Biomedical subjects

M J Su

Publications and source records attributed to M J Su.

At least 37 records · Page 2Linked to original sources

PubMed1997

Age-related propofol effects on electrophysiological properties of isolated hearts.

We compared the direct effects of propofol on the conduction system of neonatal (< 7 days) and adult (> 3 mo) rabbit hearts using intracardiac recording/ stimulation in Langendorff-perfusion and autonomic blockade. At a low concentration (3 microM), propofol caused a slight but significant lengthening of the atrio-ventricular (AV) conduction interval of the adult hearts, but not of neonatal hearts. At a higher concentration (10 microM and above), propofol significantly prolonged the AV conduction interval in a frequency-dependent manner in both neonates and adults. The AV Wenckebach cycle length was also lengthened, with the change more significant in the adults. However, with concentrations of propofol up to 100 microM, the neonatal hearts frequently (9 of 13 experiments) progressed to complete AV block, which was not observed in the adults. Conduction through the atrial tissue (SA interval) and the His-Purkinje system (HV interval), as well as the spontaneous heart rate, were all slowed by propofol at 30 microM or above. However, the lengthening of SA interval was more pronounced in the neonates, and only in the neonate was the atrial refractory period prolonged by propofol at 10 microM and above. We conclude that 3 microM propofol produces no significant direct effects on the neonatal cardiac electrophysiological properties, although AV conduction of the adult heart may be suppressed at this concentration of propofol. At higher concentrations, age-related propofol effects were demonstrated in the AV node and the atrial tissue.

Aging↗

PubMed1997

Pharmacological evaluation of ocoteine, isolated from Cassytha filiformis, as an alpha 1-adrenoceptor antagonist in rat thoracic aorta.

Ocoteine, isolated from Cassytha filiformis, was found to be an alpha 1-adrenoceptor blocking agent in rat thoracic aorta as revealed by its competitive antagonism of phenylephrine-induced vasoconstriction (pA2 = 7.67 +/- 0.09). Removal of endothelium from the aorta did not affect its antagonistic potency (pA2 = 7.97 +/- 0.07). [3H]-Inositol monophosphate formation caused by noradrenaline (3 microM) was suppressed by ocoteine (10 microM) and prazosin (3 microM). Ocoteine did not affect the contraction induced by U-46619, prostaglandin F2 alpha or angiotensin II, but inhibited slightly those by high K+ and endothelin I. Neither the cyclic AMP nor cyclic GMP content of rat thoracic aorta was changed by ocoteine (10 microM). Comparing the EC50 values, the potency of ocoteine against 5-hydroxytryptamine (5-HT) was about 60 times less than that against phenylephrine. Ocoteine (10 microM) also slightly antagonized the clonidine-induced inhibition of the twitch response evoked by field stimulation in rat vas deferens. In guinea pig trachea, the contraction caused by carbachol, histamine, neurokinin A or leukotriene C4 and beta 2-adrenoceptor-mediated relaxing responses induced by isoprenaline were not affected by ocoteine (10 microM). The voltage clamp study in rat ventricular single myocytes revealed that ocoteine (3, 10 microM) inhibited steady state outward currents, but not transient outward currents or slow inward Ca2+ currents. It is concluded that ocoteine is a selective alpha 1-adrenoceptor antagonist in isolated rat thoracic aorta. At high concentrations, it also blocks 5-HT receptors and Na+ and steady state outward currents in rat ventricular myocytes.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1997

Effects of 8-oxoberberine on sodium current in rat ventricular and human atrial myocytes.

