Effects of pimobendan, a novel inotropic agent, on intracellular calcium and tension in isolated ferret ventricular muscle

1989 ◽  
Vol 76 (6) ◽  
pp. 609-618 ◽  
Author(s):  
J. A. Lee ◽  
J. C. Ruegg ◽  
D. G. Allen
Keyword(s):  
Time Course ◽  
Positive Inotropic Effect ◽  
Inotropic Agent ◽  
Inotropic Effect ◽  
Inhibiting Activity ◽  
Papillary Muscles ◽  
Ventricular Muscle ◽  
Similar Time ◽  
Apparent Increase ◽  
Intact Muscle

1. In this study we have investigated the effects of a novel inotropic agent, pimobendan (UDCG 115-BS), on skinned and intact ventricular muscle from ferrets. 2. Pimobendan (20 or 100 μmol/l) increased tension at a given free [Ca2+] when applied to skinned ventricular muscle, i.e. it increased the Ca2+ sensitivity of the myofibrils. 3. Tension and intracellular free Ca2+ ([Ca2+]i) were measured simultaneously in intact papillary muscles using the aequorin technique. When 25 μmol/l pimobendan was added to the superfusing solution, a slowly developing positive ionotropic effect was produced, which was accompanied by an increase in the size of the systolic rise in [Ca2+]i (Ca2+ transients) with a similar time course. 4. In order to determine whether pimobendan increased the Ca2+ sensitivity of myofibrils in an intact papillary muscle, we compared the increase in Ca2+ transients and tension observed in response to changes in extracellular [Ca2+] with those observed in response to pimobendan. The result of this comparison was that in intact muscle pimobendan caused no apparent increase in myofibrillar Ca2+ sensitivity. 5. Pimobendan caused an abbreviation of the time course of the Ca2+ transients, but the twitch was slightly prolonged. 6. When isoprenaline was added to the superfusing solution, a positive inotropic effect was produced, which was accompanied by a marked increase in the size of the Ca2+ transients. Isoprenaline caused an abbreviation of the time course of both the Ca2+ transients and the twitch. When the Ca2+ sensitivity of the intact myofibrils was determined as described above, isoprenaline caused a desensitization. Pimobendan produced a sensitization when compared with isoprenaline. 7. These results are consistent with the hypothesis that pimobendan produces an inotropic effect in isolated cardiac muscle which is mediated both by an increase in Ca2+ sensitivity and by an increase in adenosine 3′: 5′-cyclic monophosphate due to its phosphodiesterase-inhibiting activity. Such a combination of activities may be particularly advantageous for an inotropic agent.

scholarly journals Positive and Negative Inotropic Effects of Elevated Extracellular Potassium Level on Mammalian Ventricular Muscle

1972 ◽  
Vol 60 (3) ◽  
pp. 351-365 ◽  
Author(s):  
Frederic Kavaler ◽  
Paul M. Hyman ◽  
Robert B. Lefkowitz
Keyword(s):  
Steady State ◽  
Action Potential ◽  
Time Course ◽  
Potassium Level ◽  
Positive Inotropic Effect ◽  
Potassium Concentration ◽  
Inotropic Effect ◽  
Extracellular Potassium ◽  
Ventricular Muscle ◽  
Inotropic Effects

The effect of moderate elevation in extracellular potassium concentration (up to 12 mM) on contraction of cat ventricular muscle was examined. Isometric force development was recorded from eight excised trabeculae and from six coronary-perfused in situ papillary muscle preparations. Contraction in the steady state was variably affected, sometimes decreasing monotonically, sometimes remaining unchanged, with increasing potassium level. In 11 of these 14 preparations, the steady state was preceded by a transient period in which the contraction was augmented. In addition, eight excised trabeculae were used in an experimental arrangement designed to distinguish between inotropic effects caused by potassium-induced alterations in the action potential and other, more direct, effects of this ion on contraction. The negative inotropic effect is attributable to a potassium-induced reduction in the amplitude and/or duration of the action potential plateau. The positive inotropic effect was found in experimental arrangements where effects of the potassium-rich medium on action potential time-course were effectively "buffered." The positive inotropic effect thus depends on the presence of the elevated potassium concentration and can occur independently of effects on the action potential time-course.

