Citral inhibits the nociception in the rat formalin test: Effect of metformin and blockers of opioid receptor and the NO-cGMP-K+ channel pathway

The objective of the present study was to scrutinize the effect of nitric oxide (NO), cGMP, potassium channel blockers and metformin on the citral-produced peripheral antinociception. The rat paw 1% formalin test was used to assess nociception and antinociception. Rats were treated with local peripheral administration of citral (10-100 µg/paw). The antinociception of citral (100 µg/paw) was evaluated with and without the local pretreatment of naloxone, NG-L-nitro-arginine methyl ester (L-NAME, a NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor), metformin, opioid receptors antagonists, and K+ channel blockers. Injection of citral in the rat paw significantly decreased the nociceptive effect of formalin administration during the two phases of the test. Local pretreatment of the paws with L-NAME and ODQ did not reduced the citral-induced antinociception. Glipizide or glibenclamide (Kir6.1-2; ATP-sensitive K+ channel blockers), tetraethylammonium or 4-aminopyridine (KV; voltage-gated K+ channel blockers) or charybdotoxin (KCa1.1; big conductance calcium-activated K+ channel blocker) or apamin (KCa2.1-3; small conductance Ca2+-activated K+ channel antagonist), or metformin, but not the opioid antagonists, reduced the antinociception of citral. Citral produced peripheral antinociception during both phases of the formalin test. These effects were due to the activation of K+ channels and a biguanide-dependent mechanism.

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Effects of potassium channel blockers on basal vascular tone and reactive hyperemia of canine diaphragm

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.1.h43 ◽

1994 ◽

Vol 266 (1) ◽

pp. H43-H51 ◽

Cited By ~ 6

Author(s):

G. Vanelli ◽

S. N. Hussain

Keyword(s):

Vascular Tone ◽

Reactive Hyperemia ◽

K Channel ◽

Channel Blockers ◽

Flow Perfusion ◽

Basal Tone ◽

Potassium Channel Blockers ◽

Anesthetized Dogs ◽

Phrenic Artery ◽

Small Conductance

Glibenclamide, iberiotoxin, and apamin (blockers of ATP-sensitive, large-conductance, and small-conductance Ca(2+)-activated potassium channels, respectively) were infused into the diaphragmatic vasculature of anesthetized dogs to assess the contribution of these channels in the regulation of basal tone and the response to brief occlusions of the left phrenic artery (reactive hyperemia). Baseline phrenic flow (Qphr), peak postocclusive flow, and reactive hyperemia duration in response to 10-, 30-, 60-, and 120-s arterial occlusions were measured before (control) and after the infusion of K+ channel blockers in three groups of animals. Glibenclamide at 5 x 10(-6), 1 x 10(-5), and 8 x 10(-5) M increased baseline phrenic resistance to 140, 204, and 192% of control values, respectively. Peak postocclusive Qphr and duration of hyperemia in response to all occlusion durations were significantly attenuated after glibenclamide infusion. Iberiotoxin infusion at 1 x 10(-8), 3 x 10(-8), and 1 x 10(-7) M increased phrenic resistance to 141, 133, and 146% of control values, respectively. By comparison, baseline phrenic resistance rose to 159 and 145% of control in response to 1 x 10(-7) and 1 x 10(-6) M apamin, respectively. Iberiotoxin and apamin reduced peak postocclusive flow and duration of hyperemia only in response to 10- and 30-s occlusions. We infused K+ channel blockers along with lemakalim into the diaphragm during constant flow perfusion in separate groups of animals. When infused alone, lemakalim reduced phrenic resistance by 60–70%.(ABSTRACT TRUNCATED AT 250 WORDS)

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State-dependent Block of CNG Channels by Dequalinium

The Journal of General Physiology ◽

10.1085/jgp.200308925 ◽

2004 ◽

Vol 123 (3) ◽

pp. 295-304 ◽

Cited By ~ 14

Author(s):

Tamara Rosenbaum ◽

Ariela Gordon-Shaag ◽

León D. Islas ◽

Jeremy Cooper ◽

Mika Munari ◽

...

