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Cellular basis of parasympathetic action on the heart
j Mel Cell Cardiol 23 (Supplement t') (1991) 10
11
12
EFFEGTOFtJK68798CNDFtAYEDK+-INcAADIpGMY-.
Leuven, Gasthuisberg, Edward Carmeliet, Laboratory of Physiology, University 3ooO Leuven, Belgium. The delayed K+ current (iK) and its change by UK 68798 was studied in single myocytes from the guinea-pig and rabbit heart. Ionic currents were estimated using the two electrode voltage clamp technique. Temperature was 37OC. Tail currents were measured at -50 mV following test depolarizations of variable duration to different voltages. Results were different for rabbit and guinea-pig preparations. In rabbit myocytes iK consisted of only one component (Kr), which developed for moderate depolarizations and with a fast time course (at 0 mV order of 350 ms). In guinea-pig myocytes activation consisted of a rapid and a slow component, the latter (KS) only became manifest for depolarizations positive to 0 mV. K, was very sensitive to UK 68798: KD was 3.9x10-9M, Hill coefficient 2.0 (n=5). The effect was voltage dependent: at 5x10-9M the activation curve shifted in the hyperpolarizing direction by 5.6 2 0.6 mV (s.e; n=4). Two-thirds of the block developed with a time constant of 4.1 f 0.9 s (n=5). KS was resistant to block by the drug. This resistance persisted after the iK current was dramatically enhanced by superfusion with Na-free K-free solution (guinea-pig). It is concluded that the fast component of iK is very sensitive to block by UK 68798; the block is voltage- and time-dependent.
CELLULAR
BASIS OF PARASYMPATHETIC
ACTION ON THE HEART
Hein Heidbiichel Laboratoryfor Electrophysiology,University of Leuven, Leuven, Belgium. Bindine of acetvlcholine to cardiac muscarinic m9-receotorscan mainlv activate three cellular pathways:7) a G4ype GTP-binding protein (GK) can &en a specific classof K+ channels,causing an inwardlv recti!ving K+ current: 2) the sameG orotein will exert an inhibitors action on adenvlvl cyclase,resulting ‘m decreasedlevels.of intracellul& CAMP: this will lead to a rkluction of the siow inward calcium current i,, of the delayed rectitier K+ current iK and of the hyperpolarisationactivated pacemakercurrent if; 3) activation of phospholipaseC vra pertussis toxin-sen&tive and -insensitiveG proteins results m the formation of IP3 and diacylglycerol which trigger Ca -release from the sarcoplasmicreticulum and activation of protein kinaseC. The presenceand relattve importanceof each of thesethree pathwaysvaries betweendjfferent cell-types (e.g. ventricular cells generally havmg no mduced K current) and betweendtfferent species(e.g. an acetylcholine-inducedK+ curfent ISpresentin ferret ventricular cells). The inhibition of adenylyl cyclasewill sometimesonly be seenafter stimulation by g-adrenergicagonistsand not under basal conditions. Therefore. the overall result of muscarinicstimulation can be diverse: as a rule hyperpolarisation and negative inotropy (by direct reduction of icp or via action potential shortening), -. but also deoolatisationand nositive inotroov have been described.Moreover, it is not clear whether also other subtypes of -the muscarinicVreceptor, or different receptors (as for somatostatine)may play a role in vagal innervation and in how far conclusions from agonistapplicationin vitro may be extrapolatedto vagal effectsin vivo.
DEVELOPMENT OF CARDIACINNERVATIONAND SUSCEPTIBILITY TO LIFE-THREATENINGARRHYTHMIAS Marco Stramba-Badiale, Marina Lazzarotti, Peter J Schwartz.. Clinica Medica II, University of Milano, Milano, Italy. The maturation of nerve control of cardiac functions occurs also after birth, but the time-course of the post-natal development of cardiac innervation and its possible effect on susceptibility to malignant arrhythmias have not been elucidated. In order to clarify this issue we assessed the influence of autonomic nerves on heart rate, CT interval and ventricular fibrillation threshold, measured in control condition, after bilateral vagotomy and after unilateral and bilateral stellectomy, in three groups of puppies respectively of one, three, five weeks of life and in adult dogs used as a reference for complete maturation of cardiac innervation. The results of the study indicate that in the first week of life the autonomic nervous system exerts its influence to the sinus node, but not at the ventricular level. In the third week of life the neural control of cardiac functions seams to be functionally developed: a sympathetic imbalance with left side nerves dominance increases the susceptibility to malignant arrhythmias also at this stage of post-natal development.
