Biomedical subjects

S Filippi

Publications and source records attributed to S Filippi.

At least 19 recordsLinked to original sources

PubMed2006

Heat transfer in Fitzhugh-Nagumo models.

An extended FitzHugh-Nagumo model coupled with dynamical heat transfer in tissue, as described by a bioheat equation, is derived and confronted with experiments. The main outcome of this analysis is that traveling pulses and spiral waves of electric activity produce temperature variations on the order of tens of mu degrees C. In particular, the model predicts that a spiral wave's tip, heating the surrounding medium as a consequence of the Joule effect, leads to characteristic hot spots. This process could possibly be used to have a direct visualization of the tip's position by using thermal detectors.

Action Potentials↗

PubMed2005

Viscoelastic Fitzhugh-Nagumo models.

An extended Fitzhugh-Nagumo model including linear viscoelasticity is derived in general and studied in detail in the one-dimensional case. The equations of the theory are numerically integrated in two situations: (i) a free insulated fiber activated by an initial Gaussian distribution of action potential, and (ii) a clamped fiber stimulated by two counter phased currents, located at both ends of the space domain. The former case accounts for a description of the physiological experiments on biological samples in which a fiber contracts because of the spread of action potential, and then relaxes. The latter case, instead, is introduced to extend recent models discussing a strongly electrically stimulated fiber so that nodal structures associated on quasistanding waves are produced. Results are qualitatively in agreement with physiological behavior of cardiac fibers. Modifications induced on the action potential of a standard Fitzhugh-Nagumo model appear to be very small even when strong external electric stimulations are activated. On the other hand, elastic backreaction is evident in the model.

Action Potentials↗

PubMed2005

Expression and functional activity of phosphodiesterase type 5 in human and rabbit vas deferens.

The molecular mechanisms underlying the regulation of vas deferens (VD) motility and semen emission are still poorly understood. We now report evidence on VD expression of phosphodiesterase type 5 (PDE5), which regulates nitric oxide (NO)-induced relaxation and cGMP breakdown in smooth muscle cells. In human VD, the PDE5 abundance was relatively high (>3 x 10(6) molecules/microg total RNA), although 10-fold lower than in corpora cavernosa (CC). Also cGMP metabolising activity was higher in CC than in VD. However, both tissues share the same sensitivity to a broad panel of cGMP-related PDE inhibitors: sildenafil, tadalafil, dipyridamole, zaprinast, vinpocetine, EHNA and cilostamide. Based on the rank order of potency of these PDE inhibitors, we found that the cGMP metabolizing activity in human VD mostly corresponds to PDE5. PDE5 was immunolocalized in all the muscular layers of human and rabbit VD and was found to be negatively involved in regulating NO-induced relaxation. In addition, by using a rabbit model of hypogonadotropic hypogonadism, we found that PDE5 gene expression and activity are androgen-dependent in VD, as previously demonstrated in CC. In fact, the sensitivity to a NO-donor (NCX4040), its enhancement by PDE5 inhibitors and the PDE5-related cGMP breakdown were all affected by androgen manipulation. Our results provide a hypothesis explaining the beneficial effects of PDE inhibitors in patients with rapid ejaculation.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2005

Peripheral regulatory mechanisms in erection.

The most important pathway underlying the penile erection is the nonadrenergic/noncholinergic signalling, which through the release of nitric oxide (NO), leads to an intracellular increase of cyclic GMP (cGMP), the main secondary messenger mediating tumescence in the penis. Interestingly, both cGMP formation and degradation are affected by testosterone (T). In fact, beyond the well-known role of T in regulating sexual desire and NO release, recent experimental evidences from our group showed that T also regulates the expression of phosphodiesterase type 5 (PDE5), the hydrolytic enzyme involved in cGMP breakdown. This antithetic role of T seems to be the main way through which the peripheral hormonal regulation of penile erections occurs, allowing an important synchronization between erectile processes and sexual desire. Hence, erections are still possible in hypogonadal conditions where a decreased cGMP formation, because of impaired NO production, is counterbalanced by a reduced cGMP hydrolysis. The purpose of this review is to describe evidences about the peripheral role of T in regulating penile erection and to justify the importance to test T plasma levels in those patients with erectile dysfunction who do not respond to PDE5 inhibitors.

Animals↗

PubMed2005

Identification, localization and functional in vitro and in vivo activity of oxytocin receptor in the rat penis.

