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PubMed2003

Capacitative calcium entry and TRPC channel proteins are expressed in rat distal pulmonary arterial smooth muscle.

Mammalian homologs of transient receptor potential (TRP) genes in Drosophila encode TRPC proteins, which make up cation channels that play several putative roles, including Ca2+ entry triggered by depletion of Ca2+ stores in endoplasmic reticulum (ER). This capacitative calcium entry (CCE) is thought to replenish Ca2+ stores and contribute to signaling in many tissues, including smooth muscle cells from main pulmonary artery (PASMCs); however, the roles of CCE and TRPC proteins in PASMCs from distal pulmonary arteries, which are thought to be the major site of pulmonary vasoreactivity, remain uncertain. As an initial test of the possibility that TRPC channels contribute to CCE and Ca2+ signaling in distal PASMCs, we measured [Ca2+]i by fura-2 fluorescence in primary cultures of myocytes isolated from rat intrapulmonary arteries (>4th generation). In cells perfused with Ca2+-free media containing cyclopiazonic acid (10 microM) and nifedipine (5 microM) to deplete ER Ca2+ stores and block voltage-dependent Ca2+ channels, restoration of extracellular Ca2+ (2.5 mM) caused marked increases in [Ca2+]i whereas MnCl2 (200 microM) quenched fura-2 fluorescence, indicating CCE. SKF-96365, LaCl3, and NiCl2, blocked CCE at concentrations that did not alter Ca2+ responses to 60 mM KCl (IC50 6.3, 40.4, and 191 microM, respectively). RT-PCR and Western blotting performed on RNA and protein isolated from distal intrapulmonary arteries and PASMCs revealed mRNA and protein expression for TRPC1, -4, and -6, but not TRPC2, -3, -5, or -7. Our results suggest that CCE through TRPC-encoded Ca2+ channels could contribute to Ca2+ signaling in myocytes from distal intrapulmonary arteries.

Animals↗
PubMed1987

Neural modulation of transcapillary exchange of fluid and solutes in whole-organ preparations.

Activation of sympathetic adrenergic postganglionic fibers that release norepinephrine at the neuromuscular junction can influence resistance, capacitance, and exchange functions in the microcirculation. Although the predominant response is an increase in precapillary resistance that reduces blood flow through the tissue (at constant pressure perfusion), there are two distinct components that can be separated into an initial (1-2-minute) and late (2-15-minute) response. The initial (1-2-minute) response is a decrease in venous and capillary pressures in passive response to decreased flow promoted by an increase in precapillary resistance. Venous pressures are reduced even though postcapillary resistance is increased. The decrease in capillary pressure promotes absorption of fluid from tissue to plasma. Venous constriction results in a translocation of blood from the terminal venous system into the larger venous conduits toward the heart. Total blood volume in an isolated organ system decreases and is manifested as a decrease in volume (plethysmographic) or weight (gravimetric). The decrease in volume is result of three interrelated factors: 1) decrease in flow through the organ, 2) active venoconstriction and a translocation of blood out of the organ, and 3) absorption of fluid from tissue to plasma, which flows out of the organ with venous drainage. With continued sympathetic nervous system stimulation, the late response (3-15 minutes) is a gradual decrease in precapillary resistance that increases blood flow through the organ. Venous and capillary pressures passively increase in association with increases in flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Methemoglobin levels during prolonged combined nitroglycerin and sodium nitroprusside infusions in infants after cardiac surgery.

Nitroglycerin (NTG) and sodium nitroprusside (SNP) are routinely used perioperatively in infants with congenital heart defects. In this study, NTG and SNP were infused in the operating room to increase venous capacitance, reduce systemic and pulmonary afterload, facilitate weaning off cardiopulmonary bypass, stabilize hemodynamics for transport to the intensive care unit (ICU), and reduce the fluid resuscitation needed upon arrival in the ICU. Because of the risk for accumulation of methemoglobin (MetHb) and cyanmethemoglobin (cyan-MetHb) during prolonged continuous infusion of NTG and SNP, it was decided to (1) quantify ICU use, (2) measure % MetHb at 12-hour intervals, and (3) look indirectly for the accumulation of cyan-MetHb by comparing simultaneous pulse oximetry (SpO2) (Nellcor N-100 [Nellcor, Haywood, CO]) and CO-oximetry (SaO2) (Corning 270 [Corning, Medfield, MA]). A total of 69 arterial samples were obtained from 16 infants (median age 4.4 months) following cardiac surgery with bypass. Median doses of NTG, 6.0 mg/kg (range 0.7 to 27.5), and SNP, 3.3 mg/kg (range 0.6 to 33.4), were infused over a median of 64.5 hours (range 12 to 183) (N = 16 patients). The median MetHb was 0.6% (range 0.0 to 1.5) after infusions of NTG, 1.8 micrograms/kg/min (range 0.5 to 4), and SNP, 1.3 micrograms/kg/min (range 0.3 to 8.4) (N = 69 measurements). Regression analysis of oximetry data yielded the equation: SpO2 = 1.04 SaO2 - 3.7%, r = 0.97. The mean difference between SpO2 and SaO2 data pairs was 0.0% (bias) with a SD (precision) of +/- 2.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac Surgical Procedures↗
PubMedDate not supplied

