Sildenafil and T-1032, phosphodiesterase type 5 inhibitors, showed a different vasorelaxant property in the isolated rat aorta

Mochida, Hideki; Inoue, Hirokazu; Takagi, Michino; Noto, Tsunehisa; Yano, Koji; Kikkawa, Kohei

doi:10.1016/s0014-2999(02)01339-0

Cited by 35 publications

(29 citation statements)

References 21 publications

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“…Sensitivity to UK-114542 was significantly higher in the uterine rings from pregnant versus non-pregnant horn with no difference in maximal effects in our study. In vascular smooth muscle, the relaxation induced by sildenafil, similar to UK-114542, at 10 -7 M or less were suggested to be attributable to their inhibitory effects on phosphodiesterase V in isolated tissues (28). Sildenafil at 10 -5 M or more caused further relaxation in the isolated rat aorta.…”

Section: Discussionmentioning

confidence: 87%

“…Sildenafil at 10 -5 M or more caused further relaxation in the isolated rat aorta. However, it is suggested that this relaxation was independent of the inhibition of phosphodiesterase V (28). On the other hand, the less sensitivity of uterine versus vascular smooth muscle to NO and differential selectivity of NO for inducing relaxation between vascular and non-vascular smooth muscle suggests the differential pharmacological properties of NO (2,29).…”

Section: Discussionmentioning

confidence: 99%

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Expression of iNOS mRNA and Inhibitory Effect of NO on Uterine Contractile Activity in Rats Are Determined by Local Rather Than Systemic Factors of Pregnancy

et al. 2004

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Abstract. Our purpose was to investigate whether the local or systemic factors of pregnancy are associated with inducible nitric oxide synthase (iNOS) mRNA expression and to determine the inhibitory effects of pharmacological agents that increase cGMP levels in rat myometrium. iNOS mRNA expression was determined in uterine tissues from nonpregnant rats and on day 17 of gestation in the pregnant and non-pregnant uterine horns by RT-PCR. In addition, uterine rings from the pregnant and non-pregnant uterine horns were placed in Krebs-Henseleit solution for isometric recordings of spontaneous contractions. Concentration-inhibition relationships to diethylamine / nitric oxide complex, 8-bromo-cGMP, and the selective phosphodiesterase V inhibitor were obtained. Compared to nonpregnant rats, expression of iNOS mRNA in myometrium increased during pregnancy, which was maximal on day 17, followed by a decrease on day 21 of gestation. Expression of iNOS mRNA at day 17 of gestation was greater in pregnant uterine horns than in nonpregnant ones. Maximal inhibition of phosphodiesterase V and increasing cGMP induced similar inhibition of spontaneous contractions in nonpregnant and pregnant uterine horns, while NO induced less inhibition in the former. The results suggest that the local pregnancy factor is needed for signal transduction from NO to soluble guanylate cyclase at a time when maximal expression of iNOS mRNA is evident.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Expression of iNOS mRNA and Inhibitory Effect of NO on Uterine Contractile Activity in Rats Are Determined by Local Rather Than Systemic Factors of Pregnancy

et al. 2004

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“…One such mechanism is the blockade of the calcium channels, which has been demonstrated for some other PDE-5 inhibitors. [15][16][17] Another possibility is an increased expression of endothelial NO synthase 18,19 or inhi- bition of superoxide formation, 20 although this latter effect is cGMP dependent.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Blood Pressure Lowering Effects of a New Long-Acting Inhibitor of Phosphodiesterase 5 in Patients With Mild to Moderate Hypertension

et al. 2009

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Abstract-Inhibition of phosphodiesterase 5 is an attractive candidate mechanism for blood pressure (BP) lowering. In this study, a novel long-acting phosphodiesterase 5 inhibitor, PF-00489791, was evaluated in 133 patients with mild to moderate hypertension, randomized into 1 of 4 groups: placebo, 4 mg, 10 mg, and 20 mg titrated after 14 days of dosing to 40 mg. Study medication was administered once daily for 28 days. Ambulatory BP monitoring was used. There was a statistically significant decrease (compared with placebo) in mean daytime systolic BP on day 28 at the 10 and 20/40 mg doses (by Ϸ5 and Ϸ7 mm Hg, respectively). Changes in mean daytime diastolic BP corresponded with those in systolic BP. The magnitude of BP lowering was greater on day 1 than on days 14 and 28, but the response was sustained between days 14 and 28. PF-00489791 also exerted BP lowering effects on mean 24-hour ambulatory BP. There was a dose-related increase in plasma cGMP concentration (statistically significant at the 20/40 mg dose). There was an increased incidence of headaches at the 10 and 20/40 mg doses (22% and 21%, respectively, compared with 12% with placebo) and an increased incidence of dyspepsia/gastroesophageal reflux disease and musculoskeletal adverse events at the 20/40 mg dose. In conclusion, PF-00489791 causes a clinically meaningful and sustained BP lowering in patients with hypertension. It is generally safe and well tolerated at the clinically efficacious doses. Key Words: hypertension Ⅲ phosphodiesterase 5 Ⅲ PDE-5 inhibition Ⅲ PF-00489791 Ⅲ ABPM Ⅲ cGMP Ⅲ blood pressure I nhibition of phosphodiesterase 5 (PDE-5) is an attractive candidate mechanism for blood pressure (BP) lowering. PDE-5 is an enzyme that, among several other tissues, is also expressed in human arterial and venous vascular smooth muscle (VSM) cells, 1,2 where it mediates the breakdown of cGMP by metabolizing it to inactive 5Ј-GMP. Elevated cGMP reduces levels of intracellular calcium and thereby produces relaxation of arterial VSM cells and hence a decrease in arterial vascular resistance. Thus, inhibition of PDE-5 should lead to an increase in intracellular cGMP, arterial and venous vasorelaxation, and a consequent reduction in systemic arterial BP. In the present study, we evaluated BP lowering effects of a novel long-acting PDE-5 inhibitor, PF-00489791, in patients with mild to moderate hypertension. Methods Study Subjects and Study DesignPatients were recruited and the study was conducted at 17 participating study centers in the United States. Written informed consent was obtained from each study participant. The final protocol and informed consent documentation were reviewed and approved by the institutional review board at each of the investigational centers. The study was registered on ClinicalTrials.gov.Study subjects included males and females of nonchildbearing potential, between the ages of 18 and 70 years, who had a history of mild to moderate hypertension that was currently controlled with antihypertensive medication, or, if untreated, ...

