Phosphodiesterase inhibition promotes the transition from compensated hypertrophy to cardiac dilatation in rats

Abstract

The cellular signaling pathways responsible for the transition from compensated left ventricular hypertrophy (LVH) to LV dilatation (remodeling) and heart failure are unclear. As chronic administration of a beta-adrenoreceptor (beta-AR) agonist mediates the premature onset of cardiac remodeling without myocyte necrosis or myocardial dysfunction in LVH, we suggest that beta-AR activation is critical in promoting the transition from compensated LVH to cardiac dilatation. However, beta-AR mediated effects in the heart can occur via either the cyclic adenosine monophosphate (cAMP) system or via cAMP independent signaling pathways. To determine the role of cAMP in promoting adverse cardiac chamber remodeling, we evaluated whether phosphodiesterase inhibition (PDEI) promotes LV dilatation in rats with compensated LVH. The impact of chronic administration of the PDEI, pentoxifylline, on LV remodeling and function was assessed in spontaneously hypertensive rats (SHR) with compensated LVH. The PDEI mediated inotropic effects and increased cAMP concentrations in SHR. This dose of the PDEI administered for 4 months to SHR did not modify LV weight or influence intrinsic myocardial systolic function (as assessed in the absence of the PDEI) in SHR. However, the PDEI mediated the development of a right shift in LV end diastolic (LVED) pressure-internal dimension and LVED pressure-volume relations, LV wall thinning, and increments in myocardial soluble (non-cross-linked) collagen concentrations. In conclusion, chronic PDEI administration induces adverse geometric and interstitial cardiac remodeling in SHR, a finding that supports the notion that the beta-AR-cAMP system is important in mediating the progression to heart failure by promoting interstitial remodeling and LV dilatation in LVH.

Parathyroid hormone accelerates decompensation following left ventricular hypertrophy

“…However, sustained LVH usually leads to the deterioration of heart functions, such as a reduced FS accompanied by wall thinning and chamber dilation. Since LVH is considered to be an independent risk factor for heart failure, intensive efforts have been focused on elucidating the signaling pathways involved in LVH (Hardt and Sadoshima, 2004) and developing strategies to prevent the transition from LVH to heart failure (Anamourlis et al, 2006).…”

Coronary vasodilator activity of vulgarenol, a sesquiterpene isolated from Magnolia grandiflora, and its possible mechanism

“…Because the NO receptor, NOsensitive guanylyl cyclase, plays a key role in the NO/cGMP signal-transduction cascade (Russwurm and Koesling, 2004), isolated and perfused guinea-pig hearts were pre-treated with 10 μM ODQ, a soluble guanylyl cyclase selective inhibitor (Isenberg et al, 2006), then without stopping 10 μM ODQ infusion, 5 μM vulgarenol was infused continuously at 0.3 mL/min. Due to the fact that cyclic nucleotides are degraded by phosphodiesterases, it was decided to investigate whether phosphodiesterase-3 selective inhibition by pentoxifylline (a highly specific type 3 phosphodiesterase inhibitor) (Anamourlis et al, 2006) could have a role in the observed pharmacological effect. In all experiments, CVR and cGMP production in the ventricular segments were evaluated.…”

Modulation of actin isoform expression before the transition from experimental compensated pressure-overload cardiac hypertrophy to decompensation

“…The fundamental mechanisms responsible for the transition from compensated to decompensated cardiac hypertrophy are only partially defined (1,31). Many studies point to death of cardiomyocytes and changes in the cellular/molecular mechanisms regulating extracellular matrix composition and organization as the most relevant factors in the transition from compensatory hypertrophy to pump failure in experimental and human hypertension (1,10,12,19,23,30,34,40,42).…”

“…The fundamental mechanisms responsible for the transition from compensated to decompensated cardiac hypertrophy are only partially defined (1,31). Many studies point to death of cardiomyocytes and changes in the cellular/molecular mechanisms regulating extracellular matrix composition and organization as the most relevant factors in the transition from compensatory hypertrophy to pump failure in experimental and human hypertension (1,10,12,19,23,30,34,40,42). It has been also suggested that the accumulation of cytoskeletal proteins, tubulin and desmin, probably counteracting the increased strain on the myocardium due to chronic pressure overload, as well as changes in intercalated disc proteins may lead to cytoskeletal stiffness and reduced intercellular communication resulting in contractile dysfunction before the transition to overt HF (18,31).…”