8-Oxoberberine (JKL1073A), a derivative of berberine, has been reported to exert positive inotropic action and antiarrhythmic activity, much like a class III antiarrhythmic agent. In addition to prolongation of cardiac action potential duration, JKL1073A also decreases the maximal rate of action potential upstroke. To characterize the mode of inhibition of action potential upstroke, the effects of JKL1073A on the sodium inward current (INa) of rat and human cardiac myocytes were examined by voltage clamp in a whole cell configuration. In rat ventricular myocytes, JKL1073A and quinidine inhibited INa with an average 50% inhibitory concentration (IC50) of 3.3 +/- 0.2 microM (n = 9) and 2.1 +/- 0.1 microM (n = 6), respectively. Voltage-dependent steady state inactivation curves of INa were shifted slightly by 10 microM JKL1073A but more significantly by 3 microM quinidine to negative potential. Though steady state inactivation of INa was not significantly changed by 3 microM JKL1073A, the time constant of INa recovery from inactivation state was partially prolonged from 51.7 +/- 18.5 ms to 74.1 +/- 23.8 ms. Quinidine (3 microM) prolonged the time course of INa recovery from inactivation with an associated increase of slow recovery component. Inhibition of INa by JKL1073A and quinidine was increased when cells were stimulated at higher frequency. The maximal INa obtained in cells held at -140 mV was significantly decreased by 10 microM quinidine to 45.3 +/- 2.5% of control but only partially suppressed by 10 microM JKL1073A to 85.9 +/- 8.6% of control. In human atrial myocytes, JKL1073A and quinidine suppressed INa with an average IC50 of 2.4 +/- 0.6 microM and 1.4 +/- 0.3 microM, respectively. Both JKL1073A and quinidine increased the time constant of INa recovery from inactivation. In conclusion, JKL1073A at concentrations of 3 microM and 10 microM may inhibit INa mainly by binding to open and inactivated channels. Quinidine 3 microM may inhibit INa by binding to resting, open and inactivated channels. Inhibition of INa by JKL1073A may explain the inhibition of the action potential upstroke and contribute partially to its antiarrhythmic activity.

Animals↗

PubMed1996

Regulation of involucrin gene expression by calcium in normal human keratinocytes.

Calcium is essential for normal epidermal differentiation. Data from Northern and nuclear run-on analysis indicate that involucrin gene transcription is induced by 1.2 mM extracellular calcium. A 3.7 Kbp fragment of the involucrin gene, which contains 2.5 Kbp of upstream region, the transcription start site, and the first intron, was sub-cloned into the pGL3-basic luciferase reporter vector and transfected into pre-confluent normal human keratinocytes (NHK). The stimulated activities of this clone were above basal levels and was further enhanced eight-fold by 1.2 mM extracelluar calcium. The results from a series of truncation and internal deletion experiments revealed multiple calcium-independent enhancer elements between -2476 and -2131 bp of the transcription start site and a calcium-dependent element between -2131 and -2028 bp. This 103 bp fragment contains sequences of an AP-1 site (TGAGTCA), a SP-1 site (GGGCGG), and shares homology with two elements in the human keratin-1 promoter, within the regions identified as mediating the calcium responsiveness of that gene in keratinocytes. One or more of these putative elements may be involved in the calcium-dependent regulation of the involucrin gene transcription in NHK.

5' Flanking Region↗

PubMed1996

Electrophysiological mechanisms for the antiarrhythmic action of (-)-caryachine in rat heart.

