piperidines and Acidosis

Topics: Acidosis; Androstanes; Anesthesia; Anesthesia, General; Anesthesia, Inhalation; Anesthesia, Obstetrical; Anesthetics; Anti-Bacterial Agents; Anxiety; Contraceptives, Oral; Female; Ferricyanides; Fever; Humans; Hypnotics and Sedatives; Hypotension; Ketones; Male; Neuromuscular Nondepolarizing Agents; Occupational Diseases; Pain; Piperidines; Pregnancy; Pregnanes; Steroids; Tranquilizing Agents

Opioid agonists are powerful drugs for managing pain. However, their central side effects are limiting their use and drugs with similar potency, but a lower risk profile are needed. (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide (NFEPP) is a novel opioid agonist that preferentially activates opioid receptors at acidic extracellular pH. NFEPP was designed to activate peripheral opioid receptors in injured tissue, therefore precluding side effects elicited at normal pH in brain or intestinal wall. Considering the common combination of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) in multimodal analgesia, we investigated the interaction between NFEPP and a widely prescribed prototypical NSAID, diclofenac (DCF), in a rat model of unilateral hindpaw inflammation induced by complete Freund's adjuvant. We evaluated the effects of systemically applied DCF on the paw tissue pH, on the expression of inflammatory mediators in immune cells from inflamed paws and on the expression of opioid receptors in dorsal root ganglia. Additionally, we investigated the antinociceptive efficacy of NFEPP injected into the inflamed paws after DCF treatment. We found that DCF reduced inflammation-induced nociceptive responses and tissue acidosis, but did not change the mRNA expression of IL-1β, TNF-α, IL-6, IL-4, NGF, or of mu-, delta-, or kappa-opioid receptors. The treatment with DCF moderately reduced the antinociceptive efficacy of NFEPP, suggesting a correlation between an increase in local tissue pH and the decreased antinociceptive effect of this pH-sensitive opioid agonist.

Topics: Acidosis; Analgesics; Analgesics, Opioid; Animals; Hydrogen-Ion Concentration; Inflammation; Piperidines; Rats; Receptors, Opioid

Use of high-dose inhalational anesthesia during open fetal surgery may induce maternal-fetal hemodynamic instability and fetal myocardial depression. The authors' preliminary human retrospective study demonstrated less fetal bradycardia and left ventricular systolic dysfunction with lower dose desflurane supplemented with propofol and remifentanil IV anesthesia (SIVA). In this animal study, the authors compare maternal-fetal effects of high-dose desflurane anesthesia (HD-DES) and SIVA.. Of 26 instrumented midgestational ewes, data from 11 animals exposed to both SIVA and HD-DES in random sequences and six animals exposed to HD-DES while maternal normotension was maintained were analyzed. Maternal electroencephalography was used to guide comparable depths of anesthesia in both techniques. Hemodynamic parameters, blood gas, and fetal cardiac function from echocardiography were recorded.. Compared with SIVA, HD-DES resulted in significant maternal hypotension (mean arterial pressure difference, 19.53 mmHg; 95% CI, 17.6-21.4; P < 0.0001), fetal acidosis (pH 7.11 vs. 7.24 at 150 min, P < 0.001), and decreased uterine blood flow. In the HD-DES group with maternal normotension, uterine blood flow still declined and fetal acidosis persisted, with no statistically significant difference from the group exposed to HD-DES that had maternal hypotension. There was no statistically significant difference in fetal cardiac function.. In sheep, SIVA affects maternal hemodynamics less and provides better fetal acid/base status than high-dose desflurane. Fetal echocardiography did not reflect myocardial dysfunction in this model.

Topics: Acid-Base Equilibrium; Acidosis; Anesthesia, Obstetrical; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Animals; Arterial Pressure; Blood Pressure; Cross-Over Studies; Desflurane; Electroencephalography; Female; Fetus; Heart Rate, Fetal; Intraoperative Complications; Isoflurane; Monitoring, Intraoperative; Piperidines; Pregnancy; Propofol; Regional Blood Flow; Remifentanil; Sheep; Uterus

