Activators of hypoxia inducible factors (HIFs), such as roxadustat, are promising agents for anemia treatment. However, since HIFs are also involved in the regulation of the pulmonary circulation, we hypothesized that roxadustat increases pulmonary vascular resistance and vasoconstrictor reactivity. Using isolated, cell-free solution perfused rat lungs, we found perfusion pressure-flow curves to be shifted to higher pressures by 2 weeks of roxadustat treatment (10 mg/kg every other day), although not as much as by chronic hypoxic exposure. Vasoconstrictor reactivity to angiotensin II and acute hypoxic challenges was not altered by roxadustat. Since roxadustat may inhibit angiotensin-converting enzyme 2 (ACE2), we also tested a purported ACE2 activator, diminazene aceturate (DIZE, 0.1 mM). It produced paradoxical, unexplained pulmonary vasoconstriction. We conclude that the risk of serious pulmonary hypertension is not high when roxadustat is given for 14 days, but monitoring is advisable.

• MeSH
• Angiotensin-Converting Enzyme 2 * MeSH
• Vascular Resistance MeSH
• Hypoxia chemically induced   MeSH
• Rats MeSH
• Vasoconstrictor Agents * pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Angiotensin-Converting Enzyme 2 * MeSH
• Vasoconstrictor Agents * MeSH

Cardiac atrophy is the most common complication of prolonged application of the left ventricle (LV) assist device (LVAD) in patients with advanced heart failure (HF). Our aim was to evaluate the course of unloading-induced cardiac atrophy in rats with failing hearts, and to examine if increased isovolumic loading obtained by intraventricular implantation of an especially designed spring expander would attenuate this process. Heterotopic abdominal heart transplantation (HTx) was used as a rat model of heart unloading. HF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). The degree of cardiac atrophy was assessed as the weight ratio of the heterotopically transplanted heart (HW) to the control heart. Isovolumic loading was increased by intraventricular implantation of a stainless steel three-branch spring expander. The course of cardiac atrophy was evaluated on days 7, 14, 21, and 28 after HTx Seven days unloading by HTx in failing hearts sufficed to substantially decrease the HW (-59 ± 3%), the decrease progressed when measured on days 14, 21, and 28 after HTx Implantation of the spring expander significantly reduced the decreases in whole HW at all the time points (-39 ± 3 compared with -59 ± 3, -52 ± 2 compared with -69 ± 3, -51 ± 2 compared with -71 ± 2, and -44 ± 2 compared with -71 ± 3%, respectively; P<0.05 in each case). We conclude that the enhanced isovolumic heart loading obtained by implantation of the spring expander attenuates the development of unloading-induced cardiac atrophy in the failing rat heart.

• Keywords
• Cardiac atrophy, heart failure, heterotopic heart transplantation, mechanical heart unloading, spring expander,
• MeSH
• Aorta surgery   MeSH
• Atrial Natriuretic Factor genetics   metabolism   MeSH
• Atrophy metabolism   physiopathology   prevention & control   surgery   MeSH
• Biomarkers metabolism   MeSH
• Equipment Design MeSH
• Implants, Experimental MeSH
• Gene Expression MeSH
• Fibroblast Growth Factor 2 genetics   metabolism   MeSH
• Transplantation, Heterotopic MeSH
• Rats MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Fistula MeSH
• Rats, Inbred Lew MeSH
• Glucose Transporter Type 1 genetics   metabolism   MeSH
• Sarcoplasmic Reticulum Calcium-Transporting ATPases genetics   metabolism   MeSH
• Heart physiopathology   MeSH
• Heart Ventricles physiopathology   surgery   MeSH
• Heart Failure metabolism   physiopathology   surgery   therapy   MeSH
• Tissue Expansion Devices * MeSH
• Heart Transplantation * MeSH
• Vena Cava, Superior surgery   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Atp2a1 protein, rat MeSH Browser
• Atrial Natriuretic Factor MeSH
• Biomarkers MeSH
• Fibroblast Growth Factor 2 MeSH
• Glucose Transporter Type 1 MeSH
• Sarcoplasmic Reticulum Calcium-Transporting ATPases MeSH
• Slc2a1 protein, rat MeSH Browser

OBJECTIVE: We evaluated the therapeutic effectiveness of a new, orally active epoxyeicosatrienoic acid analog (EET-A) in rats with angiotensin II (ANG II)-dependent malignant hypertension. METHODS: Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. EET-A treatment was started either simultaneously with I3C induction process (early treatment) or 10 days later during established hypertension (late treatment). Blood pressure (BP) (radiotelemetry), indices of renal and cardiac injury, and plasma and kidney levels of the components of the renin-angiotensin system (RAS) were determined. RESULTS: In I3C-induced hypertensive rats, early EET-A treatment attenuated BP increase (to 175 ± 3 versus 193 ± 4 mmHg, P < 0.05, on day 13), reduced albuminuria (15 ± 1 versus 28 ± 2 mg/24 h, P < 0.05), and cardiac hypertrophy as compared with untreated I3C-induced rats. This was associated with suppression of plasma and kidney ANG II levels (48 ± 6 versus 106 ± 9 and 122 ± 19 versus 346 ± 11 fmol ml or g, respectively, P < 0.05) and increases in plasma and kidney angiotensin (1-7) concentrations (84 ± 9 versus 37 ± 6 and 199 ± 12 versus 68 ± 9 fmol/ml or g, respectively, P < 0.05). Remarkably, late EET-A treatment did not lower BP or improve renal and cardiac injury; indices of RAS activity were not affected. CONCLUSION: The new, orally active EET-A attenuated the development of experimental ANG II-dependent malignant hypertension, likely via suppression of the hypertensiogenic axis and augmentation of the vasodilatory/natriuretic axis of RAS.

• MeSH
• Albuminuria drug therapy   MeSH
• Angiotensin I metabolism   MeSH
• Angiotensin II metabolism   MeSH
• Time Factors MeSH
• Cytochrome P-450 CYP1A1 genetics   MeSH
• Hypertension, Malignant chemically induced   physiopathology   prevention & control   MeSH
• Indoles MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• 8,11,14-Eicosatrienoic Acid analogs & derivatives   therapeutic use   MeSH
• Kidney metabolism   MeSH
• Peptide Fragments metabolism   MeSH
• Rats, Transgenic MeSH
• Renin-Angiotensin System drug effects   MeSH
• Renin genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• angiotensin I (1-7) MeSH Browser
• Angiotensin I MeSH
• Angiotensin II MeSH
• Cytochrome P-450 CYP1A1 MeSH
• indole-3-carbinol MeSH Browser
• Indoles MeSH
• 8,11,14-Eicosatrienoic Acid MeSH
• Peptide Fragments MeSH
• Ren2 protein, rat MeSH Browser
• Renin MeSH