We recently found that the oxytocin receptor (OTR) is expressed in the human and rabbit corpus cavernosum and mediates contractility in vitro. The present study extended our investigations to the rat, and explored whether OTR regulates penile detumescence in vivo. Real-time RT-PCR quantitatively characterized the distribution of OTR mRNA in the male genital tract. Specific transcripts for OTR were expressed in all the tissues investigated. Penile expression of OTR was comparable to that observed in testis and prostate. Western blot analysis detected a single band of the expected molecular mass for OTR in all tissues examined, including rat penis. Expression of OTR protein in rat penile extracts was further confirmed by binding studies, using the OTR selective radiolabeled ligand 125I-OTA (K(d) = 17 +/- 6.5 pM, B(max)=15.7 +/- 5 fmoles/mg protein). OTR was immunolocalized to the endothelial and smooth muscle compartments of cavernous spaces and blood vessels. In rat corpus cavernosum strips, oxytocin (OT) and an OTR selective agonist ([Thr4,Gly7]OT) induced identical increases in tension, while different vasopressin agonists were less active. In vivo, OT intra-cavernous injection (ICI) dose-dependently inhibited intracavernous pressure (ICP) increase elicited by either electrical stimulation of the cavernous nerve or ICI of papaverine with similar IC(50)s (117.7 +/- 37 mU). The OTR antagonist, atosiban, counteracted the contractile effect of OT both in vitro and in vivo. Atosiban alone significantly increased ICP at lower stimulation frequencies (2 Hz = P<0.001 and 4 Hz = P<0.05 vs control), but not at the maximal frequency (16 Hz). Our data showed that OTR is present in the rat penis and mediates contractility both in vitro and in vivo, therefore suggesting a role for OT in maintaining penile detumescence.

Animals↗

PubMed2005

Erectile dysfunction: molecular biology, pathophysiology and pharmacological treatment.

During the past decade, several progresses have been made for a deeper understanding of the regulatory factors that mediate normal erectile function, although the mechanisms involved in pathophysiology of erectile dysfunction (ED) remain to be completely elucidated. However, dramatic advances in the management of ED have occurred. Many drugs are now available, with oral pharmacotherapy representing the first-line option for most patients. ED is a common condition associated with aging but not necessarily a consequence of aging. The most important risk factors are associated to the impaired balance between contractant and relaxant mechanisms of penile structures, resulting in arterial insufficiency and defect smooth muscle relaxation. The normal erectile function involves the synthesis of NO, the main neurotransmitter mediating erectile processes, and the subsequent accumulation of cyclic GMP (cGMP). The NO formation, and therefore the erection, is strictly controlled by the activity of NO synthase (NOS) isoenzymes, whereas cGMP degradation is specifically controlled by phosphodiesterase type 5 (PDE5), which promotes smooth muscle tone and terminates erection. The regulation of the activity of these 2 counteracting enzymes allows the penis to be contracted for the majority of the time. Androgens play a pivotal role in these mechanisms by regulating both NOS and PDE5 activity. This peripheral and antithetic role of androgens seems to regulate penile erections synchronizing erectile processes to sexual desire. Moreover, the androgen-dependent activity of PDE5 mirrors the unresponsiveness of certain patients with ED to PDE5 inhibitors (PDE5i), the most widely prescribed oral drugs. In fact, PDE5i cannot work if the target enzyme is lacking. This suggests the importance to test testosterone plasma levels in those patients with ED who do not respond to PDE5i. In conclusion, a better understanding of the pathogenic factors of ED will be useful to appropriately design pharmacotherapy and improve clinical management depending on the unique condition of each patient.

Administration, Oral↗

PubMed2005

Testosterone and sexual activity.

Male sexual activity is characterized by a synchronization of sexual desire arising in the brain and its transmission to the periphery, resulting in penile tumescence necessary for sexual intercourse. Testosterone (T) has been claimed for so long as a pivotal hormone in regulating male sexual function, acting both at central and peripheral level. We believe that T is indeed the main synchronizer of sexual activity regulating libido and enzymes as nitric oxide synthase (NOS) and phosphodiesterase type 5 (PDE5), which are crucial for the erectile process. In fact, NOS increases cyclic guanosine monophosphate (cGMP) levels, while PDE5 reduces it. Because T positively controls both the initiation and the end of the penile erection, its net effect on erection is null. In fact, penile erections are often present even without T. The main action of T is to timely adjust the erectile process as a function of sexual desire, therefore finalizing erections to sex.