(-)-Caryachine (CNMe) is a pavine derivative, isolated from Cryptocarya chinensis Hemsl. We wished to illustrate the electrophysiological effect and antiarrhythmic potential of this compound on rat cardiac tissues. Action potential and ionic currents in single ventricular cells were examined by current clamp or voltage clamp in a whole-cell configuration. CNMe concentration-dependently suppressed the maximum rate of rise of the action potential upstroke (V(max)) and prolonged the action potential duration at 50% of repolarization (APD(50)). A voltage-clamp study showed that the suppression of V(max) by CNMe was associated with an inhibition of sodium inward current (I(Na), IC(50), O = 4.1 microM). The prolongation of APD(50) was associated with an inhibition of transient outward current (I(to), IC(50) = 16.1 microM). CNMe reduced the I(Na) with a negative shift of its voltage-dependent steady-state inactivation curves and slowing of its recovery from inactivation. The use-dependent inhibition of I(Na) by CNMe was enhanced at a higher stimulation rate or at a longer prepulse duration. The fraction of fast recovery of I(Na) was reduced, but the recovery time constant of fast recovery component remained unaffected. The inhibition of I(to) by CNMe (10-30 microM) was associated with an acceleration of its time constant of inactivation. According to the analysis of the time course of inhibition of I(to), CNMe inhibited I(to) in a time-dependent manner. In isolated heart, CNMe could effectively inhibit ischemia/reperfusion-induced ventricular tachycardia with an EC(50) of 3.9 microM. The results indicate that CNMe is a strong I(Na) blocker with some I(to) blocking activity. The inhibition of I(Na), and I(to) may contribute to its antiarrhythmic activity against ischemia/reperfusion arrhythmia.

Action Potentials↗

PubMed1996

Squamous carcinoma cell lines fail to respond to 1,25-Dihydroxyvitamin D despite normal levels of the vitamin D receptor.

Squamous carcinoma cells (SCC) fail to differentiate under conditions that are favorable for the growth and differentiation of normal human keratinocytes. Human keratinocytes differentiate from a highly proliferative basal cell to a terminally differentiated cornified cell in culture in the presence of physiological levels of extracellular calcium. 1,25-Dihydroxyvitamin D (1,25[OH]2D3) potentiates this process. Previous studies have shown that the differentiation process in keratinocytes is associated with increased expression of the genes for involucrin and transglutaminase, the products of which participate in cornified envelope formation. The mRNA for involucrin and transglutaminase was not detected in the SCC lines studied (viz. SCC4, 12B2, 12F2, A431, and HACAT) when they were grown in serum free medium. Addition of at least 2% fetal bovine serum for 48 h triggered the expression of these genes, which could then be maintained in the absence of serum. Serum was not required for induction of these genes in keratinocytes. In these cells, 1,25(OH)2D3 stimulated the expression of involucrin and transglutaminase in a concentration-dependent manner, while the SCC lines failed to respond to 1,25(OH)2D3 regardless of whether these cells had been pre-exposed to serum. An important factor that mediates 1,25(OH)2D3-stimulated gene expression is the vitamin D receptor, but vitamin D receptor mRNA levels in all the SCC lines examined were comparable to those in keratinocytes. Furthermore, the vitamin D receptor protein levels in SCC lines as assessed by ligand-binding analysis were comparable to those of keratinocytes. Thus, the mediators of 1,25(OH)2D3 action on gene expression other than the vitamin D receptor may be missing or defective in SCC lines, whereas the mediators of as yet undefined agents in serum may be better expressed in SCC lines than in keratinocytes. Our results indicate that, although SCC lines are capable of expressing the genes for the proteins involved in differentiation, the control of the expression of these genes by 1,25(OH)2D3 is abnormal in SCC despite the presence of a functional vitamin D receptor in concentrations equivalent to those in keratinocytes.

Animals↗

PubMed1996

Mechanical and electrophysiological effects of 8-oxoberberine (JKL1073A) on atrial tissue.

