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CARDIOVASCULAR
Department of Physiology, Medical College of Georgia, Augusta, Georgia (C.E.T., R.C.W.); and Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil (F.B.M.P.)
Received July 13, 2005; accepted October 3, 2005.
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Abstract |
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-nitro-L-arginine methyl ester, 100 µM), guanylyl cyclase (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxalin-1-one, 10 µM), or scavenging of NO ([carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide), 100 µM]) caused similar attenuation of the vasorelaxations evoked by PDE5 inhibitors. Sildenafil, tadalafil, and vardenafil significantly potentiated relaxations mediated by glyceryl trinitrate (0.0001-3 µM; 8-13-fold) and atrial natriuretic peptide (0.1-100 nM; 2-3-fold). Contractions evoked by CaCl2 (0.01-5 mM) in PE-treated rings were significantly reduced (26 ± 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 Ca2+ handling in the rat aorta in addition to increasing cGMP levels through inhibition of PDE5 to cause relaxation.
; Ignarro, 2002). The local production of NO by the endothelium regulates vascular tone through stimulation of soluble guanylyl cyclase (sGC), resulting in cGMP synthesis. The resultant increase in the intracellular concentration of cGMP activates cGMP-dependent protein kinases, which cause vasodilation via the modulation of Ca2+ channels as well as by decreasing the Ca2+ sensitivity of the vascular smooth muscle contractile proteins (Münzel et al., 2003). Intracellular cGMP is rapidly inactivated to GMP by the activity of cyclic nucleotide phosphodiesterases (PDEs; Maurice et al., 2003; Rybalkin et al., 2003). Therefore, cGMP concentration in smooth muscle cells is mainly dependent on the balance between the production by sGC and the breakdown by PDEs, which represent the unique degradation pathway for this second messenger (Maurice et al., 2003; Rybalkin et al., 2003).
Phosphodiesterase type 5 (PDE5) selectively degrades cGMP, but not cAMP; as a consequence, PDE5 activity is strongly implicated in the regulation of vascular tone; hence, the pharmacological modulation of PDE5 activity represents an effective means to achieve this control (Wallis et al., 1999; Maurice et al., 2003). The physiological importance of PDE5 has received considerable attention by the clinical use of the selective inhibitor sildenafil (Viagra) in the treatment of erectile dysfunction (Boolell et al., 1996; Rosen and Kostis, 2003; Montorsi et al., 2004). More recently, development of other drugs targeting PDE5 has been reported, and these include vardenafil (Levitra) and tadalafil (Cialis), which specifically inhibit PDE5 but differ in their inhibitory profiles toward other PDE families (Saenz de Tejada et al., 2001; Eardley and Cartledge, 2002).
It has been reported that sildenafil amplifies the vasorelaxation induced by NO donors in human vessels (Cremers et al., 2003) and causes dilation of epicardial coronary arteries when administered to patients with coronary artery disease (Halcox et al., 2002). 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. To the best of our knowledge, studies investigating the effects of vardenafil or tadalafil in blood vessels are still missing. Nevertheless, it is presumed that the vasorelaxing properties of vardenafil and tadalafil are similar to those of sildenafil in isolated arteries, despite the differences in their pharmacokinetic parameters (Sussman, 2004). Hence, the aim of the present study was to explore the mechanisms underlying the similarities and/or differences in the vascular responses of sildenafil, vardenafil, and tadalafil in the rat aorta. For this purpose, we sought to examine their effects on vascular cyclic nucleotide contents and determine the NO-dependent and -independent mechanisms accounting for vasorelaxation.
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Materials and Methods |
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Vasorelaxation Studies. After the equilibration period, aortic rings were challenged with 80 mM KCl (the same composition as Krebs' solution with NaCl replaced by equimolar KCl) to check tissue viability. Next, the endothelial integrity of the preparations or the absence of the endothelium was determined by verifying the responsiveness to acetylcholine (ACh, 1 µM) in vessels precontracted with PE (0.1-1 µM). Rings were then washed several times to restore tension to the baseline level.
