Diuretic and hypotensive actions of torasemide in hypertensive models of rat

The diuretic and the antihypertensive actions of torasemide were examined in renal and genetic hypertensive rats and compared to the effects of furosemide. Oral administration of torasemide (1 and 3 mg/kg) elicited a dose-dependent increase in the excretion of urine and electrolytes and elevated the urinary Na/K ratio in both renal and genetic hypertensive rats. Torasemide and furosemide had a similar maximum diuretic effect in the normotensive Wistar rat and the spontaneously hypertensive rat (SHR). However, the diuretic activity of furosemide was weaker in the renal hypertensive rat (RHR). Torasemide showed approximately 30 times greater diuretic potency than furosemide. Torasemide and furosemide demonstrated hypotensive action in hypertensive rat models, but not in the normotensive Wistar rat. Especially in the RHR, torasemide exhibited a more potent hypotensive action than furosemide. These results show that the diuretic and antihypertensive activities of torasemide are effective in various rat models of hypertension, while the diuretic activity of furosemide is weak in certain hypertensive rat models. © 1992 Wiley-Liss, Inc.     

三七皂甙对心肌腺苷三磷酸酶的影响(英文)

三七总皂甙(PNS)能抑制心肌总ATP酶活力,但对Na~( )-K~( )-ATP酶无明显影响。三七皂甙单体Rb_1及Rg_1对心肌总ATP酶活力均有抑制作用,但Rb_1的抑制效力显著大于Rg_1·Rb_1能抑制豚鼠离体心房肌的自律性和收缩性,Rg_1也能抑制豚鼠离体心房肌的自律性,但对心房肌的收缩性却无明显影响。提示PNS抑制心肌收缩力这一作用的主要有效成份是Rb_1·     

夹竹桃甙对Na~+、K~+-ATP酶抑制的动力学研究

本文对夹竹桃甙抑制Na~+、K~+-ATP酶的动力学作了探讨,并与乌本甙的作用进行了比较。结果表明:夹竹桃甙抑制Na~+、K~+-ATP酶,在Na~+、K~+浓度改变对均为非竞争性抑制,Na~+/K~+比例6:1时,为混合性抑制,而ATP对夹竹桃甙的作用几无影响。     

Synaptosomal Na, K-ATPase during forebrain ischemia in Mongolian gerbils

We studied the activity and kinetic parameters of synaptosomal Na, K-ATPase during 15 min of forebrain ischemia and following 60 min of reperfusion produced by reversible common carotid occlusion in Mongolian gerbils. A synaptosomal fraction was obtained by both differential centrifugation of brain tissue homogenate and centrifugation of crude mitochondrial fraction at a discontinual sucrose density gradient. We found two components of ATP concentration dependence of ATP hydrolysis that represent two types of ATP-binding sites: high affinity and low affinity. Neither ischemia nor reperfusion affected kinetic parameters of a high-affinity site. However, lowaffinity site parameters were affected by both ischemia and ischemia followed by reperfusion. Maximal velocity (V _max) decreased by 43 and 42% after ischemia and after ischemia/reperfusion, respectively. The apparentK _m for ATP decreased by 52% after ischemia and by 47% after ischemia/reperfusion. The apparent affinities for K⁺ and Na⁺ were determined from the ATP hydrolysis rate as a function of Na⁺ and K⁺ concentrations. We found the half-maximal activation constant for K⁺ (K _a K⁺) increased by 60% after ischemia and by 146% after ischemia/reperfusion. On the other hand, we found thatK _aNa⁺ decreased significantly after ischemia/reperfusion (16%). We concluded that it is the dephosphorylation step of the ATPase reation cycle that is primarily affected by both ischemia and ischemia/reperfusion. This might be caused by alteration of the protein molecule and/or its surroundings subsequent to ischemia.     

