Original ArticleContrasting Effects of Inhibition of Phosphodiesterase 3 and 5 on Cardiac Function and Interstitial Fibrosis in Rats With Isoproterenol-Induced Cardiac DysfunctionNakata, Telma Mary DVM, PhD; Suzuki, Kazuhiko DVM, PhD; Uemura, Akiko DVM; Shimada, Kazumi DVM; Tanaka, Ryou DVM, PhDAuthor Information Faculty of Veterinary Medicine, Tokyo University of Agriculture and Technology (TUAT), Tokyo, Japan. Reprints: Telma Mary Nakata, DVM, PhD, Department of Veterinary Surgery, Tokyo University of Agriculture and Technology (TUAT), 3-8-1 Harumi-cho, Fuchu, Tokyo, 183-8538 Japan (e-mail: [email protected]). The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jcvp.org). Experimental ethics: All institutional and national guidelines for the care and use of laboratory animals were followed. Institutional Animal Care and Use Committee of the Tokyo University of Agriculture and Technology approval 28–71. Journal of Cardiovascular Pharmacology: March 2019 - Volume 73 - Issue 3 - p 195-205 doi: 10.1097/FJC.0000000000000652 Buy SDC Metrics Abstract Myocardial relaxation and stiffness are influenced by fibrillar collagen content. Cyclic nucleotide signaling regulators have been investigated targeting more effective modulation of collagen deposition during myocardial healing process. To assess the effects of phosphodiesterase type 3 and phosphodiesterase type 5 inhibitors on cardiac function and left ventricular myocardial fibrosis in catecholamine-induced myocardial injury, sildenafil and pimobendan were administered to male Wistar rats 24 hours after isoproterenol injection. Echocardiography and electrocardiogram were performed to assess kinetic and rhythm changes during 45 days of drug administration. At the end of study, type I and type III collagen were measured through immunohistochemistry analysis, and left ventricular pressure was assessed through invasive method. Echocardiography assessment showed increased relative wall thickness at 45 days in pimobendan group with significant diastolic dysfunction and increased collagen I deposition compared with nontreated positive group (3.03 ± 0.31 vs. 2.73 ± 0.28%, P < 0.05). Diastolic pressure correlated positively with type I collagen (r = 0.54, P < 0.05). Type III collagen analysis did not demonstrate difference among the groups. Sildenafil administration attenuated type I collagen deposition (2.15 ± 0.51 vs. positive group, P < 0.05) and suggested to be related to arrhythmic events. Arrhythmic events were not related to the quantity of fibrillar collagen deposition. Although negative modulation of collagen synthesis through cyclic nucleotides signaling have shown promising results, in this study, pimobendan postconditioning resulted in increased collagen type I formation and severe diastolic dysfunction while sildenafil postconditioning reduced collagen type I deposition and attenuated diastolic dysfunction. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.