Heterogeneous populations of K+ channels mediate EDRF release to flow but not agonists in rabbit aorta

1994 ◽  
Vol 266 (2) ◽  
pp. H590-H596 ◽  
Author(s):  
I. R. Hutcheson ◽  
T. M. Griffith
Keyword(s):  
Shear Stress ◽  
Rabbit Aorta ◽  
Katp Channels ◽  
K Channel ◽  
K Channels ◽  
Kca Channels ◽  
Endothelium Derived Relaxing Factor ◽  
Endothelium Dependent Relaxation ◽  
High Conductance

We have investigated the role of Ca(2+)- and ATP-sensitive K+ channels (KCa and KATP, respectively) in flow- and agonist-stimulated release of endothelium-derived relaxing factor (EDRF). Segments of rabbit abdominal aorta, perfused at constant flow with buffer containing indomethacin, were used as a source of EDRF in cascade bioassay, and responses to endothelium-dependent agonists were studied isometrically in rings of the same tissue in the absence of flow. Apamin, charybdotoxin (ChTX), and tetraethylammonium (TEA) were used to block a variety of low, medium, and high conductance KCa channels, and glibenclamide was used to block KATP channels. The effects of flow pulsatility were studied at pulse frequencies ranging from 0.15 to 9.75 Hz, and time-averaged shear stress was manipulated by adding dextran (80,000 mol wt) to the perfusate to increase its viscosity. Frequency-related EDRF release was maximal at approximately 5 Hz and attenuated by apamin, TEA, and ChTX, but not by glibenclamide. EDRF release stimulated by increased viscosity was attenuated by TEA, ChTX, and glibenclamide, but not by apamin. In marked contrast, EDRF release stimulated by acetylcholine and ATP was unaffected by blockade of either KCa or KATP channels. We conclude that a spectrum of KCa channel subtypes mediates endothelial transduction of the oscillatory component of pulsatile flow and that KATP channels may be additionally involved in the transduction of time-averaged shear stress. In contrast, agonist-stimulated endothelium-dependent relaxation is independent of K+ channel activation in rabbit aorta.

Enhanced role of K+ channels in relaxations of hypercholesterolemic rabbit carotid artery to NO

1995 ◽  
Vol 269 (3) ◽  
pp. H805-H811 ◽  
Author(s):  
S. Najibi ◽  
R. A. Cohen
Keyword(s):  
Carotid Artery ◽  
Sodium Nitroprusside ◽  
Channel Blocker ◽  
Isometric Tension ◽  
K Channel ◽  
K Channels ◽  
Rabbit Carotid Artery ◽  
Cyclic Monophosphate ◽  
Endothelium Dependent Relaxation

Endothelium-dependent relaxations to acetylcholine remain normal in the carotid artery of hypercholesterolemic rabbits, but unlike endothelium-dependent relaxations of normal rabbits, they are inhibited by charybdotoxin, a specific blocker of Ca(2+)-dependent K+ channels. Because nitric oxide (NO) is the mediator of endothelium-dependent relaxation and can activate Ca(2+)-dependent K+ channels directly or via guanosine 3',5'-cyclic monophosphate, the present study investigated the role of Ca(2+)-dependent K+ channels in relaxations caused by NO, sodium nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-Brc-GMP) in hypercholesterolemic rabbit carotid artery. Isometric tension was measured in rabbit carotid artery denuded of endothelium from normal and hypercholesterolemic rabbits which were fed 0.5% cholesterol for 12 wk. Under control conditions, relaxations to all agents were similar in normal and hypercholesterolemic rabbit arteries. Charybdotoxin had no significant effect on relaxations of normal arteries to NO, sodium nitroprusside, or 8-BrcGMP, but the Ca(2+)-dependent K+ channel blocker significantly inhibited the relaxations caused by each of these agents in the arteries from hypercholesterolemic rabbits. By contrast, relaxations to the calcium channel blocker nifedipine were potentiated to a similar extent by charybdotoxin in both groups. In addition, arteries from hypercholesterolemic rabbits relaxed less than normal to sodium nitroprusside when contracted with depolarizing potassium solution. These results indicate that although nitrovasodilator relaxations are normal in the hypercholesterolemic rabbit carotid artery, they are mediated differently, and to a greater extent, by Ca(2+)-dependent K+ channels. These data also suggest that K+ channel-independent mechanism(s) are impaired in hypercholesterolemia.

Endothelium-dependent vasodilation by melittin: are lipoxygenase products involved?