Animals↗

PubMed2003

Antiangiogenic properties of selected ruthenium(III) complexes that are nitric oxide scavengers.

The nitric oxide synthase (NOS) pathway has been clearly demonstrated to regulate angiogenesis. Increased levels of NO correlate with tumour growth and spreading in different experimental and human cancers. Drugs interfering with the NOS pathway may be useful in angiogenesis-dependent tumours. The aim of this study was to pharmacologically characterise certain ruthenium-based compounds, namely NAMI-A, KP1339, and RuEDTA, as potential NO scavengers to be used as antiangiogenic/antitumour agents. NAMI-A, KP1339 and RuEDTA were able to bind tightly and inactivate free NO in solution. Formation of ruthenium-NO adducts was documented by electronic absorption, FT-IR spectroscopy and (1)H-NMR. Pretreatment of rabbit aorta rings with NAMI-A, KP1339 or RuEDTA reduced endothelium-dependent vasorelaxation elicited by acetylcholine. This effect was reversed by 8-Br-cGMP. The key steps of angiogenesis, endothelial cell proliferation and migration stimulated by vascular endothelial growth factor (VEGF) or NO donor drugs, were blocked by NAMI-A, KP1339 and RuEDTA, these compounds being devoid of any cytotoxic activity. When tested in vivo, NAMI-A inhibited angiogenesis induced by VEGF. It is likely that the antitumour properties previously observed for ruthenium-based NO scavengers, such as NAMI-A, are related to their NO-related antiangiogenic properties.

Angiogenesis Inhibitors↗

PubMed2003

Effects of NCX 4050, a new NO donor, in rabbit and human corpus cavernosum.

The effects of NCX 4050, a drug belonging to a new class of NO donors, was investigated in isolated preparations of human and rabbit corpus cavernosum (CC) and in human foetal corpora cavernosa (hfCC) smooth muscle cells. In strips of rabbit CC, NCX 4050 (0.001-100 microM) induced a concentration-dependent relaxation which was influenced neither by Nw-nitro-l-arginine-methyl-ester (l-NAME; 100 microm) nor by endothelium deprivation. The NCX 4050-induced relaxation was significantly reduced by the guanylate cyclase inhibitor 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 microm) and enhanced by a specific phosphodiesterase 5 inhibitor, sildenafil (300 nm). Moreover, NCX 4050 (0.01-1 microm), induced a concentration-dependent potentiation of the relaxant response induced by electrical field stimulation (EFS) in rabbit preparations pre-treated with guanethidine and indomethacin. The relaxant effect of NCX 4050 was similar to that obtained by increasing concentrations (0.001-100 microm) of sodium nitroprusside (SNP) in either rabbit or human preparations. To further investigate the activity of NCX 4050 on human corpora cavernosa, we exposed cultured hfCC smooth muscle cells to increasing concentrations of NCX 4050 and SNP. We found that both compounds dose-dependently reduced cell proliferation. The antiproliferative effect of all the concentration tested of NCX 4050 was completely blocked by ODQ (1 microm). These results suggest that in rabbit and human corpora cavernosa NCX 4050 acts by activating guanylate cyclase activity, induces smooth muscle relaxation and quiescence. Our results provide a rationale for a possible future use of NCX 4050 in the pharmacotherapy of erectile dysfunction linked to an impaired release of NO from the endothelium.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2003

Effects of hypoxia on endothelin-1 sensitivity in the corpus cavernosum.

The penis remains in a hypo-oxygenated, flaccid state for a large majority of the time. In this study, we investigated the effect of changing oxygen tension on the expression and functional activity of endothelin-1 (ET-1) receptors in the penis. Experiments were performed in rabbit and human corpora cavernosa (CC) as well as in human fetal penile tissue and cell cultures [human fetal penile endothelial cells (hfPECs) and human fetal smooth muscle cells (hfPSMCs)]. Endothelin A (ETA) receptors are expressed by both endothelial and muscular cells in all tissues investigated. Only penile endothelial cells express endothelin B (ETB) receptors, which are further turned on during experimental hypoxia. In addition, hypoxia also allows ETB expression in the muscular compartment without affecting ETA expression. This hypoxia-induced over-expression of ETB decreased the contractile activity of ET-1 and increased ETB-mediated relaxation. The latter was essentially related to increased ETB-mediated nitric oxide formation in hfPEC and even in hfPSMC. Hypoxia also induced a time-dependent down-regulation of RhoA and Rho kinase (ROK) expression which, in turn, participated in the decreased contractile activity of ET-1 in the hypoxic penile tissue. Accordingly, during hypoxia, an ROK inhibitor, Y27632, was less effective in relaxing ET-1-precontracted strips. In conclusion, prolonged (24 h) hypoxia stimulated several counter-regulatory mechanisms in penile tissue, including up-regulation of ETB and down-regulation of RhoA/ROK pathways, which may help to preserve CC hypo-oxygenation, allowing smooth muscle relaxation and, most probably, penile erection.