In the first set of experiments, concentration-response curves (0.0001-10 µM) for sildenafil, vardenafil, or tadalafil were constructed in endothelium-intact or -denuded preparations in the absence or in the presence of N-nitro-L-arginine methyl ester (L-NAME) (100 µM), 1H-[1,2,4] oxadiazolo [4,3,-a]quinoxalin-1-one (ODQ) (10 µM), or carboxy-PTIO (100 µM). One concentration-response curve to sildenafil, vardenafil, or tadalafil was obtained in each segment. Hence, control rings (treated with the appropriated vehicles) were run in parallel with experimental rings. In the second set of experiments, following the construction of control concentration-response curves for glyceryl trinitrate (0.001-3 µM) or atrial natriuretic peptide (ANP, 0.1-100 nM), rings were washed several times, incubated with PDE5 inhibitor (0.1 µM), and then a second curve was generated. The third set of experiments was performed using nominally Ca2+-free medium (containing 0.1 mM EGTA to chelate trace Ca2+) and consisted of concentration-response curves to CaCl2 (0.01-5 mM) in PE (1 µM)-treated rings or phorbol 12,13-dibutyrate (PDBu; 0.001-1 µM) obtained in the absence or in the presence of sildenafil, vardenafil, or tadalafil (0.1-1 µM each). In the last set of experiments, curves to each PDE5 inhibitor were constructed in endothelium-denuded rings to investigate the effects of ouabain (10 µM), cyclopiazonic acid (CPA; 10 µM), or calyculin A (50 nM).
Aortic Cyclic Nucleotide Measurements. To determine the aortic cyclic nucleotide contents under experimental conditions, endothelium-intact or -denuded rings were equilibrated for 20 min in warmed and oxygenated Krebs' solution. Tissues were then stimulated for 10 min with a single concentration (0.1 µM) of sildenafil, vardenafil, tadalafil, glyceryl trinitrate (GTN), or forskolin, alone or in combination. Next, rings were collected immediately by freezing the segments in liquid nitrogen. Some tissues were frozen following addition of vehicle to obtain baseline readings. Frozen rings were pulverized, homogenized in trichloroacetic acid (5% w/v), and then centrifuged for 10 min at 4°C at 1500g. Trichloroacetic acid was extracted from the samples with three washes of water-saturated ether. The weights of the dried pellets were used to standardize the different samples. Preparation of tracer, samples, standards, and incubation with antibody were performed as described in commercially available kits (Cayman Chemical Cyclic GMP/Cyclic AMP EIA kit; Cayman Chemical, Ann Arbor, MI). The assays were performed in duplicate using different dilutions of samples.
Drugs and Chemicals. Sildenafil citrate was obtained from Pfizer, Inc. (New York, NY). Vardenafil (Levitra, tablets containing 10 mg of vardenafil) and tadalafil (Cialis, tablets containing 20 mg of tadalafil) were prepared from commercially available sources. Acetylcholine, atrial natriuretic peptide, calyculin A, carboxy-PTIO, cyclopiazonic acid, EGTA, nifedipine, L-NAME, ouabain, ODQ, phenylephrine, phorbol 12,13-dibutyrate, and trichloroacetic acid were purchased from Sigma-Aldrich (St. Louis, MO). Glyceryl trinitrate (nitroglycerin, 5 mg/ml glass vials) was acquired from American Regent Laboratories (Shirley, NY). The compound bisindolylmaleimide I was acquired from Calbiochem (San Diego, CA). All other reagents used were of analytical grade. Stock solutions were prepared in deionized water, except sildenafil, vardenafil, tadalafil, carboxy-PTIO, ODQ, CPA, calyculin A, and PDBu, which were prepared in dimethyl sulfoxide and stored in aliquots at -20°C; dilutions were made in deionized water immediately before use. Nifedipine was initially prepared as a stock solution in ethanol and stored in aliquots at -20°C; these were diluted in deionized water before use. The final concentration of dimethyl sulfoxide or ethanol did not exceed 0.1%. Preliminary experiments ascertained the lack of response to either vehicle in the concentrations employed.
Data Analysis. Experimental values of relaxation or contraction were calculated relative to the maximal changes from the contraction produced by phenylephrine and KCl, respectively, taken as 100% in each tissue. Data are shown as the percentage of relaxation of n experiments, expressed as the mean ± S.E.M. Two-way analysis of variance and Student's paired t test were employed to evaluate the results. p < 0.05 was considered to indicate significance. A program package was used for the statistical analysis of all data (GraphPad Instat, 1997, version 3.00; GraphPad Software Inc., San Diego, CA).
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Results |
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The selective PDE5 inhibitors sildenafil, vardenafil, and tadalafil (0.0001-10 µM) evoked sustained relaxations of endothelium-intact aortic rings in a concentration-dependent manner, with pEC50 values of 8.10 ± 0.04, 8.51 ± 0.06, and 8.01 ± 0.04, respectively, with vardenafil being significantly more potent than the other two inhibitors (p < 0.01; n = 14). In endothelium-denuded vessels, the relaxations induced by the PDE5 inhibitors were greatly attenuated, as evidenced by the marked rightward shifts of 49-, 257-, and 22-fold for sildenafil, vardenafil, and tadalafil, respectively (p < 0.01; n = 14). Comparison of the relaxant effects in intact or denuded preparations is given in Fig. 1. Interestingly, maximal responses to vardenafil were not affected by endothelium denudation, whereas those elicited by sildenafil (38 ± 1% inhibition) and tadalafil (58 ± 2% inhibition) were significantly reduced.
