摘要:

Hyperammonemia increases brain glutamine levels, causes astrocytic swelling, and depresses cerebral blood flow (CBF) responsivity to CO2. Methionine sulfoximine (MSO) inhibition of glutamine synthetase activity, known to be enriched in astrocytes, prevents ammonia-induced increases in brain glutamine and water content. We tested the hypothesis that inhibition of glutamine accumulation restores CBF responsivity to CO2during acute hyperammonemia. Pentobarbital-anesthetized rats treated with either vehicle or MSO (150 mg/kg i.p.) received a 6-hour intravenous infusion of either sodium or ammonium acetate. With subsequent induction of hypercapnia, CBF increased from 113±14 (mean±SEM) to 194±9 ml/min per 100 g in control rats but was unchanged from 107±13 to 79±10 ml/min per 100 g in hyperammonemic rats. Treatment with MSO in hyperammonemic rats restored the CBF response to hypercapnia (from 73±8 to 141±14 ml/min per 100 g). With induction of hypocapnia, CBF decreased from 114+11 to 88±11 ml/min per 100 g in control rats but increased from 112±13 to 142±19 ml/min per 100 g in hyperammonemic rats. Treatment with MSO in hyperammonemic rats did not fully restore the response to hypocapnia but prevented the paradoxical increase in CBF (from 80±8 to 80±8 ml/min per 100 g). In control rats, MSO did not affect CO2responsivity. Treatment with MSO prevented ammonia-induced increases in intracranial pressure. Hyposmotic-induced increases in brain water content and intracranial pressure attenuated the CBF response to hypercapnia but, unlike hyperammonemia, did not attenuate the response to hypocapnia. In contrast to hypercapnia, vasodilation in response to arterial hypotension was intact in hyperammonemic rats. We conclude that the grossly abnormal CBF responsivity to CO2alterations during hyperammonemia is linked to glutamine accumulation rather than ammonia per se. Cerebral edema secondary to glutamine accumulation may contribute in part to abnormal CBF responses, although other aspects of astrocyte dysfunction are likely to be important.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

To investigate possible ionic current mechanisms underlying ischemic arrhythmias, we studied single Na+channel currents in rat and rabbit cardiac myocytes treated with the ischemic metabolite lysophosphatidylcholine (LPC) using the cell-attached and excised inside-out patch-clamp technique at 22°C. LPC has been reported previously to reduce open probability and to induce sustained open channel activity at depolarized potentials. We now report two new observations for Na+currents in LPC-treated patches: 1) The activation-voltage relation of the peak of the ensemble currents is shifted in the negative (hyperpolarizing) direction by approximately 20 mV compared with control currents. This effect was observed in all patches for depolarizations from a holding potential of −150 mV to different test potentials. 2) In some LPC-treated patches, Na+channels exhibited sustained bursting activity at potentials as negative as −150 mV, giving a nondecaying inward current. This bursting activity was accompanied by double and triple simultaneous openings and closings, suggesting tight cooperativity in channel gating. These LPC-modified channels were identified as Na+channels, because their unitary conductance was the same as Na+channels in control solutions, because the single channel current-voltage relation was extrapolated to reverse at the Na+Nernst potential, and because the current was blocked by the local anesthetic QX-222. This novel depolarizing current may play a role in the electrophysiological abnormalities in ischemia, including abnormal automaticity and reentrant arrhythmias, and could be a target for antiarrhythmic drugs.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Endothelin-1 (ET-1), a 21-amino acid vasoconstrictive peptide, increases intracellular Ca2+level and has hypertrophic action on ventricular myocytes. To elucidate a possible role of Ca2+entry through sarcolemmal Ca2+channels on this ET-1 action, we examined effects of ET-1 on L-type (ICa,L) and T-type (ICaT) Ca2+currents in cultured neonatal rat ventricular myocytes using the patch-clamp technique. ET-1 at a concentration of 10 nM increased the maximum current density of ICa,Tfrom −3.0±1.4 μA/cm2in the control condition to −4.4±1.6 gA/cm2(p<0.01). Although the peak amplitude of ICa,Lwas decreased during ET-1 application (from −9.7±1.9 μA/cm2in the control condition to −5.0±1.4 μA/cm2[p<0.01]), this magnitude of decrease in ICa,L(52±19%) was comparable to that of spontaneous “run-down” of ICa,L(47±26%). The enhancement of ICa,Tby ET-1 was dose dependent; it was initiated as low as 0.32 nM, and the maximal response was attained at approximately 10 nM, with a half-maximal dose of 1.26 nM. The enhancement of ICa,Tby ET-1 was antagonized by protein kinase C inhibitors staurosporine (0.2 μM) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7, 20 μM) applied