Biomedical subjects
Publications and source records attributed to J Sadoshima.
We report a case of a 40-year-old man who had a quadricuspid aortic valve associated with aortic regurgitation. The anomaly was revealed by transesophageal echocardiography (TEE), and confirmed by cardiac surgery. TEE is a useful noninvasive method for identifying the quadricuspid aortic valve.
The effect of atropine on nicotinic acetylcholine (ACh) response was studied in frog isolated sympathetic ganglion cells using a 'concentration clamp' technique which combines intra-cellular perfusion with a rapid external solution change within 3 ms. When atropine (more than 6 x 10(-7) M) was simultaneously applied to neurons with ACh (6 x 10(-6) M), the current amplitude was instantaneously reduced in a dose-dependent fashion. Further decreases in the current amplitude were observed in a time-dependent manner during about 20 min after the start of drug-application. Thereafter the current amplitude gradually restored toward the control level in the following 90-120 min in spite of the continuous presence of atropine. However, because d-tubocurarine greatly inhibited the 'restored' current, the last-mentioned is suggested to be also mediated by nicotinic ACh receptor-ionophore complex. Therefore, the inhibitory action of atropine on the peak amplitude of ACh response was examined at 15-20 min after adding the agent. It was dose-dependent but not voltage-dependent. Respective concentrations of atropine and d-tubocurarine causing half the maximum inhibition (IC50) of the peak current evoked by ACh (6 x 10(-6) M) were 1.8 x 10(-5) M and 1.8 x 10(-6) M. Thus, the inhibitory potency was 10 times less than that of d-tubocurarine, an antagonist of nicotinic ACh receptors. The blockade of ACh response by d-tubocurarine was competitive while that by atropine was non-competitive. The current elicited by ACh consisted of two (fast and slow) exponential components plus a steady-state one in the control period.(ABSTRACT TRUNCATED AT 250 WORDS)
Mechanisms of blockade of two types of Ca2+ channels by the organic Ca2+ antagonists, nicardipine, diltiazem, verapamil, and flunarizine, were examined in rat aorta smooth muscle cells in primary culture by using the whole-cell voltage-clamp method. T-type Ca2+ current (T-type ICa) was isolated by an internal perfusion of 5 mM F-, which irreversibly suppressed the L-type ICa, without affecting T-type ICa. L-type ICa was isolated by setting a holding potential at -60 mV, at which most of the T-type Ca2+ channels were inactivated. L-type ICa is halved by 0.1 microM nicardipine, 3.0 microM diltiazem, 0.6 microM verapamil, and 0.1 microM flunarizine, whereas T-type ICa is halved by the same drugs at 0.6, 30, 30, and 0.1 microM, respectively. Diltiazem and verapamil accelerated the decay of L-type ICa and cumulatively blocked L-type ICa during repetitive step depolarizations elicited every 30 seconds ("use-dependent block"). Diltiazem and verapamil neither changed the decay of T-type ICa nor showed a use-dependent block of T-type ICa. Nicardipine and flunarizine blocked both L- and T-type ICa from the first depolarization step after drug treatment ("tonic block") and shifted their steady-state inactivation curves to the left. The estimated binding constants of nicardipine and flunarizine for the inactivated state of T-type Ca2+ channels (48 and 19 nM, respectively) were smaller than those for the resting state of L-type Ca2+ channels (160 and 90 nM, respectively). A low concentration (0.1 microM) of nicardipine initially potentiated T-type ICa and then reduced it. We conclude from these results that 1) nicardipine and flunarizine block not only the resting state but, more preferentially, the inactivated state of both the L- and T-type Ca2+ channels; 2) verapamil and diltiazem preferentially act on the open state of the L-type Ca2+ channel and on the resting and inactivated state of the T-type Ca2+ channel; and 3) the T-type Ca2+ channel of the rat aorta smooth muscle cells appears to be more sensitive to nicardipine and flunarizine than does the L-type Ca2+ channel at around the resting membrane potential.