Multiple types of chloride channels in bovine pulmonary artery endothelial cells.

We have characterized two different types of Cl- currents in calf pulmonary artery endothelial (CPAE) cells by using a combined patch-clamp and Fura-2 microfluorescence technique to measure simultaneously ionic currents and the intracellular Ca2+ concentration, [Ca2+]i. Exposure of CPAE cells to 28% hypotonic solution induces cell swelling without a change in membrane capacitance and [Ca2+]i, and concomitantly activates a current. This current, I(Cl, vol), is closely correlated with the changes in cell volume and shows a modest outward rectification. It slowly inactivates at potentials more positive than +60 mV but is time- and voltage-independent at other potentials. Increase in [Ca2+]i by different maneuvers, such as application of vasoactive agonists (ATP), ionomycin, or loading of the cells directly with Ca2+ also activates a Cl- current, I(Cl, Ca). This current slowly activates at positive potentials, inactivates quickly at negative potentials and shows strong outward rectification. A time-independent component of the current activated by elevation of [Ca2+]i alone can be inhibited by cell shrinking by exposing the cells to hypertonic solution, indicating that an increase in [Ca2+]i also co-activates I(Cl, vol). Forskolin or cAMP never activated a current in CPAE cells, which indicates the lack of cAMP-activated channels in these cells. There is also no evidence for the existence of voltage-gated Cl- channels in resting, nonstimulated cells. Challenging a cell with elevated [Ca2+]i and hypotonic solutions activated I(Cl, vol) on top of I(Cl, Ca), suggesting that I(Cl, Ca) and I(Cl, vol) are different channels. We conclude that CPAE cells do not express voltage-gated (ClC-type) or cAMP-gated (CFTR-type) Cl- channels, but activate large Cl- currents after volume (mechanical?) or chemical (Ca2+) stimulation.

Animals↗
PubMed2000

Regional distribution of potassium currents in the rabbit pulmonary arterial circulation.

The response of pulmonary arteries to hypoxia varies as a function of vessel diameter. Small intrapulmonary resistance arteries are thought to be the main site of hypoxic pulmonary vasoconstriction (HPV), with hypoxia causing minimal contraction or even dilatation in large, conduit vessels. This has been proposed to reflect a differential distribution of morphologically and electrophysiologically distinct pulmonary artery smooth muscle (PASM) cells. We investigated longitudinal heterogeneity in smooth muscle cells isolated from five regions of the rabbit pulmonary vasculature and could find no evidence of morphological heterogeneity at the level of the light microscope. PASM cells from main (8 mm outer diameter) and branch (5 mm) arteries and large ( 400 m) intrapulmonary arteries (IPA) were similar in shape and size, as indicated by cell capacitance (25 pF). PASM cells from medium (200-400 m) and small ( 200 m) IPA were significantly smaller (15 pF), but had the same classical spindle shape. Cells from all five regions also had similar resting membrane potentials and displayed voltage-activated K+ currents of similar amplitude when recorded in standard physiological solution. Longitudinal heterogeneity in K+ current became apparent when tetraethylammonium ions (TEA; 10 mM) and glibenclamide (10 M) were added. The remaining delayed rectifier current (IK(V)) doubled in amplitude upon moving down the pulmonary arterial tree from the main artery (9 pA pF-1 at 40 mV) to the large IPA (17 pA pF-1), but remained constant throughout the intrapulmonary vasculature. The O2-sensitive, non-inactivating K+ current (IK(N)) showed a similar trend, but was significantly reduced in the smallest IPA, where its amplitude was comparable with the main artery. Thus the IK(N)/IK(V) ratio was relatively constant, at around 0.14, from the main pulmonary artery to medium IPA, but fell by 50% in the smallest vessels. The amplitude of the TEA-sensitive K+ current was similar (16 pA pF-1 at 40 mV) at all levels of the pulmonary arterial tree, except in the medium sized vessels where it was 50% smaller. These variations in K+ current expression correlate with reported variations in sensitivity to hypoxia and may contribute to the regional heterogeneity of HPV in the rabbit lung.