The effects of 8-oxoberberine (JKL1073A) on contractions and electrophysiological characteristics of atrial tissues were examined. In driven left atria of the rat JKL1073A (10-100 microM) increased twitch tension dose-dependently. In spontaneously beating right atria, JKL1073A increased twitch tension but decreased beating rate slightly. The positive inotropic and the negative chronotropic effect of 30 microM JKL1073A was not affected by prazosin (1 microM), propranolol (1 microM) and 3-isobutyl-1-methyl-xanthine (10 microM) but significantly suppressed by 4-aminopyridine (2 mM 4-AP). Current-clamp study revealed that JKL1073A prolonged rat atrial action potential duration (APD). This prolongation of APD by JKL1073A was decreased by pretreating the cells with 2 mM 4-AP. Voltage-clamp study showed that JKL1073A inhibited the integral of the transient outward current (I(to)) dose-dependently with a KD value of 3.66 +/- 0.93 microM in rat atrial myocytes. The equilibrium dissociation constant (Kd) for JKL1073A bindings to open state I(to) was 0.50 +/- 0.08 microM. The suppression of I(to) by 3 microM JKL1073A was accompanied by shortening of its inactivation time constant from 52.5 +/- 0.9 ms to 16.8 +/- 0.7 ms. V(0.5) for the steady-state inactivation curve of I(to) was shifted from -25.7 +/- 3.3 mV to -34.8 +/- 3.2 mV. In human atrial cells, similar inhibition of I(to) and prolongation of APD by JKL1073A was found. The KD value of JKL1073A for inhibition of the integral of I(to) in human atrial cells is 4.03 +/- 0.02 microM. The Kd for bindings to open state I(to) is 0.5 microM. Currents through K1 channels of rat and human atrial myocytes were not inhibited by JKL1073A at concentrations up to 10 microM. These results indicate that JKL1073A exerts a positive inotropic effect by inhibition of I(to). JKL1073A inhibit I(to) by binding to open state channels or shifting of the steady-state inactivation curve of I(to).

Animals↗

PubMed1996

Electrophysiological mechanisms for antiarrhythmic efficacy and positive inotropy of liriodenine, a natural aporphine alkaloid from Fissistigma glaucescens.

1. The antiarrhythmic potential and electromechanical effects of liriodenine, an aporphine alkaloid isolated from the plant, Fissistigma glaucescens, were examined. 2. In the Langendorff perfused (with constant pressure) rat heart, at a concentration of 0.3 to 3 microM, liriodenine was able to convert a polymorphic ventricular tachyrhythmia induced by the ischaemia-reperfusion (EC50 = 0.3 microM). 3. In isolated atrial and ventricular muscle, liriodenine increased the contractile force and slowed the spontaneous beating of the right atrium. 4. The liriodenine-induced positive inotropy was markedly attenuated by a transient outward K+ channel blocker, 4-aminopyridine (4-AP) but was not significantly affected by prazosin, propranolol, verapamil or carbachol. 5. In rat isolated ventricular myocytes, liriodenine prolonged action potential duration and decreased the maximal upstroke velocity of phase 0 depolarization (Vmax) and resting membrane potential in a concentration-dependent manner. The action potential amplitude was not significantly changed. 6. Whole-cell voltage clamp study revealed that liriodenine blocked the Na+ channel (INa) concentration-dependently (IC50 = 0.7 microM) and caused a leftward shift of its steady-state inactivation curve. However, its recovery rate from the inactivated state was not affected. The L-type Ca2+ currents (Ica) were also decreased, but to a lesser degree (IC50 = 2.5 microM, maximal inhibition = 35%). 7. Liriodenine inhibited the 4-AP-sensitive transient outward current (Ito) (IC50 = 2.8 microM) and moderately accelerated its rate of decay. The block of Ito was not associated with changes in the voltage-dependence of the steady-state inactivation curve or in the process of recovery from inactivation of the current. Liriodenine also reduced the amplitude of a slowly inactivating, steady-state outward current (Iss) (IC50 = 1.9 microM). These effects were consistent with its prolonging effect on action potential duration. The inwardly rectifying background K+ current (IK1), was also decreased but to a less degree. 8. Compared to quinidine, liriodenine exerted a stronger degree of block on INa, comparable degree of block on IK1, and lesser extent of block on ICa and Ito. 9. It is concluded that, through inhibition of Na+ and the Ito channel, liriodenine can suppress ventricular arrhythmias induced by myocardial ischaemia reperfusion. The positive inotropic effect can be explained by inhibition of the Ito channel and the subsequent prolongation of action potential duration. These results provide a satisfactory therapeutic potential for the treatment of cardiac arrhythmias.

