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PubMed2006

An analysis of remifentanil in the pulmonary vascular bed of the cat.

In this investigation we sought to identify the role of remifentanil in the feline pulmonary vascular bed. Using adult mongrel cats in separate experiments, the effects of glibenclamide (adenosine triphosphate-sensitive K+ channel blocker), diphenhydramine (histamine H(1)-receptor antagonist), L-N5-(1-Iminoethyl) ornithine hydrochloride (nitric oxide synthase inhibitor), and naloxone (opioid receptor antagonist) were investigated in pulmonary arterial responses to remifentanil (opioid agonist), pinacidil (adenosine triphosphate-sensitive K+ channel activator), and bradykinin (nitric oxide synthase inducer). Under increased tone conditions in the isolated left lower lobe vascular bed of the cat, remifentanil induced a dose-dependent vasodepressor response that was not significantly altered after administration of glibenclamide and L-N5-(1-Iminoethyl) ornithine hydrochloride. Responses to remifentanil were significantly attenuated after administration of diphenhydramine and naloxone. The results suggest that remifentanil has potent vasodepressor activity in the feline pulmonary vascular bed and that these responses are mediated by histamine and opioid receptor sensitive pathways.

Animals↗
PubMed2003

Chronic endothelin antagonism restores cerebrovascular function in diabetes.

OBJECTIVE: Diabetes profoundly alters vascular function and is a risk factor for cerebrovascular disease. Diabetes increases myogenic tone and decreases responsiveness to adenosine triphosphatase (ATP)-sensitive K(+) (K(ATP)) channel openers and endothelium-dependent vasodilators. The mechanism(s) by which diabetes impairs cerebrovascular function remain obscure. In the present study, the effects of the potent vasoactive peptide endothelin-1 on myogenic tone and endothelium-dependent and potassium channel-mediated vasodilation in middle cerebral arteries from diabetic and nondiabetic rats were investigated. METHODS: Twenty-eight Wistar rats were divided into four experimental groups (n = 7 per group): control (C), control treated with bosentan (an endothelin A/B receptor antagonist) (CB), diabetic (D), and diabetic bosentan-treated (DB). Diabetes was induced with streptozotocin (D and DB groups), after which chronic bosentan treatment was initiated (CB and DB groups). Middle cerebral arteries were mounted in a pressure myograph, and myogenic responses were recorded. In addition, endothelium-dependent and -independent responses and the effects of the K(ATP) channel opener pinacidil were examined. RESULTS: Cerebral arteries from the diabetic and nondiabetic rats constricted in response to graded pressure increases. Maximum myogenic responses (percent constriction at 60 mm Hg) were significantly greater in the D group (38 +/- 3% versus 25 +/- 3% in C; P < 0.02). The enhanced myogenic tone in the D group was completely prevented by bosentan treatment (DB, 23 +/- 5% versus D; P < 0.003) without an effect on the CB group. In addition, bosentan treatment improved endothelium-dependent vasomotion and improved K(ATP)-mediated vasodilation in the DB group (P < 0.001). CONCLUSION: These data describe, for the first time, the interaction between endothelin-1, myogenic tone, and endothelial function in diabetes. Chronic endothelin antagonism restores cerebrovascular function in this model of diabetes and has global implications for the management of cerebrovascular disease in diabetes.

Animals↗
PubMed2002

Vasopressin inhibits sarcolemmal ATP-sensitive K+ channels via V1 receptors activation in the guinea pig heart.

To examine the effect of vasopressin on the sarcolemmal ATP-sensitive K (K(ATP)) channel, cell-attached, insideout and open-cell-attached methods of patch clamp techniques were used in isolated guinea pig ventricular myocytes. Suppressing both glycolytic and oxidative ATP production attained K(ATP) channel activation. In the cell-attached mode, vasopressin inhibited KATP channels in a concentration-dependent manner with an IC50 of 15.1+/-1.8 nmol/L. In the inside-out configuration, vasopressin failed to block K(ATP) channels. In the cell-attached mode, manning compound (1 micromol/L), a V1 receptor-selective antagonist, blocked the inhibitory action of vasopressin, although OPC-31260 (1 micromol/L), a V2 receptor-selective antagonist could not affect the action of vasopressin. In addition, vasopressin lost its inhibitory action on K(ATP) channels when the channel was activated by pinacidil, a K channel opener and in the open-cell-attached mode effected by streptolysin-O. Thus, the inhibitory action of vasopressin K(ATP) channels may occur via V1 receptor related mechanism.