Anaerobiosis↗
PubMed2000

Functional integrity of endothelium determines Ca2+ channel availability in smooth muscle: involvement of nitric oxide.

Endothelium regulates smooth muscle contractility in part via nitric oxide (NO). We tested the hypothesis that endothelial dysfunction, either produced by injury or simulated pharmacologically by reducing the bioavailability of NO, results in elevated Ca2+ channel availability (ngmax=maximum conductance/cell capacitance) in smooth muscle cells isolated from the vessel. Using basilar arteries of normotensive Wistar rats, we measured ngmax in smooth muscle cells from control vessels, from vessels in which endothelium was injured using Na fluoroscene plus light, and from vessels in which the bioavailability of NO was reduced by pretreatment with the NO scavenger 1H-imidazol-1 -yloxy,2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-3-oxide , potassium salt (C-PTIO), or the endothelial nitric oxide synthase (eNOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Values of ngmax in these four groups of cells were 0.28+/-0.02 nS/pF (n=22), 0.51+/-0.05 nS/pF (n=15), 0.430+/-.03 nS/pF (n=12), and 0.47+/-0.04 nS/pF (n=14) (P<0.05, ANOVA), respectively. To determine whether larger currents associated with endothelial dysfunction exhibit altered sensitivity to exogenous NO, we quantified the response to various concentrations of NO donor, Na nitroprusside (SNP), in 37 cells from control vessels and 33 cells from vessels pretreated with L-NAME. SNP exhibited identical potency (half-maximum values, 18.7 and 21.1 nM) but greater apparent efficacy (maximum fractional block, 0.82 versus 0.63) in down-regulating Ca2+ channel currents in cells isolated from vessels with dysfunctional endothelium. Our results are consistent with a direct influence of endogenous NO on Ca2+ channel availability in smooth muscle cells, and indicate that Ca2+ channel availability in isolated smooth muscle cells may be a sensitive measure of the functional integrity of the endothelium in the parent vessel.

Animals↗
PubMed1993

Stimulation of the hypothalamic paraventricular nucleus causes systemic venoconstriction.

Venous capacitance plays an important role in cardiovascular homeostasis. The anatomical loci within the central nervous system involved in modulating venous function remain to be elucidated. Stimulation of the hypothalamic paraventricular nucleus is known to increase sympathoadrenal outflow and arterial blood pressure. The present study was undertaken to determine whether electrical stimulation of the paraventricular nucleus can also affect the venous circulation. Mean circulatory filling pressure (MCFP) was used as an index of venous tone. Male Long Evans rats were initially anesthetized with pentobarbital (i.p.; 60 mg/kg) and subsequently maintained with urethane (i.v.; 600 mg/kg). Blood pressure and systemic venous pressure were monitored via catheters in the femoral artery and vein and heart rate was derived from the pulsatile blood pressure signal. A latex tipped balloon was placed in the right atrium via the right jugular vein. Mean circulatory filling pressure was calculated from the arterial and venous plateau pressures recorded during five second balloon inflations. Arterial pressure, systemic venous pressure, heart rate and mean circulatory filling pressure were monitored before and during unilateral monopolar electrical stimulation (0.5 ms pulses at 50 Hz for a train duration of 10 s with constant current intensities of 100, 150, 200, and 300 microA) of the paraventricular nucleus. Increased graded stimulation of the paraventricular nucleus increased blood pressure by 6 +/- 2, 8 +/- 1, 13 +/- 2 and 26 +/- 5 mm Hg while heart rate changed by -22 +/- 6, -18 +/- 6 and -15 +/- 9 bpm and +10 +/- 10 bpm, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Inhibition of hypoxic pulmonary vasoconstriction by antagonists of store-operated Ca2+ and nonselective cation channels.

