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The effect of the inotropic agent UK-61, 260 on calcium transients in ferret heart
J Mol Cell Cardiol 24 (Supplement I) (1992)
()-15-2EFfECTS OF BDF 9148 AND DPI 201-106 ON MECHANICAL, BIOELECTRICAL AND Na ACTIVITY IN HUNAN, RAT AND GUINEA-PIG HEARTMUSCLE Andrew Hoey, Erich Wettwer, Ursula Ravens. Department of Pharmacology, University of Essen, HufelandstraBe 55, D-4300 Essen, Germany. BDF 9148 (BDF, 4-[3 I-(l"-diphenylmeth 1-azetidine-3"-oxy)-2'-hydroxypropoxy]-lH-indole-2-carbonitrile) anx DPI 201-106 (DPI, 4-[3'(4~1-diphenylmethyl-l"-piperazinyl)-2 '-hydroxypropoxyl-lH-indoJe-Z-carbonitrile) are positive inotropic agents which modulate Na channel activity. Due to the potential clinical relevance of these compounds, we have investigated their effects on contractility in isolated atria1 trabeculae from non-failing human hearts (coronary bypass surgery). BDF was more potent in increasing force than DPI. This difference was also observed in guinea-pig but not rat atria. In ventricular muscle from the three species, the action potential duration was prolonged by both drugs although to variable de rees. This prolongation was accompanied by an increase in Nil+ activ 9ty in right ventricular trabeculae from a diseased huma? heart. (NYHA IV) ., Voltage clamp studies in myocytes (rat, vinea pig) verified the inhrbi+tory effect of these compounds on Na current inactivation. The Na load induced by BDF a36 DPI increases the availability of systolic calcium via the Na’/Ca exchanger. Since the compounds were also effective in human heart muscle
they
may be potentially
useful
in heart
failure.
0-153TlIE
EFFNCT OF THE INOTROPIC AONNT UK-61,260 ON CALCIUN TRANSIENTS IN PBRIWJ! HEART Clive Orchard, Nilar Than and Colin Alabaster*, Department of Physiology, University of Leeds, Leeds LS2 9JT and *Pfizer Central Research, Sandwich, Kent CT13 9NJ, U.K.
UK-61,260 is an inotropic compound which appears to be 3-5 times more potent than the phosphodiesterasa inhibitor milrinone at stimulating dog heart, although its phosphodiesterase inhibiting activity in only 0.4 that of milrinone (unpublished data). the effect of UK-61,260, milrinone, nor drenaline and increases of We have cTared bathing [Ca ] (Ca,), on developed force andcytoplasmic (Ca 5+ ] (Cai; monitored using the photoprotein aeguorin) in papillary muscles isolated from ferret hearts. UK-61,260 Hilrinone Noradrenaline cao Control 10% Control 1034 Control 10% Control 2x10-3&l 12fl 22f3 14fl 23f2 13fl 26f2 F llf2 22f3 L 100 244f50 100 2Slf67 100 622k90 100 355f61 6 7 12 12 14 10 n 6 7 Table 1. Aequorin light transient amplitude (L; percent of control, mean $ 8.e.m.) for .). Ca,.l mM except in fLna1 column. equivalent increases in developed force (F; m/mm UK-61,260 produced less increase in Cai per unit increase in force than noradrenaline, but a similar increase in Cai per unit force to milrinone and increasing of UK-61,260 is. therefore, similar to that reoorted for Ca- (Table 1). This effect pigobendan (kin. Sci. 76, 609-618;.1989),.which was .ascribed to a Ca2+ sensitizing effect.on the myofilaments. However milrinone has no such sensitizing effects, yet had similar effects on force and cai to UK-61,260, suggesting that other factors can affect the relationship between Cai and force during stimulation by these agents.
O-15-4 INVOLVEMENT
OF PHOSPHOINOSITIDE METABOLISM IN THE POSITIVE INOTROPIC EFFECT OF ANGIOTENSIN II Akira Ishihata, Masao Endoh. Department of Pharmacology, Yamagata University School of Medicine, 990-23 Yamagata, Japan. Angiotensin II (AT) produces a positive inotropic effect (PIE)in the myocardium of human and rabbit. Since AT also increases the phosphoinositide (PI) metabolism and stimulates the protein systhesis, it is considered that AT may be involved in the myocardial hypertrophy. On the other hand, the mechanism of the PIE of AT is still unknown. We investigated the relation between the increase in PI metabolism and the PIE of AT in the rabbit ventricular myocardium. Papillary muscles were electrically driven at 1 Hz in the Krebs-Henseleit solution at 37OC and the developed tension was recorded. The products of PI metabolism were measured by the methods described by Benidge and coworkers (1982). AT (0.3 nM - 3 pM) produced the PIE in the presence of bupranolol (0.3 PM) and prazosin (0.1 pM) in a concentrationdependent manner.The PIE wasiahihitedbyanonselectiveATreceptorantagonist,saralasin(10 nM - 1 pM), aselectiveATI subtypeantagonist, MK954 (10 nM - 1 pM) and a protein kinase C activator, phorbol 12, 13-dibutyrate (PDBu, 10 nM - 1 pM) in a concentration-dependent manner. AT (10 nM - 1 pM) increased the accumulation of pH]IPi in ventricular slices prelabelled with myo-[sH]inositol. The increase in the PI metabolism was also inhibited by saralasin, MK954 and PDBu. These results indicate that AT exerts the PIE through activation of ATI subtype and subsequent increase in PI metabolism. The activation of protein kinase C by PDBu may have inhibited the increase in PI metabolism and thereby the AT-induced PIE.