CHARACTERISTICS OF MEMBRANE TRANSPORT PROCESSES OF MACULA DENSA CELLS

1. Macula densa (MD) cells are located within the thick ascending limb (TAL) and have their apical surface in contact with tubular fluid and their basilar region in contact with the glomerulus. These cells sense changes in luminal fluid sodium chloride concentration ([NaCl]) and transmit signals resulting in changes in vascular resistance (tubuloglomerular feedback) and renin release. 2. Current efforts have focused on understanding the cellular transport mechanisms of MD cells. Progress in this area has benefited from the use of the isolated perfused TAL-glomerular preparation, which permits direct access to MD cells. 3. Using microelectrodes to measure basolateral membrane potential (V_BL) of MD cells, it was found that VBL was very sensitive to changes in luminal fluid [NaCl]. As [NaCl] was elevated from 20 to 150mmol/L, V_BL was found to depolarize by over 30 mV. 4. Basolateral membrane potential measurements were also used to identify an apical Na⁺: 2CI^?: K⁺ cotransport pathway in MD cells that is the major pathway for NaCl entry into these cells. 5. Other work identified a basolateral chloride channel that is presumed to be responsible for changes in V_BL during alterations in luminal [NaCl]. This channel, which is the predominant conductance across the basolateral membrane, may be regulated by intracellular Ca²⁺ and cAMP. 6. An apical Na⁺: H⁺ exchanger in MD cells was detected by measuring changes in intracellular pH using the fluorescent probe 2′,7′-bis-(2-carboxyethyl)-5(and-6) carboxyfluorescein. 7. Using patch-clamp techniques, a high density of pH- and Ca²⁺-sensitive K⁺ channels was observed at the apical membrane of MD cells. 8. Other studies found that, at the normal physiological conditions prevailing at the end of the TAL (luminal [NaCl] of 20–60 mmol/L), reabsorption mediated by MD cells is very sensitive to changes in luminal [NaCl].     

Cytoprotective effect of epidermal growth factor on acid- and pepsininduced damage to rat gastric epithelial cells: Roles of Na+/H+ exchangers

We have previously established a cell damage model, with damage induced by either acid or pepsin treatment for 30 min, involving a rat gastric epithelial cell line (RGM1). In the present study, pretreatment of cells with epidermal growth factor (EGF; 0.1–10ng/mL) or sucralfate (0.1–3 mg/mL) for 4 h prevented such cell damage in a concentration-dependent manner. Protection of cells by these drugs was not affected by pretreatment with indomethacin (10⁻⁵ mol/L) for 4 h. Removal of Na⁻, but not Ca²⁺, from the acidified medium totally abolished the inhibitory effect of EGF, but not that of sucralfate. Genistein (a tyrosine kinase inhibitor) apparently reduced the inhibitory effect of EGF. DNA synthesis by RGM1 cells did not increase when cells were incubated with EGF for 4 h. We conclude that both EGF and sucralfate protect RGM1 cells from acid- and pepsin-induced damage and that the mechanism of protection by EGF against acid-induced damage seems to be via activation of Na⁺/H⁺ exchangers.     

EFFECTS OF STROPHANTHIDIN ON THE SLOW INWARD CURRENT IN GUINEA-PIG ISOLATED VENTRICULAR MYOCYTES

1. The effect of strophanthidin on the slow inward current (Isi) and on contractile force were studied in guinea-pig isolated ventricular myocytes and intact papillary muscles, respectively. In myocytes, both low (10 nmol/L) and high (1-10 mumols/L) concentrations had small or no effects in either direction on Isi whereas norepinephrine (10-100 nmol/L) increased it. To determine whether the same results are obtained after decreasing or increasing intracellular calcium or sodium, the same concentrations of strophanthidin were tested in different procedures that are known to (i) increase [Ca]i and decrease [Na]i (high [Ca]o, 3.6-5.4 mmol/L; low [Na]o, 112 mmol/L; (ii) decrease [Ca]i and increase [Na]i (low [Ca]o, 0.45-1 mmol/L; Sr, 1 mmol/L; (iii) decrease [Ca]i and [Na]i (Cd, 0.1-0.2 mmol/L); and (iv) increase [Ca]i and [Na]i (veratridine, 0.2 mumol/L). High [Ca]o and veratridine increased whereas low [Ca]o and Cd decreased Isi. In contrast, during these various procedures, strophanthidin had small and inconsistent effects at a low or high concentration. In intact papillary muscles, low strophanthidin decreased whereas high strophanthidin increased contractile force. It is concluded that strophanthidin has little direct or indirect effect on Isi and that the decrease in force by low and increase in force by high concentrations in intact muscle are probably related to demonstrated decrease and increase, respectively, in intracellular sodium activity.     