Previous studies indicated that acute hypoxia increased intracellular Ca(2+) concentration ([Ca(2+)](i)), Ca(2+) influx, and capacitative Ca(2+) entry (CCE) through store-operated Ca(2+) channels (SOCC) in smooth muscle cells from distal pulmonary arteries (PASMC), which are thought to be a major locus of hypoxic pulmonary vasoconstriction (HPV). Moreover, these effects were blocked by Ca(2+)-free conditions and antagonists of SOCC and nonselective cation channels (NSCC). To test the hypothesis that in vivo HPV requires CCE, we measured the effects of SOCC/NSCC antagonists (SKF-96365, NiCl(2), and LaCl(3)) on pulmonary arterial pressor responses to 2% O(2) and high-KCl concentrations in isolated rat lungs. At concentrations that blocked CCE and [Ca(2+)](i) responses to hypoxia in PASMC, SKF-96365 and NiCl(2) prevented and reversed HPV but did not alter pressor responses to KCl. At 10 microM, LaCl(3) had similar effects, but higher concentrations (30 and 100 microM) caused vasoconstriction during normoxia and potentiated HPV, indicating actions other than SOCC blockade. Ca(2+)-free perfusate and the voltage-operated Ca(2+) channel (VOCC) antagonist nifedipine were potent inhibitors of pressor responses to both hypoxia and KCl. We conclude that HPV required influx of Ca(2+) through both SOCC and VOCC. This dual requirement and virtual abolition of HPV by either SOCC or VOCC antagonists suggests that neither channel provided enough Ca(2+) on its own to trigger PASMC contraction and/or that during hypoxia, SOCC-dependent depolarization caused secondary activation of VOCC.

Animals↗
PubMed2005

Acute hypoxia increases intracellular [Ca2+] in pulmonary arterial smooth muscle by enhancing capacitative Ca2+ entry.

Hypoxic pulmonary vasoconstriction (HPV) requires influx of extracellular Ca2+ in pulmonary arterial smooth muscle cells (PASMCs). To determine whether capacitative Ca2+ entry (CCE) through store-operated Ca2+ channels (SOCCs) contributes to this influx, we used fluorescent microscopy and the Ca2+-sensitive dye fura-2 to measure effects of 4% O2 on intracellular [Ca2+] ([Ca2+]i) and CCE in primary cultures of PASMCs from rat distal pulmonary arteries. In PASMCs perfused with Ca2+-free Krebs Ringer bicarbonate solution (KRBS) containing cyclopiazonic acid to deplete Ca2+ stores in sarcoplasmic reticulum and nifedipine to prevent Ca2+ entry through L-type voltage-operated Ca2+ channels (VOCCs), hypoxia markedly enhanced both the increase in [Ca2+]i caused by restoration of extracellular [Ca2+] and the rate at which extracellular Mn2+ quenched fura-2 fluorescence. These effects, as well as the increased [Ca2+]i caused by hypoxia in PASMCs perfused with normal salt solutions, were blocked by the SOCC antagonists SKF-96365, NiCl2, and LaCl3 at concentrations that inhibited CCE >80% but did not alter [Ca2+]i responses to 60 mM KCl. In contrast, the VOCC antagonist nifedipine inhibited [Ca2+]i responses to hypoxia by only 50% at concentrations that completely blocked responses to KCl. The increased [Ca2+]i caused by hypoxia was completely reversed by perfusion with Ca2+-free KRBS. LaCl3 increased basal [Ca2+]i during normoxia, indicating effects other than inhibition of SOCCs. Our results suggest that acute hypoxia enhances CCE through SOCCs in distal PASMCs, leading to depolarization, secondary activation of VOCCs, and increased [Ca2+]i. SOCCs and CCE may play important roles in HPV.

Acute Disease↗
PubMed1998

Stealth ryanodine-sensitive Ca2+ release contributes to activity of capacitative Ca2+ entry and nitric oxide synthase in bovine endothelial cells.

