G. Lehmann et al., INFUSIONS WITH MOLSIDOMINE AND ISOSORBIDE-5-MONONITRATE IN CONGESTIVE-HEART-FAILURE - MECHANISMS UNDERLYING ATTENUATION OF EFFECTS, Journal of cardiovascular pharmacology, 31(2), 1998, pp. 212-220
The use of nitrates for treatment of heart failure is encumbered by to
lerance, caused by whatever mechanism, which has been reported only in
a few instances with sydnonimines. Accordingly, we compared molsidomi
ne (6 mg/h) and isosorbide-5-mononitrate (3.75 mg/h) with respect to m
aximal hemodynamic effects, rapidity and extent of attenuation, and un
derlying mechanisms by means of constant infusions over 24 h each in 1
5 patients with chronic congestive heart failure (NYHA II-III) with a
placebo-controlled, double-blind, randomized, crossover protocol, Hemo
dynamic measurements and determinations of neurohormones were performe
d at baseline and at 2, 8, and 24 h after the beginning of infusions,
With molsidomine, reductions of diastolic pulmonary artery pressure by
29% (p < 0.001), by 24% (p < 0.01), and by 24% (p < 0.01) versus plac
ebo were found at 2, 8, and 24 h, which amounted to 19% (p < 0.01), 10
% (NS), and 14% (NS) with the nitrate. Cardiac output was meaningfully
affected only with molsidomine (+5%, NS, at 2 h; +9%, p < 0.05, at 8
h; and +15%, p < 0.05, at 24 h), as was systemic vascular resistance (
-13%, p < 0.05; -9%, NS; and -18%, p < 0.01) at the corresponding time
s. Increases in renin activity amounted to 130% (p < 0.001). 117% (p <
0.001), and 112% (p < 0.001) with molsidomine, and to 14, 16%, and 0
(each NS) with the nitrate at the corresponding times. Hematocrit was
reduced by 5% (p < 0.001), 7% (p < 0.001), and 12% (p < 0.01) with mol
sidomine and by 5% (NS), 5% (p < 0.05), and 5% (NS) with the nitrate.
We conclude that neurohumoral counterregulation or fluid shift, which
is even mon pronounced with molsidomine despite longer-lasting effects
, has no essential role in nitrate-tolerance development. With molsido
mine, such a role cannot be ruled out, although alternatively, a fluid
shift from arterial to the low-pressure arm of circulation during the
later course of infusion would be even more likely.