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PubMed2003

Multiple cellular electrophysiological effects of azimilide in canine cardiac preparations.

The cellular electrophysiological effect of azimilide (0.1-30 microM) was analyzed in canine ventricular preparations by applying the standard microelectrode and patch-clamp techniques at 37 degrees C. In papillary muscle, the drug prolonged the action potential duration (APD) in a concentration-dependent manner at a cycle length (CL) of 1000 ms. In Purkinje fibers, at the same CL, the concentration-dependent lengthening of the APD was observed in the presence of up to 3 microM azimilide (at 3.0 microM: 24.1+/-4.2%, n=9); at higher drug concentration, no further APD prolongation was observed. Azimilide lengthened APD in a reverse frequency-dependent manner in papillary muscle and Purkinje fibers alike. Azimilide (10 microM) caused a rate-dependent depression in the maximal upstroke velocity of the action potential (V(max)) in papillary muscle. The time and rate constants of the offset and onset kinetics of this V(max) block were 1754+/-267 ms (n=6) and 5.1+/-0.4 beats (n=6), respectively. Azimilide did not prevent the APD shortening effect of 10 microM pinacidil in papillary muscle, suggesting that the drug does not influence the ATP-sensitive K(+) current. Azimilide inhibited the rapid (I(Kr)) and slow component (I(Ks)) of the delayed rectifier K(+) current and the L-type Ca(2+) current (I(Ca)). The estimated EC(50) value of the drug was 0.59 microM for I(Ks), 0.39 microM for I(Kr) and 7.5 microM for I(Ca). The transient outward (I(to)) and the inward rectifier (I(k1)) K(+) currents were not influenced by the drug. It is concluded that the site of action of azimilide is multiple, it inhibits not only K(+) (I(Kr), I(Ks)) currents but, in higher concentrations, it also exerts calcium- and use-dependent sodium channel block.

Action Potentials↗
PubMed1997

The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells.

The patch-clamp technique was used to measure currents passing through K+ channels in neuronal cell preparations. Retigabine (D-23129, N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) activated a K+ conductance in slightly depolarized NG108-15 neuronal cells in a dose-dependent manner (0.1-10 microM). At the K+ reversal potential, no current could be elicited and in hyperpolarized cells the current was reversed. A similar current was elicited in primary cultures of mouse cortical neurones and in differentiated hNT cells, a cell line derived from human neuronal cells. At higher concentrations, retigabine also partially blocked voltage activated K+ currents. None of the tested anticonvulsants, phenytoin, carbamazepine and valproate and none of the K+ channel openers cromakalim, diazoxide and pinacidil exerted a similar effect. The current was not affected by the K+ channel blocker glibenclamide (10 microM) but was fully blocked by application of Ba2+ (10.8 mM). Exchange of K+ with cesium in the intracellular space also fully abolished the current. It can be expected that the K+ channel opening effect contributes to the anticonvulsant activity of retigabine.

Animals↗
PubMed1998

Involvement of endothelium in relaxant action of glibenclamide on the rat mesenteric artery.

The present report describes the complex effect of glibenclamide, an antidiabetic sulfonylurea agent, on the rat isolated mesenteric artery. Although glibenclamide concentration dependently reversed the relaxant effect of pinacidil, an activator of ATP-sensitive K+ channels (the concentration for half-maximum reversal effect was 0.56 microM with endothelium and 0.17 microM without endothelium), in the artery precontracted with phenylephrine (1 microM), it relaxed phenylephrine-induced sustained contraction at higher concentrations (IC50: 4.4+/-1.1 microM with endothelium and 226.1+/-44.2 microM without endothelium). The relaxant effect of glibenclamide was partially inhibited by pretreatment of the artery with either NG-nitro-L-arginine (10-100 microM) or methylene blue (1 microM). Indomethacin (10 microM) had no effect. Moreover, glibenclamide also concentration dependently (3-500 microM) reduced the sustained contraction induced by 60 mM K+ (IC50: 99.5+/-16.1 microM). The relaxation induced by glibenclamide was not affected by various putative K+ channel blockers such as charybdotoxin (100 nM), tetraethylammonium ions (1 mM), apamin (100 nM) and 4-aminopyridine (1 mM). The results indicate an involvement of the endothelium, probably of nitric oxide, in the relaxation induced by glibenclamide in the endothelium-intact rat mesenteric arteries. The inhibitory effect of glibenclamide on the high-K+-induced contraction suggests that glibenclamide may interfere with Ca2+ influx, which in turn affects intracellular Ca2+ levels in arterial smooth muscle, leading to reduction of muscle contractility. It is suggested that two distinct pharmacological effects induced by glibenclamide may be mediated through different glibenclamide binding sites, however, the data show an overlap of concentrations of glibenclamide for producing the two effects in rat isolated mesenteric arteries.

