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.
Highlights
MATERIALS AND METHODSDespite the significant improvement in patient care, resistant arterial hypertension remains an unmet medical need (Carey et al, 2018)
Additional blood pressure (BP) lowering could be achieved when BTTQ was administered on top of ACE inhibitor lisinopril, a current standard of care in the treatment of hypertension
These anti-hypertensive effects are likely associated with vasodilatory properties of BTTQ that we have demonstrated in vitro, using isolated mesenteric arteries, and in vivo, using novel PK/PD model
Summary
Despite the significant improvement in patient care, resistant arterial hypertension remains an unmet medical need (Carey et al, 2018). Compounds at the appropriate concentration are pre-incubated with either of the PDE enzymes for 30 min before the reaction is started by the addition of substrate ([8-3H]-cAMP, 20.7 Ci/mmol or [8-3H]-cGMP; 6.5 Ci/mmol, Perkin Elmer). The resulting supernatant was separated on SDS-PAGE, transferred onto nitrocellulose membrane (Millipore, Bedford, MA, United States) and probed with PDE1 antibody (1:500, Thermoscintific Fisher, Invitrogen, Cat# PA5-87915), and subsequently visualized by enhanced chemiluminescence (Amersham Biosciences, Inc., Piscataway, NJ, United States) All data in this manuscript were presented as mean ± SEM with a significance level of p < 0.05, and n represents the number of individual animals. All telemetry data were analyzed with GraphPad Prism 8.3
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