Alpha 1-adrenoceptor subtypes mediating inotropic and electrophysiological effects in mammalian myocardium

1996 ◽  
Vol 271 (4) ◽  
pp. H1423-H1432
Author(s):  
M. Nagashima ◽  
Y. Hattori ◽  
Y. Akaishi ◽  
N. Tohse ◽  
I. Sakuma ◽  
...  
Keyword(s):  
Positive Inotropic Effect ◽  
Outward Current ◽  
Ventricular Myocardium ◽  
Inotropic Effect ◽  
Transient Outward Current ◽  
Papillary Muscles ◽  
Binding Studies ◽  
Positive Inotropism ◽  
Wb 4101 ◽  
Rabbit Ventricular Myocardium

Stimulation of alpha 1-adrenoceptors produces a positive inotropic effect in rat and rabbit ventricular myocardium via different mechanisms, the prolongation of action potential duration (APD) exclusively in the former and an increase in myofibrillar Ca2+ sensitivity in large part in the latter. This study was designed to determine whether the two inotropic mechanisms are mediated by different alpha 1-adrenoceptor subtypes. In rat papillary muscles, the positive inotropic effect and APD prolongation induced by phenylephrine (in the presence of propranolol) were inhibited by WB-4101, but not affected by chlorethylclonidine (CEC). WB-4101, but not CEC, blocked the phenylephrine-induced inhibition of the transient outward current (Ito) in rat ventricular cells. On the other hand, WB-4101 and CEC each antagonized the positive inotropic effect of phenylephrine in rabbit papillary muscles. However, the phenylephrine-induced APD prolongation observed in rabbit papillary muscles was blocked only by WB-4101. These results indicate that the WB-4101 sensitive alpha 1-adrenoceptor subtype mediates the positive inotropism that is correlated with the APD prolongation resulting from Ito reduction, whereas the CEC-sensitive subtype mediates the positive inotropism that is probably associated with increased myofibrillar Ca2+ sensitivity. Radioligand binding studies with [3H] prazosin showed a similar ratio of alpha 1A-to alpha 1B-adrenoceptor subtypes in rat and rabbit ventricular myocardium, implying that the different degree of contribution of each action mechanism to the overall inotropic effect in the two species cannot be explained by distribution of the alpha 1-adrenoceptor subtypes.

Effect of rate changes on strength and time course of contraction of papillary muscle

1963 ◽  
Vol 204 (3) ◽  
pp. 451-457 ◽  
Author(s):  
Jan Koch-Weser
Keyword(s):  
Entire Range ◽  
Maximum Rate ◽  
Time Course ◽  
Normal Development ◽  
Papillary Muscles ◽  
Ventricular Muscle ◽  
High Frequencies ◽  
Peak Tension ◽  
Time To Peak ◽  
Opposing Effect

The influence of 14 frequencies of contraction (between 0.2 and 300 beats/min) on the development of tension and on the time course of contraction was determined in 40 isometrically contracting, isolated cat papillary muscles at 38 C. Only cylindrical muscles with radius <0.43 mm were included, since this was found to be the maximum thickness compatible with normal development of tension at high frequencies. Increases in frequency were associated over the entire range with decreases in the time to peak tension (total 40%) and in the relaxation time (total 49%), and increases in the maximum rate of development of tension (total 560%) and in the peak tension developed (total 340%). These findings indicate that changes in heart rate alter both the degree of activation of the contractile elements and the duration of their active state. It is concluded that the opposing effect of both of these changes must be considered in any analysis of the influence of alterations in rate or rhythm of the heart on the strength of contraction of mammalian ventricular muscle.

Cyclic AMP and the positive inotropic effect of norepinephrine and phenylephrine

1977 ◽  
Vol 55 (2) ◽  
pp. 279-287 ◽  
Author(s):  
T. T. Martinez ◽  
J. H. McNeill
Keyword(s):  
Cyclic Amp ◽  
Cell Membrane ◽  
Time Course ◽  
Positive Inotropic Effect ◽  
Contractile Response ◽  
Contractile Force ◽  
Time Response ◽  
Inotropic Effect ◽  
Chronotropic Response ◽  
Right Atria

Time-response studies of the effects of norepinephrine and phenylephrine revealed that both agonists caused an increase in cyclic AMP levels before increases in contractile force in either the electrically stimulated left atria or spontaneously beating right atria of the rat. Norepinephrine caused a nearly sixfold increase in cyclic AMP, whereas phenylephrine produced only a 50% increase in the nucleotide. Pretreatment with reserpine did not affect the norepinephrine cyclic AMP response; however, the phenylephrine cyclic AMP response was abolished. Reserpine pretreatment did not significantly affect the contractile responses of either amine. In the presence of propranolol, norepinephrine was found to have the ability to produce an increase in contractile force in which cyclic AMP was apparently not involved. The time course of the contractile response induced by adrenergic amines was found to be remarkably influenced by the chronotropic response in spontaneously beating preparations while the cyclic AMP response was not greatly affected. This difference in the contractile response may be due to the ability of the chronotropic response to influence the flux of calcium through the cell membrane.