Animals↗
PubMed1998

Identification of [3H]P1075 binding sites and P1075-activated K+ currents in ovine choroid plexus cells.

This study examined the pharmacological characteristics of binding sites for the potent K+ channel opener [3H]P1075, as well as the functional effects of P1075 on ionic currents and membrane potential, in ovine choroid plexus (OCP) cells. [3H]P1075 bound to OCP cells with a Kd of 26 +/- 4 nM and a Bmax of 10400 +/- 480 sites/cell. Labelled sites were stereoselective and inhibited by potassium channel openers with a rank order of potency: P1075 > BMS-182264, ((4-[[9cyanoimino)[(1,2,2-trimethylpropyl)amino]-methyl]amino]benz onitrile) > pinacidil >> nicorandil > diazoxide. The K(ATP) channel antagonist glyburide inhibited [3H]P1075 binding with a Ki of 2 microM. The presence of K(ATP) channels on OCP cells was examined by patch clamp and fluorescent (membrane-potential sensitive dye) techniques. In some cells, P1075 activated an outward potassium current which was blocked by glyburide. P1075 produced a glyburide-sensitive, concentration-dependent, hyperpolarization of OCP cells. Levcromakalim hyperpolarized more strongly than its 3R,4S enantiomer, BRL 38226 ((3R-trans)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)- 2H-1-benzopyran-6-carbonitrile) indicating a stereoselective interaction. These data indicate that epithelial OCP cells contain glyburide-sensitive K(ATP) channels.

Adenosine Triphosphate↗
PubMed1998

Inhibitory actions of various vasorelaxants on the myogenic contraction induced by quick stretch studied in canine cerebral artery.

Quick stretch at a rate of 10 cm/s with the amount of 30% of the initial muscle length (= 100%) produced a myogenic contraction in canine cerebral artery. The inhibitory actions of various vasorelaxants on the stretch-induced contraction were investigated. Ca2+ channel blockers (nicardipine, D-cis-diltiazem) inhibited the stretch-induced contraction by 50-60% at the concentrations which abolished high KCl-induced contraction. Inhibitions of the stretch-induced contraction by nitro-compounds (nitroglycerin, sodium nitroprusside) were about 50%. In contrast, inhibitions by the compounds which activate ATP-sensitive K+ channels (cromakalim, nicorandil, pinacidil) of the myogenic contraction in response to quick stretch were only 20%. Papaverine totally abolished the stretch-induced contraction. It is likely that all the vasorelaxant compounds tested in the present study except papaverine are beneficial in the sense that they do not suppress the intrinsic myogenic contraction, which may be related to the autoregulation of local blood flow.

Animals↗
PubMed1995

Role for ATP-sensitive K+ channel in the development of A-V block during hypoxia.

