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

Asim B Dey; Sherif Khedr; James Bean; Leah L Porras; Tamika D Meredith; Francis S Willard; Joseph V Hass; Xin Zhou; Maia Terashvili; Cynthia D Jesudason; Kevin M Ruley; Michael R Wiley; Mark Kowala; Simon J Atkinson; Alexander Staruschenko; Mark D Rekhter

doi:10.3389/fphys.2020.543727

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

Front Physiol. 2020 Sep 8:11:543727. doi: 10.3389/fphys.2020.543727. eCollection 2020.

Authors

Asim B Dey¹, Sherif Khedr^{2

3}, James Bean¹, Leah L Porras¹, Tamika D Meredith¹, Francis S Willard¹, Joseph V Hass¹, Xin Zhou¹, Maia Terashvili², Cynthia D Jesudason¹, Kevin M Ruley¹, Michael R Wiley¹, Mark Kowala¹, Simon J Atkinson⁴, Alexander Staruschenko^{2

5}, Mark D Rekhter¹

Affiliations

¹ Eli Lilly and Company, Indianapolis, IN, United States.
² Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, United States.
³ Department of Physiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
⁴ Department of Biology, Indiana University - Purdue University Indianapolis, Indianapolis, IN, United States.
⁵ Clement J. Zablocki VA Medical Center, Milwaukee, WI, United States.

Abstract

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.

Keywords: Dahl salt sensitive rat; arterial hypertension; phosphodiesterase 1; spontaneously hypertensive rat; vasodilation.

Abstract

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