Keyword(s):

Specific Effect ◽

State Dependence ◽

Open Channels ◽

K Channel ◽

Channel Blockers ◽

Ion Permeation ◽

High Permeability ◽

Nonselective Cation Channels ◽

State Dependent ◽

Small Conductance

Cyclic nucleotide–gated (CNG) ion channels are nonselective cation channels with a high permeability for Ca2+. Not surprisingly, they are blocked by a number of Ca2+ channel blockers including tetracaine, pimozide, and diltiazem. We studied the effects of dequalinium, an extracellular blocker of the small conductance Ca2+-activated K+ channel. We previously noted that dequalinium is a high-affinity blocker of CNGA1 channels from the intracellular side, with little or no state dependence at 0 mV. Here we examined block by dequalinium at a broad range of voltages in both CNGA1 and CNGA2 channels. We found that dequalinium block was mildly state dependent for both channels, with the affinity for closed channels 3–5 times higher than that for open channels. Mutations in the S4-S5 linker did not alter the affinity of open channels for dequalinium, but increased the affinity of closed channels by 10–20-fold. The state-specific effect of these mutations raises the question of whether/how the S4-S5 linker alters the binding of a blocker within the ion permeation pathway.

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Stretching the limits of antiarrhythmic drug therapy: The promise of small-conductance calcium-activated potassium channel blockers

IJC Heart & Vasculature ◽

10.1016/j.ijcha.2021.100924 ◽

2021 ◽

Vol 37 ◽

pp. 100924

Author(s):

Jordi Heijman ◽

Ann-Kathrin Rahm ◽

Dobromir Dobrev

Keyword(s):

Drug Therapy ◽

Potassium Channel ◽

Antiarrhythmic Drug ◽

Channel Blockers ◽

Antiarrhythmic Drug Therapy ◽

Potassium Channel Blockers ◽

Calcium Activated Potassium Channel ◽

Small Conductance

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Vasorelaxant and Antihypertensive Effects of Neferine in Rats: An In Vitro and In Vivo Study

Planta Medica ◽

10.1055/a-1123-7852 ◽

2020 ◽

Vol 86 (07) ◽

pp. 496-504 ◽

Cited By ~ 1

Author(s):

Piyawadee Wicha ◽

Amnart Onsa-ard ◽

Waraluck Chaichompoo ◽

Apichart Suksamrarn ◽

Chainarong Tocharus

Keyword(s):

Nitric Oxide ◽

Thoracic Aorta ◽

Antihypertensive Effect ◽

Soluble Guanylyl Cyclase ◽

K Channel ◽

Channel Blockers ◽

Organ Bath ◽

Hypertensive Rats

AbstractThe present study was performed to examine the antihypertensive effect of neferine in hypertensive rats and its relaxant mechanisms in isolated rat thoracic aorta. The antihypertensive effect was evaluated by tail-cuff methods on NG-nitro-L-arginine methyl ester (L-NAME) (40 mg/kg BW) 4-week hypertensive-induced hypertensive rats. The vasorelaxant effect and its mechanisms were studied by the organ bath technique in the thoracic aorta isolated from normotensive rats. The results indicated that the treatment of neferine (1 mg/kg and 10 mg/kg) markedly decreased the systolic blood pressure (SBP) when compared with the hypertension group (137.75 ± 10.14 mmHg and 132.23 ± 9.5 mmHg, respectively, p < 0.001), without affecting the heart rate. Moreover, neferine (10−12 − 10−4 M) exhibited concentration-dependent vasorelaxation in endothelium-intact rings (Emax values = 98.95 ± 0.66% and pD2 = 7.93 ± 0.28) and endothelium-denuded rings (Emax values = 90.61 ± 1.91% and pD2 = 6.85 ± 0.36). The effects of neferine were reduced by pre-incubation with L-NAME and 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) but not with pre-incubation with indomethacin and K+channel blockers. Neferine attenuated the contractions induced by phenylephrine and caffeine in a Ca2+-free solution and also inhibited in CaCl2- and phenylephrine-induced contracted rings. Our study suggests that neferine exhibited hypertensive potential, induced vasorelaxation through the endothelium nitric oxide synthase (eNOS)/nitric oxide (NO)/soluble guanylyl cyclase (sGC) pathway and involved the modulation of Ca2+ influx through Ca2+ channels and intracellular Ca2+ release from the sarcoplasmic reticulum.