1. The involvement of ryanodine-sensitive Ca2+ release (RsCR) in bradykinin (Bk)-induced Ca2+ release, capacitative Ca2+ entry (CCE) and nitric oxide synthase (NOS) activation was assessed in freshly isolated bovine coronary artery endothelial cells. 2. Using deconvolution microscopy fura-2 was found throughout the whole cytosol, while the cell membrane impermeable dye FFP-18 was exclusively in the cell membrane. Thus, perinuclear ([Ca2+]pn) and subplasmalemmal Ca2+ concentration ([Ca2+]sp) were monitored using fura-2 and FFP-18. 3. Inhibition of Na+-Ca2+ exchange by lowering extracellular Na+ concentration augmented the Bk-induced [Ca2+]pn signal in Ca2+-free solution. This effect was abolished when RsCR was prevented with 25 micromol l-1 ryanodine, while inhibition of RsCR had no effect on Bk-induced increase in [Ca2+]pn without inhibition of Na+-Ca2+ exchange. 4. Initiating RsCR by 200 nmol l-1 ryanodine increased [Ca2+]sp, while [Ca2+]pn remained constant. However, when Na+-Ca2+ exchange was prevented, ryanodine was also able to elevate [Ca2+]pn. 5. Blockage of RsCR diminished Ca2+ extrusion in response to stimulation with Bk in normal Na+-containing solution. 6. Inhibition of RsCR blunted Bk-activated CCE, while inhibition of Na+-Ca2+ exchange during stimulation enhanced CCE. 7. Although direct activation of RsCR failed to activate NOS, inhibition of RsCR diminished the effect of ATP and Bk on NOS, while the effect of thapsigargin remained unchanged. 8. These data suggest that during stimulation subplasmalemmal RsCR occurs, which contributes to the activities of CCE and NOS. Thus, the function of the subplasmalemmal Ca2+ control unit must be extended as a regulator for CCE and NOS.

Animals↗
PubMed1996

Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain.

On the helical strip of a capacitance vessel, the pulmonary artery of the rabbit, phenylethylamine (PEA) and tyramine act solely via displacement of noradrenaline from their storage sites and this effect is inhibited by desmethylimipramine (DMI). In contrast, on a resistance vessel, the perfused central ear artery of the rabbit, PEA enhances stimulation induced contractions in 0.2-0.8 microgram/ml concentration [catecholaminergic activity enhancer (CAE) effect], and increases smooth muscle tone (noradrenaline displacing effect) in 4-6 micrograms/ml concentration. This latter effect only is blocked by DMI. Tyramine acts similarly and is more potent than PEA. On the isolated brain stem PEA, tyramine and (-)methamphetamine are, in the presence of cocaine and DMI, highly potent enhancers of stimulation induced release of 3H-noradrenaline, 3H-dopamine and 3H-serotonin. Compounds with specific CAE effect in the brain, (-)deprenyl and 1-phenyl-2-propylaminopentane [(-)PPAP], antagonize tetrabenazine-induced depression of performance of rats in the shuttle box. PEA and tyramine, which are rapidly metabolized in vivo, are ineffective in this test up to 40 mg/kg, whereas (-)methamphetamine, the stable PEA derivative, is highly effective. Compounds with CAE effect enhance at low concentrations the slow inward Ca2+ current in the sino-auricular fibers of the frog heart and inhibit it in high concentration. PEA and tyramine enhance Ca2+ influx from 0.05 to 4 micrograms/ml and inhibit it in 8 micrograms/ml. In conclusion, PEA and tyramine stimulate primarily coupling of action potential to transmitter release in the catecholaminergic neurons in the brain and displace catecholamines in higher concentration only.

Animals↗
PubMed1990

The effect of halothane on norepinephrine responsiveness in rabbit small mesenteric veins.

The effect of halothane on the response of small isolated mesenteric capacitance veins to exogenous norepinephrine and electrically induced endogenous norepinephrine release was studied. The role of extra- and intracellular Ca2+ in norepinephrine-induced contractions was also examined. Two-millimeter-long segments from the second-order branch of the mesenteric vein were stretched to twice their resting diameter, and the generated tension was measured with a force transducer. Dose-dependent effects of norepinephrine on generated tension were examined before and after exposure to 0.75 and 1.5% halothane. (These concentrations produced perfusate halothane concentrations of 0.31 and 0.49 mM respectively.) Norepinephrine produced an increase in the basal vessel tension along with a superimposed rhythmic oscillation in tension. Although the magnitude of the tension increase was not affected by either concentration of halothane, the amplitude of the oscillations was reduced. Ryanodine (a blocker of Ca2+ release from the sarcoplasmic reticulum), like halothane, decreased the amplitude of the oscillations, but did not affect overall tension development. In the Ca2(+)-free medium the contractile response to norepinephrine was greatly attenuated as compared to control, whereas the oscillatory behavior was completely abolished. Norepinephrine release was examined indirectly by measuring the increase in tension during electric field stimulation. Response to endogenously released norepinephrine was significantly decreased by exposure to halothane 1.5% (0.49 mM) and blocked by pretreating the vessel with phentolamine. At concentrations used clinically, halothane did not affect overall developed tension in response to exogenously applied norepinephrine. However, 1.5% (0.49 mM) halothane decreased both sarcoplasmic-reticulum-dependent oscillations in tension and electrically induced release of endogenous norepinephrine.