Evidence for physiological functions of protein phosphatases in the heart: evaluation with okadaic acid

1993 ◽  
Vol 265 (1) ◽  
pp. H257-H266 ◽  
Author(s):  
J. Neumann ◽  
P. Boknik ◽  
S. Herzig ◽  
W. Schmitz ◽  
H. Scholz ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Okadaic Acid ◽  
Guinea Pigs ◽  
Positive Inotropic Effect ◽  
Inotropic Effect ◽  
Papillary Muscles ◽  
Force Of Contraction ◽  
Phosphorylation State ◽  
Ventricular Cardiomyocytes ◽  
Channel Currents

Okadaic acid exerts a positive inotropic effect in cardiac preparations. We studied whether the positive inotropic effect of okadaic acid in cardiac preparations could be due to phosphatase inhibition and whether this inhibition affects the phosphorylation of cardiac proteins. In papillary muscles from guinea pigs, 30 microM okadaic acid increased force of contraction to 175% of predrug value. In isolated guinea pig ventricular cardiomyocytes, okadaic acid augmented single Ca(2+)-channel currents by enhancing channel availability. In homogenates from ventricles, 1 microM okadaic acid completely inhibited phosphorylase a phosphatase activity. In isolated 32P-labeled ventricular cardiomyocytes, 30 microM okadaic acid increased phosphorylation of phospholamban (PLB) and troponin inhibitor (TnI) to 325 and 284% of control, respectively. Furthermore, 30 microM okadaic acid increased phosphorylation of a hitherto unknown 23-kDa protein to 352% of control. It is concluded that the effects of okadaic acid could be mediated by increasing the phosphorylation state of several proteins including PLB, a 23-kDa protein, and TnI.

Dissociation between positive inotropic and alkalinizing effects of angiotensin II in feline myocardium

1997 ◽  
Vol 272 (3) ◽  
pp. H1131-H1136 ◽  
Author(s):  
A. Mattiazzi ◽  
N. G. Perez ◽  
M. G. Vila-Petroff ◽  
B. Alvarez ◽  
M. C. Camilion de Hurtado ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Simultaneous Measurement ◽  
Myocardial Contractility ◽  
Positive Inotropic Effect ◽  
Inotropic Effect ◽  
Papillary Muscles ◽  
Ang Ii ◽  
Acetoxymethyl Ester ◽  
Hepes Buffer ◽  
Ethanesulfonic Acid

The present study examines the intracellular pH (pHi) dependence of angiotensin (ANG) II-induced positive inotropic effect in cat papillary muscles contracting isometrically (0.2 Hz, 30 degrees C). Muscles were loaded with the fluorescent dye 2'-7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester for simultaneous measurement of pHi and contractility. In N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) buffer (n = 4), there was a temporal dissociation between the positive inotropic and the alkalinizing effects of ANG II (0.5 microM). The positive inotropic effect of ANG II peaked at 9.7 +/- 0.8 min (240 +/- 57% above control) without significant changes in pHi. The increase in pHi became significant (0.05 +/- 0.01 pH units) only after 16 min of exposure to the drug, when the positive inotropic effect of ANG II was already fading. In HCO3- buffer (n = 7), the ANG II-induced positive inotropic effect occurred without significant pHi changes. In the presence of 5 microM ethyl isopropyl amiloride (EIPA, to specifically inhibit the Na+/H+ exchanger), the alkalinizing effect of ANG II was changed to a significant decrease in pHi, despite which ANG II still increased contractility by 87 +/- 16% (n = 6). The results indicate that in HEPES buffer only a fraction of the ANG II-induced positive inotropic effect can be attributed to a pHi change, whereas in a physiological CO2-HCO3- medium the positive inotropic effect of ANG II is independent of pHi changes. Furthermore, an ANG II-induced increase in myocardial contractility was observed even when ANG II administration elicited a decrease in pHi, as occurred after Na+/H+ exchanger blockade. The results show that in feline myocardium, the increase in contractility evoked by ANG II in a physiological CO2-HCO3- medium is not due to an increase in Ca2+ myofilament sensitivity secondary to an increase in myocardial pHi.

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