ISCHAEMIA ENHANCES THE ROLE OF CA2+-ACTIVATED K+ CHANNELS IN ENDOTHELIUM-DEPENDENT AND NITRIC OXIDE-MEDIATED DILATATION OF THE RAT HINDQUARTERS VASCULATURE (original) (raw)
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Clinical and experimental …, 2004
1. We compared the effects of the nitric oxide synthase inhibitor N G -nitro-L -arginine ( L -NOARG) and tetraethylammonium (TEA), a blocker of large conductance Ca 2+activated K + (BK Ca ) channels, on vasodilator responses to endothelium-dependent (acetylcholine; ACh) and -independent (sodium nitroprusside; SNP) vasodilators. The mechanism of the vasodilator responses was determined in rat hindquarters under normal conditions (sham ischaemia) and after 2 h ischaemia followed by reperfusion with physiological saline.
Canadian Journal of Physiology and Pharmacology, 2012
The vascular endothelium plays a critical role in vascular health by controlling arterial diameter, regulating local cell growth, and protecting blood vessels from the deleterious consequences of platelet aggregation and activation of inflammatory responses. Circulating chemical mediators and physical forces act directly on the endothelium to release diffusible relaxing factors, such as nitric oxide (NO), and to elicit hyperpolarization of the endothelial cell membrane potential, which can spread to the surrounding smooth muscle cells via gap junctions. Endothelial hyperpolarization, mediated by activation of calcium-activated potassium (K Ca ) channels, has generally been regarded as a distinct pathway for smooth muscle relaxation. However, recent evidence supports a role for endothelial K Ca channels in production of endothelium-derived NO, and indicates that pharmacological activation of these channels can enhance NO-mediated responses. In this review we summarize the current data on the functional role of endothelial K Ca channels in regulating NO-mediated changes in arterial diameter and NO production, and explore the tempting possibility that these channels may represent a novel avenue for therapeutic intervention in conditions associated with reduced NO availability such as hypertension, hypercholesterolemia, smoking, and diabetes mellitus.
Journal of Human Hypertension, 2007
In human essential hypertension (EH), endothelium-dependent relaxation can occur independent of nitric oxide (NO) and prostacyclin (PGI 2). Recent in vivo data suggest that rapid compensatory upregulation of endothelial cytochrome P450 epoxygenase 2C9 occurs to preserve vasorelaxation under conditions of decreased NO bioavailability. As one of the vascular actions of CYP2C9 is to modulate small and intermediate conductance endothelial calcium-activated potassium channels (SK Ca and IK Ca), we examined whether endothelium-dependent relaxation is sensitive to inhibitors of these channels (apamin and charybdotoxin) in resistance-sized vessels from human with EH. Subcutaneous gluteal biopsies were performed on 12 humans with EH and 12 matched control subjects. Resistance arteries were dissected and relaxation responses to carbachol were assessed ex vivo using wire myography in the presence of: (i) N G-nitro-L-arginine (L-NOARG)/indomethacin; and (ii) apamin/charybdotoxin. Maximal carbachol relaxation was impaired in EH vs control subjects. No differences in responses were observed with the endothelium-independent agonist, Snitroso-N-acetyl-penicillamine. Relaxation to carbachol was attenuated following incubation with L-NOARG/indomethacin in vessels from control subjects (Po0.01 analysis of variance (ANOVA)), but not in vessels from patients with EH. The reverse pattern was seen following apamin/charybdotoxin with carbachol relaxation attenuated only in EH vessels (Po0.001 ANOVA). Endotheliumdependent relaxation is resistant to endothelial nitric oxide synthase inhibition but sensitive to blockade of calciumactivated potassium channels in human EH. Studies with more specific inhibitors are required to determine whether this response is mediated by endothelial potassium channel subtypes (SK Ca and IK Ca).
Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator
Journal of Clinical Investigation, 1991
Flow-mediated vasodilation is endothelium dependent. We hypothesized that flow activates a potassium channel on the endothelium, and that activation of this channel leads to the release of the endogenous nitrovasodilator, nitric oxide. To test this hypothesis, rabbit iliac arteries were perfused at varying flow rates, at a constant pressure of 60 mm Hg. Increments in flow induced proportional increases in vessel diameter, which were abolished by LN-mono-methylarginine (the antagonist of nitric-oxide synthesis). Barium chloride, depolarizing solutions of potassium, verapamil, calcium-free medium, and antagonists of the Kc. channel (charybdotoxin, iberiotoxin) also blocked flow-mediated vasodilation. Conversely, responses to other agonists of endothelium-dependent and independent vasodilation were unaffected by charybdotoxin or iberiotoxin. To confirm that flow activated a specific potassium channel to induce the release of nitric oxide, endothelial cells cultured on microcarrier beads were added to a flow chamber containing a vascular ring without endothelium. Flow-stimulated endothelial cells released a diffusible vasodilator, the degree of vasorelaxation was dependent upon the flow rate. Relaxation was abrogated by barium, tetraethylammonium ion, or charybdotoxin, but was not affected by apamin, glybenclamide, tetrodotoxin, or ouabain. The data suggest that transmission of a hyperpolarizing current from endothelium to the vascular smooth muscle is not necessary for flow-mediated vasodilation. Flow activates a potassium channel (possibly the Kc. channel) on the endothelial cell membrane that leads to the release of nitric oxide.
Circulation, 2006
Background-During septic shock, the vasoconstrictor response to norepinephrine is seriously blunted. Animal experiments suggest that hyperpolarization of smooth muscle cells by opening of potassium (K) channels underlies this phenomenon. In the present study, we examined whether K-channel blockers and/or nitric oxide (NO) synthase inhibition could restore norepinephrine sensitivity during experimental human endotoxemia. Methods and Results-Volunteers received 2 ng/kg Escherichia coli endotoxin intravenously. Forearm blood flow (FBF) was measured with venous occlusion plethysmography. Infusion of 4 dose steps of norepinephrine into the brachial artery decreased the FBF ratio (ratio of FBF in the experimental arm to FBF in the control arm) to 84Ϯ4%, 70Ϯ4%, 55Ϯ4%, and 38Ϯ4% (meanϮSEM) of its baseline value. After endotoxin administration, norepinephrine-induced vasoconstriction was attenuated (FBF ratio, 101Ϯ4%, 92Ϯ4%, 83Ϯ6%, and 56Ϯ7%; nϭ30; Pϭ0.0018; pooled data). Intrabrachial infusion of the K-channel blocker tetraethylammonium (TEA) completely restored the vasoconstrictor response to norepinephrine from 104Ϯ5%, 93Ϯ7%, 93Ϯ12%, and 69Ϯ12% to 89Ϯ9%, 73Ϯ4%, 59Ϯ5%, and 46Ϯ8% (nϭ6; Pϭ0.045). Other K-channel blockers did not affect the response to norepinephrine. The NO synthase inhibitor N G -monomethyl-L-arginine (L-NMMA; 0.2 mg · min Ϫ1 · dL Ϫ1 intra-arterially) also restored the norepinephrine sensitivity. In the presence of L-NMMA, TEA did not have an additional effect on the norepinephrine-induced vasoconstriction (nϭ6; Pϭ0.9). Conclusions-The K-channel blocker TEA restores the attenuated vasoconstrictor response to norepinephrine during experimental human endotoxemia. Coadministration of L-NMMA abolishes this potentiating effect of TEA, suggesting that NO mediates the endotoxin-induced effect on vascular K channels. In the absence of an effect of the selective adenosine triphosphate-dependent K-channel blocker tolbutamide, we conclude that the blunting effect of endotoxin on norepinephrine-induced vasoconstriction is caused by NO-mediated activation of calcium-activated K channels in the vascular wall. (Circulation. 2006;114:414-421.)
