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PubMed1991

Calcium channel currents in isolated smooth muscle cells from the basilar artery of the guinea pig.

Ca2+ channel currents were studied in smooth muscle cells from the basilar artery of the guinea pig using the whole-cell patch-clamp technique. 10 mM Ba2+ as the charge carrier and strong buffering of intracellular Ca2+ with EGTA (pCai = 8). Cell capacitance was 18.8 +/- 6.6 pF (n = 96) and maximum current density at +10 to +20 mV (holding potential less than -55 mV), measured early in dialysis, was -14.8 +/- 4.9 pA/pF (n = 83). Currents reversed at approximately +95 mV and, at more positive potentials, outward Cs+ currents were recorded that were blocked by either external Cd2+ or Ca2+. One component of current was identified that had properties consistent with L-type channels. On the basis of measurements of tail currents, its threshold for activation was -15 mV, its voltage dependence of activation was steep and it was half-activated at +8.5 mV. It inactivated very slowly at +15 mV (2787 +/- 511 ms) and it deactivated rapidly (251 +/- 55 microseconds) at -55 mV. It was quickly lost during dialysis and was largely blocked by 1 nM nifedipine (1-s pulses, holding potential = -55 mV). A second component, termed B-type current, was identified that had properties inconsistent with those of T-type channels. On the basis of tail currents, its threshold for activation was -30 mV, its voltage dependence of activation was less steep and it was half-activated at +33.7 mV.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2003

Effects of hypoxia and mitochondrial inhibition on the capacitative calcium entry in rabbit pulmonary arterial smooth muscle cells.

We have investigated the effects of hypoxia and mitochondria inhibitors on the capacitative Ca(2+) entry (CCE) in cultured smooth muscle cells from rabbit small pulmonary arteries. Cyclopiazonic acid (CPA) depleted Ca(2+) from sarcoplasmic reticulum (SR) in Ca(2+)-free medium and subsequent addition of Ca(2+) led to the nifedipine-insensitive, La(3+)-sensitive Ca(2+) influx. The presence of CCE was further verified by the measurement of unidirectional Mn(2+) influx. During the decay phase of the CCE-induced [Ca(2+)]c transients, hypoxia (P(O2) < 50 mmHg) and the mitochondria inhibitor FCCP reversibly increased [Ca(2+)]c, that is La(3+)-sensitive. Once SR is depleted by CPA, subsequent treatment of FCCP slowed the decay of CCE-induced [Ca(2+)]c transients but it did not attenuate Mn(2+) influx. Mitochondrial uptake of incoming Ca(2+) through CCE was demonstrated by additional increase in [Ca(2+)]c with Ca(2+) ionophore after terminating CCE. Together, it is suggested that the augmentation of CCE-induced [Ca(2+)]c transients by hypoxia and FCCP reflects a net gain of [Ca(2+)]c by the inhibition of mitochondrial Ca(2+) uptake.

Animals↗

PubMed2006

Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells.

Oxygen causes perinatal pulmonary dilatation. Although fetal pulmonary artery smooth muscle cells (PA SMC) normally respond to an acute increase in oxygen (O2) tension with a decrease in cytosolic calcium ([Ca2+]i), an acute increase in O2 tension has no net effect on [Ca(2+)](i) in PA SMC derived from lambs with chronic intrauterine pulmonary hypertension (PHTN). The present experimental series tests the hypothesis that an acute increase in O2 tension decreases capacitative calcium entry (CCE) in normal, but not hypertensive, fetal PA SMC. PA SMC were isolated from late-gestation fetal lambs after either ligation of the ductus arteriosus (PHTN) or sham (control) operation at 127 days gestation. PA SMC were isolated from the distal PA (>or=4th generation) and maintained under hypoxic conditions ( approximately 25 Torr) in primary culture. After fura 2 loading, apparent [Ca2+]i in PA SMC was determined as the ratio of 340- to 380-nm fluorescence intensity. Under both hypoxic and normoxic conditions, cyclopiazonic acid (CPA) increased [Ca2+]i more in PHTN than in control PA SMC. CCE was determined in PA SMC under hypoxic and normoxic conditions, after superfusion with zero extracellular Ca2+ and intracellular store depletion with CPA, followed by superfusion with Ca2+-containing solution, in the presence of the voltage-operated calcium channel blockade. CCE was increased in PHTN compared with control PA SMC under conditions of both acute and sustained normoxia. Transient receptor potential channel gene expression was greater in control compared with PHTN PA SMC. PHTN may compromise perinatal pulmonary vasodilation, in part, by modulating PA SMC CCE.

