Stimulation of Ca++ binding and ATPase activity of dog cardiac myofibrils by AR-L 115BS, a novel cardiotonic agent.

Solaro, R. John; Rüegg, J.C.

doi:10.1161/01.res.51.3.290

Cited by 144 publications

(52 citation statements)

References 8 publications

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“…Other inotropic mechanisms of compounds with PDE inhibiting properties, and which are independent of cyclic AMP include: increase in the Ca2+ sensitivity of the troponin C regulatory site in cardiac myofilaments (Herzig et al, 1981;Solaro & Ruegg, 1982;Ruegg, 1986;Bethke et al, 1988;Fujino et al, 1988;Kitada et al, 1989), stimulation of the Na+/Ca2" exchange mechanism (Alousi & Johnson, 1986;Sutko et al, 1986;Brasch & Iven, 1991), Na+ influx through Na+ channels (Grima et al, 1988;Rapundalo et al, 1988;Haleen et al, 1989), activation of membrane Ca-ATPase (Mylotte et al, 1985) and the Ca2"-release channel of the sarcoplasmic reticulum (Holmberg & Williams, 1991 (Scholz & Meyer, 1986). Both sulmazole and HN-10200 have been shown to produce an increase in the sensitivity of the contractile proteins (Solaro & Ruegg, 1982;Kuhberger et al, 1991 (Weishaar et al, 1987;Harris et al, 1989;Katano & Endoh, 1990;Shahid et al, 1990;Nicholson et al, 1991). Results obtained from isolated ventricular cardiomyocytes, however, did not indicate any such increase in contraction in the presence of forskolin.…”

Section: Effects Of Pde Inhibitors On Contractile Activitymentioning

confidence: 99%

Cardiotonic actions of selective phosphodiesterase inhibitors in rat isolated ventricular cardiomyocytes

Kelso

McDermott

Silke

1993

British J Pharmacology

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1 The contractile effects of the novel cardiotonic agent HN-10200 (2-[3-methoxy-5-methylsulphinyl-2-thienyl]-lH-imidazo-[4,5-c]-pyridine hydrochloride), were examined and comparisons made with the responses obtained to a structurally similar compound, sulmazole, and to a number of other compounds which are known to inhibit phosphodiesterase (PDE) isoenzymes with differing selectivities; namely, enoximone (PDE III inhibitor), Ro 20-1724 (PDE IV inhibitor) and 3-isobutyl-1-methylxanthine (nonselective PDE inhibitor). 2 Contractile function, as measured by mechanical shortening, and biochemical systems involving cyclic AMP were investigated in ventricular cardiomyocytes isolated from adult Sprague-Dawley rats (200-250 g). 3 HN-10200 exerted a concentration-dependent (10-8 M-10-4 M) positive contractile effect, which was independent of a-or 0-adrenoceptor, or histamine receptor stimulation. 4 The efficacies of the contractile responses to the PDE inhibitors were of the order: HN-10200> IBMX> sulmazole> enoximone and maximum stimulations, which were obtained at concentrations of 10-4M, were 54 ± 4%, 41 ± 7%, 38 ± 7% and 26 ± 5% (mean ± s.e.) greater than basal levels, respectively (n = 6); the basal value of contractile amplitude (dL), in the absence of PDE inhibitors was 7.39 ± 0.18% (mean ± s.e.). Ro 20-1724 did not have any effect on contractile activity. 5 Due to low basal levels of cyclic nucleotides in isolated cells, accumulation of cyclic AMP due to the presence of the PDE inhibitors was detected only when the levels of cyclic nucleotide were enhanced with forskolin (10 fM). 6 The PDE inhibitors increased levels of cyclic AMP only at concentrations> 10-' M. HN-10200 and sulmazole had similar concentration-dependent profiles for the accumulation of cyclic AMP; their potencies were lower than that of IBMX (concentrations of forskolin required to increase cyclic AMP by 4 pmol mg-' protein, in the presence of maximum concentrations of the PDE inhibitors, were 13 ± 3 11M, 14 ± 3 JAM and 3 ± 0.6 JAM [mean ± s.e.], respectively). 7 These results indicate that a similar mechanism, probably through a weak inhibition of the cyclic AMP-specific PDE isoenzymes, is responsible for the increase in levels of cyclic AMP by HN-10200 and sulmazole. However, cyclic AMP is only partially responsible for the positive contractile effect of HN-10200 and, similarly, sulmazole and IBMX. The lack of apparent increase in levels of cyclic AMP by enoximone, highlights its degree of selectivity for the PDE III isoenzyme, such that the PDE IV isoform is still present in sufficient quantity to degrade cyclic AMP within the cell. On the other hand, the potent action of Ro 20-1724 on accumulation of cyclic AMP, in addition to the lack of effect on contractile function, is in agreement with the selectivity of this compound for the PDE IV isoenzyme and compartmentalization of cyclic AMP in rat isolated ventricular cardiomyocytes.

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Section: Effects Of Pde Inhibitors On Contractile Activitymentioning

confidence: 99%

Cardiotonic actions of selective phosphodiesterase inhibitors in rat isolated ventricular cardiomyocytes

Kelso

McDermott

Silke

1993

British J Pharmacology

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“…Unlike MCI-154, sulmazole, pimobendan and adibendan had no such effects. Since sulmazole has been found to increase Ca2+ binding to troponin (14), the Ca2+ sensitizing effect of this drug and probably also pimo bendan and adibendan may be mainly due to an increased affinity of troponin C for Ca2} in the presence of the drugs. MCI-154 also stimulates the Ca2+ binding to troponin purified from the canine ventricular muscles and increases the activity of the myofibrillar and reconstituted actomyosin ATPases (15).…”

Section: Discussionmentioning

confidence: 99%

Comparison of the effects of MCI-154, a new cardiotonic agent, and some Ca2+-sensitizing agents on the response of the contractile system to Ca2+ in skinned cardiac muscle.