Animals↗
PubMed1991

Role of the kinin-kallikrein system in the vasodilator action of an angiotensin converting enzyme inhibitor (captopril) on the systemic resistance and capacitance vessels of dogs.

We investigated the vasodilator effects of captopril (CAP) on the systemic capacitance and resistance vessels by measuring changes in the mean circulatory pressure (MCP) and total peripheral resistance (TPR) that occurred in response to the intravenous injection of CAP (1 mg/kg) in open-chest dogs. The following five groups of dogs received CAP: (1) Group of untreated dogs, (2) TSA Group in which the dogs were subjected to total spinal anesthesia (TSA), (3) Ang II Group in which the dogs received a continuous intravenous infusion of angiotensin II (Ang II), (4) APR + Ang II Group in which the dogs received a continuous intravenous infusion of Ang II after pretreatment with aprotinin (APR, 25,000 K.I.E.), a kallikrein inhibitor, and (5) IND + APR + Ang II Group in which the dogs received a continuous intravenous infusion of Ang II after pretreatment with indomethacin (IND, 5 mg/kg), a prostaglandin synthesis inhibitor, and APR. 1) CAP significantly decreased TPR and MCP in the untreated Group. 2) CAP significantly decreased TPR and MCP in the TSA Group. There were no significant differences in percentage change of TPR (% delta TPR) and percentage change of MCP (% delta MCP) between the untreated and TSA Groups. 3) In the Ang II Group, CAP decreased the elevated TPR significantly, but hardly affected the elevated MCP. 4) CAP significantly decreased TPR without significant change in MCP in the APR + Ang II Group. The % delta TPR was significantly smaller in this Group than in the Ang II Group. 5) CAP significantly decreased TPR without significant change in MCP in the IND + APR + Ang II Group.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1996

ATP-sensitive potassium channels in cultured arterial segments.

Organ cultures of arteries have been used to study growth responses, proliferation, and contractility. However, the function of specific-ion channels in cultured arteries has not been investigated. ATP-sensitive K+ (KATP) channels play an important role in the control of arterial tone. The goal of this study was to determine the functional state of KATP channels in arteries kept in culture. Segments from rabbit mesenteric arteries were cultured in for 2-7 days. To explore the properties of KATP channels, the effects of KATP-channel modulators and other vasoactive substances on isometric force, density, and modulation of KATP currents in single smooth muscle cells isolated from cultured vessels were examined. Isometric contractions were measured with a resistance-vessel myograph. Whole cell KATP currents were recorded with the patch-clamp technique. Membrane capacitance and KATP-current density in single smooth muscle cells from freshly dissected (control) and cultured arteries were not altered. At -60 mV, glibenclamide-sensitive currents in the presence of the K(+)-channel opener pinacidil were -4.7 +/- 1.2, -4.7 +/- 0.6, and -4.6 +/- 0.7 pA/pF for control and 2- and 4-day arteries, respectively. Inhibitory modulation of KATP currents in arterial smooth muscle also remained intact for 4 days in culture; the vasoconstrictor histamine (10 microM) reduced glibenclamide-sensitive currents in the presence of pinacidil by 61.2 +/- 2.8, 42.4 +/- 10.1, and 41.2 +/- 6.1% for control and 2- and 4-day arteries, respectively. Pinacidil relaxed control and cultured arteries (1-7 days) in a dose-dependent manner. Half-maximal effective concentrations of pinacidil were 0.42, 0.24, 0.23, and 0.51 microM for control and 2-, 4-, and 7-day arteries, respectively, whereas maximal relaxations to pinacidil were 62.9, 47.5, 37.5, and 55.7% for control and 2-, 5-, and 7-day arteries, respectively. Histamine, norepinephrine, and serotonin constricted cultured arteries, although responses to histamine and norepinephrine diminished by 30-50% after 5 days in culture. The relaxant effect of acetylcholine was not maintained in cultured arteries. Sodium nitroprusside, however, effectively relaxed arteries cultured for 2-7 days. The data indicate that with the culture model described, KATP channels in arterial smooth muscle remained functional and contractile responses in arterial segments were maintained for up to 7 days. These results suggest that this approach can be used to study either long-term regulation of KATP channels or the role of this channel type in growth responses.

