The apelin peptide is the endogenous ligand for the apelin G protein-coupled receptor. The distribution of the apelin peptides and receptor are widespread in the central nervous system and periphery, with reported roles in the hypothalamic-pituitary-adrenal axis, blood pressure regulation and as one of the most potent positive inotropic substances yet identified. In this report, we show that in native tissues preproapelin exists as a dimer. Dimeric preproapelin was reduced to monomers by dithiothreitol treatment, indicating disulfide linkages. To evaluate the role of the carboxyl-terminal phenylalanine in the hypotensive action of apelin-13, analogs were generated and tested for their role on blood pressure regulation. Injections of apelin-13 and apelin-12 (15 microg/kg) into spontaneously hypertensive rats lowered systolic and diastolic blood pressure to result in decreases of approximately 60% and 15% in mean arterial blood pressure, respectively. Apelin-13(13[D-Phe]) treatment did not differ from apelin-13 in either efficacy or duration of effect, whereas apelin-13(F13A) revealed a loss of function. However, concomitant administration of apelin-13(F13A) (30 microg/kg) blocked hypotensive effects of apelin-13 (15 microg/kg), which revealed that apelin-13(F13A) behaved as an apelin-specific antagonist.
Given the intricate organization of the brain, tissue sampling for chemical profiling studies have always been a challenging task. It is often exceptionally difficult to obtain homogeneous samples for in vitro/ex vivo experiments without altering or losing valuable information. The obvious approach has been to develop in vivo analytical methods that may cause minimal perturbation to this complex chemical network so as to improve overall reliability of acquired information. Methods such as biosensors and microdialysis (MD) are among sampling methods applied to in vivo brain chemical profiling studies despite their unique challenges. MD is a well-established in vivo analytical sampling method used over the years for monitoring often low-molecular-weight hydrophilic compounds from the interstitial space. The successful application of the method to neuroscience, especially monitoring of neurotransmitters, led to its expansion to a wider range of analytes, including drugs, [1] metabolites, [2] and peptides. [3] A major challenge, however, associated with MD is its difficulty in sampling hydrophobic compounds. Hydrophobic compounds are often highly protein-bound and bind to the MD probe and tubing, thereby affecting relative recovery. The addition of modifiers, such as bovine serum albumin, glycerol in water, [4] or cyclodextrin, [5] is among the approaches that have been used to prevent hydrophobic interactions and to improve relative recoveries. But these techniques often may complicate the pharmacology of the neurological analytes, as the additives are known to interact with the tissue surrounding the probe. [6] Thus, in typical global metabolomics studies, for example, the composition of a measured metabolome can be significantly affected by the analytical procedure, leaving the analysts with results which likely do not adequately reflect accurate composition of the metabolome during sampling. [7] In effect, it will compromise the already challenging efforts in diagnosis, prognostics, and searching for potential biomarkers for therapeutic purposes. Herein, we demonstrate a novel application of solid-phase microextraction (SPME) for in vivo sampling for brain study. For the first time an application of in vivo SPME as a complementary method to MD for braintissue bioanalysis has been presented. Our technique was first validated against MD in targeted analysis of selected neurotransmitters. Their complementary nature was subsequently shown in global profiling of the brain metabolome. From the profiling study, SPME detected groups of lipids such as gangliosides, fatty acids, and lysophospholipids, which are of particular interest in relation to neurodegenerative diseases. SPME derives its selectivity from the extracting sorbent type. Thus, SPME provides the needed flexibility to analysts to tailor investigations to specific biologically hydrophilic/ hydrophobic compounds. For a global study of the metabolome, however, the sorbent choice is one of low selectivity; that is, the sorbent chemical property must enhance simu...