Animals↗

PubMed2000

An inward rectifier and a voltage-dependent K+ current in single, cultured pericytes from bovine heart.

OBJECTIVE: The purpose of this study was to describe passive electrical properties and major membrane currents in coronary pericytes. METHODS: 78 single, cultured bovine pericytes were studied with the patch-clamp technique in the whole-cell mode. RESULTS: The membrane potential of the cells was -48.9+/-9.6 mV (mean+/-S.D.) with 5 mM and -23.2+/-2.2 mV with 60 mM extracellular K+. The membrane capacitance was 150.2+/-123.2 pF. The current-voltage relation of the pericytes was dominated by an inward current at hyperpolarized potentials and an outward current at depolarized potentials. Increasing extracellular K+ from 5 to 60 mM led to an increase of the inward current and to a shift of this current to more depolarized potentials. The inward current was very sensitive to extracellular barium (50 microM). The maximum slope conductance of the cells at hyperpolarized potentials was 2.9+/-2.8 nS. Inward rectification of whole-cell currents was steep (slope factor = 6.8 mV). With elevated external K+ the outward current reversed near the potassium equilibrium potential. Onset of the outward current was sigmoid and inactivation of this current was monoexponential, slow (time constant = 12.8 s) and incomplete. Voltage-dependence of outward current steady-state activation was steep (slope factor = 4.6 mV). The outward current was very sensitive to 4-aminopyridine (dissociation constant = 0.1 mM). The maximum slope conductance at depolarized potentials was 16.6+/-15.6 nS. CONCLUSION: We report for the first time, patch-clamp recordings from coronary pericytes. An inward rectifier and a voltage-dependent K+ current were identified and characterized. Regulation of these currents may influence coronary blood flow.

Animals↗

PubMed1986

Nervous system control mechanisms in heart failure.

Alterations in the peripheral circulation by influencing aortic impedance and venous capacitance have a remarkable effect on cardiac performance in patients with left ventricular dysfunction. Systemic vasoconstriction in heart failure is influenced by activation of the sympathetic nervous system (increased plasma norepinephrine), the renin-angiotensin system (increased PRA) and the antidiuretic hormone system (increased arginine vasopressin). The level of plasma norepinephrine is related weakly to the severity of resting left ventricular dysfunction and strongly to the subsequent risk of mortality. Attenuation of reflex responsiveness to low pressure mechanoreceptors (orthostatic tilt) and to carotid and aortic baroreceptors (nitroprusside infusion) occurs in heart failure and the degree of abnormality also may be related to mortality. Vasodilation with consequent improvement in left ventricular function may be accomplished by non-specific dilators (nitroprusside, nitrates, hydralazine, nitrendipine) or by specific interference with neurohumoral mechanisms (sympathetic blockade, converting enzyme blockade, AVP blockade). Plasma norepinephrine may be reduced by central or presynaptic mechanisms (guanabenz, bromocriptine, captopril). The hemodynamic effect of this anti-sympathetic effect appears to be related to the relative influence on cardiac vs. peripheral sympathetic tone and/or concomitant effects of the drugs. Long-term trials are needed to determine whether chronic inhibition of the sympathetic nervous system will have a salutary effect on the hemodynamics, symptomatology and prognosis of cardiac failure.