Action Potentials↗

PubMed1996

Effects of Glycyrrhizae and Glycyrrhizic acid on radiation injury in mice.

The effects of Glycyrrhizae (GL) and Glycyrrhizic acid (GA) on promoting the recovery of mice from radiation injury were investigated. Two hundred ICR strain male mice, 6-8 weeks old, were randomly divided into four groups. Group A was the normal control. Group B, the experimental control, was treated with 4 Gy gamma-ray irradiation. Groups C and D, the experimental groups, were treated with 500 mg/kg of GL (oral administration) and 5 mg/kg body weight of GA (i.p.), respectively, for ten days after gamma-ray irradiation. Eight mice in each group were sacrificed on days 5, 12, 26 and 33 post irradiation to measure the weights of spleen, thymus and testes, and the biosynthetic rates of DNA in these organs. The results revealed that 4 Gy gamma-ray irradiation evidently inhibited the weights of spleen, thymus and testes, and their DNA biosynthetic rates. GL and GA enhanced the recovery of these organs in mice from the injury of gamma-ray irradiation.

Animals↗

PubMed1995

The effect of hypercholesterolemia on the sodium inward currents in cardiac myocyte.

To determine whether chronic hypercholesterolemia affects sodium inward currents in cardiac myocytes, whole-cell clamp recordings were made in single cardiac myocytes isolated from normo- and hypercholesterolemic rabbits. Modification of the serum cholesterol was accomplished by feeding ten 3-month-old male New Zealand white rabbits with control diet (group I) and ten with 0.5% cholesterol-enriched diet (group II), for 3 months. The serum cholesterol levels of group II were much higher than those of group I (2042 +/- 231 v 82 +/- 9 mg/dl, P < 0.001). The cholesterol-ester and free cholesterol component of cardiac sarcolemma of group II were also significantly higher than those of group I (26.6 +/- 12.4 v 10.8 +/- 4.5 nmole/dl, P < 0.001, and 50.9 +/- 14.8 v 27.5 +/- 6.2 nmole/dl, P < 0.001, respectively). The cell capacitance of hyperlipidemic myocytes seemed larger than that of normolipidemic ones (157.4 +/- 6.4 pF v 103.6 +/- 3.0 pF, P < 0.05). However, the sodium current density on hypercholesterolemic ventricular sarcolemma was significantly lower than that of normolipidemic sarcolemma. This effect was associated with a leftward shift in the inactivation potential and a slowing of the time course of recovery. In conclusion, hypercholesterolemia has important effects on the sodium inward currents in ventricular myocytes, which may be due to a decrease in current density and an alteration in channel functional state.

Animals↗

PubMed1995

22-Oxa calcitriol is a less potent regulator of keratinocyte proliferation and differentiation due to decreased cellular uptake and enhanced catabolism.

22-oxa calcitriol (OCT) is a recently synthesized analog of calcitriol (1,25(OH)2D3) with potent biologic actions both in vivo and in vitro. Because it is considerably less hypercalcemic than 1,25(OH)2D3 when given in vivo, OCT is of potential use for the treatment of diseases, such as psoriasis, that respond to the antiproliferative, prodifferentiating actions of 1,25(OH)2D3. To determine the potential usefulness of OCT in hyperproliferative skin diseases, we compared the ability of OCT to that of 1,25(OH)2D3 with respect to regulation of keratinocyte proliferation and differentiation in vitro. These studies were performed in serum-free media to eliminate differences in potency secondary to differences in binding to the serum vitamin D-binding protein. We observed that OCT was considerably less effective than 1,25(OH)2D3 in inhibiting keratinocyte proliferation and stimulating differentiation. The decreased potency of OCT appeared to be due to decreased uptake and increased catabolism rather than decreased affinity for the vitamin D receptor. We conclude that under the conditions of our experiments OCT was less potent than 1,25(OH)2D3 because it failed to achieve comparable concentrations within the cell.