The role of the ATP-sensitive K+ channel (IK,ATP) in the development of A-V block during hypoxic interventions was studied using Langendorff perfused rabbit hearts, multicellular rabbit A-V nodal preparations and single guinea-pig ventricular myocytes. With the Langendorff perfused hearts, hypoxic perfusion (PO2 not equal to 40 mmHg) for 30 min caused slowing of the sinus rate and prolongation of the A-H interval without the appearance of blocked beats. Substrate-free hypoxic perfusion induced second or third degree A-V block in 8/10 hearts and substrate-free hypoxic perfusion plus 2-deoxyglucose (5 mM) produced third degree A-V block in 6/6 preparations. Addition of 50 mM glucose in the perfusate restored A-V conduction during hypoxic intervention. Application of glibenclamide, a specific blocker of IK,ATP, prevented the development of second or third degree A-V block during substrate-free hypoxia (n = 6), whereas pinacidil, an opener of IK,ATP, caused development of third degree A-V block during hypoxia (n = 9). Application of theophylline (100 microM) or 8-phenyl-theophylline (10 microM) did not prevent the development of advanced degrees of A-V block during hypoxic interventions. In multicellular A-V nodal preparations, 10 microM glibenclamide prevented the shortening of action potential duration and block development without marked effects on the maximum upstroke velocity of action potentials during hypoxic intervention. In isolated ventricular myocytes studied by the patchclamp method, the substrate-free hypoxia plus 2-deoxyglucose induced the openings of IK,ATP in 9/25 preparations with cell-attached patches, while 2/20 patches exhibited sporadic channel openings in the normoxic condition during comparable observation period. These results suggest that openings of the ATP-sensitive K+ channels play a role in the development and aggravation of advanced A-V block during hypoxic interventions.

Action Potentials↗
PubMed2002

Relationship of mass of obstructed rat bladders and responsiveness to adrenergic stimulation.

PURPOSE: The effects of experimental partial bladder outlet obstruction on the bladder response to nerve stimulation and contractile agonists have been well characterized. Mildly obstructed bladders have small increases in mass and increased contractile responses to electrical field stimulation. More severely obstructed bladders become decompensated with large increases in mass and decreased functional responses. Little is known about relaxant mechanisms after obstruction. We investigated the relationship of the increase in rat bladder mass induced by outlet obstruction and responses to alpha and beta-adrenergic stimulation. MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into 3 groups, namely control, sham operated and obstructed. Surgical obstruction was done by tying a 2-zero silk ligature around the urethra. The ligature was placed around the urethra and removed in sham operated rats. At 2 and 6 weeks bladders from all groups were harvested, weighed and cut into strips. Contractile responses to electrical field stimulation and norepinephrine in the presence of propranolol were measured. Relaxant responses to norepinephrine and isoproterenol were measured after pre-contraction with KCl. RESULTS: All strips from control and sham operated rats relaxed completely in response to norepinephrine. Obstructed bladders that weighed 2 to 3-fold more than control or sham operated bladders also relaxed. In contrast, bladders that were 5 to 10-fold heavier failed to relax by at least 50% in response to norepinephrine, independent of duration of bladder outlet obstruction. These were called nonresponders. Two week nonresponders relaxed completely in response to isoproterenol, but 6-week nonresponders did not, suggesting that the duration of decompensation is important. All nonresponders relaxed in response to pinacidil (Sigma-Aldrich Corp., St. Louis, Missouri). Nonresponders tended to contract in response to norepinephrine in the presence of propranolol. Strips from the other rats were less responsive, suggesting an increase in alpha1-receptors with decompensation. Contractile responses to field stimulation were increased in obstructed strips that relaxed to norepinephrine, while responses of nonresponders were decreased compared with controls and sham operated rats. CONCLUSIONS: Severely obstructed bladders had an increase in mass and a decreased response to field stimulation, indicative of decompensation. This response was accompanied by decreased ability to relax to beta-agonists and an increased response to alpha-agonists. These changes were not seen in smaller, compensated bladders. Our findings suggest a change in detrusor alpha1 and beta-adrenergic receptor density. An increase in detrusor alpha-receptors may explain the clinical efficacy of alpha-blockers in alleviating irritative voiding symptoms in men with benign prostatic hyperplasia.

Adrenergic Fibers↗
PubMed1994

Micturition and premicturition contractions in unanesthetized rats with bladder outlet obstruction.