1985 ◽  
Vol 249 (1) ◽  
pp. H14-H19 ◽  
Author(s):  
U. Forstermann ◽  
B. Neufang
Keyword(s):  
Fatty Acids ◽  
Arachidonic Acid ◽  
Polyunsaturated Fatty Acids ◽  
Rabbit Aorta ◽  
Membrane Phospholipids ◽  
Endothelium Derived Relaxing Factor ◽  
Potential Inhibitors ◽  
Endothelium Dependent Relaxation ◽  
Acid Compound

Vascular relaxation in response to acetylcholine and other vasodilator compounds has been shown to depend on intact endothelial cells. These dilator compounds obviously induce the formation of an unstable endothelium-derived relaxing factor or factors (EDRF) from the intima which relax the subjacent smooth muscle cells. The chemical identity of this factor (these factors) is still unclear. In the present study we demonstrate that endothelium-dependent relaxation of rabbit aorta was induced by melittin, a polypeptide toxin that activates phospholipase A2 to liberate polyunsaturated fatty acids (especially arachidonic acid) from membrane phospholipids. The relaxation induced by melittin had several properties similar to the acetylcholine relaxation. It was inhibited by potential inhibitors of phospholipase (mepacrine and p-bromophenacylbromide), by inhibitors of lipoxygenase (nordi-hydroguaiaretic acid, compound BW 755C, and 5,8,11,14-eicosatetraynoic acid) but not by the cyclooxygenase inhibitor indomethacin. An exogenous preparation of phospholipase C also induced endothelium-dependent relaxations. These findings support the hypothesis that oxidized metabolites of polyunsaturated fatty acids (e.g., arachidonic acid) may be involved directly (as mediators) or indirectly in the process of endothelium-dependent relaxation. On the other hand, exogenous arachidonic acid was a comparatively weak endothelium-dependent relaxant. However, this does not exclude an important role of endogenous arachidonic acid since the exogenous acid may not sufficiently reach its site of metabolism.

Effect of basolateral or apical hyposmolarity on apical maxi K channels of everted rat collecting tubule

1995 ◽  
Vol 268 (4) ◽  
pp. F569-F580 ◽  
Author(s):  
L. C. Stoner ◽  
G. E. Morley
Keyword(s):  
Apical Membrane ◽  
Physiological Role ◽  
Reversal Potential ◽  
K Channel ◽  
Apical Surface ◽  
Open Probability ◽  
Volume Regulatory Decrease ◽  
Collecting Tubules ◽  
High Conductance

We are able to evert and perfuse rat cortical collecting tubules (CCT) at 37 degrees C. Patch-clamp techniques were used to study high-conductance potassium channels (maxi K) on the apical membrane. Under control conditions (150 mM Na+ and 5 mM K+ in pipette and bathing solutions), the slope conductance averaged 109.8 +/- 6.6 pS (12 channels), and reversal potential (expressed as pipette voltage) was +26.3 +/- 2.4 mV. The percent of time the channel spends in the open state and unitary current when voltage was clamped to 0 mV were 1.4 +/- 0.7% and 3.12 +/- 0.42 pA, respectively. In six patches voltage clamped to 0 mV, the isosmotic solution perfused through the everted tubule (basolateral surface) was exchanged for one made 70 mosmol/kgH2O hyposmotic to the control saline. Open probability increased from 0.019 to 0.258, an increase of 0.239 +/- 0.065 (P ' 0.005). In four patches where a maxi K channel was evident, no increase in open probability was observed when a hyposmotic saline was placed on the apical surface. However, when vasopressin was present on the basolateral surface, apical application of hyposmotic saline resulted in a series of bursts of channel activity. The average increase in open probability during bursts was (0.055 +/- 0.017, P < 0.005). We conclude that one function of the maxi K channel located in the apical membrane of the rat CCT may be to release intracellular solute (potassium) during a volume regulatory decrease induced by placing a dilute solution on the basolateral surface or when the apical osmolarity is reduced in the presence of vasopressin. These data are consistent with the hypothesis that the physiological role of the channel is to regulate cell volume during water reabsorption.

scholarly journals Allosteric effects of Mg2+ on the gating of Ca2+-activated K+ channels from mammalian skeletal muscle