Animals↗

PubMed2003

Role of oxytocin in the ejaculatory process.

Oxytocin (OT) is a neurohypophysial hormone with overall unclear physiological functions in the male. Several studies indicated that OT has a key role in the central regulation of penile erection. In this mini-review we summarize its possible involvement in another aspect of the male sexuality: the ejaculatory process. Because OT is released by posterior pituitary at the time of orgasm, we postulate that OT might help sperm progression during ejaculation. Our recent studies indicate that OT receptors (OTR) are present in rabbit and human epididymis and mediate contractility. Accordingly, they are immuno-localized in the smooth muscle cells of the epididymis. However, they are also present in the epithelial compartment of the tubules. In epididymal epithelial cells in culture, OT induces the release of another potent stimulator of epididymal contractility, endothelin-1 (ET-1), which most probably amplifies OT-induced contraction. Sex steroids regulate the density of OTR in epididymis. In fact, in an experimental model of hypogonadotropic hypogonadism (hypo) induced in rabbits, estrogens, but not androgens, fully restored OT-induced epididymal contractility, up-regulating OTR gene and protein expression. In addition, deprivation of endogenous estrogens, by blocking their formation using the aromatase inhibitor letrozole, induced OT hypo-responsiveness comparable to that observed in hypo rabbits. These findings suggest a new function of estrogens in the male: regulation of OT responsiveness in epididymis.

Animals↗

PubMed2002

Identification, localization and functional activity of oxytocin receptors in epididymis.

Oxytocin (OT) is a neurohypophysial hormone with unclear physiological functions in the male. Several previous studies indicated that OT might have a role in the ejaculatory process, stimulating sperm release from the epididymal storage. In this study we investigated on the presence and function of OT receptor (OTR) in rabbit and human epididymis. By using RT-PCR, Western and binding studies, we found that OTR gene and protein is expressed in the human epididymis and stimulates in vitro contractility. The immunolocalization of OTR suggests that the receptor is not only present in the smooth muscle cells of the human epididymis but also in the epithelial compartment. Experiments performed in rabbit epididymal epithelial (rEE) cells in culture indicate that OT induces the release of an other potent stimulator of epididymal contractility, endothelin-1 (ET-1), Blocking the ET(A) subtype of the ET-1 receptors, by using a specific antagonist (BQ-123), partially counteracts the contractile effect of OT, suggesting positive interactions between the two peptides in regulating epididymal contractility. Finally, to investigate whether an acute OT administration increases sperm release also in humans, we treated oligozoospermic patients with an intravenous bolus of OT (2.5 IU), just before sperm collection. In a small, single blind study, we found that OT almost doubled sperm retrieval when compared with vehicle administration. Our results indicate that OT might have physiological functions also in the male, controlling epididymal motility and sperm progression through the male genital tract.

Adult↗

PubMed2002

Endothelium-dependency of yohimbine-induced corpus cavernosum relaxation.