Adenosine Triphosphate↗
PubMed2002

Effects of arachidonic acid on ATP-sensitive K+ current in murine colonic smooth muscle cells.

The effects of arachidonic acid (AA) and the mechanism through which it modulates ATP-sensitive K+ (K(ATP)) currents were examined in single smooth muscle cells of murine proximal colon. In the current-clamping mode, AA and glibenclamide induced depolarization of membrane potential. Using 0.1 mM ATP and 140 mM K+ solution in the pipette and 90 mM K+ in the bath solution at a -80 mV of holding potential, pinacidil activated the glibenclamide-sensitive inward current. The potential of these currents was reversed to near the equilibrium potential of K+ by 60 mM K+ in the bath solution. AA inhibited K(ATP) currents in a dose-dependent manner. This inhibition was not changed when 1 mM GDPbetaS was present in the pipette. Chelerythrine, protein kinase C inhibitor, did not block the AA effects. Superoxide dismutase and metabolic inhibitors (indomethacin and nordihydroguaiacretic acid) of AA did not affect the AA-induced inhibition. Eicosatetraynoic acid, a nonmetabolizable analogue of AA, inhibited the K(ATP) currents. These results suggest that AA-induced inhibition of K(ATP) currents is not mediated by G-protein or protein kinase C activation. The inhibitory action is likely to be a possible mechanism of AA-induced membrane depolarization.

Adenosine Triphosphate↗
PubMed2001

Tedisamil: master switch of nature?

Decreasing heart rate is potentially useful in ischaemic heart disease. Tedisamil is a bradycardic agent resulting from its ability to inhibit transient outward current (I(to)) in atria. Tedisamil inhibits I(to), potassium current (IK), K(ATP) and the protein kinase A-activated chloride channel in ventricles as well as vascular IK and Ca(2+)-activated IK (IK((Ca))). Tedisamil prolongs cardiac action potentials and the corrected QT (QTc) of the ECG and also increases cardiac refractoriness. Tedisamil is anti-arrhythmic in animal models of ventricular arrhythmias and atrial flutter. The bradycardic effect of tedisamil is associated with a reduction in myocardial oxygen demand. On isolated rat ventricle, tedisamil is a positive inotrope and on isolated rabbit atria, tedisamil reverses the negative inotropic effect of pinacidil. Tedisamil contracts the isolated rat portal vein and aorta, reduces cromakalim-induced relaxations of contracted rat aorta and increases blood pressure in animals and humans. Tedisamil is 96% bound to plasma proteins, has a plasma half-life of about 10 h and is cleared from the kidney unchanged. Clinical trials have shown that the electrophysiology of tedisamil is that of a class III anti-arrhythmic. In coronary artery disease, tedisamil has no effect on inotropism and increases the threshold for angina. Potassium channel blockade with tedisamil may have advantages over calcium channel blockers or K(ATP) channel openers as an anti-ischaemic mechanism in coronary artery disease. In exercise-induced myocardial ischaemia, beta-blockers are probably favourable to tedisamil, as they will limit the increase in heart rate, contractility and blood pressure caused by sympathetic stimulation, whereas tedisamil will not. In heart failure patients, tedisamil reduces heart rate, but increases blood pressure. The usefulness of tedisamil as a bradycardic agent is limited by the increase in blood pressure. A drug that is bradycardic without increasing blood pressure would be an improvement on tedisamil as the master switch of nature for ischaemic heart disease.

Action Potentials↗
PubMed1989

Positive inotropic and negative chronotropic effects of OPC-8490, a newly developed cardiotonic, in isolated, blood-perfused canine heart preparations.