1986 ◽  
Vol 124 (1) ◽  
pp. 5-13
Author(s):  
J. Golowasch ◽  
A. Kirkwood ◽  
C. Miller
Keyword(s):  
Binding Sites ◽  
Hill Coefficient ◽  
K Channel ◽  
Activation Process ◽  
Mammalian Skeletal Muscle ◽  
Activation Curve ◽  
K Channels ◽  
The Hill ◽  
Cytoplasmic Side ◽  
High Conductance

Ca2+-activated K+ channels from rat muscle transverse tubule membranes were inserted into planar phospholipid bilayers, and the activation of these channels by Ca2+ was studied. On the cytoplasmic side of the channel, calcium ions (in the range 10–100 mumol l-1) increase the opening probability of the channel in a graded way. This ‘activation curve’ is sigmoid, with an average Hill coefficient of about 2. Magnesium ions, in the range 1–10 mmol l-1, increase the apparent affinity of the channel for Ca2+ and greatly enhance the sigmoidicity of the Ca2+ activation curve. In the presence of 10 mmol l-1 Mg2+, the Hill coefficient for Ca2+ activation is about 4.5. This effect depends upon Mg2+ concentration but not upon applied voltage. Mg2+ is effective only when added to the cytoplasmic side of the channel. The results argue that this high-conductance, Ca2+-activated K+ channel contains at least six Ca2+-binding sites involved in the activation process.

Maturational changes in endothelium-derived relaxations in newborn piglet pulmonary circulation

1993 ◽  
Vol 264 (2) ◽  
pp. H302-H309 ◽  
Author(s):  
T. Perreault ◽  
J. De Marte
Keyword(s):  
Sodium Nitroprusside ◽  
Pulmonary Circulation ◽  
Newborn Piglet ◽  
Pulmonary Vasculature ◽  
K Channel ◽  
Age Difference ◽  
K Channels ◽  
Vasoactive Substances ◽  
Dose Dependent

It is accepted knowledge that the endothelium can profoundly affect vascular tone through the release of vasoactive substances. The maturational changes in the role of the endothelium-derived relaxing factor (EDRF) and ATP-dependent K+ channels in the neonatal pulmonary circulation were investigated in isolated perfused lungs from 1- and 7-day-old piglets. The EDRF inhibitor, N omega-nitro-L-arginine (L-NNA), had potent dose-dependent constrictor effects on the pulmonary vasculature with normal and raised tone. The constrictor effect of L-NNA was greater (P < 0.05) in the 1-day-old than in the 7-day-old lungs and was significantly (P < 0.005) attenuated by pretreatment with the EDRF precursor, L-arginine. Furthermore, we studied the possibility of developmental changes in the sensitivity of smooth muscle cells to EDRF by testing sodium nitroprusside, nitric oxide, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP). All caused a decrease in perfusion pressure, but only sodium nitroprusside elicited a greater (P < 0.01) effect in the 1-day-old. Endothelin-1 (ET-1) and bradykinin (BK) elicited dilator responses that were significantly (P < 0.05) reduced in the presence of L-NNA. Interestingly, the dilator response to ET-1 was more marked (P < 0.001) in the younger group, whereas no age difference was noted with BK. Finally, lemakalim, a K+ channel activator, caused a vasodilation of equal magnitude at both ages. In summary, EDRF and ATP-dependent K+ channels appear to play a role in the control of the newborn piglet pulmonary vasculature.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Role of 20-HETE in mediating the effect of dietary K intake on the apical K channels in the mTAL

2001 ◽  
Vol 280 (2) ◽  
pp. F223-F230 ◽  
Author(s):  
Ruimin Gu ◽  
Yuan Wei ◽  
Houli Jiang ◽  
Michael Balazy ◽  
Wenhui Wang
Keyword(s):  
Gas Chromatography Mass Spectrometry ◽  
K Channel ◽  
Thick Ascending Limb ◽  
Patch Clamp Technique ◽  
Open Probability ◽  
Deficient Diet ◽  
K Channels ◽  
Medullary Thick Ascending Limb ◽  
High K

