Right ventricular myocardial oxygen tension is reduced in monocrotaline-induced pulmonary hypertension in the rat and restored by myo-inositol trispyrophosphate

Abstract

Pulmonary hypertension (PH) initially results in compensatory right ventricular (RV) hypertrophy, but eventually in RV failure. This transition is poorly understood, but may be triggered by hypoxia. Measurements of RV oxygen tension (pO2) in PH are lacking. We hypothesized that RV hypoxia occurs in monocrotaline-induced PH in rats and that myo-inositol trispyrophosphate (ITPP), facilitating oxygen dissociation from hemoglobin, can relieve it. Rats received monocrotaline (PH) or saline (control) and 24 days later echocardiograms, pressure–volume loops were obtained and myocardial pO2 was measured using a fluorescent probe. In PH mean pulmonary artery pressure more than doubled (35 ± 5 vs. 15 ± 2 in control), RV was hypertrophied, though its contractility was augmented. RV and LV pO2 was 32 ± 5 and 15 ± 8 mmHg, respectively, in control rats. In PH RV pO2 was reduced to 18 ± 9 mmHg, while LV pO2 was unchanged. RV pO2 correlated with RV diastolic wall stress (negatively) and LV systolic pressure (positively). Acute ITPP administration did not affect RV or LV pO2 in control animals, but increased RV pO2 to 26 ± 5 mmHg without affecting LV pO2 in PH. RV oxygen balance is impaired in PH and as such can be an important target for PH therapy. ITPP may be one of such potential therapies.

Effects of the peripheral CB1 receptor antagonist JD5037 in mono— and polytherapy with the AMPK activator metformin in a monocrotaline-induced rat model of pulmonary hypertension

“…The PH animals also showed increased rates of rise (dP/dt max ) and decrease (dP/dt min ) of right ventricular pressure. These data suggest that in our model RV maintains its function by increasing contractile (inotropic) and lusitropic action and is still in a compensatory phase (Vélez-Rendón et al, 2018;Oknińska et al, 2021). In addition, the histopathological results support functional and organ hypertrophic changes in RV.…”

Right Ventricle Remodelling in Left-Sided Heart Failure in Rats: The Role of Calcium Signalling

“…It is accompanied by RV failure, as evidenced by reduced RV contractility, RV dilation and ventricular–arterial uncoupling due to both increased Ea (caused by increased PVR) and reduced contractility; however, the increase in RV Ea was quite mild (approx. 30%) as compared to that in the models of monocrotaline-induced pulmonary hypertension and pulmonary artery banding, where three–five-fold increases were found [ 26 , 27 ]. Model RV is able to generate much higher systolic pressures and typically initially goes through the phase of at least a temporary compensatory increase in contractility, decompensating when Ea is increased by many fold, at much higher afterloads.…”

Work and oxygen consumption of isolated right ventricular papillary muscle in experimental pulmonary hypertension

“…We exclude experimentally induced hypoxia during the efficiency determination as a cause of reduced work. However, myocyte hypoxia cannot be excluded in hypertrophied RV myocardium in vivo (Oknińska et al 2021). The positive correlation of work and efficiency may suggest that inotropic intervention improves both cardiac output and efficiency.…”

“…Oxidative metabolism can limit ATP production either by hypoxia (Oknińska et al 2021) or otherwise (Balestra et al 2015;Fowler et al 2019;Koop et al 2019). It has been demonstrated that hypoxia-inducible transcription factor (HIF)-1a is upregulated in hypertrophied right ventricular cardiomyocytes (des Tombe et al 2002;Simonides et al 2008;Sutendra et al 2013), complex I of the electron transport chain is inhibited (Wüst et al 2016) and complex II becomes a source of reactive oxygen species (Redout et al 2007).…”