Cardiovascular Actions of DPI 201–106, a Novel Cardiotonic Agent

Salzmann, R; Scholtysik, G; Clark, Benjamin R.; Berthold, R.

doi:10.1097/00005344-198609000-00023

Cited by 19 publications

(18 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar results were observed in animal models of cardiomyopathy. In Syrian hamsters with cardiac hypertrophy (Salzmann et al, 1986) or in pressure overloaded ferret hearts (Hajjar et al, 1987), DPI 201-106 causes a greater increase in force of contraction than in hearts from the respective control animals. However, in spontaneously hypertensive rats (SHR) with cardiac hypertrophy, the positive inotropic effect of DPI 201-106 was similar to control rats but greater than the effect of isoprenaline (Bohm et al, 1988b).…”

Section: Introductionmentioning

confidence: 95%

Inotropic response to DPI 201‐106 in the failing human heart

Böhm

Diet

Kemkes

et al. 1989

British J Pharmacology

View full text Add to dashboard Cite

1 The present study was designed to characterize the positive inotropic response to in isolated papillary muscle strips obtained from heart failure patients undergoing surgery.2 The positive inotropic responses to isoprenaline and milrinone and cardiac fl-adrenoceptor density were also determined. 3 DPI 201-106 increased the force of contraction in papillary muscle strips from patients with moderate (NYHA II-III) and severe (NYHA IV) heart failure, in a concentration-dependent manner. This positive inotropic effect was more pronounced in tissues from NYHA IV patients. Furthermore, these responses were greater than those produced by milrinone or isoprenaline. The positive inotropic effects of isoprenaline and milrinone were reduced in NYHA IV compared to NYHA II-III. Consistently, there was also a smaller density of fi-adrenoceptors in myocardium from NYHA IV than in NYHA II-III. The positive inotropic effect of Ca2l was similar in tissues from both groups of patients. 4 The positive inotropic effect of DPI 201-106 was not antagonized by adenosine or carbachol, whereas both compounds reduced the positive inotropic effect of isoprenaline.5 DPI 201-106 did not increase the Ca2"-sensitivity of chemically skinned ventricular fibres, whereas a significant increase of the Ca2 +-sensitivity was obtained with trifluoperazine. 6 It is concluded that DPI 201-106 produces significant positive inotropic effects in tissue excised from the failing human heart. The lack of inhibition by adenosine and carbachol might contribute to its greater effectiveness in NYHA IV than NYHA II-III and indicates that its mechanism of action is cyclic AMP-independent. A sensitization of the contractile proteins to Ca2+ does not appear to be important for the positive inotropic action of DPI 201-106 in the failing human heart.

show abstract

Section: Introductionmentioning

confidence: 95%

Inotropic response to DPI 201‐106 in the failing human heart

Böhm

Diet

Kemkes

et al. 1989

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…3), 12 indicating its Na' channel agonist effect. DPI 201-106 reversed the negative inotropic effect of verapamil (5,6) and vanadate (21).…”

Section: Pharmacologymentioning

confidence: 91%

Dpi 201–106

Scholtysik¹,

Rüegg²

1987

Cardiovascular Drug Reviews

View full text Add to dashboard Cite

Considerable efforts have been devoted to the development of nonglycoside cardiotonics. The mechanisms of action of clinically studied new compounds involve stimulation of cardiac P-adrenoceptors, histamine H2-receptors, and adenylate cyclase activity as well as inhibition of cyclic adenosine monophosphate (CAMP)-phosphodiesterase (PDE) (4). These effects lead in time to an increase in intracellular CAMP, which is likely to be responsible for their positive inotropic action.The recently discovered drug DPI 201-106 is a novel positive inotropic nonglycoside. Its activity is CAMP-independent and involves synergistic sarcolemmal and intracellular mechanisms. The properties of DPI 201-106 are described in this chapter. CHEMISTRYThe chemical structure of DPI 201-106 together with its chemical name is presented in Fig. 1. Its formula is C29H30N402, and its molecular weight is 466.59. DPI 201-106 is a crystalline bright yellow powder. The racemic mixture as well as the two optical enantiomers are soluble in N-methyl-2-pyrrolidone in acidic environment. PHARMACOLOGYIn Vitro Positive Inotropic Activity DPI 201-106 was found to increase the force of contraction in driven left atria from guinea pigs or rats (28); in papillary muscles from guinea pigs (3,28), rats (6,7), cats (28), rabbits (22,28), and dogs (30,31); and in rabbit (28) and hamster (21) hearts perfused according to Langendorff; but not in frog ventricles (7). The positive inotropic effect was concentration-dependent between lop7 and 3 X low6 M and reached the maximum within 2 hr. In most animal species the effects were not reversible upon extensive washing (3,28). The positive inotropic potency and efficacy of DPI 201-106 in rabbit papillary muscles were equal to that of ouabain 173

show abstract

“…26 of 27 muscles were from the right ventricle; one myopathic trabecula was from the left ventricle. For control and myopathic muscles, mean fiber diameters were 1 Because it is possible for drugs to interact directly with aequorin and thereby alter the luminescent reaction or the sensitivity of aequorin to calcium (14), each ofthe drugs used in these experiments was tested in vitro as described by Blinks et al (16) exchange. To facilitate this investigation, we inhibited the contribution of calcium handling by the sarcoplasmic reticulum.…”

Section: Methodsmentioning

confidence: 99%

“…This agent does not stimulate histamine receptors, a-adrenoceptors, or 0-adrenoceptors and does not produce liberation of catecholamines (1,2). DPI does not increase cAMP levels nor does it interfere with sodium-potassium ATPase activity (1). However, DPI 201-106 has been demonstrated to be a sodium channel agonist (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

Role of intracellular sodium in the regulation of intracellular calcium and contractility. Effects of DPI 201-106 on excitation-contraction coupling in human ventricular myocardium.

Gwathmey¹,

Slawsky²,

Briggs³

et al. 1988

J. Clin. Invest.

View full text Add to dashboard Cite

Experiments were performed to investigate the mechanism of action of DPI 201-106 on human heart muscle. In both control and myopathic muscles, DPI produced concentration-dependent increases in action potential duration, resting muscle tension, peak isometric tension, and duration of isometric tension. These changes were associated with increases in resting intracellular calcium and peak calcium transients as measured by aequorin. At higher concentrations of DPI, a second delayed Ca2l transient (L') appeared. L' was inhibited by tetrodotoxin and ryanodine, suggesting that DPI acts at both the sarcolemma and the sarcoplasmic reticulum. DPI toxicity was manifested by after-glimmers and after-contractions reflecting a Ca2l-overload state: DPI effects were mimicked by veratridine, a Na' channel agonist, and reversed by tetrodotoxin, yohimbine, and cadmium, Na' channel antagonists. These results suggest that DPI acts primarily as a Na' channel agonist. DPI may produce an increase in intracellular Ca2l by increasing intracellular Na' and altering Na'-Ca2" exchange across the sarcolemma. DPI may also increase intracellular Ca2" by directly altering sarcoplasmic reticulum Ca2" handling.

show abstract

Cardiovascular Actions of DPI 201–106, a Novel Cardiotonic Agent

Cited by 19 publications

References 0 publications

Inotropic response to DPI 201‐106 in the failing human heart

Inotropic response to DPI 201‐106 in the failing human heart

Dpi 201–106

Role of intracellular sodium in the regulation of intracellular calcium and contractility. Effects of DPI 201-106 on excitation-contraction coupling in human ventricular myocardium.

Contact Info

Product

Resources

About