We have used the patch-clamp technique to study the effect of dietary K intake on the apical K channels in the medullary thick ascending limb (mTAL) of rat kidneys. The channel activity, defined by the number of channels in a patch and the open probability ( NP o), of the 30- and 70-pS K channels, was 0.18 and 0.11, respectively, in the mTAL from rats on a K-deficient diet. In contrast, NP o of the 30- and 70-pS K channels increased to 0.60 and 0.80, respectively, in the tubules from animals on a high-K diet. The concentration of 20-hydroxyeicosatetraenoic acid (20-HETE) measured with gas chromatography-mass spectrometry was 0.8 pg/μg protein in the mTAL from rats on a high-K diet and increased significantly to 4.6 pg/μg protein in the tubules from rats on a K-deficient diet. Addition of N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS) or 17-octadecynoic acid (17-ODYA), agents that inhibit the formation of 20-HETE, had no significant effect on the activity of the 30-pS K channels. However, DDMS/17-ODYA significantly increased the activity of the apical 70-pS K channel from 0.11 to 0.91 in the mTAL from rats on a K-deficient diet. In contrast, inhibition of the cytochrome P-450 metabolism of arachidonic acid increased NP o from 0.64 to 0.81 in the tubules from animals on a high-K diet. Furthermore, the sensitivity of the 70-pS K channel to 20-HETE was the same between rats on a high-K diet and on a K-deficient diet. Finally, the pretreatment of the tubules with DDMS increased NP o of the 70-pS K channels in the mTAL from rats on a K-deficient diet to 0.76. We conclude that an increase in 20-HETE production is involved in reducing the activity of the apical 70-pS K channels in the mTAL from rats on a K-deficient diet.

Mild Alkalinization and Acidification Differentially Modify the Effects of Lidocaine or Mexiletine on Vasorelaxation Mediated by ATP-sensitive K+Channels

2001 ◽  
Vol 95 (1) ◽  
pp. 200-206 ◽  
Author(s):  
Hiroyuki Kinoshita ◽  
Hiroshi Iranami ◽  
Yoshiki Kimoto ◽  
Mayuko Dojo ◽  
Yoshio Hatano
Keyword(s):  
Adenosine Triphosphate ◽  
Isometric Force ◽  
Inhibitory Effect ◽  
Rat Aorta ◽  
Ringer Solution ◽  
K Channel ◽  
K Channels ◽  
Blocking Effects ◽  
Ion Channel Blocking

Background The previous study by the authors showed that the class Ib antiarrhythmic drug lidocaine impairs but mexiletine augments vasorelaxation mediated by adenosine triphosphate-sensitive K+ channels. Lidocaine and mexiletine have different values of the negative logarithm of the drug-proton dissociation constant, indicating that the ion channel-blocking effects of these drugs under different pH levels may vary. However, the role of pH in the effects of lidocaine and mexiletine on vasodilation mediated by K+ channels has not been studied. Therefore, the current study was designed to examine whether the inhibition and augmentation of vasorelaxation in response to an adenosine triphosphate-sensitive K+ channel opener, levcromakalim, by the clinically relevant concentrations of lidocaine or mexiletine are modified by mild alkalinization or acidification in the isolated rat aorta. Methods Rings of the rat aorta without endothelium were suspended for isometric force recording. Three types of modified Krebs-Ringer solutions (pH 7.2, 7.4, and 7.6) were prepared by changing the composition of NaCl and NaHCO3. During contractions in response to phenylephrine (3 x 10(-7) M), relaxations in response to levcromakalim (10(-8) to 10(-5) M) were obtained. Lidocaine (10(-5) to 10(-4) M), mexiletine (10(-5) to 10(-4) M), or glibenclamide (10(-5) M) was applied 15 min before addition of phenylephrine. Results Relaxations in response to levcromakalim, which are abolished by the selective adenosine triphosphate-sensitive K+ channel antagonist glibenclamide (10(-5) M), were not different among the three pH groups. In the normal Krebs-Ringer solution of pH 7.4, lidocaine significantly reduced these relaxations in a concentration-dependent fashion. Alkalinization of pH 7.6 augmented the inhibitory effect of lidocaine on these relaxations, whereas acidification of pH 7.2 substantially abolished this effect. In contrast, mexiletine pH independently augmented relaxations in response to levcromakalim. Glibenclamide (10(-5) M) abolished these relaxations in arteries treated with mexiletine (10(-4) M) in any pH group. Conclusions These results suggest that even under conditions of such mild alkalosis or acidosis, vasorelaxation via adenosine triphosphate-sensitive K+ channels is dependent on pH in the presence of clinically relevant concentrations of lidocaine but not mexiletine.