1. Properties of the voltage-dependent anion-selective channel in cultured smooth muscle cells of the rat aorta were studied using the patch-clamp technique. 2. The channel had a single channel conductance of 346 +/- 4 pS (n = 43, mean +/- SEM) with symmetrical 142 mM-Cl- solution in inside-out patch configurations. 3. The channel was activated spontaneously at a potential range -20 approximately +20 mV and inactivated more rapidly with increases to more positive or negative potentials. 4. The channel was selective for anions and the permeability ratio for monovalent anion was Br-:Cl-:HCOO-:CH3COO-:propionate-:aspartate- = 1.1:1:0.7:0.4: less than 0.02: less than 0.02. 5. The openings of the channels were observed more frequently in inside-out membrane patches than in cell-attached ones, and were independent of intracellular free Ca concentrations. 6. The density of this channel was estimated to be 1.3/micron2. 7. Physiological roles of the channel were discussed.
1. Ionic mechanisms related to the caffeine-induced current (Icaffeine) were examined in the single isolated sympathetic neurones of the bull-frog. We used the 'concentration-jump' technique in combination with intracellular perfusion and a rapid external solution change, under single-electrode voltage-clamp conditions. 2. Icaffeine was pharmacologically separated into a tetraethylammonium (TEA)-sensitive transient outward current (ITO), a picrotoxin (PTX)-sensitive transient inward current (ITI) and a TEA- and PTX-insensitive sustained inward current (ISI). At low concentrations of caffeine, a sustained outward current (ISO) was observed instead of ISI. 3. All components of Icaffeine were abolished by intracellular perfusion of 30 mM-EGTA. Pre-treatment with A23187 or ryanodine or the simultaneous application of procaine either reduced or abolished all the components of Icaffeine in a dose-dependent manner. The concentration causing 50% inhibition (IC50) was 10(-8) M for A23187 and 2 mM for procaine. 4. The peak response of ITO increased abruptly at caffeine concentrations between 3 and 6 mM followed by saturation above 30 mM. A notch was observed on the rising phase of ITO. 5. The reversal potential (Ecaffeine) of ITO shifted 58 mV for a tenfold change of the extracellular K+ concentration. External application of TEA blocked ITO with an IC50 of 1 mM. ITO was relatively insensitive to apamin, 4-aminopyridine and muscarine. 6. In external solution containing 2 mM-Ca2+, ITO induced by 10 mM-caffeine recovered completely within 3 min from a previous exposure to caffeine. In the absence of extracellular Ca2+, there was little such recovery. A 5 min treatment in a Ca2+-free solution reduced ITO induced by the first application of caffeine by 5%. With a continuous application of 3 mM-caffeine, the amplitude of ITO induced by 10 mM-caffeine reduced in 1 min, and showed a partial recovery in 3 min. The amplitude of ITO increased by increasing the concentration of intracellular Cl-. 7. ITI was activated around the peak of ITO and was rapidly inactivated. ITI was evoked at caffeine concentrations of about 6-10 mM. When the intracellular Cl- concentration was changed, the amplitude of ITI behaved like a Cl- electrode. The Ecaffeine of ITI was close to the Cl- equilibrium potential (ECl). 8. ISI was a 'plateau' response and persisted for over 3 min. ISI was due to a decrease in K+ conductance. In the presence of muscarine (3 x 10(-5) M), ISI was occluded.(ABSTRACT TRUNCATED AT 400 WORDS)
1. Electrical and pharmacological properties of the low-voltage-activated Ca2+ current (ICa, LVA) in rat aorta smooth muscle cells (SMC) in primary culture were examined, particularly in comparison with the high-voltage-activated Ca2+ current (ICa, HVA). Both types of Ca2+ currents were recorded in external solution containing 20 mM-Ca2+, using the whole-cell voltage-clamp technique. 