S.8
11
12
EFFEGTOFtJK68798CNDFtAYEDK+-INcAADIpGMY-.
Leuven, Gasthuisberg, Edward Carmeliet, Laboratory of Physiology, University 3ooO Leuven, Belgium. The delayed K+ current (iK) and its change by UK 68798 was studied in single myocytes from the guinea-pig and rabbit heart. Ionic currents were estimated using the two electrode voltage clamp technique. Temperature was 37OC. Tail currents were measured at -50 mV following test depolarizations of variable duration to different voltages. Results were different for rabbit and guinea-pig preparations. In rabbit myocytes iK consisted of only one component (Kr), which developed for moderate depolarizations and with a fast time course (at 0 mV order of 350 ms). In guinea-pig myocytes activation consisted of a rapid and a slow component, the latter (KS) only became manifest for depolarizations positive to 0 mV. K, was very sensitive to UK 68798: KD was 3.9x10-9M, Hill coefficient 2.0 (n=5). The effect was voltage dependent: at 5x10-9M the activation curve shifted in the hyperpolarizing direction by 5.6 2 0.6 mV (s.e; n=4). Two-thirds of the block developed with a time constant of 4.1 f 0.9 s (n=5). KS was resistant to block by the drug. This resistance persisted after the iK current was dramatically enhanced by superfusion with Na-free K-free solution (guinea-pig). It is concluded that the fast component of iK is very sensitive to block by UK 68798; the block is voltage- and time-dependent.
CELLULAR
BASIS OF PARASYMPATHETIC
ACTION ON THE HEART
Hein Heidbiichel Laboratoryfor Electrophysiology,University of Leuven, Leuven, Belgium. Bindine of acetvlcholine to cardiac muscarinic m9-receotorscan mainlv activate three cellular pathways:7) a G4ype GTP-binding protein (GK) can &en a specific classof K+ channels,causing an inwardlv recti!ving K+ current: 2) the sameG orotein will exert an inhibitors action on adenvlvl cyclase,resulting ‘m decreasedlevels.of intracellul& CAMP: this will lead to a rkluction of the siow inward calcium current i,, of the delayed rectitier K+ current iK and of the hyperpolarisationactivated pacemakercurrent if; 3) activation of phospholipaseC vra pertussis toxin-sen&tive and -insensitiveG proteins results m the formation of IP3 and diacylglycerol which trigger Ca -release from the sarcoplasmicreticulum and activation of protein kinaseC. The presenceand relattve importanceof each of thesethree pathwaysvaries betweendjfferent cell-types (e.g. ventricular cells generally havmg no mduced K current) and betweendtfferent species(e.g. an acetylcholine-inducedK+ curfent ISpresentin ferret ventricular cells). The inhibition of adenylyl cyclasewill sometimesonly be seenafter stimulation by g-adrenergicagonistsand not under basal conditions. Therefore. the overall result of muscarinicstimulation can be diverse: as a rule hyperpolarisation and negative inotropy (by direct reduction of icp or via action potential shortening), -. but also deoolatisationand nositive inotroov have been described.Moreover, it is not clear whether also other subtypes of -the muscarinicVreceptor, or different receptors (as for somatostatine)may play a role in vagal innervation and in how far conclusions from agonistapplicationin vitro may be extrapolatedto vagal effectsin vivo.
DEVELOPMENT OF CARDIACINNERVATIONAND SUSCEPTIBILITY TO LIFE-THREATENINGARRHYTHMIAS Marco Stramba-Badiale, Marina Lazzarotti, Peter J Schwartz.. Clinica Medica II, University of Milano, Milano, Italy. The maturation of nerve control of cardiac functions occurs also after birth, but the time-course of the post-natal development of cardiac innervation and its possible effect on susceptibility to malignant arrhythmias have not been elucidated. In order to clarify this issue we assessed the influence of autonomic nerves on heart rate, CT interval and ventricular fibrillation threshold, measured in control condition, after bilateral vagotomy and after unilateral and bilateral stellectomy, in three groups of puppies respectively of one, three, five weeks of life and in adult dogs used as a reference for complete maturation of cardiac innervation. The results of the study indicate that in the first week of life the autonomic nervous system exerts its influence to the sinus node, but not at the ventricular level. In the third week of life the neural control of cardiac functions seams to be functionally developed: a sympathetic imbalance with left side nerves dominance increases the susceptibility to malignant arrhythmias also at this stage of post-natal development.
S.8