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β-adrenoceptor desensitisation, and its reversal by pertussis toxin, in myocytes isolated from noradrenaline treated guinea-pig hearts
J Mel Cell Cardiol 23 (Supplement V) (1991)
p76 P-ADRENOCEPTOR DESENSITISATION, MYOCYTES
ISOLATED
FROM
AND ITS REVERSAL BY PERTUSSIS TOXIN, IN
NORADRENALINE
TREATED
GUINEA-PIG
HEARTS.
Lesley A. Brown, Sian E. Harding & Philip A. Poole-Wilson. Dept of Cardiac Medicine, National Heart & Lung Institute, London. SW3 6LY It is thought thaf the functional fl-adrenoceptor desensitisation which occurs in human heart failure is the result of increased catecholamine levels; raised levels of Gi may also play a role. Ventricular myocytes isolated from the hearts of guinea-pigs which had been chronically infused with noradrenaline (900pg/kg/hr for 7 days) showed a reduced contractile response to the P-agonist, relative to that for maximally stimulating concentrations of calcium, giving an isoprenaline, isoprenaIine/caIcium ratio of 0.65 + 0.04 (n=6). This ratio was significantly lower than in ventricular myocytes isolated from guinea-pigs which had been sham-operated, where the isoprenaIine/caIcium ratio was 0.88 + 0.02 (n=7, p
p77
EFFECT OF BETA-BLOCKERS ON CONTRACTILITY UNDER ISCHAEMIC CONDITIONS IN RABBIT PAPILLARY MUSCLE of Pharmacology, Albert Szent-Gy6rgyi MediOtto Hdla, Julius Gy. Papp. Department cal University, Szeged, Hungary The negative inotropic action of metoprolol, pindolol and sotalol was analyzed ischaemia' (steady-state values: ~02 q 50 mmHg, [K+], = 7 during severe 'sirmlated muscles isolated from rabbit hearts. The experimental mM, pH = 6.8) in papillary conditions were as follows: driving cycle length = 800 ms, stimulus intensity = 3x threshold, auxotonic resting preload = 1 mN, temperature = 32" C. An 'ischaemic' period of 30 min proved to be long enough to produce a considerable negative inotropic effect with steady state contractile parameters and with full recovery to normal values upon 'resuperfusion' (~02 = 560 mmHg, fK+], = 4 mM, pH = 7.4). The percentage reduction of the maximum contractile force produced by each studied beta-blocker was virtually the same under control and steady state 'ischaemic' conditions. None of the examined drugs exerted a beneficial effect on the kinetics of the 'ischaemia'-induced alteration in contractile force i.e. the 'ischaemic' loss of myocardial contractitlity, as a time-process, did not become slower in the presence of any of the studied beta-blockers.
F78 EG~HAVIOLJR OF CARDIACAIXDYIAm CYC.M.Ca1darer.q Department
ACYIVITY IN AGING FATS. INFLUENCEOF POLYAMINES. B.Tantini, C.Pignatti, P.Sacchi, M.L.Zanfanti, C.Clo'. of Bicchanistry, School of Medicine, Unviersity of Eolcx~~ (Italy).
Evidence has been provide3 by us that basal and sttilated cardiac adenylate cyclase activities are strongly reduced by the pAya&nes putrescine, -dine and maximally qennine (SW. The effect is particularly evidentwithdoses in the range of those found in physiological fluids Q.m~l.ar) and it is carried out through the activation of the inhibitory G proteins (Gi). The aim of this wxk was to stud.y the behaviour of ade nylate cyclase system during the aging of rat heart (1,6,12,24 nxxths) and the influ& ce of polyamines, psrticularly of SFM,on the enzynrz. The results indicate that the ba= Sal activity of mmbrane bound (12,000 or 25,000xg) adenylate cyclase progressively in creases with the age. Comrersely, a parallel decrease in the smxnt of endcgenous plyamines is observable. Besides, the response of the enzyme to Gpp(~H)p, a stable analog of GE which directly activates the stirmlatiq G proteins (Gs), or to FGEI or iso proterenol, which activate Gs via interaction with specific receptors, shows a net & progressive decline during the aging of the heart. A similar pattern is observable withforskolin, whichdirectlyactivates the catalytic (C) cxqxxentof the enzyme, suggestthat alteration of C and/or of Gs-C ca@ex might occur in aging heart. The study of the effect in vitro of SFM (l-10$4 indicates that its capacity to inhibit ba sal and stimulate activity is highest in young hearts (1 nunthf and progressively de= clines with age. Supportea by a grant of MURST(40%). S.82
p76 P-ADRENOCEPTOR DESENSITISATION, MYOCYTES
ISOLATED
FROM
AND ITS REVERSAL BY PERTUSSIS TOXIN, IN
NORADRENALINE
TREATED
GUINEA-PIG
HEARTS.
