33 research outputs found
Rate-dependent Ca2+ signalling underlying the force-frequency response in rat ventricular myocytes: A coupled electromechanical modeling study
Rate-dependent effects on the Ca2+ sub-system in a rat ventricular myocyte are investigated. Here,
we employ a deterministic mathematical model describing various Ca2+ signalling pathways under
voltage clamp (VC) conditions, to better understand the important role of calmodulin (CaM) in modulating
the key control variables Ca2+/calmodulin-dependent protein kinase-II (CaMKII), calcineurin
(CaN), and cyclic adenosine monophosphate (cAMP) as they affect various intracellular targets. In
particular, we study the frequency dependence of the peak force generated by the myofilaments, the
force-frequency response (FFR). Our cell model incorporates frequency-dependent CaM-mediated spatially heterogenous interaction
of CaMKII and CaN with their principal targets (dihydropyridine (DHPR) and ryanodine (RyR) receptors
and the SERCA pump). It also accounts for the rate-dependent effects of phospholamban
(PLB) on the SERCA pump; the rate-dependent role of cAMP in up-regulation of the L-type Ca2+
channel (ICa;L); and the enhancement in SERCA pump activity via phosphorylation of PLB.Our model reproduces positive peak FFR observed in rat ventricular myocytes during voltage-clamp
studies both in the presence/absence of cAMP mediated -adrenergic stimulation. This study provides
quantitative insight into the rate-dependence of Ca2+-induced Ca2+-release (CICR) by investigating
the frequency-dependence of the trigger current (ICa;L) and RyR-release. It also highlights the relative
role of the sodium-calcium exchanger (NCX) and the SERCA pump at higher frequencies, as well
as the rate-dependence of sarcoplasmic reticulum (SR) Ca2+ content. A rigorous Ca2+ balance
imposed on our investigation of these Ca2+ signalling pathways clarifies their individual roles. Here,
we present a coupled electromechanical study emphasizing the rate-dependence of isometric force
developed and also investigate the temperature-dependence of FFR. Our model provides mechanistic biophysically based explanations for the rate-dependence of CICR,
generating useful and testable hypotheses. Although rat ventricular myocytes exhibit a positive peak
FFR in the presence/absence of beta-adrenergic stimulation, they show a characteristic increase in the
positive slope in FFR due to the presence of Norepinephrine or Isoproterenol. Our study identifies
cAMP-mediated stimulation, and rate-dependent CaMKII-mediated up-regulation of ICa;L as the key
mechanisms underlying the aforementioned positive FFR
Macitentan for the treatment of idiopathic pulmonary fibrosis: The randomised controlled MUSIC trial.
Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group