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Results for “Potassium Channel Blockers”

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PubMed2004

Diazoxide causes early activation of cardiac sarcolemmal KATP channels during metabolic inhibition by an indirect mechanism.

OBJECTIVE: We have used isolated myocytes to investigate the effects of diazoxide on sarcolemmal KATP channel (sarcoKATP) activity and action potential failure during metabolic inhibition, and the role of these channels in protection of functional recovery on reperfusion. MATERIALS AND METHODS: Isolated adult rat ventricular myocytes were exposed to metabolic inhibition (NaCN and iodoacetate) and reperfusion. Functional recovery was assessed from the ability of cells to contract on electrical stimulation and to recover calcium homeostasis, measured with fura-2. Action potentials and KATP currents were measured using patch clamp. RESULTS: Pretreatment with diazoxide (100 microM, 5 min) increased the proportion of cells that recovered contractile function after MI and reperfusion from 16.8 +/- 2.4% to 65.0 +/- 2.2% (p<0.001) and the proportion of cells in which [Ca2+]i recovered to <250 nM. Pretreatment also accelerated action potential and contractile failure during MI. In cell-attached patches, MI activated sarcoKATP channels after 224 +/- 11 s, and diazoxide pretreatment decreased this to 145 +/- 24 s (p<0.01). However, diazoxide present in the patch pipette did not accelerate sarcoKATP channel activation. Intracellular Mg2+ rose earlier in diazoxide-pretreated cells. The sarcoKATP blocker HMR 1883 delayed action potential failure and reduced diazoxide protection. CONCLUSIONS: Diazoxide pretreatment increases recovery of function and [Ca2+]i following reperfusion. Protection is coupled with early action potential failure, due to early activation of sarcoKATP channels during metabolic inhibition (MI), which is likely to involve an indirect effect of diazoxide.

Action Potentials↗

PubMed2001

Insulin-induced relaxation of rat mesenteric artery is mediated by Ca(2+)-activated K(+) channels.

We tested the hypothesis that relaxation of the rat mesenteric artery in response to insulin is mediated by K(+) channels. Two concentrations of insulin (10 and 100 mU/ml) induced relaxation of the artery by 6+/-1%, 24+/-3% (mean+/-S.E.M.). Denudation of the endothelium or precontraction by KCl (30 mM), clotrimazole (10 microM), a cytochrome P450 inhibitor, charybdotoxin (30 nM) an inhibitor of large-conductance Ca(2+)-activated K(+) channels, abolished the relaxation of the artery in response to insulin. However, N(omega)-nitro-L-arginine methyl ester (L-NAME; 100 microM), an inhibitor of nitric oxide synthase, apamin (1 microM), an inhibitor of small-conductance Ca(2+)-activated K(+) channels, or glibenclamide (10 microM), an ATP-sensitive K(+) channels blocker, did not attenuate the relaxation of the artery caused by insulin. These results suggest that the relaxation of rat mesenteric artery in response to insulin is mediated mostly by large-conductance Ca(2+)-activated K(+) channels, perhaps an endothelium-derived hyperpolarizing factor (EDHF).

Animals↗

PubMed1998

A human bronchial epithelial cell line releases arginine vasopressin: involvement of Ca2+ -activated K+ channels.

To determine whether airway epithelium releases arginine vasopressin (AVP) and, if so, what the mechanism of the release is, we studied cultured human bronchial epithelial cell line, 16-HBE cells, in vitro. The cells spontaneously released small but significant amounts of AVP, and this release was dose dependently increased by platelet-activating factor (PAF) or bradykinin (BK). The PAF- and BK-induced AVP release was inhibited by 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate, a phospholipase C inhibitor, and thapsigargin but not by Ca2+ -free solution. Pretreatment with the big conductance Ca2+-activated K+ channel blocker iberiotoxin attenuated the stimulated release of AVP, whereas apamin and glibenclamide were without effect. These results suggest that human bronchial epithelial cells release AVP and that the release may be stimulated by phospholipase C activation, mobilization of Ca2+ from internal stores and the concomitant activation of big conductance Ca2+-activated K+ channels.

Arginine Vasopressin↗

PubMed2004

Newly developed blockers of the M-current do not reduce spike frequency adaptation in cultured mouse sympathetic neurons.

The M-current (I(K(M))) is believed to modulate neuronal excitability by producing spike frequency adaptation (SFA). Inhibitors of M-channels, such as linopirdine and 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE991), enhance depolarization-induced transmitter release and improve learning performance in animal models. As such, they are currently being tested for their therapeutic potential for treating Alzheimer's disease. The activity of these blockers has been associated with the reduction of SFA and the depolarization of the membrane observed when I(K(M)) is inhibited. To test whether this is the case, the perforated patch technique was used to investigate the capacity of I(K(M)) inhibitors to alter the resting membrane potential and to reduce SFA in mouse superior cervical ganglion neurons in culture. Linopirdine and XE991 both proved to be potent blockers of I(K(M)) when the membrane potential was held at -30 mV (IC(50) 2.56 and 0.26 microM, respectively). However, their potency gradually declined upon membrane hyperpolarization and was almost null when the membrane potential was kept at -70 mV, indicating that their blocking activity was voltage dependent. Nevertheless, I(K(M)) could be inhibited at these hyperpolarized voltages by other inhibitors such as oxotremorine-methiodide and barium. Under current-clamp conditions, neither linopirdine (10 microM) nor XE991 (3 microM) was effective in reducing the SFA and both provoked only a small slowly developed depolarization of the membrane (2.27 and 3.0 mV, respectively). In contrast, both barium (1 mM) and oxotremorine-methiodide (10 microM) depolarized mouse superior cervical ganglion neurons by about 10 mV and reduced the SFA. In contrast to classical I(K(M)) inhibitors, the activity of linopirdine and XE991 on the I(K(M)) is voltage dependent and, thus, these newly developed I(K(M)) blockers do not reduce the SFA. These results may shed light on the mode of action of these putative cognition enhancers in vivo.

Action Potentials↗

PubMed1997

Characterization of delayed rectifier Kv channels in oligodendrocytes and progenitor cells.

We examined the molecular identity of K+ channel genes underlying the delayed rectifier (IK) in differentiated cultured oligodendrocytes (OLGs) and oligodendrocyte progenitor (OP) cells. Using reverse transcription-PCR cloning, we found that OP cells and OLGs expressed multiple Kv transcripts, namely Kv1.2, Kv1.4, Kv.1.5, and Kv1.6. Immunocytochemical and Western blot analyses revealed that Kv1.5 and Kv1.6 as well as Kv1.2 and Kv1.4 channel proteins could be detected in these cells, but definitive evidence for functional K+ channel expression was obtained only for the Kv1.5 channel. In addition, mRNA and immunoreactive protein levels of both Kv1.5 and Kv1.6 channels were significantly lower in differentiated OLGs when compared with levels in OP cells. Proliferation of OP cells was inhibited by K+ channel blockers, but not by incubation with either Kv1.5 or Kv1.6 antisense oligonucleotides. We conclude that (1) IK in OP cells and OLGs is encoded partly by Kv1.5 subunits, possibly forming heteromultimeric channels with Kv1.6 or other Kv subunits; and (2) inhibition of Kv1.5 or Kv1.6 channel expression alone does not prevent mitogenesis. Concomitant inhibition of other Kv channels underlying IK may be necessary for OP cells to exit from cell cycle.

4-Aminopyridine↗

PubMed1998

Regulation of adrenergic nerve-mediated contraction of canine pulmonary artery by K+ channels.

The aim of the present study was to investigate the role of certain subtypes of K+ channels in nerve-evoked contractions of pulmonary artery in vitro. The lobar or segmental pulmonary arteries were dissected from dogs, cut into ring segments, and the contractile responses to electrical field stimulation (EFS) and noradrenaline were measured under isometric conditions. Addition of iberiotoxin, a big conductance Ca2+-activated K+ channel blocker, and apamin, a small conductance Ca2+-activated K+ channel blocker, did not change the resting tension but augmented the contractile responses to EFS, so that the electric stimulus frequency required to produce a half-maximal contraction (ES50) was decreased from 18.2+/-3.5 to 7.4+/-2.3 Hz (p<0.01) and from 16.8+/-2.2 to 11.4+/-2.0 Hz (p<0.05), respectively, whereas glibenclamide, an adenosine triphosphate (ATP)-sensitive K+ channel blocker, had no effect. In contrast, none of the K+ channel blockers altered the contractile response to noradrenaline. Incubation of tissues with iberiotoxin and apamin increased the release of 3H-noradrenaline evoked by EFS. We conclude that big conductance Ca2+-activated K+ channels and small conductance Ca2+-activated K+ channels may play a role in the regulation of adrenergic neurotransmission in the pulmonary artery, probably by inhibiting the exocytotic release of noradrenaline from the adrenergic nerve terminals.

Animals↗

PubMed1997

Enhancement of calcium signaling and proliferation responses in activated human T lymphocytes. Inhibitory effects of K+ channel block by charybdotoxin depend on the T cell activation state.

T cell receptor (TCR) stimulation, leading to T cell activation and ultimately to cell proliferation and differentiation, evokes elevations of [Ca2+]i with a high variability between individual T lymphocytes. We have used Ca(2+)-imaging of Fura-2 loaded cells to study the origin of the variation in Ca2+ signals and its consequences for the final cellular response. We found that, compared to resting cells, the percentage of responding cells and the average amplitude of the Ca2+ signal upon TCR re-stimulation by PHA increases in the first 5 days of T cell activation and declines thereafter, with more pronounced [Ca2+]i oscillations in later stages. In parallel, an enhancement of T cell proliferation is observed. Stronger stimulation of the TCR/CD3 complex by co-crosslinking CD3 with CD4/CD8 molecules evokes oscillating Ca2+ responses irrespective of the activation state, indicating that the basic capacity for Ca2+ signaling is essentially the same in resting and activated cells. Nevertheless, also the amplitude of the CD3+CD4/8 response shows a transient additional increase during the first days of T cell activation. Experiments with the K+ channel blocker charybdotoxin (CTX) indicate that [Ca2+]i oscillations depend critically on K+ channel functioning, but suppression of these oscillations by CTX does not significantly affect the average amplitude of the Ca2+ signal nor PHA-induced proliferation. However, when applied during the first 4-5 days of activation, CTX reduces in addition the average level of the TCR evoked Ca2+ response and inhibits subsequent proliferation.

Calcium↗

PubMed1993

Quinidine-sensitive K+ channels in the basolateral membrane of embryonic coprodeum epithelium: regulation by aldosterone and thyroxine.

Basolateral K+ channels and their regulation during aldosterone- and thyroxine-stimulated Na+ transport were studied in the lower intestinal epithelium (coprodeum) of embryonic chicken in vitro. Isolated tissues of the coprodeum were mounted in Ussing chambers and investigated under voltage-clamped conditions. Simultaneous stimulation with aldosterone (1 mumol.l-1) and thyroxine (1 mumol.l-1) raised short-circuit current after a 1- to 2-h latent period. Maximal values were reached after 6-7 h of hormonal treatment, at which time transepithelial Na+ absorption was more than tripled (77 +/- 11 microA.cm-2) compared to control (24 +/- 8 microA.cm-2). K+ currents across the basolateral membrane were investigated after permeabilizing the apical membrane with the pore-forming antibiotic amphotericin B and application of a mucosal-to-serosal K+ gradient. This K+ current could be dose dependently depressed by the K+ channel blocker quinidine. Fluctuation analysis of the short-circuit current revealed a spontaneous and a blocker-induced Lorentzian noise component in the power density spectra. The Lorentzian corner frequencies increased linearly with the applied blocker concentration. This enabled the calculation of single K+ channel current and K+ channel density. Single K+ channel current was not affected by stimulation, whereas the number of quinidine-sensitive K+ channels in the basolateral membrane increased from 11 to 26.10(6).cm-2 in parallel to the hormonal stimulation transepithelial Na+ transport. This suggests that the basolateral membrane is a physiological target during synergistic aldosterone and thyroxine regulation of transepithelial Na+ transport for maintaining intracellular K+ homeostasis.

Aldosterone↗

PubMed1999

Effect of caffeine on K+ efflux in frog skeletal muscle.

The exposure of frog skeletal muscle to caffeine (3-4 mM) generates an increase of the K+ (42K+) efflux rate coefficient (kK,o) which exhibits the following characteristics. First it is promoted by the rise in cytosolic Ca2+ ([Ca2+]i), because the effect is mimicked by ionomycin (1.25 microM), a Ca2+ ionophore. Second, the inhibition of caffeine-induced Ca2+ release from the sarcoplasmic reticulum (SR) by 40 microM tetracaine significantly reduced the increase in kK,o (DeltakK,o). Third, charybdotoxin (23 nM), a blocker of the large-conductance Ca2+-dependent K+ channels (BKCa channels) reduced DeltakK,o by 22%. Fourth, apamin (10 nM), a blocker of the small-conductance Ca2+-dependent K+ channels (SKCa channels), did not affect DeltakK,o. Fifth, tolbutamide (800 microM), an inhibitor of KATP channels, reduced DeltakK,o by about 23%. Sixth, Ba2+, a blocker of most K+ channels, did not preclude the caffeine-induced DeltakK,o. Seventh, omitting Na+ from the external medium reduced DeltakK,o by about 40%. Eight, amiloride (5 mM) decreased DeltakK,o by 65%. It is concluded that the caffeine-induced rise of [Ca2+]i increases K+ efflux, through the activation of: (1) two channels (BKCa and KATP) and (2) an external Na+-dependent amiloride-sensitive process.

Amiloride↗

PubMed2003

Plasma membrane depolarization reduces nitric oxide (NO) production in P388D.1 macrophage-like cells during Leishmania major infection.

In the present study, we compare changes in host cell plasma membrane potential (V(m)), K(+) fluxes, and NO production during K(+) channel blockade with those changes that occur during infection with Leishmania major. Infection of P388D.1 cells with L. major promastigotes or treatment with K(+) channel blockers (either 1mM 4-AP, 10mM TEA, or 200 microM quinine) suppressed NO production. Inhibition of NO production correlated with depolarization of the P388D.1 cell V(m). Infection of P388D.1 cells with L. major increased the unidirectional influx of rubidium (86Rb), a tracer for K(+) flux, that was comparable to that induced by K(+) channel blockade by 1mM 4-AP. The similar effects of K(+) channel blockers and L. major on NO production, K(+) influx, and V(m) suggest that K(+) channel activity and the maintenance of V(m) is important for NO production in these cells. We suggest that intracellular parasites employ a strategy to inhibit NO production by disrupting V(m) during the invasion/infection process by altering host cell K(+) channel activity.

Animals↗

PubMed1999

Ion currents in smooth muscle cells from human small bronchioles: presence of an inward rectifier K+ current and three types of large conductance K+ channel.

Bronchoconstriction of small bronchioles plays a major role in the increase in airway resistance following agonist challenge. There is evidence that the airway smooth muscle (ASM) of small bronchioles differs functionally from that in larger airways. Little is known however about the electrophysiology of small bronchioles. Ion currents were therefore studied in airway smooth muscle cells freshly dissociated from human intralobular bronchioles, with a diameter between 0.3 and 1.0 mm. As previously reported for human large airways, the major outward current in these cells was due to activity of large conductance K+ (BK) channels, with a relatively minor component due to a voltage-gated delayed rectifier current (IDR), which was only observed in 30 % of cells. Three distinct types of iberiotoxin- and TEA-sensitive large conductance K+ channel contributed to large conductance K+ current (IBK). These included a highly voltage- and Ca2+-sensitive 200 pS channel previously reported in human large airways, and two smaller channels of 150 and 100 pS previously seen only in human fetal or cultured ASM. In contrast to large airways, ASM cells from bronchioles also demonstrated a voltage-gated inward rectifier current (IIR). IIR was activated by hyperpolarisation below the K+ equilibrium potential and could be blocked by submillimolar concentrations of Cs+ or Ba2+, and partially by physiological concentrations of Na+. Corresponding single channels with a conductance of 17 pS could also be recorded in the cell-attached configuration. A small voltage-independent current was also observed which was resistant to classic K+ and Cl- channel blockers but which could be abolished by replacement of Na+ with the impermeant cation N-methyl-D-glucamine (NMDG+). Corresponding non-selective single channels of 20 pS could be seen in inside-out mode. These results demonstrate that ASM from small bronchioles differs in terms of ion currents and channels from ASM derived from large airways, with possible implications for function.

Bronchi↗

PubMed1995

Role of ATP-sensitive K+ channels in anoxia-sensitive negative potential of endolymph.

To investigate the possible role of the ATP-sensitive K+ channels (KATP channels) in the generation of the anoxia-sensitive negative potential (ASNP), the effects of the treatment with glybenclamide and diazoxide on the endocochlear potential (EP) and K+ activity (AK) in the scala media were examined with double-barrelled K(+)-selective microelectrodes. The experiments were carried out in guinea pig cochleae, using glybenclamide as a KATP channel blocker and diazoxide as a KATP channel opener. Perilymphatic perfusion of glybenclamide decreased the amplitude of the ASNP and shortened its duration, whereas perfusion of diazoxide increased ASNP amplitude and prolonged its duration. Glybenclamide enhanced the decrease of endolymphatic AK by anoxia, whereas diazoxide suppressed this AK decrease. The results suggest that KATP channels may be involved in the generation of the ASNP.

Adenosine Triphosphate↗

PubMed2004

Role of K+ channels in M2 muscarinic receptor-mediated inhibition of noradrenaline release from the rat stomach.

Previously we reported the cholinergic M2 muscarinic receptor-mediated inhibition of noradrenaline release from the rat stomach (K. Yokotani, Y. Osumi. J Pharmacol Exp Ther. 1993;264:54-60). In the present study, we investigated the role of K+ channels in oxotremorine (a muscarinic receptor agonist)-induced inhibition of noradrenaline release using isolated, vascularly perfused rat stomach. The gastric postganglionic sympathetic nerves were electrically stimulated twice at 2.5 Hz for 1 min and test reagents were added during the second stimulation. The electrically evoked release of noradrenaline was augmented by tetraethylammonium and 4-aminopyridine (non-selective K+ channel blockers) and also by charybdotoxin (a blocker of big conductance Ca2+-activated K+ channel). On the other hand, apamin (a selective blocker of small conductance Ca2+-activated K+ channels) and glibenclamide (an ATP-activated K+ channel blocker) had no effect on the evoked noradrenaline release. Oxotremorine-induced inhibition of noradrenaline release was attenuated by tetraethylammonium and 4-aminopyridine, while the inhibition was not influenced by charybdotoxin, apamin, and glibenclamide. These results suggest that tetraethylammonium- and 4-aminopyridine-sensitive K+ channels (probably voltage-activated K+ channels) are involved in the muscarinic receptor-mediated inhibition of noradrenaline release from the rat stomach.

Animals↗

PubMed2000

Evidence of elevated intracellular calcium levels in weaver homozygote mice.

1. A mutation in the G-protein-linked, inwardly rectifying K+ channel GIRK2 leads to the loss of cerebellar and dopaminergic mesencephalic neurons in weaver mice. The steps leading to cell death are not well understood but may involve constitutive influx of Na+ and Ca2+ into the neurons. 2. We found that resting [Ca2+]i was dramatically higher in cerebellar neurons from weaver mice compared to wild-type neurons. 3. High-K+ stimuli elicited much smaller changes in [Ca2+]i in weaver cerebellar neurons compared to wild-type neurons. 4. weaver cerebellar granule cells could be rescued from cell death by the GIRK2wv cationic channel blocker, QX-314. 5. QX-314 lowered resting intracellular Ca2+ levels in weaver cerebellar granule cells. 6. These results suggest that changes in resting [Ca2+]i levels and alterations in K+ channel function are most likely to contribute to the developmental abnormalities and increased cerebellar cell death observed in weaver mice.

Animals↗

PubMed2000

Properties of a calcium-activated K(+) current on interneurons in the developing rat hippocampus.

Calcium-activated potassium currents have an essential role in regulating excitability in a variety of neurons. Although it is well established that mature CA1 pyramidal neurons possess a Ca(2+)-activated K(+) conductance (I(K(Ca))) with early and late components, modulation by various endogenous neurotransmitters, and sensitivity to K(+) channel toxins, the properties of I(K(Ca)) on hippocampal interneurons (or immature CA1 pyramidal neurons) are relatively unknown. To address this problem, whole-cell voltage-clamp recordings were made from visually identified interneurons in stratum lacunosum-moleculare (L-M) and CA1 pyramidal cells in hippocampal slices from immature rats (P3-P25). A biphasic calcium-activated K(+) tail current was elicited following a brief depolarization from the holding potential (-50 mV). Analysis of the kinetic properties of I(K(Ca)) suggests that an early current component differs between these two cell types. An early I(K(Ca)) with a large peak current amplitude (200.8 +/- 13.2 pA, mean +/- SE), slow time constant of decay (70.9 +/- 3.3 ms), and relatively rapid time to peak (within 15 ms) was observed on L-M interneurons (n = 88), whereas an early I(K(Ca)) with a small peak current amplitude (112.5 +/- 7.3 pA), a fast time constant of decay (39.4 +/- 1.6 ms), and a slower time-to-peak (within 26 ms) was observed on CA1 pyramidal neurons (n = 85). Removal of extracellular calcium or addition of inorganic Ca(2+) channel blockers (cadmium, nickel, or cobalt) was used to demonstrate the calcium dependence of these currents. Addition of norepinephrine, carbachol, and a variety of channel toxins (apamin, iberiotoxin, verruculogen, paxilline, penitrem A, and charybdotoxin) were used to further distinguish between I(K(Ca)) on these two hippocampal cell types. Verruculogen (100 nM), carbachol (100 microM), apamin (100 nM), TEA (1 mM), and iberiotoxin (50 nM) significantly reduced early I(K(Ca)) on CA1 pyramidal neurons; early I(K(Ca)) on L-M interneurons was inhibited by apamin and TEA. Combined with previous work showing that the firing properties of hippocampal interneurons and pyramidal cells differ, our kinetic and pharmacological data provide strong support for the hypothesis that different types of Ca(2+)-activated K(+) current are present on these two cell types.

Aging↗

PubMed1995

The cardioprotective actions of iloprost in myocardial ischemia of the rabbit can be separated from its vasodilatory effects mediated by KATP(+)-channel opening.

The modification of cardioprotective actions of iloprost by K(+)-channel blockade was studied in ischemic rabbit hearts. Glibenclamide, a blocker of ATP-dependent K(+)-channels, prevented coronary vasodilation mediated by the prostacyclin mimetic iloprost. In contrast, the cardioprotective effects of iloprost which were determined from prevention of ischemia induced rise in left ventricular enddiastolic pressure and loss of cytosolic troponin T in hearts made globally ischemic for two hours were not affected by glibenclamide. It is concluded that the cardioprotective action of iloprost can be separated from ist coronary vasodilator effect mediated by opening KATP(+)-channels.

Adenosine Triphosphate↗

PubMed1996

Extracellular K(+)-induced hyperpolarizations and dilatations of rat coronary and cerebral arteries involve inward rectifier K(+) channels.

1. The hypothesis that inward rectifier K(+) channels are involved in the vasodilatation of small coronary and cerebral arteries (100-200 microm diameter) in response to elevated [K+]o was tested. The diameters and membrane potentials of pressurized arteries from rat were measured using a video-imaging system and conventional microelectrodes, respectively. 2. Elevation of [K+]o from 6 to 16 mM caused the membrane potential of pressurized (60 mmHg) arteries to hyperpolarize by 12-14 mV. Extracellular Ba(2+) (Ba2+(o)) blocked K(+)-induced membrane potential hyperpolarizations at concentrations (IC(50), 6 microM) that block inward rectifier K(+) currents in smooth muscle cells isolated from these arteries. 3. Elevation of [K+]o from 6 to 16 mM caused sustained dilatations of pressurized coronary and cerebral arteries with diameters increasing from 125 to 192 microm and 110 to 180 microm in coronary and cerebral arteries, respectively. Ba2+(o) blocked K(+)-induced dilatations of pressurized coronary and cerebral arteries (IC50, 3-8 microM). 4. Elevated [K+]o-induced vasodilatation was not prevented by blockers of other types of K(+) channels (1 mM 4-aminopyridine, 1 mM TEA+, and 10 mu M glibenclamide), and blockers of Na(+)-K(+)-ATPase. Elevated [K+]o-induced vasodilatation was unaffected by removal of the endothelium. 5. These findings suggest that K+(o) dilates small rat coronary and cerebral arteries through activation of inward rectifier K(+) channels. Furthermore, these results support the hypothesis that inward rectifier K(+) channels may be involved in metabolic regulation of coronary and cerebral blood flow in response to changes in [K+]o.

Animals↗

PubMed1993

Functional role of Ca(2+)-activated K+ channels in resting state of carotid arteries from SHR.

Carotid arteries from spontaneously hypertensive rats (SHR) exhibited an active tone when exposed to a physiological salt solution; that is, the tension decreased when nifedipine was added. To determine the possible role of Ca(2+)-activated K+ (KCa) channels in the resting state of these arteries, the effects of agents that interact with these channels on tension and 86Rb efflux were compared in endothelium-denuded strips of carotid arteries from SHR and normotensive Wistar-Kyoto rats (WKY). The addition of charybdotoxin, a blocker of high-conductance KCa channels, to the resting strips produced a concentration-dependent contraction in SHR but not in WKY. In resting strips preloaded with 86Rb, the basal 86Rb efflux rate constant was significantly greater in SHR than in WKY. The addition of nifedipine to the resting strips decreased the basal 86Rb efflux rate constant only in SHR. The effect of nifedipine on tension and 86Rb efflux in 25.9 mM K(+)-contracted strips of WKY was comparable to the effect of this blocker in the resting strips of SHR. The basal 45Ca influx in resting strips of SHR was significantly increased when compared with WKY, and this increase in SHR was abolished by nifedipine. These results suggest that the transmembrane Ca2+ influx via L-type voltage-dependent Ca2+ channels was significantly increased in the resting state of carotid arteries from SHR and that the KCa channels were highly activated.

Animals↗