When a new cardiotonic, OPC-8490 (3, 4-dihydro-6-[4-(4-oxo-4-phenylbutyl)-1-piperazinylcarbonyl]- 2(1H)- quinolinone citrate), was administered into the jugular vein of a support dog, at doses of 0.1, 0.3 and 1 mumol/kg, decreases in heart rate and arterial blood pressure were dose-dependently induced in intact support dogs. One and a half min after administration, positive inotropic and slight negative chronotropic responses were observed in isolated right atria perfused with arterial blood of support dogs. Administration of OPC-8490 into the sinus node artery of the isolated atrium induced positive inotropic and biphasic chronotropic effects, an initial brief positive (Ph1) followed by a long-lasting negative (Ph2) chronotropic effect in a dose-related manner. OPC-8490 at 1000 nmol caused a triphasic, Ph1 followed by Ph2 and slight positive (Ph3) chronotropic effects and an inotropic effect. In the left ventricular muscle preparation driven electrically at 2 Hz, 10-3000 nmol of OPC-8490 increased contractile force in a dose related manner. OPC-8490-induced responses were not significantly modified by propranolol or atropine. When isoproterenol (0.04 nmol/min) increased the basal sinus rate and contractile force of isolated atria, the Ph1 was suppressed and the Ph3 became clear, although the negative phase (Ph2) was not changed. The positive inotropic effect was not significantly changed. When intramural vagal nerve stimulation decreased sinus rate and contractile force, the positive inotropic and negative (Ph2) chronotropic effects were depressed. Verapamil significantly depressed the positive inotropic but not the chronotropic responses to OPC-8490. The positive inotropic effect of OPC-8490 was depressed by pinacidil but not changed by ouabain, although the chronotropic responses to OPC-8490 were not changed. These results suggest that cardiac responses to OPC-8490 involve several mechanisms including cyclic AMP dependent, Ca channel-dependent, potassium current-inhibitory and/or other mechanisms in the dog heart.

Animals↗
PubMed2003

Novel hypotensive agents from Verbesina caracasana: structure, synthesis and pharmacology.

The number and the pharmacological activities of drugs featuring a guanidine group is actually amazing. Many synthetic guanidine derivatives have attracted pharmacologists in search of new antihypertensive drugs for their ability to block adrenergic nerve activity through central and/or peripheral mechanisms. As a result, compounds such as guanethidine, guanabenz, guanfacine, and pinacidil have been introduced in antihypertensive drug therapy. A crude methanol extract of the Venezuelan plant Verbesina caracasana Fries (Compositae), intravenously administered to mice, was found to induce biological effects such as erection of hair, initial stimulation and subsequent blockade of breathing. Biologically controlled purification yielded a series of active guanidine derivatives, namely G1-G7, which were extensively studied with the focus on the following items: (1) The structure determination of the active compounds by spectral data and a set of reactions; (2) The confirmation of the structures by a biogenetically oriented synthesis; (3) The study of the pharmacological profiles of the isolated drugs; (4) The synthesis of analogous and homologous products in the effort to shed some light on the structure-activity relationship. The metabolites of V. caracasana were characterized, in anesthetized rats, as hypotensive drugs of high (G2), mild (G1, G7) and low (G3,G5,G6) potency, devoid of consistent actions in heart rate, and provided with moderate stimulatory effects on cardiac inotropism and breathing (at selected non-toxic intravenous doses). Autonomic neurogenic components and/or peripheral adrenergic and cholinergic receptor-related pathways were involved in the cardiovascular effects. Synthetic analogs and homologs of G1 and G5 were all shown to be hypotensive drugs of low-mild potency, not affecting appreciably cardiac inotropism and/or breathing. The pharmacodynamic differences among the studied compounds were likely to depend on their ability to cross the blood-brain barrier, lipophilicity and pharmacokinetics. Since most of the compounds did not induce reflex tachycardia and depression of myocardial contractility as the majority of the antihypertensive drugs, they might be useful in the treatment of arterial hypertension of various genesis.

Animals↗
PubMed2004

Preconditioning of the myocardium by volatile anesthetics.

Cardiovascular disease continues to be a major health problem. Tremendous efforts have been invested in clinical and laboratory research in the hopes of decreasing the risk of patients with cardiovascular disease undergoing cardiac and non-cardiac surgeries. A powerful endogenous mechanism of cardioprotection, termed ischemic preconditioning, was reported in a laboratory setting whereby the myocardium can be preconditioned by a brief ischemic episode and protected against a subsequent prolonged ischemic attack. Since this initial observation, several pharmacological agents have been demonstrated to mimic ischemic preconditioning. These include opioids, potassium channel openers such as pinacidil and diazoxide, and adenosine agonists. Recently, volatile anesthetics were found to be powerful cardiac preconditioning agents. Infarct size reduction as the result of anesthetic-induced preconditioning paralleled that of ischemic preconditioning. The use of volatile anesthetics as preconditioning agents in high-risk patients undergoing cardiac and non-cardiac surgeries can potentially result in the reduction of morbidity and disability in this class of patients. However, to fully realize the potential use of this novel property of volatile anesthetics, the underlying mechanism of anesthetic-induced preconditioning would need to be elucidated. This review highlights the major recent findings on the cardioprotective effects of volatile anesthetics.