The cholinergic and purinergic neurotransmission involved in micturition contraction and premicturition contractile activity (bladder hyperactivity) were investigated by continuous cystometry in unanesthetized rats with outlet obstruction. Adenosine triphosphate (ATP), administered intra-arterially close to the bladder, produced rapid, phasic dose-dependent increases in bladder pressure and micturition immediately after the injections. The percentage volume expelled was 74 +/- 9% after 5 mg/kg. Intra-arterial alpha,beta-methylene ATP also produced a rapid, phasic increase in bladder pressure and micturition immediately after the injection. The percentage volume expelled was 96 +/- 3% after 1 mg./kg; the residual volume of the following voidings increased, and the micturition pressure tended to decrease. However, dribbling incontinence was not produced. The amplitude of the premicturition contractions decreased significantly (p < 0.01) after the administration. Intra-arterial carbachol produced rapid, longlasting dose-dependent increases in bladder pressure and micturition. The percentage volume expelled was 88 +/- 4 after 5 micrograms./kg. Bladder capacity and micturition volume decreased significantly (p < 0.05) during the following spontaneous voidings. Intra-arterial atropine (1 mg./kg.) increased bladder capacity (p < 0.01) and residual volume (p < 0.01), and tended to decrease micturition pressure (by 25%) and micturition volume. However, micturition contractions still remained after the injection, even if they changed appearance, and were of shorter duration. Atropine had no effect on the premicturition contractions. In the presence of atropine, alpha,beta-methylene ATP initially produced a rapid, phasic increase in bladder pressure with micturition. Then, dribbling incontinence was observed in 1 of 5 animals. Hexamethonium, administered intra-arterially in doses producing urinary retention and dribbling incontinence (20 or 40 mg./kg.), increased the amplitude of the premicturition contractions, but decreased the frequency of the contractions. Intra-arterial tetrodotoxin (15 micrograms./kg.) inhibited micturition, and produced dribbling incontinence in all animals tested (n = 6). However, the amplitude of the premicturition contractions was not suppressed. Intra-arterial (+/-)-pinacidil (0.2 mg./kg.) significantly (p < 0.05) decreased both amplitude and frequency of these contractions. It is concluded that both cholinergic and purinergic transmission seem to be of importance for pressure generation and emptying of the bladder in rats with outlet obstruction. The present results also give further support for the view that the premicturition contractions seen in these animals are of myogenic origin.

Adenosine Triphosphate↗
PubMed1998

Endothelium-dependent relaxation induced by hawthorn extract in rat mesenteric artery.

The extract prepared from hawthorn (Crataegus fruit) was examined for its relaxant effect in rat isolated mesenteric arteries. Hawthorn extract induced concentration-dependent relaxation of the U46619-precontracted artery with an IC50 of 0.22 +/- 0.02 mg/ml. Removal of the functional endothelium reduced by approximately 85% the maximum relaxant response to hawthorn extract. Pretreatment of the arterial tissues with N(G)-nitro-L-arginine methyl ester (3-10 microM) or methylene blue (3-10 microM) inhibited the relaxation induced by hawthorn extract, while indomethacin (10 microM) had no effect. L-arginine (3 mM) did not affect the relaxation induced by hawthorn extract but partially reversed the effect of 10 microM N(G)-nitro-L-arginine methyl ester. Iberiotoxin (100 nM) slightly but significantly inhibited the relaxant effect of hawthorn extract whilst glibenclamide (3 microM) was ineffective. Glibenclamide at 3 microM reversed the relaxation induced by pinacidil. N(G)-nitro-L-arginine methyl ester and methylene blue markedly inhibited acetylcholine-induced relaxation in endothelium-intact arteries. Hawthorn extract also reduced the contraction induced by phenylephrine (1 microM) or high Ki (60 mM) with respective IC50 values of 0.13 +/- 0.01 mg/ml and 0.11 +/- 0.01 mg/ml. In high K+-contracted arteries, hawthorn extract induced only 55% of relaxation while it caused a complete inhibition of the U46619- or phenylephrine-induced contraction. These results suggest that hawthorn contains active components which cause vasorelaxation in rat isolated mesenteric arteries. Nitric oxide but not other endothelium-derived vasoactive factors was probably involved in the relaxation induced by hawthorn extract.

Animals↗
PubMed2001

Involvement of potassium channels in amitriptyline and clomipramine analgesia.