5.84
()-15-2EFfECTS OF BDF 9148 AND DPI 201-106 ON MECHANICAL, BIOELECTRICAL AND Na ACTIVITY IN HUNAN, RAT AND GUINEA-PIG HEARTMUSCLE Andrew Hoey, Erich Wettwer, Ursula Ravens. Department of Pharmacology, University of Essen, HufelandstraBe 55, D-4300 Essen, Germany. BDF 9148 (BDF, 4-[3 I-(l"-diphenylmeth 1-azetidine-3"-oxy)-2'-hydroxypropoxy]-lH-indole-2-carbonitrile) anx DPI 201-106 (DPI, 4-[3'(4~1-diphenylmethyl-l"-piperazinyl)-2 '-hydroxypropoxyl-lH-indoJe-Z-carbonitrile) are positive inotropic agents which modulate Na channel activity. Due to the potential clinical relevance of these compounds, we have investigated their effects on contractility in isolated atria1 trabeculae from non-failing human hearts (coronary bypass surgery). BDF was more potent in increasing force than DPI. This difference was also observed in guinea-pig but not rat atria. In ventricular muscle from the three species, the action potential duration was prolonged by both drugs although to variable de rees. This prolongation was accompanied by an increase in Nil+ activ 9ty in right ventricular trabeculae from a diseased huma? heart. (NYHA IV) ., Voltage clamp studies in myocytes (rat, vinea pig) verified the inhrbi+tory effect of these compounds on Na current inactivation. The Na load induced by BDF a36 DPI increases the availability of systolic calcium via the Na’/Ca exchanger. Since the compounds were also effective in human heart muscle
they
may be potentially
useful
in heart
failure.
0-153TlIE
EFFNCT OF THE INOTROPIC AONNT UK-61,260 ON CALCIUN TRANSIENTS IN PBRIWJ! HEART Clive Orchard, Nilar Than and Colin Alabaster*, Department of Physiology, University of Leeds, Leeds LS2 9JT and *Pfizer Central Research, Sandwich, Kent CT13 9NJ, U.K.
UK-61,260 is an inotropic compound which appears to be 3-5 times more potent than the phosphodiesterasa inhibitor milrinone at stimulating dog heart, although its phosphodiesterase inhibiting activity in only 0.4 that of milrinone (unpublished data). the effect of UK-61,260, milrinone, nor drenaline and increases of We have cTared bathing [Ca ] (Ca,), on developed force andcytoplasmic (Ca 5+ ] (Cai; monitored using the photoprotein aeguorin) in papillary muscles isolated from ferret hearts. UK-61,260 Hilrinone Noradrenaline cao Control 10% Control 1034 Control 10% Control 2x10-3&l 12fl 22f3 14fl 23f2 13fl 26f2 F llf2 22f3 L 100 244f50 100 2Slf67 100 622k90 100 355f61 6 7 12 12 14 10 n 6 7 Table 1. Aequorin light transient amplitude (L; percent of control, mean $ 8.e.m.) for .). Ca,.l mM except in fLna1 column. equivalent increases in developed force (F; m/mm UK-61,260 produced less increase in Cai per unit increase in force than noradrenaline, but a similar increase in Cai per unit force to milrinone and increasing of UK-61,260 is. therefore, similar to that reoorted for Ca- (Table 1). This effect pigobendan (kin. Sci. 76, 609-618;.1989),.which was .ascribed to a Ca2+ sensitizing effect.on the myofilaments. However milrinone has no such sensitizing effects, yet had similar effects on force and cai to UK-61,260, suggesting that other factors can affect the relationship between Cai and force during stimulation by these agents.
O-15-4 INVOLVEMENT
OF PHOSPHOINOSITIDE METABOLISM IN THE POSITIVE INOTROPIC EFFECT OF ANGIOTENSIN II Akira Ishihata, Masao Endoh. Department of Pharmacology, Yamagata University School of Medicine, 990-23 Yamagata, Japan. Angiotensin II (AT) produces a positive inotropic effect (PIE)in the myocardium of human and rabbit. Since AT also increases the phosphoinositide (PI) metabolism and stimulates the protein systhesis, it is considered that AT may be involved in the myocardial hypertrophy. On the other hand, the mechanism of the PIE of AT is still unknown. We investigated the relation between the increase in PI metabolism and the PIE of AT in the rabbit ventricular myocardium. Papillary muscles were electrically driven at 1 Hz in the Krebs-Henseleit solution at 37OC and the developed tension was recorded. The products of PI metabolism were measured by the methods described by Benidge and coworkers (1982). AT (0.3 nM - 3 pM) produced the PIE in the presence of bupranolol (0.3 PM) and prazosin (0.1 pM) in a concentrationdependent manner.The PIE wasiahihitedbyanonselectiveATreceptorantagonist,saralasin(10 nM - 1 pM), aselectiveATI subtypeantagonist, MK954 (10 nM - 1 pM) and a protein kinase C activator, phorbol 12, 13-dibutyrate (PDBu, 10 nM - 1 pM) in a concentration-dependent manner. AT (10 nM - 1 pM) increased the accumulation of pH]IPi in ventricular slices prelabelled with myo-[sH]inositol. The increase in the PI metabolism was also inhibited by saralasin, MK954 and PDBu. These results indicate that AT exerts the PIE through activation of ATI subtype and subsequent increase in PI metabolism. The activation of protein kinase C by PDBu may have inhibited the increase in PI metabolism and thereby the AT-induced PIE.
5.84