| Synonyms | PST2744 ; Istaroxime hydrochloride; (5S,8R,9S,10R,13S,14S)-3-(2-aminoethoxyimino)-10,13-dimethyl-1,2,4,5,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene-6,17-dione;hydrochloride
|
| Reference | 1. J Pharmacol Exp Ther. 2008 Sep;326(3):957-65. doi: 10.1124/jpet.108.138701. Epub
2008 Jun 6.
<br>
Modulation of sarcoplasmic reticulum function by PST2744 [istaroxime;
(E,Z)-3-((2-aminoethoxy)imino) androstane-6,17-dione hydrochloride)] in a
pressure-overload heart failure model.
<br>
Rocchetti M(1), Alemanni M, Mostacciuolo G, Barassi P, Altomare C, Chisci R,
Micheletti R, Ferrari P, Zaza A.
<br>
Author information: <br>
(1)Dipartimento di Biotecnologie e Bioscienze, Università degli Studi
Milano-Bicocca, P.zza della Scienza 2, 20126 Milano, Italy.
<br>
PST2744 [Istaroxime; (E,Z)-3-((2-aminoethoxy)imino) androstane-6,17-dione
hydrochloride)] is a novel inotropic agent that enhances sarco(endo)plasmic
reticulum Ca(2+) ATPase (SERCA) 2 activity. We investigated the istaroxime effect
on Ca(2+) handling abnormalities in myocardial hypertrophy/failure (HF). Guinea
pig myocytes were studied 12 weeks after aortic banding (AoB) and compared with
those of sham-operated animals (sham). The gain of calcium-induced Ca(2+) release
(CICR), sarcoplasmic reticulum (SR) Ca(2+) content, Na(+)/Ca(2+) exchanger (NCX)
function, and the rate of SR reloading after caffeine-induced depletion (SR
Ca(2+) uptake, measured during NCX blockade) were evaluated by measurement of
cytosolic Ca(2+) and membrane currents. HF characterization: AoB caused
hypertrophy and failure in 100 and 25% of animals, respectively. Although CICR
gain during constant pacing was preserved, SR Ca(2+) content and SR Ca(2+) uptake
were strongly depressed. Resting Ca(2+) and the slope of the Na(+)/Ca(2+)
exchanger current (I(NCX))/Ca(2+) relationship were unchanged by AoB. Istaroxime
effects: CICR gain, SR Ca(2+) content, and SR Ca(2+) uptake rate were increased
by istaroxime in sham myocytes and, to a significantly larger extent, in AoB
myocytes; this led to almost complete recovery of SR Ca(2+) uptake in AoB
myocytes. Istaroxime increased resting Ca(2+) and the slope of the I(NCX)/Ca(2+)
relationship similarly in sham and AoB myocytes. Istaroxime failed to increase
SERCA activity in skeletal muscle microsomes devoid of phospholamban. Thus,
clear-cut abnormalities in Ca(2+) handling occurred in this model of hypertrophy,
with mild decompensation. Istaroxime enhanced SR function more in HF myocytes
than in normal ones; almost complete drug-induced recovery suggests a purely
functional nature of SR dysfunction in this HF model.
<br>
2. J Pharmacol Exp Ther. 2005 Apr;313(1):207-15. Epub 2004 Dec 2.
<br>
Modulation of sarcoplasmic reticulum function by Na+/K+ pump inhibitors with
different toxicity: digoxin and PST2744
[(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride].
<br>
Rocchetti M(1), Besana A, Mostacciuolo G, Micheletti R, Ferrari P, Sarkozi S,
Szegedi C, Jona I, Zaza A.
<br>
Author information: <br>
(1)Dipartimento di Biotecnologie e Bioscienze, Università degli Studi
Milano-Bicocca, P.zza della Scienza 2, 20126 Milano, Italy.
<br>
OBJECTIVE: To gain some insight on the lesser arrhythmogenic properties of
PST2744 [(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride]
compared with digoxin, we compared modulation of intracellular Ca2+ dynamics by
the two agents.<br>
METHODS: SERCA (sarcoplasmic reticulum Ca2+-ATPase) activity and Ca2+ leak rate
were measured in sarcoplasmic reticulum (SR) vesicles from guinea pig ventricles.