Antineoplastic Agents↗

PubMed1995

Electrophysiological basis for antiarrhythmic efficacy, positive inotropy and low proarrhythmic potential of (-)-caryachine.

1. (-)-Caryachine, isolated from the plant (Cryptocarya chinensis), increased the contractility of atrial and right ventricular strips and significantly suppressed the reperfusion arrhythmias in adult rabbit heart (ED50 = 1.27 microM). 2. Data obtained by the whole-cell voltage clamp technique has shown that (-)-caryachine causes a negative shift of the steady-state Na channel inactivation and a slower rate of recovery from inactivation. The maximal Na current amplitude decreased to 67 +/- 7%, 29 +/- 8% and 12 +/- 5% after 0.5, 1.5 and 4.5 microM (-)-caryachine, respectively. 3. This agent also had effects on the time- and voltage-dependent K currents. (-)-Caryachine markedly suppressed the 4-AP-sensitive transient outward current (I10). However, it produced very little voltage-dependent shift in inactivation. After 0.5, 1.5 and 4.5 microM of the compound, the respective value of I10 elicited at +60 mV was 80 +/- 7%, 45 +/- 8% and 15 +/- 3%. At higher concentrations, the inward rectifier K current (IK1) was also inhibited but to a much smaller extent. Its slope conductance after 0.5, 1.5 and 4.5 microM (-)-caryachine was reduced to 71 +/- 9%, 51 +/- 12% and 42 +/- 11%, respectively. The outward hump of inward rectification was not changed. 4. In contrast, the L-type Ca current was not significantly changed by (-)-caryachine. 5. Electrophysiological studies in perfused whole heart preparations revealed that (-)-caryachine increased the intra-atrial conduction interval and also prolonged the atrial refractory period. No proarrhythmic effects were induced during the infusion of this compound (up to 13.5 microM). 6. We conclude that (-)-caryachine predominantly blocks the Na and I10 currents. These changes alter the electrophysiological properties of the heart and terminate the induced ventricular arrhythmias. The relatively selective I10 inhibition, safety margin of Ik1 suppression and lack of effect on Ica-L will provide an opportunity to develop an effective antiarrhythmic agent with positive inotropy as well as low proarrhythmic potential.

Animals↗

PubMed1995

1,25-Dihydroxyvitamin D3 upregulates the phosphatidylinositol signaling pathway in human keratinocytes by increasing phospholipase C levels.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) induces the differentiation of normal human keratinocytes, in part by increasing their basal intracellular calcium levels (Cai) over a period of hours. Agonists such as ATP acting through membrane receptors cause an immediate but transient increase in Cai accompanied by an increase in inositol trisphosphate (IP3). Treatment of keratinocytes for 24 h with 1 nM 1,25(OH)2D3 resulted in a two- to four-fold potentiation of the Cai response of these cells to ATP. This potentiation was inhibitable with cycloheximide, unaccompanied by a change in total intracellular calcium pools, but associated with an increase in basal IP3 levels and ATP-stimulated IP3 production. Treatment with 1,25(OH)2D3 raised the protein and mRNA levels of phospholipase C isoenzymes, particularly phospholipase C-beta 1 in a dose-dependent manner. These studies indicate that 1,25(OH)2D3 modulates the keratinocyte signal transduction pathway by induction of phospholipase isoenzymes, a previously undescribed action for this hormone.

Adenosine Triphosphate↗

PubMed1995

Studies on the development of the articular part of the temporal bone with special reference to the postglenoid process.