The effect of the administration of modulators of different subtypes of K(+) channels on antinociception induced by the tricyclic antidepressants amitriptyline and clomipramine was evaluated in the mouse hot plate test. The administration of the voltage-gated K(+) channel blocker tetraethylammonium (0.01-0.5 microg per mouse i.c.v. ) prevented antinociception induced by both amitriptyline (15 mg kg(-1) s.c.) and clomipramine (25 mg kg(-1) s.c.). The K(ATP) channel blocker gliquidone (0.1-1.0 microg per mouse i.c.v.) prevented antinociception produced by amitriptyline and clomipramine whereas the K(ATP) channel openers minoxidil (10 microg per mouse i. c.v.) and pinacidil (25 microg per mouse i.c.v.) potentiated tricyclic antidepressant-induced analgesia. The administration of the Ca(2+)-gated K(+) channel blocker apamin (0.1-1.0 ng per mouse i. c.v.) completely prevented amitriptyline and clomipramine analgesia. At the highest effective doses, none of the drugs used induced behavioural side effects or impaired motor coordination, as revealed by the rota-rod test, spontaneous motility or inspection activity, as revealed by the hole board test. The present results demonstrate that central antinociception induced by amitriptyline and clomipramine involves the opening of different subtypes of K(+) channels (voltage-gated, K(ATP) and Ca(2+)-gated) which, therefore, represent a step in the transduction mechanism of tricyclic antidepressant analgesia.

Amitriptyline↗
PubMed1999

The role of potassium channels in antihistamine analgesia.

The effect of the administration of pertussis toxin as well as modulators of different subtypes of K+ channels on the antinociception induced by the H1-antihistamines pyrilamine, diphenhydramine and promethazine was evaluated in the mouse hot plate test. Pretreatment with pertussis toxin (0.25 microg/mouse i.c.v.) prevented pyrilamine, diphenhydramine and promethazine antinociception. The K(ATP) channel openers minoxidil and pinacidil potentiated the antinociception produced by the H1-antihistamines whereas the K(ATP) channel blocker gliquidone prevented the anti H1-induced analgesia. The Ca2+-gated K+ channel blocker apamin antagonized pyrilamine, diphenhydramine and promethazine analgesia. Pretreatment with an antisense oligonucleotide (aODN) to mKv1.1, a voltage-gated K+ channel, at the dose of 3.0 nmol/single i.c.v. injection, never modified the antinociception induced by the H1-antihistamines in comparison with degenerate oligonucleotide (dODN)-treated mice. At the highest effective doses, none of the drugs used modified animals' gross behaviour nor impaired motor coordination, as revealed by the rota rod test. The present data demonstrate that both K(ATP) and Ca2+-gated K+ channels, contrary to voltage-gated K+ channel Kv1.1, represent an important step in the transduction mechanism underlying central antinociception induced by H1-antihistamines.

Animals↗
PubMed2000

Molecular aspects of ATP-sensitive K+ channels in the cardiovascular system and K+ channel openers.

ATP-sensitive K+ (K(ATP)) channels are inhibited by intracellular ATP (ATPi) and activated by intracellular nucleoside diphosphates and thus, provide a link between cellular metabolism and excitability. K(ATP) channels are widely distributed in various tissues and may be associated with diverse cellular functions. In the heart, the K(ATP) channel appears to be activated during ischemic or hypoxic conditions, and may be responsible for the increase of K+ efflux and shortening of the action potential duration. Therefore, opening of this channel may result in cardioprotective, as well as proarrhythmic, effects. These channels are clearly heterogeneous. The cardiac K(ATP) channel is the prototype of K(ATP) channels possessing approximately 80 pS of single-channel conductance in the presence of approximately 150 mM extracellular K+ and opens spontaneously in the absence of ATPi. A vascular K(ATP) channel called a nucleoside diphosphate-dependent K+ (K(NDP)) channel exhibits properties significantly different from those of the cardiac K(ATP) channel. The K(NDP) channel has the single-channel conductance of approximately 30-40 pS in the presence of approximately 150 mM extracellular K+, is closed in the absence of ATPi, and requires intracellular nucleoside di- or triphosphates, including ATPi to open. Nevertheless, K(ATP) and K(NDP) channels are both activated by K+ channel openers, including pinacidil and nicorandil, and inhibited by sulfonylurea derivatives such as glibenclamide. It recently was found that the cardiac K(ATP) channel is composed of a sulfonylurea receptor (SUR)2A and a two-transmembrane-type K+ channel subunit Kir6.2, while the vascular K(NDP) channel may be the complex of SUR2B and Kir6.1. By precisely comparing the functional properties of the SUR2A/Kir6.2 and the SUR2B/Kir6.1 channels, we shall show that the single-channel characteristics and pharmacological properties of SUR/Kir6.0 channels are determined by Kir and SUR subunits, respectively, while responses to intracellular nucleotides are determined by both SUR and Kir subunits.