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Synthesis and Quantitative Structure−Activity Relationship of a Novel Series of Small Conductance Ca2+-Activated K+Channel Blockers Related to Dequalinium

Journal of Medicinal Chemistry ◽

10.1021/jm950520i ◽

1996 ◽

Vol 39 (2) ◽

pp. 359-370 ◽

Cited By ~ 19

Author(s):

Dimitrios Galanakis ◽

Carole A. Davis ◽

C. Robin Ganellin ◽

Philip M. Dunn

Keyword(s):

Quantitative Structure Activity Relationship ◽

Structure Activity Relationship ◽

Activity Relationship ◽

K Channel ◽

Channel Blockers ◽

Quantitative Structure ◽

Structure Activity ◽

Relationship Of ◽

Small Conductance

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Inhibition of small conductance K+-channels attenuated melatonin-induced relaxation of serotonin-contracted rat gastric fundus

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y00-059 ◽

2000 ◽

Vol 78 (10) ◽

pp. 799-806 ◽

Cited By ~ 15

Author(s):

M Storr ◽

V Schusdziarra ◽

H -D Allescher

Keyword(s):

Smooth Muscle ◽

Potassium Channel ◽

Guanylate Cyclase ◽

Inhibitory Effect ◽

Gastric Fundus ◽

Channel Blockers ◽

Basal Tone ◽

Potassium Channel Blockers ◽

Rat Gastric Fundus ◽

Small Conductance

The aim of this study was to investigate the effects of melatonin on rat gastric fundus smooth muscle. Melatonin (10-4 to10-3 M) had no effect on the basal tone of gastric smooth muscle. After precontraction with carbachol (10-6 M) or serotonin (10-7 M), melatonin caused a concentration dependent inhibitory action. The half maximal effect on serotonin-induced contraction was found with 1.12 beta 0.86 beta 10-5 M of melatonin. Increasing concentrations of melatonin (10-5 to 10-3 M) resulted in a right shift of the serotonin concentration response curve (10-10 to10-5 M). This inhibitory effect of melatonin was partially blocked in the presence of apamin (10-10 to 10-7 M), a specific blocker of the small conductance calcium-dependent potassium channel, but not in the presence of other potassium channel blockers like charybdotoxin (10-8 M), glibenclamide (10-5 M), or tetraethylammonium (ODQ, 10-4 M). The inhibitory effect was not changed in the presence of the neuronal blocker tetrodotoxin (10-6 M), the selective P2-receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (3 × 10-5 M), the nitric-oxide synthase inhibitor N-nitro-L-arginine (3 × 10-4 M), or the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one (10-4 M), suggesting that neither the purinergic, nitrergic, nor guanylate cyclase pathways were involved. We further investigated inhibitory responses to electrical field stimulation (EFS) at different frequencies under non-adrenergic, non-cholinergic (NANC) conditions on a serotonin-induced contraction in the presence of melatonin (10-5 to 10-4 M). Melatonin significantly reduced these inhibitory NANC responses in higher (8-32 Hz), but not lower (05-4 Hz), frequencies (16 Hz without melatonin, 103 ± 6.3%; melatonin 10-5 M, 80.4 ± 7.5%; melatonin 10-4 M, 39.1 ± 17.1%). Melatonin had no effect on contractile responses induced by EFS under basal tone. These results demonstrate that the inhibitory effect of melatonin in rat gastric fundus smooth muscle is apamin sensitive, but is not affected by other potassium channel blockers. This suggests that melatonin may be another transmitter candidate for the apamin sensitive responses within the gastrointestinal tract.Key words: melatonin, smooth muscle, apamin, NANC-inhibition, gastric, potassium channels.