Membrane current, intracellular Ca2+, and twitch amplitude were evaluated in
guinea pig ventricular myocytes with or without blockade of the Na+/Ca2+
exchanger.<br>
RESULTS: In SR vesicles, PST2744 (30-300 nM), but not digoxin, increased SERCA
activity; digoxin only (> or =0.1 nM) increased SR Ca2+ leak. In myocytes with
blocked Na+/Ca2+ exchanger, Ca2+ reloading of caffeine-depleted SR was enhanced
by PST2744 and slightly inhibited by digoxin. In myocytes with functioning
Na+/Ca2+ exchanger, both agents increased diastolic Ca2+, SR Ca2+ content, the
gain of Ca2+-induced Ca2+ release, the rate of cytosolic Ca2+ decay, twitch
amplitude, and relaxation rate. Consistent with the observations in SR vesicles,
the effects on SR Ca2+ content and Ca2+ decay rate were significantly larger for
PST2744 than for digoxin.<br>
CONCLUSIONS: In isolated SR vesicles, PST2744 and digoxin directly affected SR
function in opposite ways; this could be reproduced in myocytes during Na+/Ca2+
exchanger blockade. Under physiological conditions (functioning Na+/Ca2+
exchanger), the two agents affected Ca2+ dynamics in the same direction, as
expected by their Na+/K+ pump inhibition; however, differential SR modulation was
still expressed by quantitative differences. Thus, the more favorable
inotropy-to-toxicity ratio previously described for PST2744 appears to be
associated with direct SERCA stimulation and/or lack of enhancement of Ca2+ leak.
<br>
3. J Pharmacol Exp Ther. 2002 Nov;303(2):592-600.
<br>
Pharmacological profile of the novel inotropic agent
(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride (PST2744).
<br>
Micheletti R(1), Mattera GG, Rocchetti M, Schiavone A, Loi MF, Zaza A, Gagnol RJ,
De Munari S, Melloni P, Carminati P, Bianchi G, Ferrari P.
<br>
Author information: <br>
(1)Prassis Sigma-Tau Research Institute, Via Forlanini 1/3, 20019 Settimo
Milanese, Italy. [email protected]
<br>
The novel Na(+)/K(+)-ATPase inhibitor
(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride (PST2744) was
characterized for its inotropic and toxic properties. Inhibition potency on dog
kidney Na(+)/K(+)-ATPase was comparable (0.43 microM) to that of digoxin (0.45
microM). PST2744 concentration-dependently increased force of contraction in
guinea pig atria and twitch amplitude in isolated guinea pig myocytes; in the
latter, aftercontractions developed significantly less than with digoxin.
Intravenous infusion of 0.2 mg/kg/min PST2744 in anesthetized guinea pigs exerted
an immediate and long-lasting inotropic effect (ED(80) of 1.89 +/- 0.37 mg/kg)
without causing lethal arrhythmias up to a cumulative dose of 18 mg/kg.
Conversely, an equieffective infusion of digoxin (0.016 mg/kg/min; ED(80) of 0.32
mg/kg) caused lethal arrhythmias at a cumulative dose of 0.81 mg/kg. At a higher
rate (0.4 mg/kg/min), PST2744 induced lethal arrhythmias, with a lethal
dose/ED(80) ratio significantly greater than digoxin (20.2 +/- 6.3 versus 3.23
+/- 0.55, p < 0.05). Decay of the inotropic effect (t(1/2), min) was
significantly faster for PST2744 (6.0 +/- 0.39) than for digoxin (18.3 +/- 4.5, p
< 0.05). In anesthetized dogs, PST2744 dose-dependently increased maximum
velocity of pressure rise (+dP/dt(max)) in the range 32 to 500 microg/kg i.v. and
was safer than digoxin. In conscious dogs with a healed myocardial infarction,
PST2744 significantly increased resting values of +dP/dt(max), left ventricular
pressure, and SPB, and increased +dP/dt(max) throughout treadmill exercise while
reverting the increase in left ventricular end diastolic pressure seen in control
animals. Digoxin significantly decreased basal heart rate, while not affecting
the hemodynamic response to exercise. Thus, PST2744 represents a new class of
Na(+)/K(+)-ATPase inhibitors endowed with inotropic activity comparable with that
of digitalis but having greater safety.
<br>
|
