Phosphodiesterase inhibition and Ca2+ sensitization

Ravens, Ursula; Himmel, Herbert M.; Flüss, Michael; Davia, Kerry; Harding, Siân E.

doi:10.1007/978-1-4613-1275-8_32

Cited by 6 publications

(10 citation statements)

References 18 publications

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“…It has been proposed that in vitro EMD 57033 exerts, besides its Ca 2+ ‐sensitizing effects, phosphodiesterase inhibiting actions (Solaro et al ., 1993; Ravens et al ., 1996). In the present study, blockade of α‐ and β‐adrenoceptors did not modulate the inotropic responses to EMD 57033 in normal myocardium in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…In rat skinned right ventricular trabeculae these authors have shown that EMD 57033 can even cause contraction in the absence of Ca 2+ . Consequently, contraction could be prolonged thereby delaying the onset of relaxation (Solaro et al ., 1993; Ravens et al ., 1996), the rate of relaxation could be attenuated (Hajjar et al ., 1997; Korbmacher et al ., 1997) and end‐diastolic stiffness could be increased (Hgashiyama et al ., 1995; Hajjar et al ., 1997) even when Ca 2+ concentrations are normal.…”

Section: Discussionmentioning

confidence: 99%

“…In view of these considerations, we studied the effects of EMD 57033 on regional systolic and diastolic function in an in vivo porcine model of stunned and normal myocardium. EMD 57033 was chosen because it is a thiadiazinone derivative, that lacks the inhibitory action on the delayed rectifier inward current that is exhibited by EMD 60263 and which may potentially modify systolic and diastolic responses by prolongation of the action potential duration (Ravens et al ., 1996). However, EMD 57033 possesses phosphodiesterase III inhibiting properties (which EMD 60263 lacks) that could act to enhance systolic and diastolic function (Ravens et al ., 1996).…”

Section: Introductionmentioning

confidence: 99%

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Cardiovascular profile of the calcium sensitizer EMD 57033 in open‐chest anaesthetized pigs with regionally stunned myocardium

Zeeuw

Trines

Krams

et al. 2000

British J Pharmacology

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1 Ca 2+ sensitizers enhance systolic function, but may impair relaxation in vitro; these e ects may di er in stunned and normal myocardium. We therefore studied the e ect of EMD 57033 on systolic and diastolic function of normal and stunned porcine myocardium in vivo. 2 Myocardial stunning by 15 min coronary occlusion and 30 min reperfusion abolished systolic shortening (SS) (baseline 13+1%) and decreased end-systolic elastance (E es ) from 67+7 to 47+5 mmHg mm 71 (both P50.05). Maximum rate of fall of myocardial elastance (dE/dt min ) decreased from 7850+100 to 7320+30 mmHg mm 71 s 71 , while the time constant t e of the decay of elastance increased from 58+3 to 68+6 ms (both P50.05). End-diastolic elastance (E ed ) was unchanged although the zero pressure intercept (L 0,ed ) had increased. 3 In the stunned region, EMD 57033 (0.2 mg kg 71 min 71 for 60 min, i.v., n=7) increased SS to 19+2%, E es to 287+40 mmHg mm 71 , dE/dt min to 73630+640 mmHg mm 71 s 71 and decreased t e to 50+3 ms, while E ed remained unchanged. In the normal region, EMD 57033 increased SS from 14+2 to 18+3%, E es from 59+4 to 263+23 mmHg mm 71 , dE/dt min from 7480+70 to 72280+700 mmHg mm 71 s 71 and decreased t e from 91+12 to 61+3 ms (all P50.05), while E ed remained unchanged. These responses were minimally a ected by adrenoceptor blockade (n=7). Vehicle (n=7) had no e ect on either region. 4 EMD 57033 increased cardiac output (up to 27+8%) and LVdP/dt max (86+19%). Mean aortic pressure decreased (19+7%) due to systemic vasodilation that was not amenable to blockade of adrenoceptors or NO synthesis. 5 In conclusion, EMD 57033 restored systolic and diastolic function of stunned myocardium, and produced similar improvements in systolic and diastolic function in normal myocardium. British Journal of Pharmacology (2000)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cardiovascular profile of the calcium sensitizer EMD 57033 in open‐chest anaesthetized pigs with regionally stunned myocardium

Zeeuw

Trines

Krams

et al. 2000

British J Pharmacology

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“…Hence, disparity observed between the reduced contractility and increased Ca 2+ amplitudes by DCM‐Abs may show altered sensitivity of the myofilaments to Ca 2+ at the higher stimulating frequency. Although this is known to occur secondary to phosphorlylation by protein kinase A, some agents have been shown to have direct Ca 2+ ‐sensitizing effects (23), and this may represent one mechanism of immune‐mediated functional effects at the cellular level in clinical DCM.…”