The development and significance of the postglenoid process on the articular surface of the temporal bone were studied using 217 Indian skulls, which were divided by their level of tooth eruption into 6 developmental stages; preeruption period (Stage I), initial stage (m1 eruption) of the deciduous dentition period (Stage II), middle stage (m2 eruption) of the deciduous dentition period (Stage III), late state (eruption of 20 deciduous teeth) of the deciduous dentition period (Stage IV), mixed dentition period (Stage V), and permanent dentition period (Stage VI). Each skull was mounted on a Kraniophor in such a way that the auriculoorbital (Frankfurt) plane was positioned vertical to the horizontal plane and photographed at a focal distance of 40 cm. Using the Frankfurt plane as a base line, the vertical distances to the lowest point of the postglenoid process (a-A), to the deepest point of the mandibular fossa (b-B), and to the mid-point of the articular tubercle (c-C) were measured. The distances from various points of the mandibular fossa to the articular surface of the temporal bone were measured at the level of the Frankfurt plane. The results may be summarized as follows: The length of the postglenoid process as measured from the Frankfurt plane was 0.58 mm at Stage I and 0.75 mm at Stage II. It increased by 0.6-1.0 mm at each developmental stage. By Stage VI, it had increased to 3.85 mm (six- to seven-fold increase from the initial value). The anteroposterior width of the postglenoid process remained almost unchanged throughout the developmental stages. The growth of the articular structures of the temporal bone from the preeruption to deciduous dentition period increased 73% in the total anteroposterior dimension (5.22 mm) and 44% in the total vertical dimension (3.32 mm). The vertical dimension of the mandibular fossa began to rapidly increase following the eruption of the deciduous first molars.

Adolescent↗

PubMed1995

Effects of prazosin on rat, guinea pig and human cardiac tissues.

In this study, the mechanical and electrophysiological effects of prazosin were examined in rat, guinea pig and human cardiac preparations. Prazosin (0.3 to 10 microM) inhibited the spontaneous beating rate of rat right atria and the twitch tension of driven left atria and right ventricular strips dose-dependently. Inward sodium current (INa) in isolated rat ventricular and guinea pig and human atrial cells was also inhibited by prazosin (1 to 10 microM) dose-dependently. Inhibition of INa in rat ventricular and guinea pig atrial cells by prazosin (1 to 10 microM) was not associated with the left shift of the voltage-dependent steady-state inactivation curves of INa. The time constant of recovery of INa from inactivation state was also unchanged. Compared with the inhibition of INa, the transient outward current (Ito), inwardly rectifying potassium current (IK1) and calcium inward current (ICa) in rat ventricular cells were unaffected by prazosin. The Ito in human atrial cells was also not affected by prazosin. It is concluded that prazosin inhibited INa by selective binding to open state of Na+ channels. The inhibition of INa is unrelated to the blockade of myocardial alpha 1-adrenoceptors but contribute to the negative inotropic effect of prazosin.

Animals↗

PubMed1994

1,25-Dihydroxyvitamin D3 potentiates the keratinocyte response to calcium.

Extracellular calcium (Cao) stimulates the differentiation of keratinocytes; 1,25 dihydroxyvitamin D3 1,25(OH)2D3) does likewise. Since 1,25(OH)2D3 regulates calcium flux in other cells, we hypothesized that 1,25(OH)2D)3 acted through and promoted the effects of calcium on keratinocyte differentiation. To test this hypothesis, we evaluated the effects of calcium and 1,25(OH)2D3 alone and in combination on the mRNA and protein levels of involucrin and transglutaminase in neonatal human keratinocytes. Cao alone increased these mRNA levels in a dose-dependent fashion (0.03 to 1.2 mM) over a 24-h period. This increase in mRNA levels was associated with a stimulation by calcium of involucrin and transglutaminase gene transcription. However, by 72 h, the mRNA levels of involucrin and transglutaminase decreased. At 0.03 mM Cao, 1,25(OH)2D3 showed a dose-dependent stimulation of involucrin and transglutaminase mRNA for up to 48 h and potentiated the initial (4-h) stimulation by Cao of involucrin and transglutaminase mRNA. As for calcium alone, this increase in mRNA was associated with an increase in transcription of the involucrin and transglutaminase genes. However, by 24 h of exposure to both calcium and 1,25(OH)2D3, a dose-dependent fall in mRNA levels was seen. The mRNA levels of involucrin and transglutaminase were stable for 24 h when neonatal human keratinocytes were grown in serum-free keratinocyte growth medium containing 0.03 or 1.2 mM Cao alone. However, the mRNAs of both genes underwent rapid degradation when neonatal human keratinocytes were treated with 1,25(OH)2D3, especially in high Cao. 1,25(OH)2D3 and Cao increased the protein levels of involucrin and transglutaminase activity in a synergistic fashion throughout the 48-h time course. These data support the hypothesis that 1,25(OH)2D3 promotes calcium-induced differentiation at the level of both gene expression and mRNA stability.