British Journal of Pharmacology, 2001
1 We investigated whether K + can act as an endothelium-derived hyperpolarizing factor (EDHF) in isolated small renal arteries of Wistar-Kyoto rats. 2 Acetylcholine (0.001 ± 3 mM) caused relaxations that were abolished by removal of the endothelium. However, acetylcholine-induced relaxations were not aected by the nitric oxide (NO) synthase inhibitor N o -nitro-L-arginine methyl ester (L-NAME, 100 mM), by L-NAME plus the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 1 mM) or by L-NAME plus the cyclo-oxygenase inhibitor indomethacin (10 mM). In rings precontracted with high-K + (60 mM) physiological salt solution in the presence of L-NAME, acetylcholine-induced relaxations were abolished. 3 L-NAME-resistant relaxations were abolished by the large-conductance Ca 2+ -activated K + channel inhibitor charybdotoxin plus the small-conductance Ca 2+ -activated K + channel inhibitor apamin, while the inward recti®er K + channel inhibitor Ba 2+ or the gap junction inhibitor 18aglycyrrhetinic acid had no eect. Acetylcholine-induced relaxation was unchanged by ouabain (10 mM) but was partially inhibited by a higher concentration (100 mM). 4 In half of the tissues tested, K + (10 mM) itself produced L-NAME-resistant relaxations that were blocked by ouabain (10 mM) and partially reduced by charybdotoxin plus apamin, but not aected by 18a-glycyrrhetinic acid or Ba 2+ . However, K + did not induce relaxations in endothelium-denuded tissues. 5 In conclusion, acetylcholine-induced relaxations in this tissue are largely dependent upon hyperpolarization mechanisms that are initiated in the endothelium but do not depend upon NO release. K + release cannot account for endothelium-dependent relaxation and cannot be an EDHF in this artery. However, K + itself can initiate endothelium-dependent relaxations via a dierent pathway from acetylcholine, but the mechanisms of K + -induced relaxations remain to be clari®ed.
Nitric oxide lowers the calcium sensitivity of tension in the rat tail artery
The Journal of Physiology, 1998
The intracellular calcium concentration ([Ca¥]é) plays an important role in regulating vascular smooth muscle contractility through calmodulin and the myosin light chain kinase which activates the contractile apparatus (Kamm & Stull, 1985). However, there may not be a direct relationship between [Ca¥]é and contractility as factors downstream of [Ca¥]é mobilization such as the [Ca¥]é sensitivity of myosin phosphorylation are known to vary (Rembold, 1990). Thus, vasodilators could produce smooth muscle cell relaxation by lowering [Ca¥]é, [Ca¥]é sensitivity of myosin phosphorylation, or [Ca¥]é sensitivity of contraction. Endothelium-derived or exogenous nitric oxide (NO) increases the concentration of cGMP in vascular smooth muscle cells and this is an essential step in relaxation (Murad, 1987; Moncada & Biggs, 1995). In cultured smooth muscle cells high concentrations of an exogenous NO donor (sodium nitroprusside) and 8-bromoguanosine 3',5' cyclic monophosphate block extracellular Ca¥ entry (Magliola & Jones, 1990; Blatter & Wier, 1994). In addition to a reduction in [Ca¥]é, endogenous and exogenous NO may cause dilatation via [Ca¥]é-independent mechanisms (Abe, Kanaide & Nakamura, 1990; Chen & Rembold, 1996). We describe a series of experiments designed to test the hypothesis that NO causes vasodilatation by lowering the [Ca¥]é sensitivity of force. We used the fura_2 perfusionloaded rat tail artery (
British Journal of Pharmacology, 1996
We have used the isolated buffer‐perfused mesenteric arterial bed of the rat to assess the modulation of vasorelaxation to potassium channel openers (KCOs) by basal nitric oxide. The dose‐response curves to the KCOs, levcromakalim and pinacidil, in preconstricted preparations were significantly shifted to the left in the presence of the nitric oxide synthase inhibitor (100 μm) NG‐nitro‐L‐arginine methyl ester (levcromakalim, ED50=4.47±0.70 nmol vs. 1.73±0.26 nmol, P<0.001; pinacidil, ED50=16.1±4.8 nmol vs. 5.43±1.10 nmol, P<0.001). The vasorelaxant responses to papaverine, a vasodilator which acts independently of potassium channels was unaffected by NG‐nitro‐L‐arginine methyl ester (L‐NAME). Removal of the endothelium, by perfusion with the detergent CHAPS (0.3%), significantly (P<0.001) increased the potency of levcromakalim as a vasodilator (ED50 4.47±0.70 nmol vs. 2.59±0.31 nmol). The subsequent administration of L‐NAME following perfusion with CHAPS did not lead to any...