2. ICa, LVA was evoked by step depolarizations to potentials more positive than -60 mV from a holding potential of -100 mV, and reached a peak in the current-voltage (I-V) relationship around -30 mV. ICa, HVA was activated at -20 mV, and reached a peak at +20 mV. 3. The intracellular dialysis of 5 mM-F- irreversibly suppressed ICa, HVA, with time, while it has little effect on the ICa, LVA. The ICa, LVA could be separated from the ICa, HVA by either selecting the holding and test potential levels or by perfusing intracellularly with F-. 4. The ratio of peak amplitude of Ba2+, Sr2+ and Ca2+ currents in the respective I-V relationship was 1.6:1.2:1.0 for high-voltage-activated Ca2+ channels and was 1.0:1.4:1.0 for low-voltage-activated ones. 5. The inactivation phase of ICa, HVA was fitted by a sum of double-exponential functions, the time constants of which were larger when the current was carried by Ba2+ than by Ca2+. The inactivation time course of ICa, LVA was fitted by a single-exponential function, and the time constant was practically the same when the current was carried by Ba2+ or by Ca2+. Activation and inactivation processes of ICa, LVA were potential-dependent. 6. The steady-state inactivation curve of ICa, LVA was fitted by the Boltzmann equation, having a mid-potential of -80 mV and a slope factor of 5.0. The recovery time course from steady-state inactivation was fitted by a sum of two exponential functions. The time constants of the faster phase were 230 and 380 ms, and those of slower phase were 2.8 and 1.8 s at the repolarization potentials of -120 and -100 mV, respectively. 7. The amplitude of ICa, LVA depended on the external Ca2+ concentration ([Ca2+]o), approaching saturation at 95 mM [Ca2+]o. 8. Various polyvalent cations blocked both types of Ca2+ current reversibly in the order (IC50 in M): La3+ (8 x 10(-8)) greater than Cd2+ (6 x 10(-6)) greater than Ni2+ (1 x 10(-5)) greater than Zn2+ (2 x 10(-5)) for ICa, HVA, and La3+ (6 x 10(-7)) greater than Zn2+ (3 x 10(-5)) greater than Cd2+ (4 x 10(-4)) greater than Ni2+ (6 x 10(-4)) for ICa, LVA.(ABSTRACT TRUNCATED AT 400 WORDS)
The action of lidocaine on the Ca2+ current (ICa) was studied on single isolated neurons of frog dorsal root ganglia using a 'concentration-clamp' technique which combines intracellular perfusion with a rapid external solution change. Lidocaine decreased the peak amplitude of ICa at a threshold concentration of 10 microM. Higher concentrations gave a dose-dependent increase in inhibition of ICa. Lidocaine also depressed the Na+ current (INa) at a threshold concentration 10 times lower than that for decreasing the amplitude of ICa of neurons isolated from same ganglia. The rate of inhibitory action on ICa was slowed at more negative holding potentials (VH). Lidocaine appears to block both closed and open Ca2+ channels, but acts more profoundly on open channels.
1. The effects of neostigmine and physostigmine, reversible carbamate acetylcholinesterase (AChE)-inhibitors, on nicotinic acetylcholine-induced inward currents (IACh) were investigated in enzymatically isolated single sympathetic ganglion cells from the bullfrog. The 'concentration clamp' technique which combines intracellular perfusion with a rapid external solution change under single electrode voltage-clamp conditions was used. 2. Pretreatment with neostigmine and physostigmine did not enhance IACh at any concentrations, suggesting that AChE activity had already disappeared during the enzymatic treatment of the preparation. 3. Both neostigmine and physostigmine inhibited IACh in a dose-dependent manner with IC50 values of 7.0 x 10(-4) M and 1.1 x 10(-4) M, respectively. The blockade by neostigmine was competitive, while that by physostigmine was non-competitive. 4. The inhibition of IACh by neostigmine and physostigmine showed no apparent voltage dependency. 5. Neostigmine did not cause obvious changes of the kinetics of IACh. However, physostigmine reduced both the fast and slow time constants of inactivation of IACh, thus facilitating the rate of inactivation without affecting the activation kinetics of IACh. 6. These results suggest that neostigmine and physostigmine have different direct actions on the ACh receptor-ionophore complex. Neostigmine may act on the ACh-receptor (the binding site of ACh) while physostigmine may interact with the ACh-gated cation channels.