Acetylcholine↗
PubMed1999

Changes in resistance vessels during hemorrhagic shock and resuscitation in conscious hamster model.

The unanesthetized hamster dorsal skinfold preparation was used to monitor diameters and blood flow rates in resistance arteries (small arteries, A0: diameter, 156 +/- 23 micrometers) and capacitance vessels (small veins, V0: 365 +/- 64 micrometers), during 45 min of hemorrhagic shock at 40 mmHg mean arterial pressure (MAP) and resuscitation. A0 and V0 vessels constricted significantly to 52 and 70% of the basal values, respectively, whereas precapillary arterioles (A1-A4, 8-60 micrometers) and collecting venules (VC-VL, 26-80 micrometers) did not change or tended to dilate. Blood flow rates in the microvessels declined to <20% of the basal values. Resuscitation with shed autologous blood (SAB) showed incomplete recovery of A0 and V0 diameters even 2 h after resuscitation (71 +/- 14% and 81 +/- 18%, respectively, of basal value), whereas other vessels did not change significantly. The behavior of A0 diameter coincided with the incomplete recovery of blood flow rates in all the vessels (ca. 50%) according to Poiseuille's law, and the incomplete recovery of functional capillary density (ca. 75%). Resuscitation with 8% human serum albumin in saline (HSA) tended to show higher levels of A0 constriction and A4 dilation and lowered blood flow rates. Resuscitation with SAB restored tissue PO2 27 +/- 10 mmHg after 2 h, which was near control levels (28 +/- 5 mmHg), whereas resuscitation with HSA caused tissue PO2 to remain significantly depressed (6 +/- 2 mmHg), and flow rates were significantly lower than resuscitation with SAB. These results indicate that response of the A0 vessels is the crucial determinant of blood flow in the observed area. The constriction of A0 may help sustain MAP, and constriction of V0 may enhance blood redistribution from the skin to the vital organs under the hypotensive condition.

Animals↗
PubMed2003

Mitochondria efficiently buffer subplasmalemmal Ca2+ elevation during agonist stimulation.

In endothelial cells, local Ca(2+) release from superficial endoplasmic reticulum (ER) activates BK(Ca) channels. The resulting hyperpolarization promotes capacitative Ca(2+) entry (CCE), which, unlike BK(Ca) channels, is inhibited by high Ca(2+). To understand how the coordinated activation of plasma membrane ion channels with opposite Ca(2+) sensitivity is orchestrated, the individual contribution of mitochondria and ER in regulation of subplasmalemmal Ca(2+) concentration ([Ca(2+)](pm)) was investigated. For organelle visualization, cells were transfected with DsRed and yellow cameleon targeted to mitochondria and ER. The patch pipette was placed far from any organelle (L1), close to ER (L3), or mitochondria (L2) and activity of BK(Ca) channels was used to estimate local [Ca(2+)](pm). Under standard patch conditions (130 mm K(+) in the bath), histamine increased [Ca(2+)](pm) at L1 and L3 to approximately 1.6 microm, whereas close to mitochondria [Ca(2+)](pm) remained unchanged. If mitochondria moved apart from the pipette or in the presence of carbonyl cyanide-4-trifluoromethoxyphenylhyrazone, [Ca(2+)](pm) at L2 increased in response to histamine. Under standard patch conditions Ca(2+) entry was negligible due to cell depolarization. Using a physiological patch approach (5.6 mm K(+) in the bath), changes in [Ca(2+)](pm) to histamine could be monitored without cell depolarization and, thus, in conditions where Ca(2+) entry occurred. Here, histamine induced an initial transient Ca(2+) elevation to > or =3.5 microm followed by a long lasting plateau at approximately 1.2 microm in L1 and L3, whereas mitochondria kept neighboring [Ca(2+)](pm) low during stimulation. Thus, superficial mitochondria and ER generate local domains of low and high Ca(2+) allowing simultaneous activation of BK(Ca) and CCE, despite their opposite Ca(2+) sensitivity.