Metabolically generated acid is the major physiological stimulus for increasing proximal tubule citrate reabsorption, which leads to a decrease in citrate excretion. The activity of the Na-citrate cotransporter, NaDC-1, is increased in vivo by acid ingestion and in vitro by an acidic pH medium. In opossum kidney cells the acid stimulatory effect and the ability of endothelin-1 (ET-1) to stimulate NaDC-1 activity are both blocked by the endothelin B (ET(B)) receptor antagonist, BQ788. Acid feeding had no effect on brush border membrane NaDC-1 activity in mice in which ET(B) receptor expression was knocked out, whereas a stimulatory effect was found in wild-type mice. Using ET(A)/ET(B) chimeric and ET(B) C-terminal tail truncated constructs, ET-1 stimulation of NaDC-1 required a receptor C-terminal tail from either ET(A) or ET(B). The ET-1 effect was greatest when either the ET(B) transmembrane domain and C-terminal tail were present or the ET(B) C-terminal tail was linked to the ET(A) transmembrane domain. This effect was smaller when the ET(B) transmembrane domain was linked to the ET(A) C-terminal tail. Thus, the acid-activated pathway mediating stimulation of NaDC-1 activity requires a functional ET(B) receptor in vivo and in vitro, as does acid stimulation of NHE3 activity. Since increased NaDC-1 and NHE3 activities constitute part of the proximal tubule adaptation to an acid load, these studies indicate that there are similarities in the signaling pathway mediating these responses.

Topics: Acidosis; Animals; Biological Transport; Cell Line; Dicarboxylic Acid Transporters; Disease Models, Animal; Endothelin B Receptor Antagonists; Endothelin-1; Hydrogen-Ion Concentration; Kidney; Mice; Mice, Knockout; Microvilli; Oligopeptides; Opossums; Organic Anion Transporters, Sodium-Dependent; Piperidines; Protein Structure, Tertiary; Receptor, Endothelin A; Receptor, Endothelin B; Recombinant Fusion Proteins; Signal Transduction; Symporters; Time Factors; Transfection

Recent evidence from intact hearts suggests that the function of cardiac nodal tissue may be particularly susceptible to acidosis. Little is currently known, however, about the effects of acidosis on the cellular electrophysiology of the atrioventricular node (AVN). This study was conducted, therefore, to determine the effect of acidosis on the spontaneous activity and membrane currents of myocytes isolated from the rabbit AVN, recorded at 35-37 degrees C using whole-cell patch-clamp. Reduction of extracellular pH (pH(e); from 7.4 to 6.8 or 6.3) produced pH-dependent slowing of spontaneous action potential rate and upstroke velocity, and reductions in maximum diastolic potential and action potential amplitude. Ionic current recordings under voltage-clamp indicated that acidosis (pH(e) 6.3) decreased L-type Ca current (I(Ca,L)), without significant changes in voltage-dependent activation or inactivation. Acidosis reduced the E-4031-sensitive, rapid delayed rectifier current (I(Kr)) tail amplitude at -40 mV following command pulses to between -30 and +50 mV, and accelerated tail-current deactivation. In contrast, the time-dependent hyperpolarisation-activated current, I(f), was unaffected by acidosis. Background current insensitive to E-4031 and nifedipine was reduced by acidosis. Measurement of intracellular pH (pH(i)) from undialysed cells using BCECF showed a reduction in mean pH(i) from 7.24 to 6.45 (n=17) when pH(e) was lowered from 7.4 to 6.3. We conclude that I(f) is unlikely to be involved in the response of the AVN to acidosis, whilst inhibition of I(Ca,L) and I(Kr) by acidosis are likely to play a significant role in effects on AVN cellular electrophysiology.

Topics: Acidosis; Animals; Atrioventricular Node; Calcium Channels, L-Type; Electrophysiology; Hydrogen-Ion Concentration; Ions; Male; Myocytes, Cardiac; Nifedipine; Patch-Clamp Techniques; Piperidines; Pyridines; Rabbits; Sensitivity and Specificity; Temperature

Topics: Abnormalities, Multiple; Acidosis; Anesthesia; Anesthetics, Inhalation; Anesthetics, Intravenous; Atracurium; Blood Gas Analysis; Child, Preschool; Chromosome Disorders; Chromosomes, Human, Pair 9; Female; Fundoplication; Gastroesophageal Reflux; Humans; Intellectual Disability; Intubation, Intratracheal; Laryngoscopy; Methyl Ethers; Neuromuscular Nondepolarizing Agents; Piperidines; Propofol; Rare Diseases; Remifentanil; Sevoflurane

