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

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.

Selective Phosphodiesterase 1 Inhibition Ameliorates Vascular Function, Reduces Inflammatory Response, and Lowers Blood Pressure in Aging Animals

“…The observed improvement in vascular function is independent of blood pressure-lowering effects, as we have previously shown that systolic and diastolic blood pressure lowering by the Ang II type 1 receptor antagonist losartan, did not improve vascular aging features in the Ercc1 Δ/model (Wu et al, 2017). Similar to our present study it was recently shown in hypertensive Dahl salt-sensitive rats on 4% NaCl chow that another selective PDE1 inhibiter (BTTQ) has an antihypertensive effect, both acutely as well as chronically (Dey et al, 2020). In these rats, a vasodilator response of isolated, preconstricted mesenteric arteries to BTTQ was observed in Dahl SS rats on 0.4 % NaCl.…”

“…It is highly expressed in the smooth muscle cell, and appears to contribute to the lack of vasodilation capacity in Ercc1 ∆/arteries, as demonstrated with the non-selective PDE inhibitor vinpocetine (Bautista et al, 2015). The potentially important role of PDE1 in vascular function and its correlation with several risk factors in cardiovascular diseases, including heart pressure-overload, hypertrophy, pulmonary arterial hypertension (PAH), and post-myocardial infarction, has been highlighted in several key studies (Fiona et al, 2007;Miller et al, 2009;Miller et al, 2011;Hashimoto et al, 2018;Dey et al, 2020).…”