Anesthetics, Inhalation↗
PubMed2002

The novel diazoxide analog 3-isopropylamino-7-methoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide is a selective Kir6.2/SUR1 channel opener.

ATP-sensitive K(+) (K(ATP)) channels are activated by a diverse group of compounds known as potassium channel openers (PCOs). Here, we report functional studies of the Kir6.2/SUR1 Selective PCO 3-isopropylamino-7-methoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide (NNC 55-9216). We recorded cloned K(ATP) channel currents from inside-out patches excised from Xenopus laevis oocytes heterologously expressing Kir6.2/SUR1, Kir6.2/SUR2A, or Kir6.2/SUR2B, corresponding to the beta-cell, cardiac, and smooth muscle types of the K(ATP) channel. NNC 55-9216 reversibly activated Kir6.2/SUR1 currents (EC(50) = 16 micromol/l). This activation was dependent on intracellular MgATP and was abolished by mutation of a single residue in the Walker A motifs of either nucleotide-binding domain of SUR1. The drug had no effect on Kir6.2/SUR2A or Kir6.2/SUR2B currents. We therefore used chimeras of SUR1 and SUR2A to identify regions of SUR1 involved in the response to NNC 55-9216. Activation was completely abolished and significantly reduced by swapping transmembrane domains 8-11. The reverse chimera consisting of SUR2A with transmembrane domains 8-11 and NBD2 consisting SUR1 was activated by NNC 55-9216, indicating that these SUR1 regions are important for drug activation. [(3)H]glibenclamide binding to membranes from HEK293 cells transfected with SUR1 was displaced by NNC 55-9216 (IC(50) = 105 micromol/l), and this effect was impaired when NBD2 of SUR1 was replaced by that of SUR2A. These results suggest NNC 55-9216 is a SUR1-selective PCO that requires structural determinants, which differ from those needed for activation of the K(ATP) channel by pinacidil and cromakalim. The high selectivity of NNC 55-9216 may prove to be useful for studies of the molecular mechanism of PCO action.

Adenosine Triphosphate↗
PubMed2004

A new ATP-sensitive K+ channel-independent mechanism is involved in glucose-excited neurons of mouse arcuate nucleus.

Glucose is known to modify electrical activity of neurons in different hypothalamic areas such as the arcuate nucleus (ARC) or the ventromedian nucleus. In these structures, it has been demonstrated that glucose-induced excitation of neurons involves ATP-sensitive K(+) (K(ATP)) channel closure. The aim of the present study was to determine whether ARC neurons were able to detect high extracellular glucose concentrations and which mechanisms were involved in this detection by using whole-cell and cell-attached patch-clamp techniques in acute mouse brain slices. An increase from 5 to 20 mmol/l glucose stimulated 19% and inhibited 9% of ARC neurons. Because of the high-glucose concentrations used, we called these neurons high-glucose-excited (HGE) and high-glucose-inhibited (HGI) neurons, respectively. Glucose-induced depolarization of HGE neurons was not abolished by tetrodotoxin treatment and was correlated with an increase of membrane conductance that reversed at approximately 20 mV. Experiments with diazoxide, pinacidil, or tolbutamide showed that K(ATP) channels were present and functional in most of the ARC neurons but were mostly closed at 5 mmol/l glucose. Moreover, HGE neurons were also present in ARC of Kir6.2 null mice. These results suggested that ARC neurons have the ability to sense higher glucose concentrations than 5 mmol/l through a new K(ATP) channel-independent mechanism.

Animals↗
PubMed2004

Effect of two amino acids in TM17 of Sulfonylurea receptor SUR1 on the binding of ATP-sensitive K+ channel modulators.

