Myocardial dysfunction and neurohumoral activation without remodeling in left ventricle of monocrotaline-induced pulmonary hypertensive rats

Abstract

In monocrotaline (MCT)-induced pulmonary hypertension (PH), only the right ventricle (RV) endures overload, but both ventricles are exposed to enhanced neuroendocrine stimulation. To assess whether in long-standing PH the left ventricular (LV) myocardium molecular/contractile phenotype can be disturbed, we evaluated myocardial function, histology, and gene expression of autocrine/paracrine systems in rats with severe PH 6 wk after subcutaneous injection of 60 mg/kg MCT. The overloaded RV underwent myocardial hypertrophy (P < 0.001) and fibrosis (P = 0.014) as well as increased expression of angiotensin-converting enzyme (ACE) (8-fold; P < 0.001), endothelin-1 (ET-1) (6-fold; P < 0.001), and type B natriuretic peptide (BNP) (15-fold; P < 0.001). Despite the similar upregulation of ET-1 (8-fold; P < 0.001) and overexpression of ACE (4-fold; P < 0.001) without BNP elevation, the nonoverloaded LV myocardium was neither hypertrophic nor fibrotic. LV indexes of contractility (P < 0.001) and relaxation (P = 0.03) were abnormal, however, and LV muscle strips from MCT-treated compared with sham rats presented negative (P = 0.003) force-frequency relationships (FFR). Despite higher ET-1 production, BQ-123 (ET(A) antagonist) did not alter LV MCT-treated muscle strip contractility distinctly (P = 0.005) from the negative inotropic effect exerted on shams. Chronic daily therapy with 250 mg/kg bosentan (dual endothelin receptor antagonist) after MCT injection not only attenuated RV hypertrophy and local neuroendocrine activation but also completely reverted FFR of LV muscle strips to positive values. In conclusion, the LV myocardium is altered in advanced MCT-induced PH, undergoing neuroendocrine activation and contractile dysfunction in the absence of hypertrophy or fibrosis. Neuroendocrine mediators, particularly ET-1, may participate in this functional deterioration.

Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension

“…As previously reported [33], MCT-6 rats showed clinical signs of congestive heart failure, disturbed indexes of LV contractility and relaxation, and increased expression of ACE and ET-1 in the LV myocardium. A more detailed discussion on the possible causes of neuroendocrine activation in the non-overloaded LV is provided elsewhere [33].…”

“…Relative quantification of mRNA Two-step Real-time RT-PCR was performed as previously described [14,15,33,40]. Briefly, after total mRNA extraction (no.…”

“…Echocardiography-based studies carried out in PH patients suggested that one of the mechanisms contributing to LV dysfunction is ventricular interdependence and impaired LV filling [35]. Other studies, however, provide evidences that intrinsic LV myocardial abnormalities also contribute to LV dysfunction in severe PH [11,12,24,33].…”

“…In fact, the LV of rats with severe longstanding PH induced by monocrotaline (MCT) presents local autocrine/paracrine system activation and muscle strips dissected from the LV myocardium show, in vitro, negative force-frequency relationships (FFR) [33]. Intrinsic LV myocardial abnormalities might help to explain late recovery of LV filling after single-lung transplantation in patients with PH, even if LV geometry and RV function are immediately restored [50].…”

The Obestatin/Ghrelin System as a Novel Regulatory Mechanism of Iris Muscle Contraction

“…The Wistar rat model has been used for heart-rate analysis research by some centres (Moraru et al 2004, Murasato et al 1998, and it is a model particularly well known at our institution in cardiovascular research (Henriques-Coelho et al 2004, Lourenço et al 2006. Moraru et al (2004) have studied linear and nonlinear HR dynamics in rats recovering from an episode of cardiac arrest.…”