Selective Phosphodiesterase 1 Inhibitor BTTQ Reduces Blood Pressure in Spontaneously Hypertensive and Dahl Salt Sensitive Rats: Role of Peripheral Vasodilation.

Autor:	Dey AB; Eli Lilly and Company, Indianapolis, IN, United States., Khedr S; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, United States.; Department of Physiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt., Bean J; Eli Lilly and Company, Indianapolis, IN, United States., Porras LL; Eli Lilly and Company, Indianapolis, IN, United States., Meredith TD; Eli Lilly and Company, Indianapolis, IN, United States., Willard FS; Eli Lilly and Company, Indianapolis, IN, United States., Hass JV; Eli Lilly and Company, Indianapolis, IN, United States., Zhou X; Eli Lilly and Company, Indianapolis, IN, United States., Terashvili M; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, United States., Jesudason CD; Eli Lilly and Company, Indianapolis, IN, United States., Ruley KM; Eli Lilly and Company, Indianapolis, IN, United States., Wiley MR; Eli Lilly and Company, Indianapolis, IN, United States., Kowala M; Eli Lilly and Company, Indianapolis, IN, United States., Atkinson SJ; Department of Biology, Indiana University - Purdue University Indianapolis, Indianapolis, IN, United States., Staruschenko A; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, United States.; Clement J. Zablocki VA Medical Center, Milwaukee, WI, United States., Rekhter MD; Eli Lilly and Company, Indianapolis, IN, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in physiology [Front Physiol] 2020 Sep 08; Vol. 11, pp. 543727. Date of Electronic Publication: 2020 Sep 08 (Print Publication: 2020).
DOI:	10.3389/fphys.2020.543727
Abstrakt:	Regulation of the peripheral vascular resistance via modulating the vessel diameter has been considered as a main determinant of the arterial blood pressure. Phosphodiesterase enzymes (PDE1-11) hydrolyse cyclic nucleotides, which are key players controlling the vessel diameter and, thus, peripheral resistance. Here, we have tested and reported the effects of a novel selective PDE1 inhibitor (BTTQ) on the cardiovascular system. Normal Sprague Dawley, spontaneously hypertensive (SHR), and Dahl salt-sensitive rats were used to test in vivo the efficacy of the compound. Phosphodiesterase radiometric enzyme assay revealed that BTTQ inhibited all three isoforms of PDE1 in nanomolar concentration, while micromolar concentrations were needed to induce effective inhibition for other PDEs. The myography study conducted on mesenteric arteries revealed a potent vasodilatory effect of the drug, which was confirmed in vivo by an increase in the blood flow in the rat ear arteriols reflected by the rise in the temperature. Furthermore, BTTQ proved a high efficacy in lowering the blood pressure about 9, 36, and 24 mmHg in normal Sprague Dawley, SHR and, Dahl salt-sensitive rats, respectively, compared to the vehicle-treated group. Moreover, additional blood pressure lowering of about 22 mmHg could be achieved when BTTQ was administered on top of ACE inhibitor lisinopril, a current standard of care in the treatment of hypertension. Therefore, PDE1 inhibition induced efficient vasodilation that was accompanied by a significant reduction of blood pressure in different hypertensive rat models. Administration of BTTQ was also associated with increased heart rate in both models of hypertension as well as in the normotensive rats. Thus, PDE1 appears to be an attractive therapeutic target for the treatment of resistant hypertension, while tachycardia needs to be addressed by further compound structural optimization. (Copyright © 2020 Dey, Khedr, Bean, Porras, Meredith, Willard, Hass, Zhou, Terashvili, Jesudason, Ruley, Wiley, Kowala, Atkinson, Staruschenko and Rekhter.)
Databáze:	MEDLINE
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