system. In FVB/NJ mice, we studied mRNA and protein expression, as well as promoter DNA methylation and miRNA levels in response to 48 hours hypoxia (10.5% O2) at 15.5 day post coitum (DPC). In response to AMH, the pulmonary mRNA levels of angiotensin converting enzyme (ACE) 1.2, ACE‐2 and angiotensin II type 1b (AT‐1b) receptors were increased significantly, as compared to controls (N=4). In hypoxia fetal lungs, protein levels of renin and ACE‐2 also were increased significantly, whereas ACE‐1 protein expression was reduced. In hypoxic fetal lungs, we also observed reduced expression of the miRNAs: mmu‐mir −199b, −27b, −200b, and −468 that putatively increase the translation of renin, ACE‐1, ACE‐2, and AT‐1 receptors, respectively. Promoter methylation of ACE did not change with AMH. We conclude that AMH leads to changes in expression of pulmonary RAS of fetal mice. This may have significant implications for the regulation of pulmonary vascular contractility in the lung.

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ObjectiveWe hypothesized that maternal isocaloric, low‐protein, diet during pregnancy programs the Renin Angiotensin System in the fetus leading to hypertension in the adult. We conducted studies on pregnant mice, on isocaloric, normal or low protein diet (50% and 33% less protein).MethodsProteins and mRNA levels were measured using western blot and real time PCR technique and blood pressure was recorded by the non‐invasive tail cuff system.ResultsMaternal low protein diet (MLPD) resulted in low birth weight and rapid catch up growth in both male and female offspring. MLPD induced hypertension in female mice offspring at 11 weeks of age, whereas no hypertension was observed in male offspring by 20th week of age. Our results indicate increased AGT and ACE, but decreased AT2, expression of mRNA, with no change in the protein expression of AGT but decreased protein expression of both, ACE and AT2 receptors with MLPD. Promoter methylation analysis of ACE gene showed hypo‐methylation of the CpG islands as a consequence of maternal protein deprivation.ConclusionsOur studies establish that MLPD programs hypertension in female offspring by epigenetic programming of the renin‐angiotensin system.