1989

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Abstract-Several cardiotonic agents (MCI-154, sulmazole, pimobendan and adibendan) were examined for their ability to influence Ca2+-activated tension development and MgATP-activated tension development in the absence of free Ca2+ (rigor tension), using the chemically skinned fiber from guinea pig papillary muscles. MCI-154, sulmazole, pimobendan and adibendan all increased the tension development induced by pCa (-log[Ca2+]M) 5.8 in a concentration dependent manner (10-6 to 10-4 M). The order of the potency was as follows: MCI-1 54>pimobendan>adibendan>sulmazole.MCI-154 enhanced the maximum tension developed at pCa 4.4 but sulmazole, pimobendan and adibendan did not enhance it. MCI-154, but not sulmazole, pimobendan and adibendan, enhanced the tension development induced by pMgATP (-log[MgATP]M) 6.0 in the absence of free Ca2+. MCI-154, sulmazole, pimobendan and adibendan concentration dependently (10-7 to 10-4 M) increased the force of contraction in isolated guinea pig papillary muscles. The order of the potency was as follows: MCI-154> adibendan>pimobendan>sulmazole.These results demonstrated that the Ca2+ sensitizing action on the contractile system may be involved in the positive inotropic action of MCI-154, sulmazole, pimobendan and adibendan, and that MCI-154 is the most potent among these drugs. Furthermore, sulmazole, pimobendan and adibendan did not enhance the interaction of actin and myosin, suggesting that the mechanism of actions of these drugs are qualitatively different from that of MCI-154.

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“…There is also some evidence to suggest that the imidazo-pyridines increase the sensitivity of the contractile machinery of myocardial cells to Ca2". Sul-mazole has been demonstrated to increase the sensitivity of the myofibrils to Ca2" (Herzig et al, 1981;Solaro & Ruegg, 1982;Blinks & Endoh, 1984). This would have the same net effect on the development of contractile tension, as would an increase in the availability of intracellular Ca2".…”

Section: Discussionmentioning

confidence: 99%

A comparative study of the cardiovascular and biochemical actions of the imidazo [4,5b] pyridine sulmazole and an imidazo [4,5c] pyridine analogue, BW A746C

Allan

Cambridge

Follenfant

et al. 1988

British J Pharmacology

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A comparative study of the cardiovascular and biochemical actions of the imidazo [4,5b] pyridine sulmazole and an imidazo [4,5c] 2 In anaesthetized guinea-pigs, dogs and primates, a bolus i.v. injection of BWA746C, (0.001-1.0 mg kg-') caused a significant, dose-related increase in ventricular dP/dt, and reduction in diastolic blood pressure, with small increases in heart rate. In these species, a significantly higher dose of BW A746C was required to lower blood pressure by 30% from basal, than was needed to raise ventricular dP/dt by 50% over basal.3 In anaesthetized guinea-pigs and dogs, bolus i.v. injections of sulmazole (0.1-10.0mg kg-')caused similar effects to those observed with BW A746C. In these species, however, there was no significant difference between the dose of sulmazole required to lower blood pressure by 30% from basal and that required to raise ventricular dP/dt by 50%. 4 In conscious dogs, i.v. infusion of BW A746C (to a total dose of 0.3 mg kg-') caused a significant increase in ventricular dP/dt, but no significant change in either diastolic blood pressure or heart rate. 5 In cell-free biochemical assays, there were no clear differences between the observed activities of BW A746C and sulmazole. Both compounds are cyclic nucleotide phosphodiesterase inhibitors with similar potencies and selectivities for the Type III enzyme (IC-, BW A746C = 3.0 ± 0.5 x 10-'M, sulmazole 5.0 ± 1.9 x 10-' M). The compounds had little or no effects on sarcolemmal Na+/ K+-ATPase, Ca"+ ATPase or Na+/Ca2" exchange, and sulmazole, but not BW A746C, had a small, stimulatory effect on myofibrillar ATPase.6 In anaesthetized guinea-pigs and dogs, BW A746C was significantly more potent as a positive inotrope than sulmazole. In contrast with sulmazole, BW A746C produced its inotropic effects at significantly lower doses than those required to reduce diastolic blood pressure. This was also apparent from the results obtained in the anaesthetised primates and the conscious dogs. It was therefore concluded that the inotropic/vasodilator profile of BW A746C favours its positive inotrope activity.This profile cannot be explained on the basis of any biochemical differences from sulmazole.

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Stimulation of Ca++ binding and ATPase activity of dog cardiac myofibrils by AR-L 115BS, a novel cardiotonic agent.

Cited by 144 publications

References 8 publications

Cardiotonic actions of selective phosphodiesterase inhibitors in rat isolated ventricular cardiomyocytes

Cardiotonic actions of selective phosphodiesterase inhibitors in rat isolated ventricular cardiomyocytes

Comparison of the effects of MCI-154, a new cardiotonic agent, and some Ca2+-sensitizing agents on the response of the contractile system to Ca2+ in skinned cardiac muscle.

A comparative study of the cardiovascular and biochemical actions of the imidazo [4,5b] pyridine sulmazole and an imidazo [4,5c] pyridine analogue, BW A746C

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