The sulfonylurea receptor (SUR) is the important regulatory subunit of ATP-sensitive K+ channels. It is an ATP-binding cassette protein comprising 17 transmembrane helices. SUR is endowed with binding sites for channel blockers like the antidiabetic sulfonylurea glibenclamide and for the chemically very heterogeneous channel openers. SUR1, the typical pancreatic SUR isoform, shows much higher affinity for glibenclamide but considerably lower affinity for most openers than SUR2. In radioligand binding assays, we investigated the role of two amino acids, T1285 and M1289, located in transmembrane helix (TM)-17, in opener binding to SUR1. These amino acids were exchanged for the corresponding amino acids of SUR2. In competition experiments using [3H]glibenclamide as radioligand, SUR1(T1285L, M1289T) showed much higher affinity toward the cyanoguanidine openers pinacidil and P1075 than SUR1 wild type. The affinity for the thioformamide aprikalim was also markedly increased. In contrast, the affinity for the benzopyrans rilmakalim and levcromakalim was unaffected; however, the amount of displaced [3H]glibenclamide binding was nearly doubled. The binding properties of the opener diazoxide and the blocker glibenclamide were unchanged. In conclusion, mutation of two amino acids in TM17 of SUR1, especially of M1289, leads to class-specific effects on opener binding by increasing opener affinity or by changing allosteric coupling between opener and glibenclamide binding.

ATP-Binding Cassette Transporters↗
PubMed1995

Activation of Ca(2+)-activated K+ channels by beta agonist in rabbit coronary smooth muscle cells.

Isoproterenol (ISO), a beta agonist, causes hyperpolarization of coronary smooth muscle cells via an increase in K+ conductance. This hyperpolarization may cause the coronary vasorelaxation by decreasing the cytoplasmic Ca2+ concentration. It is well known that the activation of beta adrenoreceptors stimulates the adenylate cyclase activity, and the resulting K+ channel phosphorylation by cAMP-dependent protein kinase may be responsible for ISO-induced increase in K+ channel activity. However, it is not clear whether the increase in K+ channel activity by ISO is exclusively due to the activation of adenylate cyclase or not. In this research, the effect of ISO on the isometric tension and the mechanism of ISO-induced K+ channel activation were investigated in various patch clamp conditions. The summarized results are as follows. ISO- and pinacidil induced vasorelaxation was significantly inhibited by the application of TEA or by increasing the external K+ concentration. In the whole cell clamp mode, application of ISO increased K+ outward current, and this effect was completely eliminated by propranolol. In the cell-attached patch, application of ISO or forskolin increased Ca(2+)-activated K+ channel activity. Application of ISO to the bath in the outside-out patches or GTP in the inside-out patches stimulated Ca(2+)-activated K+ channels. From the above results, both A-kinase dependent channel phosphorylation and direct GTP-binding protein mediated effect might be responsible for the the activation of Ca(2+)-activated K+ channel by ISO in rabbit coronary smooth muscle cells. And this K+ channel activation also contributes to the ISO-induced vasorelaxation.

Animals↗
PubMed1999

[The effect of membrane channel agonists and antagonists on hemodynamics and vascular tonus].

Compound "C" which was synthesized in Institute of Organic Chemistry NA of Science unite in one molecule remnant of 4-aril-1,4-dihydropyridin kernek cause it as calcium channel block-up property and group of molecule pinacidil which determine if effect as activation potassium channels. This compound cause essential decrease arterial pressure and total periphery resistance of vessels. The decrease this figures of hemodynamic connect with reducing vessels tone. This is proved by substantial decrease contractile activity isolated strips of aorta and portal vein by compound "C". The mechanism reducing tone, as demonstrate investigations on isolated solitary smooth muscle mesenterial arteries, cause with increase potassium current, hyperpolarization of cell's membrane, and with depresses calcium current in L-type Ca(2+) channels.

Animals↗
PubMed1999

Relationship between adenosine-induced vascular effects and ATP-sensitive K+ channels.

AIM: To study the relationship between adenosine (Ade) receptors and adenosine 5'-triphosphate (ATP)-sensitive potassium (KATP) channels in rat aorta. METHODS: Isolated rat aorta rings were suspended for isometric force recording. The vascular effects of Ade were assessed in the presence or absence of functional endothelium. The interactions of Ade and pinacidil (Pin) or glibenclamide (Gli) were investigated. RESULTS: In isolated aorta preconstricted with KCl 20 mmol.L-1, Ade 3-300 mumol.L-1 induced relaxation in a concentration-dependent manner; and in 48/99 preparations from 32 rats, Ade induced initial transient constriction followed by sustained relaxation. When the functions of KATP channels were blocked with Gli 1 or 100 mumol.L-1, effects of Ade were characterized by vasoconstriction rather than vasorelaxation. The combination of Pin 1 mumol.L-1 with Ade 100 mumol.L-1 showed no synergic vasodilatory effects and did not affect Ade-induced vasoconstriction. After the removal of endothelium, Ade still induced vasoconstriction and vasorelaxation, and the constrictive effects showed no difference from those in the presence of endothelium, but the potency of vasodilatory effects became weaker with slower decrease in tension. CONCLUSION: The activation of KATP channels is involved in Ade receptor-induced vasodilation.

