Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats.

Abstract

Pulmonary hypertension (PH) is a fatal disease, characterized by the progressive elevation of pulmonary arterial resistance. Although the causes of this disorder are complicated, abnormal vasoconstriction appears to be a primary factor in the development of PH. 1,2) Although some kinds of vasodilators, such as calcium blockers and prostacyclin, have been used in the treatment of PH, 3,4) they cause several side effects due to systemic vasodilation. Recent studies have demonstrated that nitric oxide inhalation produces selective pulmonary vasodilation without affecting systemic blood pressure in patients with PH. 5,6) However, since the safety of nitric oxide inhalation has not been established, 7) its doses have been restricted. Phosphodiesterases (PDEs) are enzymes, which break down cAMP and/or cGMP, and they play a key role in the regulation of intracellular cyclic nucleotide levels. A phosphodiesterase type 5 (PDE5) is classified as cGMP-bind, cGMP-specific phosphodiesterase. 8,9) PDE5 is abundantly expressed in some specific tissues, including the lung and pulmonary artery.10-12) Therefore, the inhibition of PDE5 is considered to produce an increase in cGMP levels in the lung and pulmonary artery. It has been reported that PDE5 inhibitors such as zaprinast, E-4021 and sildenafil preferably dilate the pulmonary artery in vivo and in vitro experimental conditions. [13][14][15][16][17][18] T-1032 (methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate) is a novel inhibitor of PDE5 (IC 50 ϭ0.001 mM; canine lung). The selectivity for PDE5 over other PDEs in T-1032 is similar to that of sildenafil (IC 50 : PDE1; 3 mM, PDE2; 9.7 mM, PDE3; Ͼ100 mM, PDE4; 3.3 mM).19) T-1032 shows potentiating effects on the nitric oxide/cGMP signaling pathway in isolated rat aorta and rabbit corpus cavernosum. 20) In addition, an intraduodenal administration of T-1032 potentiates the penile tumescence induced by pelvic nerve stimulation, probably through the blockade of PDE5 in anesthetized dogs.21) These results suggest that T-1032 potentiates a nitric oxide/cGMP pathway inhibitor and is orally active compound in animal studies.The acute hemodynamic effects by PDE5 inhibitors on pulmonary circulation have been examined in animal models with PH. 13,15,18) However, only a few studies have reported whether the chronic treatment is effective for improving cardiac remodeling and its related death in an animal model with PH. 22) In this study, we first examined the hemodynamic properties of T-1032 in MCT-induced PH rats, and we next evaluated the chronic effect of T-1032 on cardiac remodeling and its related death in MCT-induced PH rats. MATERIAL AND METHODSThis study was approved by the Animal Research Committee of Tanabe Seiyaku Co., Ltd.Animal Preparation Monocrotaline (MCT, 70 mg/kg) was subcutaneously administered in male Wistar rats weighing 94-107 g, as described previously. 23)Acute Hemodynamic Effects in MCT Rats Twenty-six days after MCT (70 mg/kg) or vehicle...

3-Hydroxy-3-Methylglutaryl-COA Reductase Inhibitors and Phosphodiesterase Type V Inhibitors Attenuate Right Ventricular Pressure and Remodeling in a Rat Model of Pulmonary Hypertension

“…In the present study, we also observed elevation of RVSP, development of RV remodeling, and an increase in lung weight 28 days after monocrotaline injection ( Figure 2 and Table 2). These changes were typical of the manifestations of pulmonary hypertension reported previously [27].…”

“…Typical tracings of right ventricular pressure in normal rats (Sham), monocrotaline-treated rats (Vehicle), and monocrotaline-treated rats subjected to repeated administration of atorvastatin (Atorva 0-28 ), simvastatin (Simva 0-28 and Simva [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] ) and pravastatin (Prava 0-28 ). Sham: water was administered orally from the time of saline injection to 24 h before measurement of right ventricular pressure.…”

A Cell-Based β-Lactamase Reporter Gene Assay for the CREB Signaling Pathway

“…The relatively high active rate (3.4%) is likely due to both the nature of the LOPAC library comprised of pharmacologically active compounds, and the nature of the assay, which detects compounds active against any molecular target in the CREB pathway. Among the 44 compounds, twelve were known PDE inhibitors, including papverine [22], trequinsin [23], Ro20-1724 [23–24], rolipram [23–24], zardaverine [24], diprydamole [23], IBMX, methoxymethyl-IBMX, etazolate [25], ibudilast [26], T-1032 [27], and propentofylline [28]. Inhibition of PDE leads to a decrease in the cAMP degradation, which enhances CREB signaling.…”