Catecholamines↗

PubMed1999

Cell proliferation is associated with enhanced capacitative Ca(2+) entry in human arterial myocytes.

Depletion of Ca(2+) stores in the sarcoplasmic reticulum (SR) activates extracellular Ca(2+) influx via capacitative Ca(2+) entry (CCE). Here, CCE levels in proliferating and growth-arrested human pulmonary artery smooth muscle cells (PASMCs) were compared by digital imaging fluorescence microscopy. Resting cytosolic free Ca(2+) concentration ([Ca(2+)](cyt)) in proliferating PASMCs was twofold higher than that in growth-arrested cells. Cyclopiazonic acid (CPA; 10 microM), which inhibits SR Ca(2+)-ATPase and depletes inositol 1,4,5-trisphosphate-sensitive Ca(2+) stores, transiently increased [Ca(2+)](cyt) in the absence of extracellular Ca(2+). The addition of 1.8 mM Ca(2+) to the extracellular solution in the presence of CPA induced large increases in [Ca(2+)](cyt), indicative of CCE. The CPA-induced SR Ca(2+) release in proliferating PASMCs was twofold higher than that in growth-arrested cells, whereas the transient rise of [Ca(2+)](cyt) due to CCE was fivefold greater in proliferating cells. CCE was insensitive to nifedipine but was significantly inhibited by 50 mM K(+), which reduces the driving force for Ca(2+) influx, and by 0.5 mM Ni(2+), a putative blocker of store-operated Ca(2+) channels. These data show that augmented CCE is associated with proliferation of human PASMCs and may be involved in stimulating and maintaining cell growth.

Calcium↗

PubMed1990

The inhibitory action of halothane on reflex constriction in mesenteric capacitance veins.

Potent inhalational anesthetics depress autonomic reflex responses at multiple sites. Most studies emphasize cardiac chronotropic changes and changes in systemic blood pressure. Recently, active reflex venoconstriction of 500-1,000 microns O.D. mesenteric veins has been demonstrated. In the current study, the effects of halothane on the reflex responses of similar mesenteric veins were measured. Mesenteric vein diameter and intravenous pressure were measured in 500-1,000 microns O.D. veins from the mesentery of segments of terminal ileum externalized in situ from 27 New Zealand white rabbits anesthetized with alpha-chloralose. Mean arterial pressure was measured with femoral arterial cannulation, and heart rate was determined from the arterial pressure signal. In a separate group of six animals, sympathetic efferent nerve activity was measured from a postganglionic splanchnic nerve. Reflex venoconstriction and increases in mean arterial pressure and mesenteric vein pressure in response to bilateral carotid occlusion were attenuated by 0.5% and 1% inhaled halothane but not by superfusate equilibrated with 3% halothane. Decreases in mesenteric vein diameter and increases in mesenteric vein pressure in response to celiac ganglion stimulation were unaffected by both 0.5% inhaled halothane and superfusate equilibrated with 5% halothane. The bilateral carotid occlusion reflex-mediated increase in sympathetic efferent nerve activity was depressed by both 0.5% and 1% inhaled halothane. The effect of inhaled halothane on prestimulation baseline vein diameter was inconsistent. Superfusate equilibrated with 5% but not 3% halothane caused baseline venodilation. These results suggest a mechanism whereby control of venous tone is inhibited by halothane proximal to the postganglionic neuron. This could involve central or ganglionic inhibition.

Animals↗

PubMed1993

Voltage-dependent Ca2+ channels in resistance arteries from spontaneously hypertensive rats.