Section: Discussionmentioning

confidence: 99%

Human cardiac myosin autoantibodies impair myocyte contractility: a cause‐and‐effect relationship

et al. 2006

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The functional relevance of autoantibodies (Abs) against cardiac myosin (CM) in clinical idiopathic dilated cardiomyopathy (DCM) remains controversial. The study sought to determine effects of human Abs affinity-purified (AF) by immunoaffinity column chromotography on excitation-contraction coupling in isolated myocytes. Effects of CM-Abs from heart failure patients with DCM (n=19) and ischemic heart disease (IHD, n=19) on contractility, L-type Ca2+ current, and Ca2+ transients in continuously perfused rat ventricular myocytes were studied. Immunofluorescence studies using confocal microscopy were carried out to determine whether Abs were internalized. AF-Abs from either group did not differ in IgG titer but differed in their elution profiles. The IgG3 subclass response was higher in AF fractions from DCM (21%) than IHD (5%) patients. The Abs reduced the capacity of field-stimulated myocytes to contract in a dose-dependent manner. Inhibition of contraction, as a percentage of untreated cells, was greater with DCM than IHD-Abs (P=0.004), and the effect was independent of Ab titer. An increase in frequency of the beating myocytes (0.2 to 3.0 Hz) raised peak systolic and diastolic levels of [Ca2+]i of cells treated with DCM but not IHD-Abs (P<0.005). The AF-Abs were not internalized by myocytes and had no effect on L-type Ca2+ currents. The altered sensitivity of the myofilaments to [Ca2+]i by CM-Abs may represent a potential mechanism of autoantibody-mediated impairment in clinical DCM.

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“…The principal mode of action EMD 57033 appears to be Ca 2+ sensitization, both in vitro (Lues et al ., 1993; White et al ., 1993; Ventura et al ., 1992) and in vivo (de zeeuw et al ., 2000a; Haeusler et al ., 1997), although the drug possesses some minor PDE‐III inhibitory effects in vitro (Ravens et al ., 1996). Indeed, the inotropic responses to EMD 57033 were not affected by β‐adrenoceptor blockade (de zeeuw et al ., 2000b; Stubenitsky et al ., 1997), which explains why in the present study the effects of EMD 57033 in MI were virtually identical to those in N, despite a reduced β‐adrenergic responsiveness (van woerkens et al ., 1993).…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of the Ca²⁺ sensitizer EMD 57033 in exercising pigs with infarction‐induced chronic left ventricular dysfunction

Duncker

Haitsma

Liem

et al. 2001

British J Pharmacology

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1 It is unknown how cardiac stimulation by Ca 2+ sensitization modulates the cardiovascular response to exercise when left ventricular (LV) function is chronically depressed following a myocardial infarction. We therefore investigated the eects of EMD 57033 at rest and during exercise and compared these to those of the mixed Ca 2+ -sensitizer/phosphodiesterase-III inhibitor pimobendan. 2 Pigs were chronically instrumented for measurement of cardiovascular performance. At the time of instrumentation, infarction was produced by coronary artery ligation (MI, n=12). Studies in MI were performed in the awake state, 2 ± 3 weeks after infarction. 3 MI were characterized by a lower resting cardiac output (18%), stroke volume (30%) and LVdP/ dt max (18%), and a doubling of LV end-diastolic pressure, compared to normal pigs (N, n=13). 4 In 11 resting MI, intravenous EMD 57033 (0.2 ± 0.8 mg kg 71 min 71) increased LVdP/dt max (57+5%) and stroke volume (26+6%) with no eect on heart rate, LV ®lling pressure, and myocardial O 2 -consumption, similar to N. 5 In MI, the eects of EMD 57033 (0.4 mg kg 71 min 71, IV) on stroke volume and LVdP/dt max were maintained during treadmill exercise up to 85% of maximal heart rate, while heart rate was lower compared to control exercise (all P50.05). In contrast, the eects of EMD57033 gradually waned in N at increasing intensity of exercise. 6 Compared to N, the cardiostimulatory eects of pimobendan (20 mg kg 71 min 71, IV) were blunted in MI both at rest and during exercise compared to N. 7 In conclusion, the positive inotropic actions of the Ca 2+ sensitizer EMD 57033 are unmitigated in resting and exercising MI compared to N, while those of the mixed Ca 2+ -sensitizer/ phosphodiesterase-III inhibitor pimobendan are blunted.

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Phosphodiesterase inhibition and Ca2+ sensitization

Cited by 6 publications

References 18 publications

Cardiovascular profile of the calcium sensitizer EMD 57033 in open‐chest anaesthetized pigs with regionally stunned myocardium

Cardiovascular profile of the calcium sensitizer EMD 57033 in open‐chest anaesthetized pigs with regionally stunned myocardium

Human cardiac myosin autoantibodies impair myocyte contractility: a cause‐and‐effect relationship

Beneficial effects of the Ca²⁺ sensitizer EMD 57033 in exercising pigs with infarction‐induced chronic left ventricular dysfunction

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Phosphodiesterase inhibition and Ca2+ sensitization

Cited by 6 publications

References 18 publications

Cardiovascular profile of the calcium sensitizer EMD 57033 in open‐chest anaesthetized pigs with regionally stunned myocardium

Cardiovascular profile of the calcium sensitizer EMD 57033 in open‐chest anaesthetized pigs with regionally stunned myocardium

Human cardiac myosin autoantibodies impair myocyte contractility: a cause‐and‐effect relationship

Beneficial effects of the Ca2+ sensitizer EMD 57033 in exercising pigs with infarction‐induced chronic left ventricular dysfunction

Contact Info

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Beneficial effects of the Ca²⁺ sensitizer EMD 57033 in exercising pigs with infarction‐induced chronic left ventricular dysfunction