Calcitriol↗

PubMed1994

Thaliporphine, a positive inotropic agent with a negative chronotropic action.

The effects of thaliporphine on contractions and electrophysiological properties of cardiac tissues were examined. In driven rat left atria and right ventricular strips, thaliporphine (1-30 microM) increased twitch tension dose-dependently. The positive inotropic effect of thaliporphine was unaffected by atenolol (3 microM) and prazosin (1 microM) but was significantly suppressed by verapamil (1 microM). An electrophysiological study revealed that thaliporphine (3-10 microM) markedly inhibited the action potential upstroke and prolonged the action potential duration (APD50) in rat and guinea pig atrial and ventricular cells. At 1-30 microM, thaliporphine reduced the transient outward current (Ito) of the rat ventricular cells in a dose-dependent manner. The peak Ito in rat ventricular cells and the delayed rectifying K+ current (Ik in guinea pig ventricular cells were reduced by thaliporphine (10 microM) to 37.3 +/- 2.1% (n = 8) and 45.3 +/- 1.8% (n = 4), respectively. In rat ventricular cells and guinea pig atrial cells, thaliporphine (1.5 microM) reduced the Na+ inward current (INa) with a negative shift (4-5 mV) relative to its half inactivation potential. For the Ca2+ inward current (ICa) in rat ventricular cells, 10 microM of thaliporphine caused a smaller increase in the peak ICa than 0.5 microM of Bay K 8644. The increase in ICa elicited by both agents was associated with a negative shift of its half activation potential from -10 +/- 2 mV to -18 +/- 2 mV (n = 6) by thaliporphine and -11 +/- 2 to -19 +/- 2 mV (n = 4) by Bay K 8644. These results indicate that thaliporphine is a weak Ca2+ channel agonist with strong Na+ and K+ channel blocking activities. The positive inotropic effect may be due to an increase in calcium entry mediated via partial activation of calcium channels or by inhibition of K+ efflux. Inhibition of K+ efflux would result in prolongation of APD50 and contribute to the negative chronotropic effect of thaliporphine.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1994

Age-related quinidine effects on ionic currents of rabbit cardiac myocytes.

Age-related cardiac actions of quinidine have been shown in prolongation of action potential duration, but not in the tonic and use-dependent block of the maximal velocity of action potential upstroke. To elucidate the underlying ionic mechanisms, currents through the Na, Ca and K channels were examined by using a whole-cell voltage clamp technique on isolated neonatal (< 5 day) and adult (> 3 months) rabbit cardiac myocytes under various concentrations (0.5, 1.5 and 4.5 microM) of quinidine. In neonatal and adult myocytes, quinidine caused a comparable degree of dose-dependent effects on Na currents including decrease in peak Na currents, left-shift of steady-state availability curve and slowing of the recovery from inactivation. However, the inwardly rectifier K current and the transient outward current were suppressed to a greater extent in the neonatal myocytes than in the adult (P = 0.0002 and 0.02, respectively). On the contrary, the magnitude of decrease in peak Ca currents after quinidine treatment was much smaller in the neonatal myocytes than in the adult (P = 0.01). These findings indicate that age-related ionic channel-block by quinidine is complex; and shows major differences in the Ca and K currents of cardiac myocytes. Accordingly, a differential therapeutic potential of quinidine may exist in hearts of different ages.

Action Potentials↗