Alterations in voltage-dependent Ca2+ channels in the arterial smooth muscle cells of spontaneously hypertensive rats (SHR) were investigated using the whole-cell voltage clamp and compared with Wistar-Kyoto (WKY) rats. Single cells were freshly isolated from resistance mesenteric arteries from 4- to 5-week-old (young) and 16- to 18-week-old (adult) SHR. Elevated blood pressure was only evident in adult SHR, not in young SHR. In young rats, the Ca2+ channel current density (current amplitude normalized by cell capacitance) was significantly higher (P < .01) in SHR than in WKY rats at the command potential of -10 mV or higher (with 50 mmol/L Ba2+): The current density at 20 mV was -16.8 +/- 1.1 pA/pF in SHR (n = 38 cells) and -11.0 +/- 0.8 pA/pF in WKY rats (n = 30 cells). In adult rats, the difference in current densities disappeared: -15.9 +/- 1.3 pA/pF in SHR (n = 25 cells) and -15.6 +/- 1.5 pA/pF in WKY rats (n = 29 cells). The ratio of maximal amplitude of T-type current to that of L-type current was low in young SHR (0.10 +/- 0.01) compared with the other three groups (0.16 to 0.20). Neither the activation curve nor the steady-state inactivation curve of SHR was different from that of age-matched WKY rats. However, the activation curves in adult rats were shifted to a hyperpolarized direction compared with those of young rats in both strains. These results suggest that the increased activity of voltage-dependent L-type Ca2+ channels of resistance arteries in young SHR may be related to the development of hypertension. The changes observed in adult rats may be due to a secondary modification of the channel during maturation and the presence of hypertension.

Animals↗

PubMed1975

Hemodynamic and metabolic effects of isosorbide dinitrate in chronic congestive heart failure.

To assess the potential beneficial effects of a nonparenteral vasodilator, sublingual isosorbide dinitrate (5 to 15 mg.) was administered in 12 patients with chronic congestive heart failure refractory to conventional therapy. Hemodynamic measurements were performed before and at 15 minute intervals after drug administration for 90 minutes. Venous capacitance was measured at 5 minute intervals. Myocardial metabolism was also studied in five patients before and after drug administration. Hemodynamic effects were characterized by a modest decrease in mean arterial pressure (85 +/- 3 to 78 +/- 2 [S.E.M.] mm. Hg) and substantial decrease in right atrial (10 +/- 1 to 6 +/- 1), pulmonary arterial (39 +/- 4 to 30 +/- 4) and pulmonary capillary wedge pressures (28 +/- 2 to 21 +h- 2). These changes were accompanied by an increase in venous capacitance (2.46 +/- 0.16 to 3.99 +/- 0.24 c.c./100 c.c. of tissue). Along with a decrease in left ventricular filling pressure, cardiac index increased (1.99 +/- 0.13 to 2.37 +/- 0.15 L./min/M.2). No significant effect on heart rate was seen. Delta P/delta t, an index related to left ventricular dp/dt, increased in all but one patient (253 +/- 31 to 298 +/- 39 mm. Hg/sec.) (p less than 0.02 for all changes) in the face of decreased preload and afterload and unchanged heart rate, suggesting improved contractile state. A decrease in coronary blood flow (165 +/- 13 to 131 +/- 15 c.c./min.) and myocardial oxygen consumption (18.1 +/- 1.6 to 14.5 +/- 1.6 c.c./min.) was noted (p less than 0.02). No change in arterial-coronary sinus oxygen difference or lactate extraction was observed. These data demonstrate that the objectives of therapy in congestive heart failure, namely improved forward output and decreased ventricular filling pressures, can be achieved without metabolic deterioration by using sublingual isosorbide. The mechanisms responsible are related to diminished impedence to ventricular ejection and peripheral pooling of blood. Since the duration of action does not usually exceed 90 minutes, frequent drug administration may be a source of patient inconvience.

Administration, Oral↗

PubMed1999

Receptors linked to polyphosphoinositide hydrolysis stimulate Ca2+ extrusion by a phospholipase C-independent mechanism.