Endothelin (ET) and nitric oxide (NO) modulate ion transport in the kidney. In this study, we defined the function of ET receptor subtypes and the NO guanylate cyclase signaling pathway in mediating the adaptation of the rabbit cortical collecting duct (CCD) to metabolic acidosis. CCDs were perfused in vitro and incubated for 3 h at pH 6.8, and bicarbonate transport or cell pH was measured before and after acid incubation. Luminal chloride was reversibly removed to isolate H(+) and HCO(3)(-) secretory fluxes and to raise the pH of beta-intercalated cells. Acid incubation caused reversal of polarity of net HCO(3)(-) transport from secretion to absorption, comprised of a 40% increase in H(+) secretion and a 75% decrease in HCO(3)(-) secretion. The ET(B) receptor antagonist BQ-788, as well as the NO synthase inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME), attenuated the adaptive decrease in HCO(3)(-) secretion by 40%, but only BQ-788 inhibited the adaptive increase in H(+) secretion. There was no effect of inactive d-NAME or the ET(A) receptor antagonist BQ-123. Both BQ-788 and l-NAME inhibited the acid-induced inactivation (endocytosis) of the apical Cl(-)/HCO(3)(-) exchanger. The guanylate cyclase inhibitor LY-83583 and cGMP-dependent protein kinase inhibitor KT-5823 affected HCO(3)(-) transport similarly to l-NAME. These data indicate that signaling via the ET(B) receptor regulates the adaptation of the CCD to metabolic acidosis and that the NO guanylate cyclase component of ET(B) receptor signaling mediates downregulation of Cl(-)/HCO(3)(-) exchange and HCO(3)(-) secretion.

Topics: Acclimatization; Acidosis; Animals; Bicarbonates; Biological Transport; Cell Polarity; Chlorides; Disease Models, Animal; Endothelins; Hydrogen-Ion Concentration; Kidney Tubules, Collecting; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oligopeptides; Piperidines; Rabbits

Chronic hypokalemia increases NHE3 activity in OKP cells. The aim of the present study was to determine whether an autocrine mechanism is involved in this activation.. After incubation of OKP cells in normal-K(+) and low-K(+) media for 24 h, the potassium concentration in the low-K(+) media was adjusted to a normal level. These conditioned media were then used as the normal-K(+) and low-K(+) supernatants. Other OKP cells were incubated in these normal-K(+) and low-K(+) supernatants and the mechanism of Na(+)/H(+) antiporter activation was examined.. The EIPA-resistant Na(+)/H(+) antiporter activity of OKP cells increased after 4 h incubation in the low-K(+) supernatant, and the amount of NHE3 protein increased at 24 h. Since both BQ788 and saralasin blocked this antiporter activation, the supernatant concentration of endothelin I (ET-I) and angiotensin II (Ang-II) were measured. The ET-I concentration was reduced, but the Ang-II concentration remained unchanged. There was a significant association between a reduction in the ET-I concentration and an increase in Na(+)/H(+) antiporter activity, but only when Ang-II was present in the supernatant.. An autocrine mechanism is involved in the activation of NHE3 in OKP cells. Both ET-I and Ang-II play a role in this activation.

Topics: Acidosis; Amiloride; Angiotensin II; Animals; Autocrine Communication; Benzoquinones; Cell Line; Culture Media, Conditioned; Dose-Response Relationship, Drug; Endothelin B Receptor Antagonists; Endothelin-1; Hydrogen-Ion Concentration; Kidney; Lactams, Macrocyclic; Oligopeptides; Opossums; Piperidines; Potassium; Protein-Tyrosine Kinases; Quinones; Receptor, Endothelin B; Rifabutin; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Time Factors

The intrarenal localization and role of the V1a vasopressin receptor in body fluid homeostasis are unclear. We investigated the intranephron localization of V1a receptor mRNA and protein using reverse transcription (RT)-competitive polymerase chain reaction (PCR) and immunohistochemistry with a specific polyclonal antibody. To determine whether the V1a receptor is involved in the regulation of acid-base balance, we also examined the effects of acute and chronic metabolic acidosis and dehydration on V1a receptor expression. V1a mRNA was expressed most abundantly in the cortical collecting ducts (CCD) and decreased in the deeper CD. Expression in the glomeruli and thick ascending limbs was low. The immunohistochemical study revealed the presence of the V1a receptor in the glomeruli, the thick ascending limbs and the CD. Dehydration decreased V1a mRNA expression in the CD. Chronic metabolic acidosis increased V1a receptor mRNA expression in the CD but decreased V2 receptor mRNA expression. Western blot analysis revealed up-regulation of the V1a receptor protein in chronic metabolic acidosis. Incubation of microdissected CCD or outer medullary CD (OMCD) in a low-pH (or or low-HCO3-) medium increased the levels of V1a receptor mRNA but decreased V2 receptor mRNA expression. Incubating OMCD with arginine vasopressin (AVP) and the V1a receptor antagonist (OPC21268) increased V2 receptor mRNA expression compared with incubation with AVP alone. These data suggest that V1a receptors are present primarily in the principal and intercalated cells in the CD and that these receptors are involved in the regulation of water and acid-base balance.

Topics: Acidosis; Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Bicarbonates; Dehydration; Down-Regulation; Homeostasis; Immunohistochemistry; Male; Nephrons; Piperidines; Polymerase Chain Reaction; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin; RNA, Messenger; Up-Regulation; Vacuolar Proton-Translocating ATPases