to the pipette solution. Extracellular application of tumor-promoting phorbol esters, phorbol 12,13-dibutyrate (PDBu) and 4β-phorbol 12-myristate 13-acetate, augmentedCa,TPDBu (0.2 μM) increased the maximal current density of ICa,Tfrom −4.2±0.5 μA/cm2in the control condition to −5.5±1.0 μA/cm2(p<00.01). In the presence of H-7 (20 μM) in the pipette solution, PDBu failed to enhance ICa,T, and an inactive isomer of PDBu (4α-phorbol 12, 13-dibutyrate, 0.2 μM) did not augment ICa,T. Thus, ET-1 enhances Ca2+entry through the sarcolemmal T-type Ca2+channel, possibly through a pathway involving activation of protein kinase C. This ET-1 action may be involved in the rise of the intracellular Ca2+level and may contribute to the induction of cardiac hypertrophy by ET-1.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Cholinergic agonists and vagal stimulation potentiate the inducibility of atrial fibrillation. To describe the activation patterns and determine the mechanisms that sustain cholinergic fibrillation, tachyarrhythmias were induced with a single extrastimulus in the isolated Krebs-Henseleit-perfused canine right atrium (n=11) at increasing concentrations of acetylcholine (from 10−7.5to 10−4.5M). Bipolar electrograms were recorded from 250 epicardial sites simultaneously during control conditions and during extrastimulation (S1S1, 300 msec; S1S2, effective refractory period +5 msec) with and without acetylcholine. Activation sequence maps were constructed from each recording. Without acetylcholine, no tachyarrhythmias were induced. With increasing concentrations of acetylcholine, the refractory period decreased, and nonsus-tained (<2 seconds) rapid repetitive responses were induced. At higher concentrations, a sustained (>2-minute) fibrillation was induced. Activation sequence maps revealed that the rapid repetitive responses were characterized by multiple reentrant circuits. The number of circuits and wavelets increased in a dose-dependent fashion. However, unexpectedly, this trend did not continue when the tachyarrhythmia became sustained. Instead, the reentry tended to stabilize to a small, single, relatively stable reentrant circuit. In conclusion, the data suggest that, in this model, below a critical level of refractory period (<95 msec) atrial reentrant circuits, unassociated with anatomic obstacles, can become stable and dominate activation.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Nitric oxide (NO) is an important signal substance in cell-cell communication and can induce relaxation of blood vessels by activating guanylate cyclase in smooth muscle cells (SMCs). NO is synthesized from L-arginine by the enzyme NO synthase, which is present in endothelial cells. It was recently shown that SMCs may themselves produce NO or an NO-related compound. We have studied NO production and its effects on energy metabolism in cultured rat aortic smooth muscle cells. It was observed that the cytokines, interferon-γ and tumor necrosis factor-ar, synergistically induced an arginine-dependent production of NO in these cells. This was associated with an inhibition of complex I (NADH: ubiquinone oxidoreductase) and complex II (succinate: ubiquinone oxidoreductase) activities of the mitochondrial respiratory chain, suggesting that NO blocks mitochondrial respiration in these cells. Lactate accumulated in the media of the cells, implying an increased anaerobic glycolysis, but there was no reduction of viability. An NO-dependent inhibition of mitochondrial respiration and a switch to anaerobic glycolysis would reduce the energy production of the SMCs. This would in turn reduce the contractile capacity of the cell and might represent another NO-dependent vasodilatory mechanism. It could be of particular importance in inflammation, since cytokines released by inflammatory cells may induce autocrine NO production in SMCs.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Multiple gap junction proteins (connexins) and channels have been identified in developing and adult heart. Functional expression of the three connexins found in chick heart (connexin42, connexin43, and connexin45) by stable transfection of communication-deficient neuro2A (N2A) cells revealed that all three connexin cDNAs are capable of forming physiologically distinct gap junctions that differ in their transjunctional voltage dependence and unitary channel conductances. The transjunctional voltage dependences of connexin45 and connexin42 closely resembled those of 4-day and 18-day embryonic chick heart gap junctions, respectively. The multiple channel conductances between 80 and 240 pS, including the predominant 160 pS channel, observed in embryonic chick heart were also common to connexin42. The expression of multiple gap junction channels with distinct conductance and regulatory properties within a given tissue may account for developmental changes in intercellular communication.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID