Mechanisms Underlying the QT Interval-prolonging Effects of Sevoflurane and Its Interactions with Other QT-prolonging Drugs

Background: Sevoflurane prolongs ventricular repolarization in patients, but the mechanisms are not fully characterized. The effects of sevoflurane on many cloned human cardiac ion channels have not been studied, and the interactions between sevoflurane and other drugs that prolong cardiac repolarization have not been detailed.

Methods: The effects of sevoflurane on action potentials and L-type Ca2+ channels in guinea pig myocytes were examined. Sevoflurane's effects on cloned human cardiac K+ channels and the cloned human cardiac Na+ channel were studied. The consequences of combining sevoflurane and the class III antiarrhythmic drugs sotalol or dofetilide on action potential duration were also examined.

Results: Sevoflurane produced an increase in action potential duration at concentrations of 0.3-1 mm. Contrary to most drugs that delay ventricular repolarization, sevoflurane was without effect on the human ether-a-go-go-related gene cardiac potassium channel but instead produced a reduction in KvLQT1/minK K+ channel currents and inhibited the Kv4.3 K+ channel by speeding its apparent rate of inactivation. Sevoflurane had little effect on Na+ and Ca2+ channel currents at concentrations of 1 mm or less. When the authors coadministered sevoflurane with sotalol or dofetilide, synergistic effects on repolarization were observed, resulting in large increases in action potential duration (up to 66%).     

Mechanisms underlying the QT interval-prolonging effects of sevoflurane and its interactions with other QT-prolonging drugs

BACKGROUND: Sevoflurane prolongs ventricular repolarization in patients, but the mechanisms are not fully characterized. The effects of sevoflurane on many cloned human cardiac ion channels have not been studied, and the interactions between sevoflurane and other drugs that prolong cardiac repolarization have not been detailed. METHODS: The effects of sevoflurane on action potentials and L-type Ca channels in guinea pig myocytes were examined. Sevoflurane's effects on cloned human cardiac K channels and the cloned human cardiac Na channel were studied. The consequences of combining sevoflurane and the class III antiarrhythmic drugs sotalol or dofetilide on action potential duration were also examined. RESULTS: Sevoflurane produced an increase in action potential duration at concentrations of 0.3-1 mm. Contrary to most drugs that delay ventricular repolarization, sevoflurane was without effect on the human ether-a-go-go-related gene cardiac potassium channel but instead produced a reduction in KvLQT1/minK K channel currents and inhibited the Kv4.3 K channel by speeding its apparent rate of inactivation. Sevoflurane had little effect on Na and Ca channel currents at concentrations of 1 mm or less. When the authors coadministered sevoflurane with sotalol or dofetilide, synergistic effects on repolarization were observed, resulting in large increases in action potential duration (up to 66%). CONCLUSION: Prolonged ventricular repolarization observed with administration of sevoflurane results from inhibition of KvLQT1/minK and Kv4.3 cardiac K channels. Combining sevoflurane with class III antiarrhythmic drugs results in supra-additive effects on action potential duration. The results indicate that sevoflurane, when administered with this class of drug, could result in excessive delays in ventricular repolarization. The results suggest the need for further clinical studies.     

The antiallodynic action target of intrathecal gabapentin: Ca2+ channels, KATP channels or N-methyl-d-aspartic acid receptors?

Gabapentin is a novel analgesic whose mechanism of action is not known. We investigated in a postoperative pain model whether adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channels, N-methyl-d-aspartic acid (NMDA) receptors, and Ca2+ channels are involved in the antiallodynic effect of intrathecal gabapentin. Mechanical allodynia was induced by a paw incision in isoflurane-anesthetized rats. Withdrawal thresholds to von Frey filament stimulation near the incision site were measured before and after incision and after intrathecal drug administration. The antiallodynic effect of gabapentin (100 mug) was not affected by intrathecal pretreatment with antagonists of K(ATP) channels, NMDA receptors or gamma-aminobutyric acid (GABA)(A) receptors. K(ATP) channel openers and GABA(A) receptor agonist, per se, had little effect on the postincision allodynic response. The Ca2+ channel blocker of N-type (omega-conotoxin GVIA, 0.1-3 microg), but not of P/Q-type (omega-agatoxin IVA), L-type (verapamil, diltiazem or nimodipine), or T-type (mibefradil), attenuated the incision-induced allodynia, as did gabapentin. Both the antiallodynic effects of gabapentin and omega-conotoxin GVIA were attenuated by Bay K 8644, an L-type Ca2+ channel activator. These results provide correlative evidence to support the contention that N-type Ca2+ channels, but not K(ATP) channels or NMDA or GABA(A) receptors, might be involved in the antiallodynic effect of intrathecal gabapentin.     

Clodronate inhibits contraction and prevents the action of L-type calcium channel antagonists in vascular smooth muscle.

Clodronate (dichloromethylenebisphosphonate) decreased vasoconstriction of the isolated perfused rat tail artery mediated by norepinephrine and by Ca2+ in a K(+)-depolarizing solution. The norepinephrine contractile response was divided into two components by sequential manipulation of the composition of the perfusion fluid, where the first component is due to the release of Ca2+ from intracellular stores and the second to the influx of Ca2+ from extracellular fluid. Clodronate (20 microM) decreased only the first component of the response at a norepinephrine concentration of 50 nM, and both components of the response at a higher norepinephrine concentration (100 nM). The L-type Ca2+ channel blocking drugs, nicardipine (10 nM) and verapamil (1 microM), reduced the second component of the norepinephrine-mediated vasoconstriction, but in the presence of clodronate (20 microM) this blocking action was prevented. These results were confirmed by examining the interaction between clodronate and nicardipine on norepinephrine and K(+)-mediated lanthanum (La(3+)-resistant unidirectional 45Ca uptake. Nicardipine (1-10 nM) decreased the norepinephrine (100 nM) and K(+)-induced (60 mM) La(3+)-resistant unidirection 45Ca uptake in a concentration-dependent manner, but in the presence of clodronate (20 microM) this concentration-dependent response was abolished. Thus, clodronate not only reduced agonist-induced Ca2+ release from intracellular stores and Ca2+ influx through L-type Ca2+ channels but also prevented L-type Ca2+ channel antagonists from exerting their effect. These results indicate clodronate has two sites of action during vascular smooth muscle contraction: the first on intracellular mobilization of Ca2+ and the second on L-type Ca2+ channels.     

Effects of volatile anesthetics on cardiac ion channels

The focus of the present review is on how interference with various ion channels in the heart may be the molecular basis for cardiac side-effects of gaseous anesthetics. Electrophysiological studies in isolated animal and human cardiomyocytes have identified the L-type Ca(2+) channel as a prominent target of anesthetics. Since this ion channel is of fundamental importance for the plateau phase of the cardiac action potential as well as for Ca(2+)-mediated electromechanical coupling, its inhibition may facilitate arrhythmias by shortening the refractory period and may decrease the contractile force. Effective inhibition of this ion channel has been shown for clinically used concentrations of halothane and, to a lesser extent, of isoflurane and sevoflurane, whereas xenon was without effect. Anesthetics furthermore inhibit several types of voltage-gated K(+) channels. Thereby, they may disturb the repolarization and bear a considerable risk for the induction of ventricular tachycardia in predisposed patients. In future, an advanced understanding of cardiac side-effects of anesthetics will derive from more detailed analyses of how and which channels are affected as well as from a better comprehension of how altered channel function influences heart function.     

Aprikalim reduces the Na+-Ca2+ exchange outward current enhanced by hyperkalemia in rat ventricular myocytes

BACGROUND: Aprikalim, an adenosine triphosphate (ATP) sensitive K+ (K(ATP)) channel opener, attenuates the elevation of intracellular Ca2+ concentration ([Ca2+]i) and improves the contractile functions after hyperkalemic and hypothermic cardioplegia. There is evidence that cardioplegia increases the Na+-Ca2+ exchange activity without affecting Ca2+ influx through L-type Ca2+ channels or Ca2+ content in the sarcoplasmic reticulum, the intracellular Ca2+ store. METHODS: We measured the Na+-Ca2+ exchange outward current with the patch-clamp technique in single rat ventricular myocytes exposed to hyperkalemia and hypothermia in the presence of aprikalim. The intracellular calcium concentration ([Ca2+]i) during cardioplegia, and the contractile function and [Ca2+]i transients induced by electrical stimulation or caffeine during rewarming and reperfusion in single ventricular myocytes were also determined. Contraction and [Ca2+]i were determined with video tracking and spectrofluorometry, respectively. RESULTS: Aprikalim, 100 micromol/L, the effect of which was blocked by glibamclamide, a K(ATP) inhibitor, significantly attenuated the hyperkalemia-elevated Na+-Ca2+ exchange current by 26% and 11% at 22 degrees C and 4 degrees C, respectively. Aprikalim also attenuated significantly the [Ca2+]i elevated during cardioplegia. Furthermore aprikalim significantly attenuated the reduction in amplitude and prolongation in duration of contraction of myocytes after cardioplegia. The effects of aprikalim mimicked those of nickle (Ni2+), a Na+-Ca2+ exchange blocker. The electrically or caffeine-induced [Ca2+]i transients were unaltered by cardioplegia or aprikalim. CONCLUSIONS: Aprikalim attenuates the Na+-Ca2+ exchange outward current elevated by hyperkalemia, which may attenuate the [Ca2+]i elevation during hyperkalemia and improve the contractile function after cardioplegia in the ventricular myocyte. The study provides further support that addition of a K(ATP) channel opener to the cardioplegic solution may produce beneficial effects in open heart surgery.     

Effect of arginine vasopressin on vascular reactivity and calcium sensitivity after hemorrhagic shock in rats and its relationship to Rho-kinase

BACKGROUND: Our previous study showed that vascular smooth muscle was desensitized to calcium after hemorrhagic shock, which is associated with the development of vascular hyporeactivity. Arginine vasopressin (AVP) can constrict blood vessels by the activation of Rho-kinase and had a beneficial effect on endotoxic and hemorrhagic shock. The present study investigated the effects of AVP on vascular reactivity and calcium sensitivity after hemorrhagic shock in rats and its relations with Rho-kinase. METHODS: Experiments were conducted in vivo and in vitro. In vivo, anesthetized Wistar rats were hemorrhaged to and maintained at a mean arterial pressure (MAP) of 30 mm Hg for 2 hours. The effect of AVP (0.1 and 0.4 U/kg) on the pressor effect of norepinephrine (NE, 3 microg/kg) and contractile response of the superior mesenteric artery (SMA) to NE were observed. In vitro, SMA from hemorrhaged rats was used to evaluate the effects of AVP on vascular reactivity and calcium sensitivity and its relationship with Rho-kinase. Vascular reactivity was determined by observing the contractile response of the SMA to NE and calcium sensitivity was determined by observing the contractile response of the SMA to Ca2+ under depolarizing conditions (120 mmol/L K+). RESULTS: In vivo NE-induced pressor response and contraction of the SMA after hemorrhagic shock were significantly decreased. AVP (0.4 U/kg) significantly increased the pressor response of NE and the contractile response of the SMA to NE. In vitro, the contractile response of SMA to NE and Ca after hemorrhagic shock was significantly decreased as compared with the control group. AVP pretreatment significantly increased the contractile response of SMA to NE and Ca2+ and made the cumulative dose-response curve of NE and Ca2+ shift to the left. HA-1077, the Rho-kinase antagonist, prevented AVP-induced leftward shift of the dose-response curve of NE and Ca2+. CONCLUSIONS: AVP can increase the vascular reactivity and calcium sensitivity of SMA in hemorrhagic shock rats. Action of AVP appears to be regulated through a Rho-kinase signaling pathway.     

依托咪酯和咪唑安定对离体兔肺动脉的作用

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Calcium entry through L-type calcium channels is essential for neurite regeneration in cultured sympathetic neurons

Previous work showed that a post-neuritotomy rise in [Ca2+]i is required for regeneration. We tested the following hypotheses in cultured sympathetic neurons: (1) blocking L-type channels at the time of injury inhibits regeneration; (2) enhancing Ca2+ entry through L-type Ca2+ channels enhances regeneration; (3) L-type Ca2+ channel distribution is predominantly on the soma and proximal neurites of uninjured and injured neurons. To visualize L-type Ca2+ channels and block Ca2+ influx, the fluorescent dihydropyridine antagonist, DM-BODIPY, was used. Our results show that regeneration is markedly inhibited by the antagonist when administered 20 min. prior to injury, in the presence or absence of nerve growth factor (NGF) (p < 0.0001). Severe degeneration of proximal and distal neurites was seen 48 h after injury. Regeneration was minimally inhibited by the antagonist when administered 5 min after injury (p < 0.05), but not inhibited when administered 2 or 24 h after injury (p > 0.05). We found that L-type channels are distributed ubiquitously on the soma and neurites of uninjured and injured cells, and on regenerating neurites. The addition of the L-type channel agonist, BayK8644, (1 microM) 20 min prior to injury enhanced neurite length at 24 h post-injury (p = 0.002). Blocking L-type channels did not affect the viability of uninjured or injured cells. For the first time, it has been shown that Ca2+ entry through L-type Ca2+ channels is essential for post-neuritotomy sympathetic neurite regeneration, and that this effect shows a strict temporal dependency. We also demonstrated that regeneration can be enhanced by increasing Ca2+ influx through L-type channels.     

Differential vascular reactivity of canine mesenteric arteries and veins to sevoflurane

Purpose The aim of this study was to compare the vascular reactivities of canine mesenteric arteries and veins to sevoflurane and to elucidate the underlying mechanism that is responsible for sevoflurane-induced hypotension. Methods Vascular rings of canine mesenteric arteries and veins were suspended in organ baths, and the effect of 2.3% and 4.6% sevoflurane on the contractile responses to transmural electrical stimulation (ES) and to norepinephrine (NE) were determined by recording isometric tension changes. The rings were contracted to a stable tension by the addition of NE and then exposed to increasing concentrations of sevoflurane (0%–5.1%). Results Sevoflurane attenuated the contractile responses to transmural ES in veins but not in arteries. The concentration responses to NE were not affected by sevoflurane in arteries or in veins. At stable precontraction induced by NE, when sevoflurane was placed in the bathing medium, arteries with intact endothelium had significant contraction at 1.7% and 3.4% sevoflurane, followed by relaxation at 5.1%. On the contrary, sevoflurane produced dose-dependent relaxation in endothelium-denuded arteries and endothelium-intact veins Conclusion It is suggested that the relaxation of the veins by sevoflurane may be due to the inhibition of NE release from sympathetic nerve endings and to the direct inhibition of the contractile mechanisms of vascular smooth muscle. In arteries, sevoflurane causes endothelium-dependent vasocontraction, probably by inhibiting the release of basal endothelium-derived relaxing factor (EDRF).     

Glucose-induced electrical activity in beta-cells. Feedback control of ATP-sensitive K+ channels by Ca2+? [corrected

Glucose regulates Ca2+ influx in beta-cells by controlling a rhythmic electrical activity (slow waves with spikes). However, the glucose-sensitive feedback system that triggers repolarization at the end of the slow waves, and thus stops Ca2+ influx, is unknown. Raising extracellular Ca2+ to 10 mM shortened slow waves in mouse beta-cells perifused with medium containing 15 mM glucose and restored slow waves when persistent depolarization and continuous spike activity were induced by 30 mM glucose. The effects of high Ca2+ were reversed or prevented by tolbutamide, whereas 1 mM tetraethylammonium only increased spike amplitude. This suggests that a feedback action of Ca2+ on ATP-sensitive K+ channels rather than on voltage- and Ca2(+)-activated K+ channels may be involved in slow wave generation. Metabolic modulation of this feedback could be central in the regulation of electrical activity and, hence, insulin release.     

Human diabetes is associated with hyperreactivity of vascular smooth muscle cells due to altered subcellular Ca2+ distribution.

Alterations of vascular smooth muscle function have been implicated in the development of vascular complications and circulatory dysfunction in diabetes. However, little is known about changes in smooth muscle contractility and the intracellular mechanisms contributing to altered responsiveness of blood vessels of diabetic patients. Therefore, smooth muscle and endothelial cell function were assessed in 20 patients with diabetes and compared with 41 age-matched control subjects. In rings from uterine arteries, smooth muscle sensitivity to K+, norepinephrine (NE), and phenylephrine (PE) was enhanced by 1.4-, 2.3-, and 9.7-fold, respectively, and endothelium-dependent relaxation was reduced by 64% in diabetic patients, as compared with control subjects. In addition, in freshly isolated smooth muscle cells from diabetic patients, an increased perinuclear Ca2+ signaling to K+ (30 mmol/l >73%; 60 mmol/l >68%) and NE (300 nmol/l >86%; 10 micromol/l >67%) was found. In contrast, subplasmalemmal Ca2+ response, which favors smooth muscle relaxation caused by activation of Ca2+-activated K+ channels, was reduced by 38% in diabetic patients as compared with control subjects, indicating a significant change in the subcellular Ca2+ distribution in vascular smooth muscle cells in diabetic patients. In contrast to the altered Ca2+ signaling found in freshly isolated cells from diabetic patients, in cultured smooth muscle cells isolated from control subjects and diabetic patients, no difference in the intracellular Ca2+ signaling to stimulation with either K+ or NE was found. Furthermore, production of superoxide anion (*O2-) in intact and endothelium-denuded arteries from diabetic patients was increased by 150 and 136%, respectively. Incubation of freshly isolated smooth muscle cells from control subjects with the *O2- -generating system xanthine oxidase/hypoxanthine mimicked the effect of diabetic patients on subcellular Ca2+ distribution in a superoxide dismutase-sensitive manner. We conclude that in diabetic subjects, smooth muscle reactivity is increased because of changes in subcellular Ca2+ distribution on cell activation. Increased *O2- production may play a crucial role in the alteration of smooth muscle function.     

Etomidate attenuates phenylephrine-induced contraction in isolated rat aorta

PURPOSE: A previous study has shown that etomidate inhibits the angiotensin II-induced calcium influx in rat aortic smooth muscle cells. The goals of our current in vitro study were to investigate the effect of etomidate on phenylephrine-induced contraction in rat aorta, and to elucidate the associated signalling pathway. METHODS: Endothelium-denuded aortic rings were suspended for isometric tension recording. Concentration-response curves for phenylephrine (10(-9) to 10(-6) M), 5-hydroxytryptamine (10(-7) to 10(-4) M) and potassium chloride (10 to 60 mM) were generated in the presence and absence of etomidate (5 x 10(-6), 3 x 10(-5), 5 x 10(-5) M). For the rings pretreated with verapamil (10(-5) M), the phenylephrine concentration-response curves were generated in the presence and absence of etomidate (5 x 10(-5) M). In the rings exposed to calcium-free isotonic depolarizing solution, the contractile response induced by the addition of calcium was assessed in the presence and absence of etomidate (5 x 10(-5) M). RESULTS: Etomidate (5 x 10(-5) M) produced a significant rightward shift in the concentration-response curves for phenylephrine, 5-hydroxytryptamine and potassium chloride. Etomidate (5 x 10(-5) M) did not alter phenylephrine-induced contraction in the rings pretreated with verapamil. Etomidate (5 x 10(-5) M) significantly attenuated the contractile response induced by the addition of calcium in the calcium-free isotonic depolarizing solution. CONCLUSION: The results suggest that etomidate, which exceeds the clinically relevant concentration, attenuates the phenylephrine-induced contraction by having an inhibitory effect on the calcium influx by blocking the L-type calcium channels in the rat aortic vascular smooth muscle.     

Endothelium-dependent and -independent coronary relaxation induced by urocortin

Urocortin, a newly identified polypeptide, possesses cardiac effects. However, the underlying mechanism of its coronary action is still unclear. In the present study we investigated the possible role of endothelial nitric oxide and Ba2+-sensitive K+ channels in the endothelium-dependent relaxant response to urocortin in the isolated rat left anterior descending coronary arteries. Changes of vessel tone were measured in microvessel myographs. Urocortin produced both endothelium-dependent and -independent relaxation with IC50 of 2.52 nM and 16.5 nM, respectively. Denuation of endothelium decreased the relaxing potency of urocortin. In the endothelium-intact rings pretreated with 100 microM N(G)-nitro-L-arginine methyl ester (L-NAME) or 10 microM 1H-[1,2,4]oxadiazolo[4,2-alpha]quinoxalin-1-one (ODQ), the urocortin-induced relaxation was similar to that observed in endothelium-denuded rings. The relaxant response to urocortin was markedly reduced in endothelium-intact rings preconstricted by 35 mM K+. Pretreatment with 100 microM BaCl2 significantly reduced urocortin-induced relaxation without an effect on the maximum relaxation. Combined treatment with BaCl2 plus L-NAME did not produce additive inhibition. In contrast, BaCl2 did not alter urocortin-induced relaxation in the endothelium-denuded rings. In the endothelium-denuded rings, BaCl2 at 100 microM also inhibited nitric oxide donor-induced relaxation. In conclusion, our results suggest that urocortin-induced endothelium-dependent relaxation of rat coronary arteries is primarily mediated by endothelial nitric oxide and subsequent activation of Ba2+-sensitive K+ channels. The urocortin-induced endothelium-dependent relaxation appears to be cyclic GMP-dependent.     

Inhibitory effects of etomidate and ketamine on adenosine triphosphate-sensitive potassium channel relaxation in canine pulmonary artery

BACKGROUND: The authors recently demonstrated that etomidate and ketamine attenuated endothelium-dependent pulmonary vasorelaxation mediated by nitric oxide and Ca -activated K + channels. In the current study, they tested the hypothesis that these intravenous anesthetics inhibit pulmonary vasorelaxation mediated by adenosine triphosphate-sensitive potassium (K + ATP ) channel activation. METHODS: Endothelium intact and denuded pulmonary arterial rings were suspended in organ chambers for isometric tension recording. The effects of etomidate (5 x 10(-6) and 5 x 10(-5) m) and ketamine (5 x 10(-5) and 10(-4) m) on vasorelaxation responses to lemakalim (K + ATP channel activator), prostacyclin, and papaverine were assessed in phenylephrine-precontracted rings. The effect of cyclooxygenase inhibition with indomethacin was assessed in some protocols. RESULTS: Etomidate (5 x 10(-6) m) only inhibited the vasorelaxant response to lemakalim in endothelium intact rings, whereas a higher concentration of etomidate (5 x 10(-5) m) inhibited relaxation in both intact and endothelium-denuded rings. Pretreatment with indomethacin abolished the endothelium-dependent attenuation of lemakalim-induced relaxation caused by etomidate. Ketamine (5 x 10(-5) and 10(-5) m) inhibited the relaxation response to lemakalim to the same extent in both endothelium-intact and -denuded rings, and this effect was not prevented by indomethacin pretreatment. Etomidate and ketamine had no effect on the relaxation responses to prostacyclin or papaverine. CONCLUSIONS: These results indicate that etomidate, but not ketamine, attenuates the endothelium-dependent component of lemakalim-induced pulmonary vasorelaxation an inhibitory effect on the cyclooxygenase pathway. Both anesthetics inhibit K + ATP -mediated pulmonary vasorelaxation a direct effect on pulmonary vascular smooth muscle.     

Activation of the K+ channel BK(Ca) is involved in the relaxing effect of propofol on coronary arteries

BACKGROUND AND OBJECTIVE: Propofol may cause undesirable hypotension due to vasodilation. The underlying mechanisms are not completely understood. We investigated the mechanisms by which propofol relaxes vascular segments. METHODS: We studied the effect of propofol on isolated porcine coronary artery rings precontracted with potassium chloride or prostaglandin F2alpha. RESULTS: Propofol, in a concentration-dependent manner, relaxed all segments at concentrations of 5 microg mL(-1) and above. This relaxation was unaltered in the presence of N(omega)-nitro-L-arginine, indomethacin, diltiazem and glibenclamide. Tetraethylammonium chloride, an inhibitor of the BK(Ca) K+ channel (a high conductance Ca2+-sensitive K+ channel), dose-dependently attenuated the vasodilating effect of propofol (P < 0.001). CONCLUSIONS: Our results suggests that the activation of the BK(Ca) channel may contribute to the vasodilating effect of propofol, hereby causing hyperpolarization of the smooth muscle membrane and reduction of smooth muscle tone.     

Gap junctions and ion channels: relevance to erectile dysfunction

The corporal myocyte is a critical determinant of erectile capacity whose functional integrity, in the vast majority of impotent patients, is sufficient to guarantee its relevance as a therapeutic target. As with numerous other smooth muscle cell types, ion channels are important modulators of corporal smooth muscle tone/contractility. As such, the transmembrane flow of ions (ie Ca(2+), K(+) and Cl(-)) plays an important role in modulating membrane potential and contractile status in individual human corporal smooth muscle cells, while intercellular ion flow ensures the functionality of myocyte cellular networks. The integral membrane proteins that selectively regulate many aspects of these critical transmembrane (eg K(+) and Ca(2+) channels) and intercellular (eg gap junctions) ionic movements have been identified. To date, the large conductance calcium-sensitive K(+) channel (ie K(Ca)), the metabolically regulated K+ channel (ie K(ATP)), and the L-type voltage-dependent Ca(2+) channel appear to be the most physiologically relevant nonjunctional ion channels. With respect to intercellular ionic/solute/second messenger movement, connexin43-derived gap junction channels are widely recognized as an obligatory component to normal integrative erectile biology. The presence of an intercellular pathway ensures that individual cellular alterations are carefully orchestrated in the rapid and syncytial fashion required for normal erectile function. This report reviews the known details concerning junctional and nonjunctional ion channels in human corporal tissue, and illustrates how one particular application of this knowledge, that is, preclinical studies utilizing low efficacy gene therapy (ie low transfection efficiency) with the K(Ca) channel has further confirmed the physiological relevance and therapeutic potential of gap junctions and ion channels to erectile physiology/dysfunction. International Journal of Impotence Research (2000) 12, Suppl 4, S15-S25.     

The effects of morphine, nalbuphine, and butorphanol on adrenergic function in canine saphenous veins

Saphenous vein rings mounted in organ chambers containing Krebs-Ringer solution were used to determine if the venodilator effects of morphine, nalbuphine, and butorphanol are the result of interference with adrenergic neurotransmission or are caused by direct depressant actions on venous smooth muscle cells. Morphine (5 X 10(-5) M and 2 X 10(-4) M) caused a dose-dependent depression of the contractile response to transmural electrical stimulation. H1- and H2- histamine antagonists did not attenuate the inhibitory effect of morphine. Concentrations of morphine and nalbuphine lower than 5 X 10(-5) M had no effect, whereas 5 X 10(-6) M butorphanol significantly depressed the evoked tension response to electrical stimulation. The contractile responses of the veins to exogenous norepinephrine (NE) were not altered by morphine, indicating a presynaptic site of action rather than a direct action on the venous smooth muscle. Transmural electrical stimulation was used to evoke release of endogenous NE. Morphine (5 X 10(-5) M and 2 X 10(-4) M), nalbuphine (2 X 10(-4) M), and butorphanol (4 X 10(-6) M) significantly decreased release of NE. Naloxone did not alter NE release and did not attenuate the inhibition of NE release observed with the opiates, indicating that the effect of morphine on this neuroeffector junction is not mediated by a naloxone-sensitive opiate receptor. Blockade of presynaptic alpha receptors by phenoxybenzamine or phentolamine augments NE release caused by transmural electrical stimulation; morphine inhibited this augmentation. The results of these experiments indicate that high concentrations of morphine may decrease NE release, an effect that may contribute to the venodilation and hypotension observed following administration of high doses of morphine in humans. In the usual analgesic doses, the venodilatory effects of morphine cannot be explained by local action on either NE release or venous smooth muscle contractility.     

Inhibitory Effects of Etomidate and Ketamine on Adenosine Triphosphate-Sensitive Potassium Channel Relaxation in Canine Pulmonary Artery

Background: The authors recently demonstrated that etomidate and ketamine attenuated endothelium-dependent pulmonary vasorelaxation mediated by nitric oxide and Ca2+-activated K+ channels. In the current study, they tested the hypothesis that these intravenous anesthetics inhibit pulmonary vasorelaxation mediated by adenosine triphosphate-sensitive potassium (K+ATP) channel activation.

Methods: Endothelium intact and denuded pulmonary arterial rings were suspended in organ chambers for isometric tension recording. The effects of etomidate (5 x 10-6 and 5 x 10-5 m) and ketamine (5 x 10-5 and 10-4 m) on vasorelaxation responses to lemakalim (K+ATP channel activator), prostacyclin, and papaverine were assessed in phenylephrine-precontracted rings. The effect of cyclooxygenase inhibition with indomethacin was assessed in some protocols.

Results: Etomidate (5 x 10-6 m) only inhibited the vasorelaxant response to lemakalim in endothelium intact rings, whereas a higher concentration of etomidate (5 x 10-5 m) inhibited relaxation in both intact and endothelium-denuded rings. Pretreatment with indomethacin abolished the endothelium-dependent attenuation of lemakalim-induced relaxation caused by etomidate. Ketamine (5 x 10-5 and 10-4 m) inhibited the relaxation response to lemakalim to the same extent in both endothelium-intact and -denuded rings, and this effect was not prevented by indomethacin pretreatment. Etomidate and ketamine had no effect on the relaxation responses to prostacyclin or papaverine.     

Effects of ultrasonic skeletonization on internal thoracic and gastroepiploic arteries for coronary artery bypass grafting.

OBJECTIVE: There are few data available on the effect of ultrasonic skeletonization with the harmonic scalpel on internal thoracic artery (ITA) and gastroepiploic artery (GEA) vessel function. METHODS: Rings of segments of the skeletonized ITA, pedicled ITA, skeletonized GEA, and pedicled GEA were studied. Arterial segments were treated with high KCl and norepinephrine (NE) to obtain smooth muscle contractions. Endothelium-dependent and independent vasorelaxant potencies in 10(-6)mol/l NE-pre-constricted arteries were assessed by acetylcholine (ACh), and isosorbide dinitrate (ISDN) and diltiazem, respectively. RESULTS: There were no differences in contractile potencies induced by high KCl and NE between the rings cut from skeletonized and pedicled grafts. The rings from skeletonized and pedicled vessels also showed equal sensitivity to ISDN and diltiazem. However, the rings from pedicled grafts showed greater relaxation responses to ACh than rings from skeletonized grafts. CONCLUSION: Ultrasonic complete skeletonization with the harmonic scalpel may retain smooth muscle function of skeletonized grafts, whereas endothelial function of ultrasonic skeletonized grafts may be significantly compromised.