In A7r5 cells with empty intracellular Ca(2+) stores in which the cytosolic free Ca(2+) concentration ([Ca(2+)](i)) had been increased by capacitative Ca(2+) entry, stimulation of receptors linked to phospholipase C (PLC), including those for Arg(8)-vasopressin (AVP) and platelet-derived growth factor (PDGF), caused a decrease in [Ca(2+)](i.) This effect was further examined in a stable variant of the A7r5 cell line in which the usual ability of hormones to stimulate non-capacitative Ca(2+) entry is not expresssed. In thapsigargin-treated cells, neither AVP nor PDGF affected capacitative Mn(2+) or Ba(2+) entry, but both stimulated the rate of Ca(2+) extrusion, and their abilities to decrease [Ca(2+)](i) were only partially inhibited by removal of extracellular Na(+). These results suggest that receptors linked to PLC also stimulate plasma membrane Ca(2+) pumps. Activation of protein kinase C by phorbol 12, 13-dibutyrate (PDBu, 1 microM) also caused a decrease in [Ca(2+)](i) by accelerating Ca(2+) removal from the cytosol; the effect was again only partially inhibited by removal of extracellular Na(+). An inhibitor of PKC, Ro31-8220 (10 microM), abolished the ability of PDBu to decrease [Ca(2+)](i), without affecting the response to maximal or submaximal concentrations of AVP. Similar experiments with PDGF were impracticable because Ro31-8220, presumably by inhibiting the tyrosine kinase activity of the PDGF receptor, abolished all responses to PDGF. U73122 (10 microM), an inhibitor of PLC, completely inhibited PDGF- or AVP-evoked Ca(2+) mobilization, without preventing either stimulus from causing a decrease in [Ca(2+)](i). We conclude that receptors coupled to PLC, whether via G-proteins or protein tyrosine kinase activity, also share an ability to stimulate the plasma membrane Ca(2+) pump via a mechanism that does not require PLC activity.

Animals↗

PubMedDate not supplied

Voltage-gated sodium channels in human aortic smooth muscle cells.

Whole-cell, voltage clamp methods were used to study inward currents in human aortic smooth muscle cells in culture. Cells were plated on glass coverslips, cultured in supplemented M-199 media with 5% serum and studied as primary cells and at passages 2-5. Inward currents were measured with a pipette solution containing Cs+ and TEA+ to block K+ currents and with 2.5 mM [Ca2+]0 in the perfusate. Inward currents activated at about -50 mV, peaked at about -15 mV and reversed at about +30 mV. Values of peak inward current averaged 14. 7 +/- 3.3 pA/pF and cell capacitance averaged 124 +/- 10 pF (n = 35). These currents activated rapidly with a time-to-peak current of 2.4 +/- 0.3 ms at a test potential of -10 mV from a holding potential of -80 mV. The current also inactivated rapidly with a time course that could be described by two components with time constants of 1.8 +/- 0.2 and 17.8 +/- 3.5 ms at -10 mV. The currents decreased when extracellular Na+ was reduced and were completely inhibited by 50 nM tetrodotoxin (TTX), suggesting that they represented voltage-gated Na+ currents (INa). Activation curves were characterized with a V0.5 = -16.6 +/- 2.4 mV and a slope factor k = -5.2 +/- 0.2 mV while inactivation curves were characterized with a V0.5 = -60.9 +/- 1.7 mV and a slope factor k = 8.8 +/- 0.4 mV. Lowering external [Ca2+] to zero increased the maximum INa, shifted its voltage dependence in the hyperpolarizing direction and increased the rate of INa inactivation. Increasing external [Ca2+] or [Mg2+]decreased INa and slowed its rate of inactivation. These studies demonstrate the presence of voltage-gated Na+ channels with high TTX sensitivity that are modulated by extracellular divalent cations in human aortic smooth muscle cells maintained in cell culture. Window currents were found in the voltage range of -50 to -20 mV, suggesting that these channels could contribute to the resting membrane potential.