In this study we report the effect on splanchnic hemodynamics of acute oral ethanol at doses ranging from 0.25 to 4.0 g/kg body wt. Flows were determined by use of a radioactive microsphere technique. Ethanol was found to increase portal blood flow by 23-57%. In awake rats this increase reached a plateau at the 0.5 g/kg dose. In ketamine-anesthetized rats, the increase was observed only at doses of 3.0 g/kg or more, with the response at doses of 0.5, 1.0, and 2.0 g/kg being suppressed by ketamine. Inhibition of alcohol dehydrogenase by intra-arterial administration of 4-methylpyrazole resulted in suppression of the liver blood flow increase after ethanol was administered to awake animals. Ethanol in the range of doses studied did not result in changes in blood glucagon levels. Rats fed ethanol-containing diets for 4 wk and withdrawn for 18 h had the same response to acute oral ethanol as did naive rats. It is suggested that ethanol metabolism mediates the effects of ethanol on splanchnic blood flow. An increase in splanchnic blood flow when concurrent with an increase in liver O2 consumption induced by ethanol might protect the liver from hypoxic damage.
Intracerebral microdialysis was utilized to investigate the effect of P-glycoprotein (a drug efflux transporter) induction at the mouse blood-brain barrier (BBB) on brain extracellular fluid concentrations of quinidine, an established substrate of P-glycoprotein. Induction was achieved by treating male CD-1 mice for 3 days with 5 mg/kg/day dexamethasone (DEX), a ligand of the nuclear receptor, pregnane X receptor, and a P-glycoprotein inducer. Tandem liquid chromatography mass spectrometric method was used to quantify analytes in dialysate, blood and plasma. P-glycoprotein, pregnane X receptor and Cyp3a11 (metabolizing enzyme for quinidine) protein expression in capillaries and brain homogenates was measured by immunoblot analysis. Following quinidine i.v. administration, the average ratio of unbound quinidine concentrations in brain extracellular fluid (determined from dialysate samples) to plasma at steady state (375-495 min) or K p, uu, ECF/Plasma in the DEX-treated animals was 2.5-fold lower compared with vehicle-treated animals. In DEX-treated animals, P-glycoprotein expression in brain capillaries was 1.5-fold higher compared with vehicle-treated animals while Cyp3a11 expression in brain capillaries was not significantly different between the two groups. These data demonstrate that P-gp induction mediated by DEX at the BBB can significantly reduce quinidine brain extracellular fluid concentrations by decreasing its brain permeability and further suggest that drug-drug interactions as a result of P-gp induction at the BBB are possible.
This study compared systemic hemodynamic and organ blood flow responses to equipotent concentrations of halothane and sevoflurane during spontaneous ventilation in the rat. The MAC values for halothane and sevoflurane were determined. Cardiac output and organ blood flows were measured using radiolabeled microspheres. Measurements were obtained in awake rats (control values) and at 1.0 MAC halothane or sevoflurane. The MAC values (mean +/- SEM) for halothane and sevoflurane were 1.10% +/- 0.05% and 2.40% +/- 0.05%, respectively. The PaCO2 increased to a similar extent in both groups compared with control values. During halothane anesthesia, heart rate decreased by 12% (P < 0.01), cardiac index by 26% (P < 0.01), and mean arterial blood pressure by 18% (P < 0.01) compared with control values. Stroke volume index and systemic vascular resistance did not change. During sevoflurane anesthesia, hemodynamic variables remained unchanged compared with control values. Coronary blood flow decreased by 21% (P < 0.01) and renal blood flow by 18% (P < 0.01) at 1.0 MAC halothane, whereas both remained unchanged at 1.0 MAC sevoflurane. Cerebral blood flow increased to a greater extent with halothane (63%; P < 0.01) than with sevoflurane (35%; P < 0.05). During halothane anesthesia, hepatic arterial blood flow increased by 48% (P < 0.01), whereas portal tributary blood flow decreased by 28% (P < 0.01). During sevoflurane anesthesia, hepatic arterial blood flow increased by 70% (P < 0.01) without a concomitant reduction in portal tributary blood flow. Total liver blood flow decreased only with halothane (16%; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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