Selective Phosphodiesterase 1 Inhibitor LY1 Reduces Blood Pressure in Spontaneously Hypertensive and Dahl Salt Sensitive Rats

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, aiming at achieving and maintaining a homeostatic balance between their production and destruction. On the contrary, pathological shift in the balance to words the destruction leads to depletion of the cyclic nucleotides and dysregulation of the blood pressure. Here, we have tested and reported the effects of a novel selective PDE1 inhibitor (LY1) on the cardiovascular system. In vitro experiments have been conducted to determine the IC50 of LY1 using phosphodiesterase radiometric enzyme assay. We used rat mesenteric artery to conduct myogrphy study to determine the effect of the drug on the vessel diameter. Also, short as well as long term telemetric studies were done on normal Sprague Dawley (SD), spontaneously hypertensive (SHR), and Dahl salt sensitive (SS) rats to document the in vivo efficacy of the compound. LY1 inhibited all three isoforms of PDE1 in nanomolar concentration (1.74 nM, 2.44 nM and 1.20 nM for PDE1A, PDE1B and PDE1C, respectively), while micromolar concentrations were needed to induce effective inhibition for other PDEs. The myography study revealed a potent vasodilatory effect of the drug, which was confirmed in vivo by an increase in the blood flow in the rat ear arteriole reflected by the rise in the temperature. LY1 proved a high efficacy in lowering the blood pressure in two animal models for hypertension i.e. SHR and SS rats. 3 mg/kg of LY1 twice daily through oral gavage could efficiently reduce the blood pressure in both SHR and SS rats approximately 40 mmHg compared to the untreated control group. Therefore, LY1 induced an efficient vasodilation that was accompanied by a significant reduction of blood pressure in different hypertensive rat models. Thus, PDE1 appears to be a tempting therapeutic target for treatment of resistant hypertension.