ATP-Binding Cassette Transporters↗
PubMed1997

Effects of captopril on responses to bradykinin in the hindquarters vascular bed of the rat.

The effects of captopril, and angiotensin converting enzyme (ACE) inhibitor, on responses to bradykinin (BK), to angiotensin (Ang) I and II, and to other agonists were investigated in the hindquarters vascular bed of the rat. Under conditions of controlled flow, intra-arterial (i.a.) injections of BK in doses of 0.1-1.0 microgram, produced dose related decreases in hindquarters perfusion pressure and evoked decreases in systemic arterial pressure. Intra-arterial injections of Ang I and II produced dose-related increases in hindquarters perfusion pressure. Following administration of captopril in a dose of 2 mg/kg i.v., vasodilator responses to i.a. injections of BK were only slightly enhanced in the hindquarters vascular bed, whereas the evoked systemic vasodepressor responses to i.a. injections of BK were markedly enhanced by the ACE inhibitor. Captopril significantly reduced vasoconstrictor responses to i.a. injections of Ang I, whereas vasoconstrictor responses to i.a. injections of Ang II were significantly enhanced. The ACE inhibitor did not significantly alter vasodilator responses to i.a. injections of acetylcholine, nitroglycerin, nitric oxide, albuterol, or pinacidil. The present data show that BK has potent vasodilator activity in the hindquarters vascular bed of the rat and suggest that the site of action is most likely upstream from the site of inactivation, whereas the site of action of Ang I is at or near the site of conversion to Ang II in the hindquarters vascular bed. The observation that the evoked systemic vasodepressor responses to i.a. injections of BK were greatly enhanced, suggest that the lung is the major site of inactivation of BK.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Attenuation of the locomotor activating effects of D-amphetamine, cocaine, and scopolamine by potassium channel modulators.

1. Locomotor activating effects of D-amphetamine, cocaine, and scopolamine were determined alone and after pretreatment with K-channel modulators in mice. 2. When administered alone, D-amphetamine (1.0- 30 mg/kg) and cocaine (3.0- 56 mg/kg) produced inverted U-shaped dose-effect curves characteristic of psychomotor stimulant drugs. 3. When administered alone, scopolamine (3.0-56 mg/kg) also produced dose-dependent increases in locomotor activity but these effects plateaued with similar increases in locomotor activity induced by 10-56 mg/kg of scopolamine. 4. Pretreatment with the K-channel blockers 4-aminopyridine (0.3-1.7 mg/kg), quinine (30-100 mg/kg) or apamin (0.3-1.0 mg/kg) attenuated the locomotor increases induced by d-amphetamine, cocaine, and scopolamine. 5. Like the K-channel blockers, pretreatment with the K-channel openers cromakalim (1.0-3.0 mg/kg) and pinacidil (3.0-10 mg/kg) also attenuated the locomotor increases induced by D-amphetamine and scopolamine but did not modify the locomotor activating effects of cocaine. 6. These results demonstrate that K-channel modulation modifies the effects of D-amphetamine, cocaine, and scopolamine. 7. The results also demonstrate that K-channel openers can differentially alter the behavioral effects of cocaine and D-amphetamine.