The role of Na+/K+ ATPase activity during low flow ischemia in preventing myocardial injury: A 31P, 23Na and 87Rb NMR spectroscopic study

An increase in intracellular Na⁺ during ischaemia has been associated with myocardial injury. In this study, we determined whether inhibition of Na⁺/K⁺ ATPase activity contributes to this increase and whether Na⁺/K⁺ ATPase activity can be maintained by provision of glucose to perfused rat hearts during low flow, 0.5 ml/min, ischemia. We used ³¹P NMR spectroscopy to determine changes in myocardial energetics and intracellular and extracellular volumes. ²³Na NMR spectroscopy, with DyTTHA^3- present as a shift reagent, was used to measure changes in intracellular Na⁺ and ⁸⁷Rb NMR spectroscopy was used to estimate Na⁺/K⁺ ATPase activity from Rb⁺ influx rates, Rb⁺ being an NMR-sensitive congener of K⁺. In hearts provided with 11 mM glucose throughout ischemia, glycolysis continued and ATP was twofold higher than in hearts without glucose. In the glucose-hearts, Rb⁺ influx rate was threefold higher, intracellular Na⁺ was fivefold lower at the end of ischemia and functional recovery during reperfusion was twofold higher. We propose that continuation of glycolysis throughout low flow ischemia allowed maintenance of sufficient Na⁺/K⁺ ATPase activity to prevent the increase in intracellular Na⁺ that would otherwise have led to myocardial injury.     

Blockade of K+ channels induced by AMPA/kainate receptor activation in mouse oligodendrocyte precursor cells is mediated by NA+ entry

AMPA/kainate receptor activation in cultured oligodendrocyte precursor cells from embryonic mouse cortex leads to a blockade of delayed rectifying K⁺ currents. In the present study, we provide evidence using the patch-clamp technique in the whole-cell configuration that the mechanism linking kainate receptor activation and K⁺ conductance blockade is due to the receptor-mediated Na⁺ entry: (1) The blockade was not observed in Na⁺ -free bathing solution nor when intracellular [Na⁺] was elevated by dialzying the cell with a pipette solution containing high [Na⁺]. (2) Elevation of intracellular [Na⁺] alone led to a blockade of outward currents in contrast to cells dialyzed by sucrose. High [Li⁺]_i also reduced the outward currents, and in Li⁺-containing bathing solution the kainate-induced blockade of K⁺ channels was more pronounced. Probably, Li⁺ accumulates intracellularly after permeation through the receptor pore due to slower extrusion mechanisms. Experiments with GTPγS or GDPβS and pertussis toxin indicated that GTP-binding protein-mediated mechanisms were not of importance for the kainate-induced K⁺ conductance blockade. Our data suggest that in glial precursor cells AMPA/kainate receptor activation leads to an intracellular [Na⁺] increase which blocks delayed rectifying K⁺ channels. © 1995 Wiley-Liss, Inc.     

The dependence of twitch relaxation on sodium ions and on internal Ca2+ stores in voltage clamped frog atrial fibres

Frog heart relaxation was analyzed under voltage clamp conditions as the tension decay observed after the membrane potential had been returned to its resting value. The tension decayed exponentially with a time constant of 188±3.8 ms SEM. The relaxation rate decreased with the external Na concentration. It fell to about one tenth in a Na-free solution. Increasing the intracellular Na-content by an application of veratrine also decreased the relaxation rate. Thus relaxation seems dependent on the Na gradient. The relaxation rate decreased within one second upon switching from a high to a low Na-containing solution. The relaxation rate reached a minimum before rising slightly to a new steady state value. This rebound may reflect the partial recovery of the Na gradient since a fast variation in [Na]_i follows alteration of [Na]_o. Mn and La ions also slowed relaxation. In a Na-free solution, adrenaline accelerated tension decay, an effect not noticeable in frog heart contained in Ringer solution. Other cAMP-promoting agents, such as dibutyryl-cAMP and aminophylline, also increased relaxation rate.It is concluded that in frog myocardium, part of the decrease of the intracellular Ca²⁺-concentration which occurs during each cardiac cycle could be dependent on a Na–Ca exchange mechanism. The relative importance of this mechanism, versus internal Ca sequestration, in the relaxation of tension may well be greater in contractile tissues whose cells have a large surface/volume ratio.