Calcium↗

PubMed1994

Electrophysiological characteristics of cultured human umbilical vein endothelial cells.

Electrophysiological characteristics of cultured human umbilical vein endothelial cells (HUVEC) were determined using the patch-clamp technique in the whole cell configuration. In isolated cells, membrane potential, capacitance, and input resistance were (Mean +/- SD) - 16.3 +/- 12.7 mV, 53.9 +/- 26 pF, and 2.3 +/- 1.3 G omega, respectively (N = 26); and in confluent cells - 23.6 +/- 5.5 mV, 127 +/- 59 pF, and 0.254 +/- 0.077 G omega, respectively (N = 6). The almost 10 times higher input resistance, and smaller capacitance of isolated versus confluent cells, indicated that the latter were in electrical communication, presumably through open gap junctions, which was confirmed by intercellular diffusion of Lucifer Yellow. Whole-cell currents of isolated cells were made up of at least three components: First, two outward currents, an early transient one with activation-inactivation kinetics and a small delayed sustained component with 6.75 +/- 4.8 and 0.73 +/- 0.089 nS conductance, respectively. Second, an inward component which was rectified and had 1.58 +/-1.2 nS conductance. In contrast to a reported lack of voltage-gated channels in HUVEC, the above currents were voltage dependent. Inhibition of the whole-cell currents by external Ba2, internal Cs, and other K+ blockers indicates that the three observed currents are carried by K+. This was confirmed by changes of outside K+ concentrations shifting the I-V curve intercept in the direction expected for K(+)-selective channels. Voltage-gated Ca2+ currents were not apparent in the whole-cell current records. HUVEC membrane potential was as low as that of microvascular cells, while inward current rectification at normal external K+ was like that in arterial endothelial cells. This mixed phenotypic expression and multipotential behavior suggests that the electrical features of HUVEC may be primarily determined by embryonic origin and the local effect of the microenvironment rather than strictly by vessel size.

Calcium Channels↗

PubMed2003

Electroporation: theory and methods, perspectives for drug delivery, gene therapy and research.

Electroporation designates the use of short high-voltage pulses to overcome the barrier of the cell membrane. By applying an external electric field, which just surpasses the capacitance of the cell membrane, transient and reversible breakdown of the membrane can be induced. This transient, permeabilized state can be used to load cells with a variety of different molecules, either through simple diffusion in the case of small molecules, or through electrophoretically driven processes allowing passage through the destabilized membrane--as is the case for DNA transfer. Initially developed for gene transfer, electroporation is now in use for delivery of a large variety of molecules: From ions to drugs, dyes, tracers, antibodies, and oligonucleotides to RNA and DNA. Electroporation has proven useful both in vitro, in vivo and in patients, where drug delivery to malignant tumours has been performed. Whereas initial electroporation procedures caused considerable cell damage, developments over the past decades have led to sophistication of equipment and optimization of protocols. The electroporation procedures used in many laboratories could be optimized with limited effort. This review (i) outlines the theory of electroporation, (ii) discusses factors of importance for optimization of electroporation protocols for mammalian cells, (iii) addresses particular concerns when using electroporation in vivo, e.g. effects on blood flow and considerations regarding choice of electrodes, (iv) describes DNA electrotransfer with emphasis on use in the in vivo setting, and (v) sums up data on safety and efficacy of electroporation used to enhance delivery of chemotherapy to tumours in cancer patients.

Animals↗

PubMed1990

The role of alpha 1- and alpha 2-adrenoceptors in canine systemic capacitance vessels--a study with measurement of mean circulatory pressure.