Adenosine↗
PubMed1992

Potassium channel opening drugs and the airways.

1. Potassium channel opening drugs (KCOs) include benzopyrans such as cromakalim, cyanoguanidines such as pinacidil and tetrahydrothiopyrans such as RP 49356. 2. While clinical trials have indicated that cromakalim may be of benefit in the treatment of nocturnal asthma, it remains to be determined whether KCOs will find a place in our armamentarium of clinically useful anti-asthma agents. 3. KCOs inhibit the spontaneous tone of airways smooth muscle in vitro, an action associated with membrane hyperpolarization towards the potassium equilibrium potential and with the promotion of 86Rb+ or 42K+ efflux from the muscle cells. KCOs suppress spasm of airways smooth muscle evoked by low (< 40 mM) but not high (> 40 mM) concentrations of KCl. Their relaxant effects in airways smooth muscle can be attenuated by a variety of agents (including sulphonylureas) known to inhibit the opening of plasmalemmal K(+)-channels. 4. The KCOs open an ATP-sensitive K(+)-channel (KATP) in the plasmalemma. KATP is not open under normal circumstances and does not play an important role in determining the strong outward rectifying behavior of the cell membrane. The biochemical mechanisms by which the KCOs promote the opening of KATP remain to be elucidated but probably do not involve channel phosphorylation consequent to the intracellular accumulation of cAMP. 5. By causing hyperpolarization of the plasmalemma, the KCOs inhibit the cellular influx of Ca2+ through voltage-dependent channels. Relaxation follows both as a direct consequence of the fall in cytosolic free Ca2+ and also as a consequence of reduced production of phosphoinositide second messengers. The KCOs may also inhibit Ca2+ uptake by, and hence Ca2+ release from, the sarcoplasmic reticulum. 6. KCOs can inhibit cholinergic and non-adrenergic, non-cholinergic (NANC) excitatory neuroeffector transmission in the airways by glibenclamide-sensitive mechanisms which may involve inhibition of neurotransmitter release. The KCOs do not attenuate NANC inhibitory neuroeffector transmission, suggesting that KATP may not be expressed in neurones of this type. 7. The active enantiomer of cromakalim has been found to be effective in alleviating nocturnal asthma at plasma concentrations just threshold for relaxing human airways smooth muscle in vitro. The clinical efficacy of cromakalim may therefore depend on an action other than the direct relaxation of airways smooth muscle. Animal studies indicate that KCOs can reduce airway hyper-reactivity at sub-bronchodilator doses. The mechanism of this effect remains to be elucidated and may not crucially depend upon inhibition of neurotransmitter release within the lung.

Animals↗
PubMed2003

Functional coupling between sulfonylurea receptor type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain.

We previously identified a novel, nonselective cation channel in native reactive (type R1) astrocytes (NR1As) from injured rat brain that is regulated by cytoplasmic Ca2+ and ATP (NC(Ca-ATP)) and exhibits sensitivity to block by adenine nucleotides similar to that of sulfonylurea receptor type 1 (SUR1). Here we show that SUR1 is involved in regulation of this channel. NR1As within the site of injury and after isolation exhibited specific binding of FITC-tagged glibenclamide and were immunolabeled with anti-SUR1 antibody, but not with anti-SUR2, anti-Kir6.1 or anti-Kir6.2 antibodies, indicating absence of ATP-sensitive K+ (KATP) channels. RT-PCR confirmed transcription of mRNA for SUR1 but not SUR2. Several properties previously associated exclusively with SUR1-regulated KATP channels were observed in patch-clamp experiments using Cs+ as the charge carrier: (1) the sulfonylureas, glibenclamide and tolbutamide, inhibited NCCa-ATP channels with EC50 values of 48 nm and 16.1 microm, respectively; (2) inhibition by sulfonylureas was lost after exposure of the intracellular face to trypsin or anti-SUR1 antibody; (3) channel inhibition was caused by a change in kinetics of channel closing, with no change in channel amplitude or open-channel dwell times; and (4) the SUR activator ("KATP channel opener"), diazoxide, activated the NCCa-ATP channel, whereas pinacidil and cromakalin did not. Also, glibenclamide prevented cell blebbing after ATP depletion, whereas blebbing was produced by exposure to diazoxide. Our data indicate that SUR1 is functionally coupled to the pore-forming portion of the NC(Ca-ATP) channel, providing the first demonstration of promiscuity of SUR1 outside of the K+ inward rectifier family of channels.