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Involvement of the NO/cGMP Pathway in PDE5 Inhibitor-Induced Relaxations. In endothelium-intact, but not -denuded rings, addition of the NO synthesis inhibitor L-NAME (100 µM; Fig. 2, n = 6) or the sGC inhibitor ODQ (10 µM; Fig. 3, n = 6) caused a further increase in tone (14 ± 2% and 19 ± 5%, respectively) induced by PE. At the concentrations employed, L-NAME or ODQ virtually abolished the endothelium-dependent relaxations mediated by ACh (0.001-10 µM; n = 6 each). Pretreatment of the tissues with L-NAME or ODQ caused marked rightward shifts in the curves to sildenafil, vardenafil, and tadalafil in endothelium-intact rings (p < 0.01). L-NAME and ODQ partially reduced the maximal relaxations to sildenafil (40 ± 2% and 46 ± 2%, respectively; p < 0.01) and tadalafil (59 ± 4% and 60 ± 3%, respectively; p < 0.01), without affecting those elicited by vardenafil (1 ± 1% and 3 ± 2%, respectively) in intact vessels. Neither L-NAME nor ODQ had any significant effect on the relaxant responses mediated by the PDE5 inhibitors in rubbed aortic segments.
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Effect of PDE5 Inhibitors on GTN- and ANP-Evoked Relaxations. The NO donor GTN (0.0001-3 µM) evoked concentration-dependent relaxations of endothelium-denuded arterial segments, which were fully blocked by ODQ (10 µM; n = 4). The relaxant responses induced by GTN were shifted approximately 8-, 13-, and 10-fold to the left by sildenafil (control, 7.44 ± 0.05; treated, 8.31 ± 0.08; p < 0.01), vardenafil (control, 7.43 ± 0.07; treated, 8.53 ± 0.09; p < 0.01), and tadalafil (control, 7.39 ± 0.06; treated, 8.38 ± 0.09; p < 0.01), respectively (0.1 µM; n = 4, each). The PDE5 inhibitors did not affect the maximal responses induced by GTN.
Addition of ANP (0.1-100 nM) relaxed endothelium-denuded aortic rings with a pEC50 value of 8.30 ± 0.09 and maximum response of 59 ± 2%. The PDE5 inhibitors enhanced the sensitivity to ANP by approximately 2-fold, and maximal relaxations elicited by this peptide were significantly potentiated by 61 ± 6%, 70 ± 12%, and 72 ± 10% in the presence of sildenafil, vardenafil, and tadalafil, respectively (n = 6).
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Effects of Ouabain, Cyclopiazonic Acid, and Calyculin A on Relaxations Induced by PDE5 Inhibitors. To further explore the mechanisms underlying the relaxations of endothelium-denuded rings induced by PDE5 inhibitors, we investigated the effects of the Na+/K+-ATPase inhibitor ouabain (10 µM), the sarco(endo)plasmic reticulum ATPase (SERCA) inhibitor CPA (10 µM), or the phosphatase inhibitor calyculin A (50 nM), alone or coincubated with ODQ (10 µM), on the curves for sildenafil (n = 5), vardenafil (n = 4), and tadalafil (n = 4). As summarized in Table 2, these treatments did not affect the relaxant responses evoked by the PDE5 inhibitors.
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Effects of PDE5 Inhibitors on Cyclic Nucleotide Levels. The basal cGMP and cAMP contents averaged 0.70 ± 0.21 and 5.89 ± 1.01 pmol/mg in endothelium-intact and 0.12 ± 0.04 and 5.05 ± 1.56 pmol/mg in denuded aortic rings, respectively (n = 4). In rings treated with sildenafil, vardenafil, or tadalafil (0.1 µM each), the cGMP levels were significantly increased above control values in both intact (9.0-, 11.7-, and 4.1-fold, respectively) and denuded (7.2-, 16.3-, and 3.8-fold, respectively) preparations (n = 4). Treatment with sildenafil, vardenafil, or tadalafil resulted in marked potentiation of GTN (0.1 µM)-induced increases in cGMP concentration (p < 0.01) in denuded vessels. The adenylyl cyclase activator forskolin (0.1 µM) significantly increased cAMP, but not cGMP, levels (p < 0.01). However, the PDE5 inhibitors had no effect on baseline cAMP concentrations in rat aortic rings (Fig. 6).