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“…In isolated aorta and mesenteric and coronary arteries, sildenafil increases cGMP levels and induces vasorelaxation in the absence of exogenous NO, probably because of the amplification of a preexisting NO/cGMP system in these vessels (Buvinic and Huidobro-Toro, 2001;Mochida et al, 2002;Sakuma et al, 2002). Therefore, PDE5 inhibitors have become a focal point in the search for novel vasodilators for clinical use.…”

mentioning

confidence: 99%

Differential Effects of the Phosphodiesterase Type 5 Inhibitors Sildenafil, Vardenafil, and Tadalafil in Rat Aorta

Teixeira¹,

Priviero²,

Webb³

2005

J Pharmacol Exp Ther

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Presumably, the vasorelaxant properties of phosphodiesterase type 5 (PDE5) inhibitors are similar in isolated blood vessels. We aimed to explore the mechanisms underlying the vasorelaxation induced by the selective PDE5 inhibitors sildenafil, vardenafil, and tadalafil in the rat aorta. Aortic rings were mounted in 5-ml organ baths, and concentration-response curves for PDE5 inhibitors (0.0001-10 M) were constructed in phenylephrine (PE)-precontracted endothelium-intact and -denuded rings. Cyclic nucleotides were measured using enzyme immunoassay kits. Sildenafil, vardenafil, and tadalafil concentration dependently relaxed aortic rings and increased cGMP, but not cAMP, concentrations. Endothelium denudation caused marked rightward shifts in the curves to sildenafil (45-fold), tadalafil (21-fold), and vardenafil (251-fold). Maximal responses to sildenafil and tadalafil were substantially reduced (38 Ϯ 1% and 53 Ϯ 2%, respectively), whereas that evoked by vardenafil was not affected. Likewise, inhibition of NO synthase (N -nitro-Larginine methyl ester, 100 M), guanylyl cyclase (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxalin-1-one, 10 M), or scavenging of NO ([carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide), 100 M]) caused similar attenuation of the vasorelaxations evoked by PDE5 inhibitors. Sildenafil, tadalafil, and vardenafil significantly potentiated relaxations mediated by glyceryl trinitrate (0.0001-3 M; 8 -13-fold) and atrial natriuretic peptide (0.1-100 nM; 2-3-fold). Contractions evoked by CaCl 2 (0.01-5 mM) in PE-treated rings were significantly reduced (26 Ϯ 4%) by vardenafil, but not sildenafil or tadalafil, whereas phorbol 12,13-dibutyrate-induced contractions were not affected. Ouabain, cyclopiazonic acid, and calyculin A failed to affect vasorelaxations induced by the PDE5 inhibitors. These results suggest that vardenafil, but not sildenafil or tadalafil, affects Ca 2ϩ handling in the rat aorta in addition to increasing cGMP levels through inhibition of PDE5 to cause relaxation.

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Sildenafil and T-1032, phosphodiesterase type 5 inhibitors, showed a different vasorelaxant property in the isolated rat aorta

Cited by 35 publications

References 21 publications

Expression of iNOS mRNA and Inhibitory Effect of NO on Uterine Contractile Activity in Rats Are Determined by Local Rather Than Systemic Factors of Pregnancy

Expression of iNOS mRNA and Inhibitory Effect of NO on Uterine Contractile Activity in Rats Are Determined by Local Rather Than Systemic Factors of Pregnancy

Blood Pressure Lowering Effects of a New Long-Acting Inhibitor of Phosphodiesterase 5 in Patients With Mild to Moderate Hypertension

Differential Effects of the Phosphodiesterase Type 5 Inhibitors Sildenafil, Vardenafil, and Tadalafil in Rat Aorta

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