Lesley A. Brown, Sian E. Harding & Philip A. Poole-Wilson. Dept of Cardiac Medicine, National Heart & Lung Institute, London. SW3 6LY It is thought thaf the functional fl-adrenoceptor desensitisation which occurs in human heart failure is the result of increased catecholamine levels; raised levels of Gi may also play a role. Ventricular myocytes isolated from the hearts of guinea-pigs which had been chronically infused with noradrenaline (900pg/kg/hr for 7 days) showed a reduced contractile response to the P-agonist, relative to that for maximally stimulating concentrations of calcium, giving an isoprenaline, isoprenaIine/caIcium ratio of 0.65 + 0.04 (n=6). This ratio was significantly lower than in ventricular myocytes isolated from guinea-pigs which had been sham-operated, where the isoprenaIine/caIcium ratio was 0.88 + 0.02 (n=7, p
p77
EFFECT OF BETA-BLOCKERS ON CONTRACTILITY UNDER ISCHAEMIC CONDITIONS IN RABBIT PAPILLARY MUSCLE of Pharmacology, Albert Szent-Gy6rgyi MediOtto Hdla, Julius Gy. Papp. Department cal University, Szeged, Hungary The negative inotropic action of metoprolol, pindolol and sotalol was analyzed ischaemia' (steady-state values: ~02 q 50 mmHg, [K+], = 7 during severe 'sirmlated muscles isolated from rabbit hearts. The experimental mM, pH = 6.8) in papillary conditions were as follows: driving cycle length = 800 ms, stimulus intensity = 3x threshold, auxotonic resting preload = 1 mN, temperature = 32" C. An 'ischaemic' period of 30 min proved to be long enough to produce a considerable negative inotropic effect with steady state contractile parameters and with full recovery to normal values upon 'resuperfusion' (~02 = 560 mmHg, fK+], = 4 mM, pH = 7.4). The percentage reduction of the maximum contractile force produced by each studied beta-blocker was virtually the same under control and steady state 'ischaemic' conditions. None of the examined drugs exerted a beneficial effect on the kinetics of the 'ischaemia'-induced alteration in contractile force i.e. the 'ischaemic' loss of myocardial contractitlity, as a time-process, did not become slower in the presence of any of the studied beta-blockers.
F78 EG~HAVIOLJR OF CARDIACAIXDYIAm CYC.M.Ca1darer.q Department
ACYIVITY IN AGING FATS. INFLUENCEOF POLYAMINES. B.Tantini, C.Pignatti, P.Sacchi, M.L.Zanfanti, C.Clo'. of Bicchanistry, School of Medicine, Unviersity of Eolcx~~ (Italy).
Evidence has been provide3 by us that basal and sttilated cardiac adenylate cyclase activities are strongly reduced by the pAya&nes putrescine, -dine and maximally qennine (SW. The effect is particularly evidentwithdoses in the range of those found in physiological fluids Q.m~l.ar) and it is carried out through the activation of the inhibitory G proteins (Gi). The aim of this wxk was to stud.y the behaviour of ade nylate cyclase system during the aging of rat heart (1,6,12,24 nxxths) and the influ& ce of polyamines, psrticularly of SFM,on the enzynrz. The results indicate that the ba= Sal activity of mmbrane bound (12,000 or 25,000xg) adenylate cyclase progressively in creases with the age. Comrersely, a parallel decrease in the smxnt of endcgenous plyamines is observable. Besides, the response of the enzyme to Gpp(~H)p, a stable analog of GE which directly activates the stirmlatiq G proteins (Gs), or to FGEI or iso proterenol, which activate Gs via interaction with specific receptors, shows a net & progressive decline during the aging of the heart. A similar pattern is observable withforskolin, whichdirectlyactivates the catalytic (C) cxqxxentof the enzyme, suggestthat alteration of C and/or of Gs-C ca@ex might occur in aging heart. The study of the effect in vitro of SFM (l-10$4 indicates that its capacity to inhibit ba sal and stimulate activity is highest in young hearts (1 nunthf and progressively de= clines with age. Supportea by a grant of MURST(40%). S.82