The effect of several “new and novel” cardiotonic agents on key subcellular processes involved in the regulation of myocardial contractility: Implications for mechanism of action

Weishaar, Ronald E.; Quade, Mary M.; Boyd, Denise K.; Schenden, J A; Marks, Steven L.; Kaplan, Harvey

doi:10.1002/ddr.430030604

Cited by 30 publications

(13 citation statements)

References 26 publications

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“…Nevertheless, it is possible that they influence this Ca2" movement directly by acting upon myocardial cellular structures such as the sarcolemma or the sarcoplasmic reticulum. Weishaar et al (1983) and Hayes et al (1986) have been unable to find any convincing evidence for such an action for either sulmazole or BW A746C. Our own studies have found only weak actions for sulmazole and BW A746C upon these structures (Na+/Ca2"-exchange and Ca2l-ATPase activity at the sarcolemma; Ca2"-uptake at sarcoplasmic reticulum).…”

Section: Discussioncontrasting

confidence: 50%

“…Most studies with sulmazole have indicated that a glycoside-like mechanism can be ruled out (Diederen & Weisenberger, 1981;From & Pierpoint, 1981;Hayes et al, 1985b), although Weishaar et al (1983) have demonstrated inhibition of myocardial Na'-K' ATPase by sulmazole at concentrations which are inotropic in vitro. In the studies presented here, inhibition of this APTase by sulmazole and BW A746C was also observed, but only at high doses.…”

Section: Discussionmentioning

confidence: 99%

“…This can be achieved by the stimulation of myocardial adenyl cyclase (as with P-adrenoceptor stimulation) or by inhibition ofmyocardial cyclic AMP-phosphodiesterase. There is little evidence to support the notion that the imidazo-pyridines act by stimulating adenyl cyclase (Hayes et al, 1986), but it has been shown that sulmazole inhibits myocardial cyclic AMP-phosphodiesterase (Diederen & Wiesenberger, 1981;Weishaar et al, 1983). However this enzyme exists as at least three isoenzymes, of which the most important, with regard to positive inotropic stimulation, is that described as PDE-III.…”

Section: Discussionmentioning

confidence: 99%

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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] 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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Section: Discussioncontrasting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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] pyridine analogue, BW A746C

Allan

Cambridge

Follenfant

et al. 1988

British J Pharmacology

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“…Carbazeran is a phthalazine compound that is susceptible to AO and forms a phthalazone metabolite (Fig. 6) (Weishaar et al, 1983;Kaye et al, 1985). Whereas the phthalazone metabolite has been previously characterized using MS and tandem mass spectrometry techniques, a complete NMR characterization has not been performed.…”

Section: Downloaded Frommentioning

confidence: 99%

Validation of Isolated Metabolites from Drug Metabolism Studies as Analytical Standards by Quantitative NMR

Walker

Ryder²,

Sharma³

et al. 2010

Drug Metab Dispos

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ABSTRACT:In discovery and development, having a qualified metabolite standard is advantageous. Chemical synthesis of metabolite standards is often difficult and expensive. As an alternative, biological generation and isolation of metabolites in the nanomole range are readily feasible. However, without an accurately defined concentration, these isolates have limited utility as standards. There is a significant history of NMR as both a qualitative and a quantitative technique, and these concepts have been merged recently to provide both structural and quantitative information on biologically generated isolates from drug metabolism studies. Previous methodologies relied on either specialized equipment or the use of an internal standard to the isolate. We have developed a technique in which a mathematically generated signal can be inserted into a spectrum postacquisition and used as a quantitative reference: artificial signal insertion for calculation of concentration observed (aSICCO). This technique has several advantages over previous methodologies. Any region in the analyte spectra, free from interference, can be chosen for the reference signal. In addition, the magnitude of the inserted signal can be modified to appropriately match the intensity of the sample resonances. Because this is postacquisition quantification, no special equipment or pulse sequence is needed. Compared with quantitation via the addition of an internal standard (10 mM maleic acid), the signal insertion method produced similar results. For each method, precision and accuracy were within ؎5%, stability of signal response over 8 days was ؎5%, and the dynamic range was more than 3 orders of magnitude: 10 to 0.01 mM.

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“…These other agents include pimobendan [54], MCI-154 [57], BM 14.578 [58], APP 201-533 [55], and DPI-201-106 [59]. Most of these agents, however, have been shown to exert other actions that could increase cardiac contractility, including inhibition of phosphodiesterase (pimobendan and sulmazole), inhibition of Na, KATPase (sulmazole), and stimulation of the sodium fast channel (DPI-201-106) [60][61][62][63]. In addition, agents that do not produce a positive inotropic response, such as bepridil and calmodizolium, have also been shown to increase calcium sensitivity [64,65].…”

Section: Calcium Sensitizersmentioning

confidence: 99%

New mechanisms for positive inotropic agents: Focus on the discovery and development of imazodan

Weishaar¹,

Kobylarz-Singer²,

Klinkefus³

1989

Cardiovasc Drug Ther

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Intense efforts during the last decade to identify a useful positive inotropic agent to replace digitalis for the treatment of congestive heart failure have led to the discovery of several dozen potential substitutes, of which a number are currently undergoing clinical trials. In addition to producing a variety of new therapeutic entities, research in this area has also yielded valuable new information regarding the fundamental events that regulate calcium homeostasis and contractile function in the cardiac cell. For example, several of these new inotropic agents, including the calcium-channel stimulator BAY-k 8644, the sodium-channel stimulator DPI-201-186, and the sodium-calcium exchange inhibitor dichlorobenzamil, have provided considerable insight into the role of sodium and calcium in regulating contractility and the molecular events that mediate potential-dependent ion channels. Likewise, the discovery and development of agents like imazodan, amrinone, enoximone, and other selective type III phosphodiesterase inhibitors have provided new information regarding multiple molecular forms of cyclic nucleotide phosphodiesterase, compartmentation of cyclic AMP, and the importance of soluble vs. membrane-bound phosphodiesterases.

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The effect of several “new and novel” cardiotonic agents on key subcellular processes involved in the regulation of myocardial contractility: Implications for mechanism of action

Cited by 30 publications

References 26 publications

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

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

Validation of Isolated Metabolites from Drug Metabolism Studies as Analytical Standards by Quantitative NMR

New mechanisms for positive inotropic agents: Focus on the discovery and development of imazodan

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