ATP-Binding Cassette Transporters↗
PubMed1992

Identification of a specific binding site for K+ channel openers in rat aorta.

The K+ channel openers (KCOs) form a structurally heterogeneous group of compounds which relax smooth muscle by opening K+ channels in the plasmalemma. At present it is not known whether these drugs open the same K+ channel in smooth muscle and, if so, whether they bind to the same site of this channel. To address these questions we present the first binding study with KCOs in a smooth muscle preparation. In intact rat aortic strips, the novel tritiated KCO, 3H-P1075 (N-cyano-N'-(1,1-dimethyl[2,2,3,3(3)H]propyl)-N"-3-pyridylguanidine++ +), a potent pinacidil analogue, showed saturable specific binding of high affinity (KD = 6 +/- 1 nM, Bmax = 23 +/- 3 fmol/mg tissue wet weight). Specific binding of 3H-P1075 was inhibited stereospecifically by representatives from all major families of K+ channel openers, with a rank order of potency that correlated well with the potencies for vasorelaxation in rat aorta. The sulfonylurea glibenclamide, a relatively specific blocker of ATP-sensitive K+ channels and an inhibitor of the effects of KCOs, also inhibited 3H-P1075 binding and increased the rate of dissociation of 3H-P1075 from the tissue in a concentration-dependent manner. Lowering temperature (from 37 degrees C to 2 degrees C) and decreasing intracellular ATP levels by metabolic poisoning, diminished specific 3H-P1075 binding by reducing Bmax. However, depolarization (KCl = 55 mM) or lowering pH from 7.4 to 6.0 did not influence binding. The data demonstrate the existence of a specific binding site for the KCO 3H-P10756 in rat isolated aorta, which seems to be of functional relevance.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Activation of a relaxation cascade in isolated coronary arteries by brief electrical pulses.

Superfused cattle coronary artery rings contracted with endothelin or with a thromboxane A2 mimetic respond to transmural stimulation with relaxation. These relaxations are not reduced by denudation of the endothelium, or by combined pretreatment with quanethidine, atropine and propranolol, nor do they involve free radicals. Stimulation at 0.5 Hz with an increasing number of pulses, from 1 to 50, each of 500 microseconds in duration, produced progressively greater and more prolonged relaxations. Human coronary arteries, denuded and pretreated with guanethidine or tetrodotoxin, also showed prominent relaxations of both spontaneous and induced contractions with minimal transmural stimulation at 0.5 Hz. The delivery of 10 pulses briefly depressed near-maximal contractions to combinations of two or even three spasmogens in the cattle preparations. Reduction of extracellular potassium to near zero did not reduce stimulation-induced relaxations, but decreases in extracellular calcium did. The participation of ATP-sensitive potassium channels in stimulation-induced relaxations was unlikely because glibencamide did not reduce them, although it antagonized the relaxation produced by the potassium channel opener pinacidil. Tetraethylammonium blocked the relaxations to stimulation, indicating the involvement of calcium-dependent potassium channels, but block of small to moderate conductance SK channels with apamin was ineffective in antagonizing relaxations, making it likely that activation of large conductance SK channels or maxi-K channels was involved. Blockade of stimulation-induced relaxation in low sodium Krebs', but not by vanadate (1 mM), indicated the likely involvement of the Na+/Ca++ exchanger rather than a Ca(++)-ATPase as the calcium extrusion component of the relaxation process. Restoration of prestimulation tone required calcium influx through nifedipine-sensitive channels. It is concluded that a highly effective relaxation cascade is initiated by the delivery of one to five 0.5-msec pulses at 0.5 Hz, whose effects long outlast the stimulation parameters. The significance of this finding for coronary pathophysiology and as a means of selectively activating a relaxation cascade in an intact coronary artery segment is discussed.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