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Discussion |
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In precontracted aortic rings, the EC50 values obtained from concentration-response curves for sildenafil, tadalafil, and vardenafil averaged 8, 10, and 3 nM, respectively, indicating a higher potency of vardenafil versus the other two inhibitors. In a series of head-to-head assays measuring potency and binding strength, Blount et al. (2004) demonstrated that vardenafil has a higher potency along with a slower dissociation rate from PDE5 compared with sildenafil and tadalafil. Moreover, the higher biochemical potency of vardenafil over sildenafil is caused by differences within their core ring systems because the methyl/ethyl appended group on the piperazine moiety plays very little role in the difference in potency between sildenafil and vardenafil for inhibiting PDE5 (Blount et al., 2004; Corbin et al., 2004). Thus, the present results are in good agreement with the data reported using purified PDE5 (Blount et al., 2004). The longer lasting clinical effects of tadalafil might be related to different pharmacokinetic properties like slower absorption and/or degradation (Fazio and Brock, 2004).
The relaxations evoked by PDE5 inhibitors involve the NO/cGMP pathway because they were markedly reduced after endothelial cell removal as well as following inhibition of NO synthesis by L-NAME, inhibition of sGC by ODQ, or trapping of endothelium-derived NO by carboxy-PTIO. These results demonstrate that basal activity of sGC (probably driven by NO) in aortic smooth muscle produces cGMP concentrations sufficient to induce strong vasorelaxation when PDE5-dependent cGMP breakdown is reduced. These findings corroborate previous reports where vascular relaxation mediated by PDE5 inhibitors (e.g., sildenafil, zaprinast) was found to be related to the NO/cGMP signaling pathway in rat aorta (Mochida et al., 2002) and intrapulmonary arteries (Andersen et al., 2005), guinea pig basilar artery (Kruuse et al., 2001), or rabbit ductus arteriosus (Thébaud et al., 2002). However, our results are in striking contrast to previous reports showing that endothelium denudation is ineffective against sildenafil-induced relaxations in piglet (Moreno et al., 2004) and rat main pulmonary artery (Pauvert et al., 2003).
Although cardiovascular effects of PDE5 inhibitors are usually minor and associated with vasodilation, significant hypotension can occur in individuals who take organic nitrates because a considerable potential exists for synergistic interaction between PDE5 inhibitors and NO-donating drugs (Cheitlin et al., 1999). The biochemical basis for such an interaction rests on the fact that NO and PDE5 inhibitors operate through a common cGMP signaling pathway, where the former causes sustained stimulation of sGC and the latter produces a progressive cGMP accumulation. In the present investigation, sildenafil, vardenafil, and tadalafil significantly enhanced both endothelium-independent GTN-induced vasorelaxations and cGMP accumulation in a similar fashion, confirming a synergistic mechanism of action of the two classes of drugs. This is in accordance with in vitro studies of various vascular preparations (Sampson et al., 2001; Sakuma et al., 2002; Cremers et al., 2003; Moreno et al., 2004), studies in healthy subjects (Dishy et al., 2001), as well as clinical trials, where significant interactions of nitrates and PDE5 inhibitors were observed (Webb et al., 2000; Kloner et al., 2003). Synthesis of cGMP also occurs subsequent to activation of particulate guanylyl cyclase in response to natriuretic peptides, such as ANP (Lucas et al., 2000). Sildenafil, vardenafil, and tadalafil clearly potentiated ANP-induced relaxations of aortic rings, indicating that regardless of the source of cGMP, prevention of its hydrolysis by PDE5 inhibitors is efficacious in enhancing vasorelaxation.
Besides causing potent relaxations in isolated aorta, sildenafil, vardenafil, and tadalafil at the concentration of 0.1 µM caused marked increases in intracellular cGMP concentrations in both endothelium-intact and -denuded preparations, suggesting that sGC has a basal activity even in the absence of endogenous NO. Interestingly, higher concentrations of sildenafil, vardenafil, or tadalafil were still able to induce relaxation of endothelium-denuded aortic rings, even in the presence of ODQ, suggesting that either these inhibitors potentiate basal cGMP effects (Wedel et al., 1995), which are not affected by ODQ (Basini et al., 2000; Zhao et al., 2000), or else additional inhibitory effects of these agents are involved. It has been shown that sildenafil causes a gradual increase in cAMP levels (Chiu and Reid, 2002). However, the involvement of cAMP in the ODQ-resistant component of the vasorelaxation evoked by PDE5 inhibitors can be ruled out since sildenafil, vardenafil, or tadalafil failed to affect cAMP levels in the present study, supporting previous observations.