Role of ATP-sensitive K+ channels in cGMP-mediated pial artery vasodilation

1996 ◽  
Vol 270 (2) ◽  
pp. H423-H426 ◽  
Author(s):  
W. M. Armstead
Keyword(s):  
Soluble Guanylate Cyclase ◽  
K Channel ◽  
K Channels ◽  
Control Value ◽  
Cranial Window ◽  
Pial Artery ◽  
Newborn Pigs ◽  
Percentage Basis ◽  
Ly 83583

The present study was designed to investigate the role of ATP-sensitive K+ channels in guanosine 3',5'-cyclic monophosphate (cGMP)-mediated pial artery vasodilation in newborn pigs equipped with a closed cranial window. Sodium nitroprusside (SNP) (10(-8), 10(-6) M), a nitrovasodilator, elicited pial artery dilation that was attenuated by the ATP-sensitive K+ channel antagonist glibenclamide (10(-6) M). On a percentage basis, these responses were 25 +/- 1% for the presence of SNP (10(-6) M) alone, whereas 15 +/- 1% dilation was observed for SNP (10(-6) M) in the presence of glibenclamide (n = 5 pigs). Dilation produced by the cGMP analogue, 8-BrcGMP (10(-8), 10(-6) M), was similarly attenuated by glibenclamide. SNP-induced pial dilation was accompanied by increased cortical periarachnoid cerebrospinal fluid (CSF) cGMP levels, and these biochemical changes were blocked by the soluble guanylate cyclase inhibitor, LY-83583 (10(-5) M). SNP (10(-6) M) alone increased CSF cGMP concentration from 407 +/- 14 to 956 +/- 41 fmol/ml, whereas SNP in the presence of LY-83583 yielded a CSF cGMP concentration of 340 +/- 13, which was no different from the control value of 335 +/- 23 fmol/ml (n = 5 pigs). SNP-induced pial dilation was blunted by LY-83583, whereas 8-BrcGMP-induced dilation was unchanged. Cromakalim (10(-8), 10(-6) M), an ATP-sensitive K+ channel agonist, produced dilation that was blocked by glibenclamide (24 +/- 1 vs. 5 +/- 1% for cromakalim 10(-6) M, in the absence and presence of glibenclamide, respectively, n = 5). These data indicate that activation of ATP-sensitive K+ channels contribute to cGMP-mediated pial artery dilation.

scholarly journals Endothelium-dependent responses in human isolated thyroid arteries from donors

2004 ◽  
Vol 181 (3) ◽  
pp. 379-384 ◽  
Author(s):  
B Torondel ◽  
JM Vila ◽  
G Segarra ◽  
P Lluch ◽  
P Medina ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Dominant Role ◽  
Human Thyroid ◽  
K Channel ◽  
Organ Donors ◽  
Inhibitory Effects ◽  
K Channels ◽  
High K ◽  
Inwardly Rectifying ◽  
Endothelium Dependent Relaxation

The functional properties of the endothelium of human thyroid arteries remain unexplored. We investigated the intervention of nitric oxide (NO), prostacyclin (PGI(2)) and endothelium-derived hyperpolarizing factor (EDHF) in the responses to acetylcholine and noradrenaline in isolated thyroid arteries obtained from multi-organ donors. Artery rings were suspended in organ baths for isometric recording of tension. The contribution of NO, PGI(2) and EDHF to endothelium-dependent relaxation was determined by the inhibitory effects of N(G)-monomethyl-L-arginine (L-NMMA), indomethacin, and K(+) channel inhibitors respectively. Acetylcholine induced concentration-dependent relaxation; this effect was not modified by indomethacin and was only partly reduced by L-NMMA, but was abolished in endothelium-denuded rings. The relaxation resistant to indomethacin and L-NMMA was abolished by using either apamin combined with charybdotoxin, ouabain plus barium, or a high-K(+) solution. Noradrenaline induced concentration-dependent contractions which were of greater magnitude in arteries denuded of endothelium or in the presence of L-NMMA.In conclusion, the results indicate that in human thyroid arteries the endothelium significantly modulates responses to acetylcholine and noradrenaline through the release of NO and EDHF. EDHF plays a dominant role in acetylcholine-induced relaxation through activation of Ca(2+)-activated K(+) channels, inwardly rectifying K(+) channels and Na(+)-K(+)-ATPase.

Role of glycolytic and oxidative metabolism in endothelium-dependent relaxation in isolated rabbit aorta

1992 ◽  
Vol 26 ◽  
pp. 248
Author(s):  
Maurizio Cappelli-Bigazzi ◽  
Giuseppe Ambrosio ◽  
Carmine Battaglia ◽  
Massimo Chiariello
Keyword(s):  
Oxidative Metabolism ◽  
Rabbit Aorta ◽  
Isolated Rabbit Aorta ◽  
Endothelium Dependent Relaxation
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