title: Acute exposure to progesterone attenuates cardiac contraction by modifying myofilament calcium sensitivity in the female mouse heart.
abstract: Acute application of progesterone attenuates cardiac contraction, although the underlying mechanisms are unclear. We investigated whether progesterone modified contraction in isolated ventricular myocytes and identified the Ca2+handling mechanisms involved in female C57BL/6 mice (6-9 mo; sodium pentobarbital anesthesia). Cells were field-stimulated (4 Hz; 37°C) and exposed to progesterone (0.001-10.0 μM) or vehicle (35 min). Ca2+transients (fura-2) and cell shortening were recorded simultaneously. Maximal concentrations of progesterone inhibited peak contraction by 71.4% (IC50= 160 ± 50 nM; n = 12) and slowed relaxation by 75.4%. By contrast, progesterone had no effect on amplitudes or time courses of underlying Ca2+transients. Progesterone (1 µM) also abbreviated action potential duration. When the duration of depolarization was controlled by voltage-clamp, progesterone attenuated contraction and slowed relaxation but did not affect Ca2+currents, Ca2+transients, sarcoplasmic reticulum (SR) content, or fractional release of SR Ca2+Actomyosin MgATPase activity was assayed in myofilaments from hearts perfused with progesterone (1 μM) or vehicle (35 min). While maximal responses to Ca2+were not affected by progesterone, myofilament Ca2+sensitivity was reduced (EC50= 0.94 ± 0.01 µM for control, n = 7 vs. 1.13 ± 0.05 μM for progesterone, n = 6; P < 0.05) and progesterone increased phosphorylation of myosin binding protein C. The effects on contraction were inhibited by lonaprisan (progesterone receptor antagonist) and levosimendan (Ca2+sensitizer). Unlike results in females, progesterone had no effect on contraction or myofilament Ca2+sensitivity in age-matched male mice. These data indicate that progesterone reduces myofilament Ca2+sensitivity in female hearts, which may exacerbate manifestations of cardiovascular disease late in pregnancy when progesterone levels are high.
  We investigated myocardial effects of acute application of progesterone. In females, but not males, progesterone attenuates and slows cardiomyocyte contraction with no effect on calcium transients. Progesterone also reduces myofilament calcium sensitivity in female hearts. This may adversely affect heart function, especially when serum progesterone levels are high in pregnancy.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/acute-progesterone-modifies-cardiac-contraction/.
authors: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Hirad A
authors: HA
authors: Feridooni
authors: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Jennifer K
authors: JK
authors: MacDonald
authors: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Anjali
authors: A
authors: Ghimire
authors: Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada; and.
authors: W Glen
authors: WG
authors: Pyle
authors: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada; Susan.Howlett@dal.ca.|Department of Medicine (Geriatric Medicine), Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Susan E
authors: http://orcid.org/0000-0001-5351-6308
authors: SE
authors: Howlett
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D004963:Estrenes / Q000494:pharmacology; D005260:Female; D006352:Heart Ventricles / Q000166:cytology; D006835:Hydrazones / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009210:Myofibrils / Q000187:drug effects* / Q000378:metabolism; D009218:Myosins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011374:Progesterone / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000077464:Simendan; D000099163:Myosin Binding Protein C; D005466:Fluorocarbons
chemical_list: D002118:Calcium; D002316:Cardiotonic Agents; D002352:Carrier Proteins; D004963:Estrenes; D006835:Hydrazones; D009218:Myosins; D011374:Progesterone; D011372:Progestins; D011724:Pyridazines; D011980:Receptors, Progesterone; D000077464:Simendan; D000099163:Myosin Binding Protein C; C419162:lonaprisan; D005466:Fluorocarbons
keywords: excitation-contraction coupling; gender; sex differences; sex hormones