β 3-Adrenergic Receptor Agonist Prevents Diastolic Dysfunction in an Angiotensin II-Induced Cardiomyopathy Mouse Model.

Abstract

β3-Adrenergic receptor expression is enhanced in the failing heart, but its functional effects are unclear. We tested the hypothesis that a β3-agonist improves left ventricular (LV) performance in heart failure. We examined the chronic effects of a β3-agonist in the angiotensin II (Ang II)-induced cardiomyopathy mouse model. C57BL/6J mice were treated with Ang II alone or Ang II + BRL 37344 (β3-agonist, BRL) for 4 weeks. Systolic blood pressure in conscious mice was significantly elevated in Ang II and Ang II + BRL mice compared with control mice. Heart rate was not different among the three groups. Systolic performance parameters that were measured by echocardiography and an LV catheter were similar among the groups. LV end-diastolic pressure and end-diastolic pressure-volume relationships were higher in Ang II mice compared with control mice. However, the increase in these parameters was prevented in Ang II + BRL mice, which suggested improvement in myocardial stiffness by BRL. Pathologic analysis showed that LV hypertrophy was induced in Ang II mice and failed to be prevented by BRL. However, increased collagen I/III synthesis, cardiac fibrosis, and lung congestion observed in Ang II mice were inhibited by BRL treatment. The cardioprotective benefits of BRL were associated with downregulation of transforming growth factor-β1 expression and phosphorylated-Smad2/3. Chronic infusion of a β3-agonist has a beneficial effect on LV diastolic function independent of blood pressure in the Ang II-induced cardiomyopathy mouse model. SIGNIFICANCE STATEMENT: Chronic infusion of a β3-adrenergic receptor agonist attenuates cardiac fibrosis and improves diastolic dysfunction independently of blood pressure in an angiotensin II-induced hypertensive mouse model. This drug might be an effective treatment of heart failure with preserved ejection fraction.

• Authors: Masataka Kamiya, Kuniya Asai, Yasuhiro Maejima, Akihiro Shirakabe, Koji Murai, Satsuki Noma, Hidenori Komiyama, Naoki Sato, Kyoichi Mizuno, Wataru Shimizu
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 376 Issue 3 Pg. 473-481 (03 2021) ISSN: 1521-0103 [Electronic] United States
• PMID: 33318077 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Adrenergic beta-3 Receptor Agonists
• Receptors, Adrenergic, beta-3
• Angiotensin II

Topics

• Adrenergic beta-3 Receptor Agonists (pharmacology)
• Angiotensin II (pharmacology)
• Animals
• Blood Pressure (drug effects)
• Cardiomyopathies (chemically induced, pathology, physiopathology)
• Diastole (drug effects)
• Disease Models, Animal
• Echocardiography
• Heart Rate (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Receptors, Adrenergic, beta-3 (metabolism)
• Ventricular Function, Left (drug effects)
• Ventricular Remodeling (drug effects)