Positive inotropism and myocardial energetics: influence of beta receptor agonist stimulation, phosphodiesterase inhibition, and ouabain.
OBJECTIVE
The aim was to study the effect of three positive inotropic interventions on myocardial force development and heat production in guinea pig papillary muscles in order to investigate the energetic consequences.


METHODS
The positive inotropic agents used were epinine (beta adrenoceptor stimulation), E-1020 (phosphodiesterase inhibition), and ouabain (sodium-potassium ATPase inhibition). Heat measurements were accomplished using antimony-bismuth thermopiles, and initial heat was separated into tension dependent and tension independent heat using the butanedione-monoxime (BDM) and the shortening methods.


RESULTS
Optimal concentrations of epinine, E-1020, and ouabain increased peak developed force from 20.0(SD 6.6) to 55.5(9.3) (n = 5; p < 0.01), from 20.9(9.1) to 27.2(7.2) (n = 6; p < 0.05), and from 23.4(9.2) to 44.9(18.0) mN.mm-2 (n = 6; p < 0.01), respectively. Epinine and E-1020 decreased the tension-time integral per unit initial heat, ie, the economy of isometric contraction, from 5.5(1.4) to 3.6(0.5) (p < 0.01) and from 5.5(1.4) to 3.1(0.9) N.m.s.J-1 (p < 0.01), respectively; no significant change was observed with ouabain [6.7(1.4) to 8.3(0.5) N.m.s.J-1]. The tension independent heat (calcium turnover) was measured in two different ways using BDM or shortening to abolish force production. It was increased significantly by epinine (by 141-243%), E-1020 (by 77-114%), and ouabain (by 23-38%). The first measurement in brackets is the BDM estimate, the second is the shortening estimate. From the tension-time integral and the tension dependent heat the crossbridge force-time integral was analysed: epinine and E-1020 decreased the crossbridge force-time integral from 0.46(0.16) to 0.31(0.06) pN.s (p < 0.01) and from 0.50(0.19) to 0.31(0.08) pN.s (p < 0.01), respectively, while ouabain left the force-time integral unchanged [0.59(0.27) to 0.63(0.20) pN.s].


CONCLUSIONS
(1) The inotropic effect of ouabain results from an increase in muscle activation with no change in crossbridge kinetics; (2) epinine and E-1020 increase the tension independent heat and decrease the crossbridge force-time integral, both effects reducing the overall economy; and (3) the shortening and BDM methods for measuring the tension independent heat give qualitatively similar but quantitatively different results.
Department of Physiology and Biophysics, University of Vermont, Burlington.
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Holubarsch
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Hasenfuss
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Just
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Alpert
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D003846:Deoxyepinephrine / Q000494:pharmacology*; D006168:Guinea Pigs; D006358:Hot Temperature; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D010042:Ouabain / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D013268:Stimulation, Chemical
D000318:Adrenergic beta-Agonists; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; C059498:olprinone; D010042:Ouabain; D003846:Deoxyepinephrine