We investigated the presence of alpha-adrenoceptor subtypes in systemic capacitance vessels by examining the effects of alpha 1- and alpha 2-agonists or antagonists on the mean circulatory pressure (MCP). Dogs were anesthetized with pentobarbital, and after total spinal anesthesia, epinephrine was given intravenously to maintain mean blood pressure at about 80 mmHg. 1. With intravenous injection of phenylephrine (alpha 1-agonist, 10 micrograms/kg, n = 7), and of BHT 920 (alpha 2-agonist, 5 micrograms/kg, n = 7), MCP increased significantly from 9.8 +/- 0.4 (mean +/- SE) to 10.9 +/- 0.3 mmHg (+11.2%, p less than 0.01), and from 9.3 +/- 0.4 to 10.3 +/- 0.4 mmHg (+10.8%, p less than 0.05), respectively. 2. Intravenous injection of prazosin (alpha 1-antagonist, 150 micrograms/kg, n = 7) and of yohimbine (alpha 2-antagonist, 30 micrograms/kg, n = 7) decreased MCP significantly from 9.9 +/- 0.4 to 8.2 +/- 0.5 mmHg (-17.2%, p less than 0.01), and from 9.8 +/- 0.2 to 7.6 +/- 0.3 mmHg (-22.4%, p less than 0.01), respectively. 3. Intravenous injection of phenylephrine (10 micrograms/kg, n = 7) after pretreatment with prazosin (150 micrograms/kg) decreased MCP significantly from 9.5 +/- 0.3 to 7.8 +/- 0.3 mmHg (-17.9%, p less than 0.01). MCP decreased significantly from 9.9 +/- 0.3 to 8.2 +/- 0.3 mmHg (-17.2%, p less than 0.01) after intravenous injection of BHT 920 (5 micrograms/kg, n = 7) following pretreatment with yohimbine (30 micrograms/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed2004

Mobilization of sarcoplasmic reticulum stores by hypoxia leads to consequent activation of capacitative Ca2+ entry in isolated canine pulmonary arterial smooth muscle cells.

Capacitative Ca2+ entry (CCE) has been speculated to contribute to Ca2+ influx during hypoxic pulmonary vasoconstriction (HPV). The aim of the present study was to directly test if acute hypoxia causes intracellular Ca2+ concentration ([Ca2+]i) rises through CCE in canine pulmonary artery smooth muscle cells (PASMCs). In PASMCs loaded with fura-2, hypoxia produced a transient rise in [Ca2+]i in Ca2+-free solution, indicating Ca2+ release from the intracellular Ca2+ stores. Subsequent addition of 2 mm Ca2+ in hypoxia elicited a sustained rise in [Ca2+]i, which was partially inhibited by 10 microm nisoldipine. The dihydropyridine-insensitive rise in [Ca2+]i was due to increased Ca2+ influx, because it was abolished in Ca2+-free solution and hypoxia was shown to significantly enhance the rate of Mn2+ quench of fura-2 fluorescence. The dihyropyridine-insensitive rise in [Ca2+]i and the increased rate of Mn2+ quench of fura-2 fluorescence were inhibited by 50 microm SKF 96365 and 500 microm Ni2+, but not by 100 microm La3+ or 100 microm Gd3+, exhibiting pharmacological properties characteristic of CCE. In addition, predepletion of the intracellular Ca2+ stores inhibited the rise in [Ca2+]i induced by hypoxia. These results provide the first direct evidence that acute hypoxia, by causing Ca2+ release from the intracellular stores, activates CCE in isolated canine PASMCs, which may contribute to HPV.

Animals↗

PubMed1995

The myogenic response of arterial vessels is increased in fetal pulmonary hypertension.