Electrical and pharmacological properties of the single Ca-activated K channel in cultured smooth muscle cells (SMC) of the rat aorta were studied with the patch-clamp technique. The Ca-activated K channel had a slope conductance (gamma K) of 135 +/- 2 pS (mean +/- SE; n = 5) in symmetrical 142 mM K solutions. The reversal potentials show a 56-mV change for a 10-fold change in the external K concentration. Probability of the channel opening increased when the intracellular Ca concentration ([Ca]i) was increased over 10(-7) M or the membrane was depolarized. The channel was blocked by either external tetraethylammonium (TEA, 10-30 mM) or by internal Ba (1-5 mM). Channel activities were characterized by burst-like openings. Open-time histogram was fitted with a single exponential (tau = 1.3 ms at +10 mV and 10(-7) M [Ca]i), whereas the closed-time histogram was fitted with two exponentials (tau 1 = 0.7 ms and tau 2 = 111 ms). The permeability ratio for monovalent cations calculated with the Goldman-Hodgkin-Katz equation was K:Rb:Na = 1:0.7: less than 0.01. We conclude from these observations that the Ca-activated K channel in cultured SMC of the rat aorta is characterized by a middle size gamma K, activation by [Ca]i increase and depolarization, relatively low sensitivity to TEA, and high selectivity for K ions.
Effects of adenosine 3',5'-cyclic monophosphate (cAMP) on single Ca-activated K current (IK(Ca)) in cultured smooth muscle cells of the rat aorta were investigated with the patch-clamp technique. In cell-attached patch configurations, extracellular application of isoproterenol (10(-5) M) increased the Ca-activated K currents. The increase in the currents was due to an increase in the probability of channel openings (Po). Neither unit conductance nor the maximum number of the channel in the patch was affected by the drug. The effects were inhibited by adding propranolol (10(-6) M). The extracellular application of forskolin (10(-5) M) or dibutyryl cAMP (10(-4) M) mimicked the effects of isoproterenol. In inside-out patch configurations, activated cAMP-dependent protein kinase (A kinase) in the bathing solution increased the sensitivity of the Ca-activated K channels to intracellular free calcium concentration ([Ca]i) and enhanced Po. Kinetic analyses of the IK(Ca) showed that cAMP-dependent phosphorylation of the Ca-activated K channels significantly reduced the mean closed time between bursting openings. We conclude from these observations that the Ca-activated K channels in aortic cells may increase Po through cAMP-dependent phosphorylation.
The effects of voltage-dependent Ca2+ current (ICa) on resting and gamma-aminobutyric acid (GABA)-gated Cl- conductances were studied in isolated frog sensory neurons. The amplitude of GABA-gated Cl- current (ICl) was greatly suppressed by a preceding ICa. The GABA dose-response curve was shifted to the right without changing the maximum response by increasing [Ca2+]i. An ICa-activated ICl was observed as an inward tail current on the 'off' phase of ICa. This tail current was easily saturated by increasing the amount of Ca2+ influx.
This report describes two patients with dilated cardiomyopathy associated with angiographically proven left ventricular aneurysm. There was no apparent history of myocardial infarction and coronary arteries were angiographically normal in both cases.
A 37-year-old woman was admitted with an acute anterior myocardial infarction. Coronary arteriography revealed a dissecting aneurysm of the left main coronary artery. The patient died from perioperative myocardial infarction following aortocoronary bypass surgery on the 102nd hospital day. Histologic sections of the aneurysm revealed that granulation tissue had replaced the aneurysm, suggesting spontaneous healing of the dissecting aneurysm.
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