4-Aminopyridine↗
PubMed2000

Enhancement of hydralazine hypotension by low doses of isoniazid. Possible role of semicarbazide-sensitive amine oxidase inhibition.

The influence of pretreatment with 1 through 300 mg/kg ip of isoniazid (ISO) on blood pressure and heart rate responses to 0.1 mg/kg iv of hydralazine (HYD) was assessed in rats anesthetized with chloralose--urethane. HYD hypotension was significantly enhanced by ISO at doses between 3 and 300 mg/kg ip. Heart rate was not influenced by HYD in control or pretreated animals. Depressor responses to 0.2 mg/kg iv of pinacidil (PIN) were also potentiated by ISO at 100 and 300, but not at 30 mg/kg. Similarly, ISO decreased cerebral gamma-aminobutyric acid (GABA) at the two highest doses; 30 mg/kg was without effect. Pretreatment of rats with ISO at 1 through 300 mg/kg failed to influence HYD-induced relaxation of aortic rings. These results were interpreted as indicating that potentiation of HYD hypotension by high doses of ISO is not specific for that vasodilator and is related to decreased cerebral GABA, as postulated previously. Lower doses could specifically potentiate the HYD-induced hypotensive effect by inhibition of semicarbazide-sensitive amine oxidase (SSAO), since both ISO and HYD are potent inhibitors of this enzyme. In support of this hypothesis, the SSAO inhibitors, benserazide (100 mg/kg ip) and mexiletine (50 mg/kg ip), were also found to enhance HYD hypotension.

Amine Oxidase (Copper-Containing)↗
PubMed1999

Rapid preconditioning neuroprotection following anoxia in hippocampal slices: role of the K+ ATP channel and protein kinase C.

Sublethal cerebral anoxic/ischemic insults may "precondition" and thereby protect brain from subsequent anoxic/ischemic insults. We tested two hypotheses in hippocampal slices: (i) that short periods of anoxia, each followed by reoxygenation, precondition and thereby improve recovery of synaptic activity following "lethal" anoxic insults; and (ii) that the ATP-sensitive potassium channel [K+ ATP] or protein kinase C mediates anoxic preconditioning neuroprotection in hippocampal slices. Hippocampal slices were subjected to three short periods of anoxia, each separated by 10 min of reoxygenation. These anoxic insults were prolonged only until the onset of anoxic depolarization. Thirty minutes following these insults, slices underwent a "test" anoxic insult, which was characterized by an anoxic insult that lasted 1 min of anoxic depolarization. Recovery of evoked potential amplitudes was followed for 30 min of reoxygenation. The beneficial effects of preconditioning was shown by the significant recovery of evoked potentials after "test" anoxic insults in preconditioned slices, when compared to controls that only underwent a "test" anoxic insult. In control slices, transient superfusion with an ATP-sensitive potassium channel agonist (10 microM pinacidil) 30 min prior to "test" anoxia markedly improved evoked potential recovery. Administration of 5 microM of the sulfonylurea tolbutamide, an ATP-sensitive potassium channel antagonist during preconditioning insults, blocked the protection afforded by preconditioning. Transient superfusion of a protein kinase C activator (500 nM phorbol 12-myristate 13-acetate) did not improve evoked potential recovery. Administration of 50 nM chelerythrine, a protein kinase C inhibitor during preconditioning insults did not block the protection afforded by preconditioning. These data support the hypothesis that the ATP-sensitive potassium channel is involved in the neuroprotection afforded by anoxic preconditioning in hippocampal slices. However, protein kinase C activation does not appear to play a role in this neuroprotection.

Adenosine Triphosphate↗
PubMed2002

17Beta-estradiol regulates expression of K(ATP) channels in heart-derived H9c2 cells.