Ca2+ influx through L-type Ca2+ channels represents one of the major pathways to increase intracellular Ca2+ concentration, and blockade of Ca2+ entry causes vasorelaxation in precontracted vessels (Kuriyama et al., 1995). Hence, we sought to investigate the effects of PDE5 inhibitors on contractions induced by CaCl2 in Ca2+-free medium containing phenylephrine. At concentrations of 0.1 and 1 µM, sildenafil or tadalafil had no appreciable effects on CaCl2-induced contractions. Nevertheless, vardenafil concentration dependently shifted the curves for CaCl2 to the right along with significant reductions in maximal responses. At its highest concentration, vardenafil caused a shift almost twice as great as that to nifedipine. These findings suggest that, at least in the concentrations employed in this study, vardenafil, but not sildenafil or tadalafil, inhibits the external Ca2+ entry. This possibility is in agreement with previous work showing that sildenafil has affinity for binding sites at L-type Ca2+ channels (Mochida et al., 2002), although in that study, higher concentrations of sildenafil were used. In isolated pulmonary artery myocytes, sildenafil has been shown to antagonize ATP- and endothelin-1-induced Ca2+ oscillations at the nanomolar concentration range (Pauvert et al., 2003). Moreover, sildenafil was also demonstrated to normalize chronic hypoxia-induced increases in resting Ca2+ as well as to inhibit Ca2+ increases in response to G-coupled membrane receptor agonists, by a mechanism thought to involve acceleration of Ca2+ reuptake via SERCA (Pauvert et al., 2004). To test this hypothesis in the present investigation, we examined the effects of the SERCA inhibitor CPA on relaxations induced by the PDE5 inhibitors in endothelium-denuded aortic rings, in the absence or in the presence of ODQ. However, CPA failed to antagonize the vasorelaxations, thus excluding the possibility that PDE5 inhibitors stimulate SERCA to relax aortic rings.
In aortic smooth muscle, the sarcolemmal Na+-K+-ATPase is critical in the regulation of vascular tone and has been associated with both cGMP-dependent (Ferrer et al., 1999) and -independent (Gupta et al., 1994) vasodilation. Nonetheless, the Na+-K+-ATPase inhibitor ouabain had no significant effect on the NO-independent component of the relaxant responses evoked by sildenafil, vardenafil, and tadalafil. Because the sensitivity of the contractile elements to Ca2+ can also be affected by cGMP (Ungvari and Koller, 2001; Bolz et al., 2003), we also examined the effects of the phosphatase inhibitor calyculin A on the relaxant responses elicited by PDE5 inhibitors in denuded arteries, which were shown to be unaffected by this treatment. In addition, the PDE5 inhibitors did not affect the contractions to PDBu in Ca2+-free conditions, ruling out an interference with a protein kinase C-related pathway in their relaxant responses. Although this study only presents indirect evidence, it is possible that the more pronounced relaxant effect of vardenafil in endothelium-denuded aortic rings involves an impairment of Ca2+ release from the sarcoplasmic reticulum because vardenafil markedly inhibited phasic contractions to phenylephrine.
Collectively, the data reported herein show that sildenafil, vardenafil, and tadalafil increase cGMP and potently relax aortic rings through NO-dependent and -independent mechanisms. The latter component of the vasorelaxation induced by PDE5 inhibitors is likely to be comprised of an ODQ-resistant basal production of cGMP. In addition, vardenafil-induced relaxations involve blockade of Ca2+ entry and possibly inhibition of Ca2+ release from inositol 1,4,5-trisphosphate-sensitive intracellular stores. The present work provides important comparative information about the pharmacological profiles of the commercially available PDE5 inhibitors in vascular smooth muscle.
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Footnotes |
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ABBREVIATIONS: NO, nitric oxide; sGC, soluble guanylyl cyclase; PDE, phosphodiesterase; PDE5, phosphodiesterase type 5; ACh, acetylcholine; PE, phenylephrine; L-NAME, N-nitro-L-arginine methyl ester; ODQ, 1H-[1,2,4] oxadiazolo [4,3,-a]quinoxalin-1-one; ANP, atrial natriuretic peptide; PDBu, phorbol 12,13-dibutyrate; CPA, cyclopiazonic acid; carboxy-PTIO, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; GTN, glyceryl trinitrate; SERCA, sarco(endo)plasmic reticulum ATPase.
Address correspondence to: Dr. Cleber E. Teixeira, Department of Physiology, Medical College of Georgia, 1120 Fifteenth Street, CA-3101, Augusta, GA 30912-3000. E-mail: cteixeira{at}mail.mcg.edu
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