Buffers↗
PubMed2004

Plantar vibration improves leg fluid flow in perimenopausal women.

Recent studies have indicated that plantar-based vibration may be an effective approach for the prevention and treatment of osteoporosis. We addressed the hypothesis of whether the plantar vibration operated by way of the skeletal muscle pump, resulting in enhanced blood and fluid flow to the lower body. We combined plantar stimulation with upright tilt table testing in 18 women aged 46-63 yr. We used strain-gauge plethysmography to measure calf blood flow, venous capacitance, and the microvascular filtration relation, as well as impedance plethysmography to examine changes in leg, splanchnic, and thoracic blood flow while supine at a 35 degrees upright tilt. A vibrating platform was placed on the footboard of a tilt table, and measurements were made at 0, 15, and 45 Hz with an amplitude of 0.2 g point to point, presented in random order. Impedance-measured supine blood flows were significantly (P = 0.05) increased in the calf (30%), pelvic (26%), and thoracic regions (20%) by plantar vibration at 45 Hz. Moreover, the 25-35% decreases in calf and pelvic blood flows associated with upright tilt were reversed by plantar vibration, and the decrease in thoracic blood flow was significantly attenuated. Strain-gauge measurements showed an attenuation of upright calf blood flow. In addition, the microvascular filtration relation was shifted with vibration, producing a pronounced increase in the threshold for edema, P(i), due to enhanced lymphatic flow. Supine values for P(i) increased from 24 +/- 2 mmHg at 0 Hz to 27 +/- 3 mmHg at 15 Hz, and finally to 31 +/- 2 mmHg at 45 Hz (P < 0.01). Upright values for P(i) increased from 25 +/- 3 mmHg at 0 Hz, to 28 +/- 4 mmHg at 15 Hz, and finally to 35 +/- 4 mmHg at 45 Hz. The results suggest that plantar vibration serves to significantly enhance peripheral and systemic blood flow, peripheral lymphatic flow, and venous drainage, which may account for the apparent ability of such stimuli to influence bone mass.

Blood Pressure↗
PubMed2005

Histamine-mediated increases in cytosolic [Ca2+] involve different mechanisms in human pulmonary artery smooth muscle and endothelial cells.

Agonist stimulation of human pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) with histamine showed similar spatiotemporal patterns of Ca(2+) release. Both sustained elevation and oscillatory patterns of changes in cytosolic Ca(2+) concentration ([Ca(2+)](cyt)) were observed in the absence of extracellular Ca(2+). Capacitative Ca(2+) entry (CCE) was induced in PASMC and PAEC by passive depletion of intracellular Ca(2+) stores with 10 microM cyclopiazonic acid (CPA; 15-30 min). The pyrazole derivative BTP2 inhibited CPA-activated Ca(2+) influx, suggesting that depletion of CPA-sensitive internal stores is sufficient to induce CCE in both PASMC and PAEC. The recourse of histamine-mediated Ca(2+) release was examined after exposure of cells to CPA, thapsigargin, caffeine, ryanodine, FCCP, or bafilomycin. In PASMC bathed in Ca(2+)-free solution, treatment with CPA almost abolished histamine-induced rises in [Ca(2+)](cyt). In PAEC bathed in Ca(2+)-free solution, however, treatment with CPA eliminated histamine-induced sustained and oscillatory rises in [Ca(2+)](cyt) but did not affect initial transient increase in [Ca(2+)](cyt). Furthermore, treatment of PAEC with a combination of CPA (or thapsigargin) and caffeine (and ryanodine), FCCP, or bafilomycin did not abolish histamine-induced transient [Ca(2+)](cyt) increases. These observations indicate that 1) depletion of CPA-sensitive stores is sufficient to cause CCE in both PASMC and PAEC; 2) induction of CCE in PAEC does not require depletion of all internal Ca(2+) stores; 3) the histamine-releasable internal stores in PASMC are mainly CPA-sensitive stores; 4) PAEC, in addition to a CPA-sensitive functional pool, contain other stores insensitive to CPA, thapsigargin, caffeine, ryanodine, FCCP, and bafilomycin; and 5) although the CPA-insensitive stores in PAEC may not contribute to CCE, they contribute to histamine-mediated Ca(2+) release.

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