OBJECTIVES: The main objective of the present study was to establish whether 17beta-estradiol (E2) regulates expression of cardiac adenosine triphosphate-sensitive potassium (K(ATP)) channel. BACKGROUND: Based on our previous studies that demonstrate gender-specific differences in sarcolemmal K(ATP) channels, we have hypothesized that the main estrogen, E2, may regulate expression of cardiac K(ATP) channels. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) using primers specific for Kir6.2 and sulfonylurea receptor 2A (SUR2A) subunits was performed on total ribonucleic acid (RNA) from rat embryonic heart-derived H9c2 cells. Immunoprecipitation and Western blotting using anti-Kir6.2 and anti-SUR2A antibodies was done on membrane fraction of H9c2 cells. Whole cell electrophysiology and digital epifluorescent Ca(2+) imaging were performed on living H9c2 cells. All experiments were done in cells incubated 24 h with or without 100 nM E2. RESULTS: The RT-PCR revealed higher levels of SUR2A, but not Kir6.2, messenger RNA (mRNA) in E2-treated, relative to untreated, cells. Increase of the level of only the SUR2A subunit could change the number of sarcolemmal K(ATP) channels only if the Kir6.2 is in excess over SUR2A. Indeed, RT-PCR analysis demonstrated considerably lower levels of SUR2A mRNA compared with Kir6.2 mRNA. Significantly higher levels of both Kir6.2 and SUR2A protein subunits were found in the membrane fraction of E2-treated cells compared with untreated ones, and the density of current evoked by pinacidil (100 microM), a K(ATP) channel opener, was significantly higher in E2-treated compared with untreated cells. To test the effect of E2 on cellular response to hypoxia-reoxygenation, we have measured on-line, intracellular concentration of Ca(2+) in H9c2 cells exposed to hypoxia-reoxygenation. Intracellular Ca(2+) loading induced by hypoxia-reoxygenation was significantly decreased by treatment with E2. This E2-mediated protection was inhibited by HMR 1098 (30 microM), but not by 5-hydroxydecanoate (50 microM). CONCLUSIONS: In conclusion, this study has demonstrated that E2 increases levels of SUR2A subunit, stimulates K(ATP) channel formation and protects cardiac cells from hypoxiareoxygenation.

Adenosine Triphosphate↗
PubMed2002

Influence of propranolol, enalaprilat, verapamil, and caffeine on adenosine A(2A)-receptor-mediated coronary vasodilation.

OBJECTIVES: The study was done to determine the effects of propranolol, enalaprilat, verapamil, and caffeine on the vasodilatory properties of the adenosine A(2A)-receptor agonist ATL-146e (ATL). BACKGROUND: ATL is a new adenosine A(2A)-receptor agonist proposed as a vasodilator for myocardial stress perfusion imaging. Beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium blockers are commonly used for the treatment of coronary artery disease (CAD), and their effect on ATL-mediated vasodilation is unknown. Dietary intake of caffeine is also common. METHODS: In 19 anesthetized, open-chest dogs, hemodynamic responses to bolus injections of ATL (1.0 microg/kg) and adenosine (60 microg/kg) were recorded before and after administration of propranolol (1.0 mg/kg, ATL only), enalaprilat (0.3 mg/kg, ATL only), caffeine (5.0 mg/kg, ATL only), and verapamil (0.2 mg/kg bolus, ATL and adenosine). RESULTS: Neither propranolol nor enalaprilat attenuated the ATL-mediated vasodilation (225 +/- 86% and 237 +/- 67% increase, respectively, p = NS vs. control). Caffeine had an inhibitory effect (97 +/- 28% increase, p < 0.05 vs. control). Verapamil blunted both ATL- and adenosine-induced vasodilation (63 +/- 20% and 35 +/- 7%, respectively, p < 0.05 vs. baseline), and also inhibited the vasodilation induced by the adenosine triphosphate-sensitive potassium (K(ATP)) channel activator pinacidil. CONCLUSIONS: Beta-blockers and ACE inhibitors do not reduce the maximal coronary flow response to adenosine A(2A)-agonists, whereas verapamil attenuated this vasodilation through inhibition of K(ATP) channels. The inhibitory effect of verapamil and K(ATP) channel inhibitors like glybenclamide on pharmacologic stress using adenosine or adenosine A(2A)-receptor agonists should be evaluated in the clinical setting to determine their potential for reducing the sensitivity of CAD detection with perfusion imaging.

Adrenergic beta-Antagonists↗