thiourea and Hypercapnia

To assess the time course of phosphorylation of phospholamban residues, the underlying mechanisms determining these phosphorylations, and their functional impact on the mechanical recovery during acidosis.. Langendorff perfused rat hearts were submitted to 30 min of hypercapnic acidosis. Contractility, relaxation, and phosphorylation of phospholamban residues, immunodetected by specific antibodies, were determined.. Acidosis produced a mechanical impairment followed by a spontaneous recovery, most of which occurred within the first 3 min of acidosis (early recovery). During this period, contractility and relaxation recovered by 67+/-9% and 77+/-11%, respectively, from its maximal depression, together with an increase in the Ca(2+)-calmodulin-dependent protein kinase II (CaMKII)-dependent phosphorylation of Thr(17). The CaMKII inhibitor KN-93, at 1, 5 and 10 microM, decreased Thr(17) phosphorylation to basal levels and produced a similar impairment of the early relaxation recovery (50%). However, only 5 and 10 microM KN-93 inhibited the early contractile recovery and completely blunted the late mechanical recovery. Inhibition of the reverse mode of the Na(+)/Ca(2+) exchanger by KB-R7943 decreased Thr(17) phosphorylation but accelerated the early contractile recovery.. CaMKII-dependent Thr(17) phosphorylation significantly increased at the beginning of acidosis, is responsible for 50% of the early relaxation recovery, and is linked to the activation of the reverse Na(+)/Ca(2+) mode. The early contractile recovery and the late mechanical recovery are dependent on CaMKII but independent of the phosphorylation of the Thr(17) residue of phospholamban. The reverse Na(+)/Ca(2+) mode has an additional negative effect that opposes the early mechanical recovery.

Topics: Acidosis; Animals; Benzylamines; Blotting, Western; Calcium-Binding Proteins; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Depression, Chemical; Electrophoresis, Polyacrylamide Gel; Hypercapnia; Male; Myocardial Contraction; Perfusion; Phosphorylation; Protein Kinase Inhibitors; Rats; Rats, Wistar; Sodium-Calcium Exchanger; Sulfonamides; Thiourea; Threonine; Time Factors

Nitric oxide synthase (NOS) blockade was used to test the cardioventilatory responses to hypercapnia and hypoxia in freely behaving animals. Chronically instrumented adult Sprague-Dawley rats were studied before and after intravenous administration of either 100 mg/kg of NG-nitro-L-arginine methyl ester (L-NAME), a nonspecific NOS blocker, or 10 mg/kg of S-methyl-L-thiocitrulline (SMTC), a selective neural NOS inhibitor. L-NAME injection induced sustained blood pressure (BP) elevation with transient tachycardia and increased minute ventilation (VE), which returned to baseline within minutes. SMTC elicited similar, although transient, BP increases; however, heart rate and VE decreased. L-NAME and SMTC did not modify overall steady-state hypercapnic responses. In control conditions, hypoxia induced early VE increases with further VE enhancements at 30 min. L-NAME increased the early VE response to 10% O2 but induced late VE reductions in hypoxia. SMTC did not change early VE responses but induced marked reductions in the later VE hypoxic responses. In control animals, hypoxia induced a significant heart rate increase. This increase was absent during the early response after SMTC and was followed in both L-NAME- and SMTC-treated animals by significant heart rate reductions to values below room air. Similarly, the sustained BP response to hypoxia in control animals was absent after administration of NOS inhibitors. These findings suggest that NOS activity exerts excitatory influences on respiration and cardiac chronotropy and sustained vasomotor tone during hypoxia. We speculate that NOS-mediated mechanisms may play an important role in hypoxia-induced ventilatory roll-off during wakefulness.

Topics: Animals; Blood Gas Analysis; Blood Pressure; Citrulline; Enzyme Inhibitors; Heart Rate; Hemodynamics; Hypercapnia; Hypoxia; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Respiratory Mechanics; Thiourea

The blood-brain barrier (BBB) in man was studied during various conditions using the indicator dilution method of Crone [8]. Using 113m In-DTPA as reference substance the extraction, E, of the small test substances 24Na+, 36Cl-, 14C-urea and 14C-thiourea was estimated from the areas under the venous outflow curves following intracarotid slug injection of tracers. Interlaminar diffusion and red cell carriage were taken into consideration when calculating E. Cerebral blood flow (CBF) was measured using the intra-arterial 133Xe-injection method. Twenty-two patients receiving electroconvulsive therapy (ECT) were studied before and during seizures and during hypercapnia. Before seizures the extraction values in % were as follows: ENa+ 1.6, ECl- 1.9, Eurea 3.9 and Ethiourea 7.8; the corresponding values for the permeability-surface area products (PS) in ml/100 g x min were 0.5, 0.3, 0.7, 4.1, respectively. During seizure a decrease of Ethiourea and an increase of PSurea were significant. During hypercapnia PSNa and PSthiourea rose significantly. Due to the similarity of the findings in those two high flow situations it is suggested that the changes of CBF and not the epileptic activity are responsible for the changes in permeability. The mechanism of action may be a stretching of endothelial cells in the cerebral vessels or an opening up of new capillaries, or a combination of both.

Topics: Adult; Aged; Blood-Brain Barrier; Cerebrovascular Circulation; Chlorides; Electroconvulsive Therapy; Humans; Hypercapnia; Middle Aged; Pentetic Acid; Sodium; Thiourea; Urea

The effect of electrically induced seizures on the permeability of the rat blood-brain barrier was investigated. The small radioactive tracers sodium (24Na+), chloride (36Cl-) carbon labelled thiourea (14C-thiourea) and glucose (14C-D-glucose) were studied in indicator dilution experiments with indium labelled diethylenetriaminepenta-acetic acid (113mIn-DTPA) as reference substance. This method allows a quantitative estimate of the transcapillary loss of solutes, the extraction (E), during a single passage through the brain. Passage of macromolecules was studied using as marker substance Evans Blue which binds to plasma albumin. In the resting state ENa, ECl, Ethiourea and Eglucose were 2.9, 4.8, 9.3 and 12.5%, respectively. During seizures and during shortlasting hypercapnia E glucose decreased while E for the other tracers was unchanged. As cerebral blood flow increased, there must be an increased transfer of test substances into the brain. This finding is in agreement with recent human studies [15]. When Evans Blue was injected intravenously prior to electroshock, there was no staining of brain tissue after one electroshock but following repeated electroshocks some staining was observed. In an attempt quantify this transcapillary loss of albumin by means of indicator dilution, 51Cr-labelled erythrocytes were used as intravascular reference substance against 113mIn-DTPA (a plasma tracer). However, the albumin loss (by pinocytosis or otherwise) occurring after ten electroshocks could not be detected during a single passage through the brain.

Topics: Animals; Blood-Brain Barrier; Cerebrovascular Circulation; Chlorides; Electroconvulsive Therapy; Evans Blue; Glucose; Hypercapnia; Male; Pentetic Acid; Rats; Sodium; Thiourea