The stretch-induced myogenic response (MR) of large-capacitance pulmonary arteries were studied in normal and pulmonary hypertensive fetuses as well as normal newborn and adult sheep. Pulmonary hypertension in the fetus was induced by ligation of the ductus arteriosus for 12 d. The MR was obtained by stretching the vessel segments in vitro from their resting diameter (no load) to the diameter at which the muscle fibers were at optimal length (Lo), and the response was measured as a percentage of force obtained after supramaximal electrical stimulation (Po). In five control and four pulmonary hypertensive fetuses, the MR was also obtained after a stretch of 140% of Lo. The pulmonary hypertensive fetal arteries had a lower stress (1.3 +/- 0.4 versus 4.0 +/- 0.5 mN/mm2; p < 0.001) and shortening capacity compared with the fetal control (5.1 +/- 1.6 versus 9.9 +/- 0.8% of Lo; p < 0.01). The MR was observed in 21% of the control and 30% of the experimental fetuses, and it was of greater magnitude in the latter (14.8 +/- 1.9 of Po versus 34.3 +/- 2.5%, respectively; p < 0.01). When stretched to 140% of Lo, the MR was also greater in the experimental (514 +/- 148% of Po) than the control fetuses (142 +/- 68; p < 0.05). Postnatally, the MR was present in 67% of the newborn and 15% of the adult pulmonary artery segments, and the response was greatest in the newborn (23.1 +/- 4.2% of Po) compared with the adult (2.3 +/- 0.8; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Plant alkaloids, tetrandrine and hernandezine, inhibit calcium-depletion stimulated calcium entry in human and bovine endothelial cells.

Depletion of internal Ca2+ stores causes capacitative Ca2+ entry which occurs through non-selective cation channels sensitive to blockade by SK&F 96365. Recently, alkaloids of Chinese herbal medicinal origin, tetrandrine and hernandezine, have been shown to possess actions including inhibition of Ca2+ channels in non-excitable cell types. In this study, we compared the actions of these novel inhibitors to those of SK&F 96365 in fura-2-loaded endothelial cells from human umbilical vein and bovine pulmonary artery. Depletion of Ca2+ from the internal stores was accomplished in Ca(2+)-free medium using an endoplasmic reticulum Ca2+ pump inhibitor, cyclopiazonic acid (CPA) or receptor agonists, histamine and bradykinin. Stimulation with histamine or bradykinin caused a marked and rapid transient increase in Ca2+ signal whereas CPA caused a smaller amplitude increase of longer duration. Restoring Ca2+ to the medium caused marked and sustained increases in the fluorescence indicating movement of Ca2+ into the cytosol presumably stimulated by the emptied Ca2+ stores. SK&F 96365 as well as tetrandrine and hernandezine antagonized depletion-induced Ca2+ entry. The results suggest that these putative inhibitors interact with Ca2+ entry triggered by depletion of the internal Ca2+ stores and their action is presumed to be on the non-selective cation channels. Their effectiveness may be enhanced by the mechanisms which lead to the opening of the Ca2+ influx channel.

Alkaloids↗

PubMed1991

[Properties of arteries, cardiac function and structure in chronic hypertension].

Hypertension is a condition which demonstrates the relationship between the properties of the left ventricle and arterial system. The spectrum of aortic impedence expresses the principal factors which oppose LV ejection into the initial aorta: 1) capacitive forces related to the viscoelastic properties of the arterial wall, directly proportional to its rigidity, 2) forces of inertia which increase with the acceleration of the blood and which are inversely proportional to the aortic cross sectional area, 3) reflection. With respect to a stroke volume which is usually normal, hypertension is characterised by: 1) an increase in mean aortic pressure (MAP), 2) with respect to the increase in MAP, an increase in systolic, late systolic and differential pressures. These changes in the level and morphology of aortic pressure are due to: a) the increase in systemic arterial resistances, a continuous expression of the spectrum of the module, b) an increase in the elastic forces (increased rigidity of the aorta related to increased pressure and structural wall changes) usually insufficiently compensated by a decrease in the inertial forces (aortic dilatation), c) an earlier return of the reflected pulse wave, well before the end of the anterograde wave. Overall, there is a relationship between the mass, the geometry (concentric hypertrophy) and pump function of the left ventricle and the properties of the arterial system expressed in terms of pulse wave velocity, characteristic impedence or the late systolic pressure/stroke volume ratio. The relationship is much closer than that of the properties of the LV and aortic pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