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Potassium-channel blockers inhibit inositol trisphosphate-induced calcium release in the microsomal fractions isolated from the rat brain

Biochemical Journal ◽

10.1042/bj2500617 ◽

1988 ◽

Vol 250 (2) ◽

pp. 617-620 ◽

Cited By ~ 37

Author(s):

J Shah ◽

H C Pant

Keyword(s):

Rat Brain ◽

Calcium Release ◽

Inositol Trisphosphate ◽

K Channel ◽

Channel Blockers ◽

Ionic Mechanism ◽

Tetraethylammonium Chloride ◽

Potassium Channel Blockers ◽

Brain Microsomes ◽

86Rb Influx

The ionic mechanism of inositol trisphosphate (InsP3)-induced Ca2+ release was investigated in microsomes (microsomal fractions) isolated from rat brain. InsP3 stimulated Ca2+ release from microsomes incubated in media containing 100 mM-KCl. The InsP3-induced Ca2+ release was insensitive to a variety of Ca2+-channel blockers; however, the K+-channel blockers tetraethylammonium chloride (TEA; 1 mM) and 9-tetraethylammonium chloride (9-TEA; 1 mM) blocked InsP3-induced Ca2+ release. Moreover, addition of InsP3 increased 86Rb+ influx into the microsomes. The influx of 86Rb+ also was sensitive to TEA and 9-TEA. The above results suggest that InsP3-induced Ca2+ release requires an opposite flow of K+ ions, and modulation of K+ channels by TEA and 9-TEA may underlie the inhibition of InsP3-induced Ca2+ release from brain microsomes by these agents.

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Potassium channels are not involved in vasopressin-induced vasodilation in the rat lung

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.2.h491 ◽

1994 ◽

Vol 266 (2) ◽

pp. H491-H495 ◽

Cited By ~ 1

Author(s):

M. R. Eichinger ◽

R. D. Russ ◽

B. R. Walker

Keyword(s):

Physiological Saline ◽

K Channel ◽

Channel Blockers ◽

Sprague Dawley ◽

Synthesis Inhibitor ◽

K Channels ◽

Vasodilatory Response ◽

Physiological Saline Solution ◽

High Doses ◽

Vasodilator Action

We have previously observed that arginine vasopressin (AVP)-induced pulmonary vasodilation is attenuated by nitric oxide (NO) synthesis inhibition; however, blockade of the response is incomplete even at very high doses of the inhibitor. Thus it was hypothesized that the remaining vasodilation might be due to release of an endothelium-derived hyperpolarizing factor acting to open vascular smooth muscle K+ channels. Lungs were isolated from male Sprague-Dawley rats and perfused at constant flow with physiological saline solution containing 4% albumin. After equilibration, lungs were treated with either glibenclamide (50 microM), Ba2+ (100 microM), tetraethylammonium (10 mM), or the respective vehicle and were then constricted with the thromboxane mimetic U-46619. Upon development of a stable degree of vasoconstriction, AVP (2.5 x 10(-9) M) was administered and its vasodilator action noted. AVP caused an approximately 60% reversal of U-46619 vasoconstriction in control lungs, and this response was not affected by any of the K+ channel blockers. In contrast, administration of the NO synthesis inhibitor N omega-nitro-L-arginine (L-NNA; 300 microM) significantly attenuated AVP-induced dilation to approximately 25%. The addition of K+ channel blockers did not further diminish the vasodilatory response in L-NNA-treated lungs. In conclusion, these results suggest that ATP- and Ca(2+)-sensitive K+ channels are not involved in the pulmonary vasodilatory response to AVP.

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