Development and maintenance of penile erection requires the relaxation of the smooth muscle cells in the cavernous bodies and is essentially mediated by nitric oxide (NO). The penile flaccid state is conversely maintained by the alpha adrenergic neuroeffector system and by other vasoconstrictors, such as endothelin-1 (ET-1). In this study we examined the mechanisms involved in yohimbine-induced relaxation in human and rabbit corpora cavernosa (CC). We essentially found that yohimbine not only blocks contractions induced by adrenergic agonists, but also by non-adrenergic substances, such as ET-1. This effect was unrelated to antagonism at the level of ET receptors, because yohimbine did not affect ET-1-induced increase in intracellular calcium in isolated CC cells. Conversely, our data suggest that yohimbine counteracts ET-1-induced contractions by interfering with NO release from the endothelium. In fact, yohimbine-induced CC relaxation was inhibited by the mechanical removing of the endothelium and by blocking NO formation or signalling via guanylate cyclase and cGMP formation. Conversely, yohimbine activity was strongly increased by inhibiting cGMP degradation. In an experimental model of hypogonadism, performed on rabbits by chronic treatment with a long-lasting GnRH agonist, the relaxant yohimbine activity was also decreased, but completely restored by androgen supplementation. This effect was evident only in preparations in which the main source of NO was present (endothelium) or in which NO formation was not impaired by L-NAME. Our data indicate that the relaxant effect of yohimbine is both endothelium and androgen-dependent. This might justify the lack of efficacy of this drug in treatment of some form of organic erectile dysfunction.

Adrenergic alpha-Agonists↗

PubMed2002

Expression and regulation of endothelin-1 and its receptors in human penile smooth muscle cells.

We report for the first time that penile smooth muscle cells (SMC) not only respond to, but also synthesize, endothelin-1 (ET-1), one of the main regulators of SMC activity. Immunohistochemical studies indicated that, beside endothelial cells (EC), SMC of the human adult and fetal penis also express ET-1 and its converting enzyme, ECE-1. Accordingly, cultures of adult penile stromal cells express these genes. We also prepared and characterized penile SMC from human fetuses. These cells express SMC specific markers such as alpha smooth muscle actin and phosphodiesterase type 5A3 along with hallmarks of androgen-dependent cells (androgen receptor and 5alpha reductase type 2). Human fetal penile SMC (hfPSMC) are immunopositive for ET-1 and release ET-1. ET-1 expression in hfPSMC was strongly increased by several factors such as transforming growth factor-beta1 (TGF-beta1), interleukin-1alpha (IL-1alpha), ET-1 itself and prolonged (24 h) hypoxia. This latter condition not only affected ET-1 expression but also responsiveness. While at normal oxygen tension, hfPSMC responded to ET-1 with a decreased proliferation mediated by the endothelin-A receptors and TGF-beta1; however, during hypoxia, ET-1 stimulated cell growth. Accordingly, prolonged hypoxia up-regulated endothelin-B receptor mRNA expression. In conclusion, our results indicate that in penile tissues SMC produce ET-1 and that such production is modulated by factors involved in penile physiology and tissue remodelling. In addition, the hfPSMC we have characterized might be a useful model for studying biochemical aspects of the human erectile process in vitro.

Aspartic Acid Endopeptidases↗

PubMed2001

alpha(1D)-adrenoceptors cause endothelium-dependent vasodilatation in the rat mesenteric vascular bed.

The vasodilator activity of alpha(1)-adrenoceptor agonists was tested in the rat mesenteric vascular bed (MVB), and the mechanism involved was investigated in cultured endothelial cells isolated from the bovine coronary vascular bed. In preparations preconstricted by U46619, noradrenaline and phenylephrine induced a slight relaxant effect at nanomolar concentrations. This effect was abolished in endothelium-denuded preparations and in preparations pretreated with 100 microM N(omega)-nitro-L-arginine methyl ester plus 3 microM indomethacin. Both the phospholipase C inhibitor U73122 and the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin inhibited the vasorelaxant effect of phenylephrine. The cellular level of inositol monophosphate (IP(1)) in bovine endothelial cells doubled after a 15-min exposure to 0.03 to 0.1 nM phenylephrine. The activity of cNOS was significantly increased following exposure to the same concentrations of phenylephrine. Both chloroethylclonidine and the selective alpha(1D)-adrenoceptor antagonist BMY 7378 reduced, in a concentration-dependent manner, the relaxant effect induced by phenylephrine, whereas the selective alpha(1A)-adrenoceptor antagonist (+)-niguldipine was ineffective. BMY 7378 also blocked the cNOS activation induced by phenylephrine. Conversely, the increase in perfusion pressure induced by micromolar concentrations of phenylephrine was blocked by 1 nM (+)-niguldipine, but was unaffected by BMY 7378. These findings demonstrate that nanomolar concentrations of phenylephrine, which are devoid of any contractile effect, induced a slight endothelium-dependent vasorelaxation in the rat MVB through the stimulation of alpha(1D)-adrenoceptors, located on endothelial cells, which act through phospholipase C stimulation, followed by IP(1) generation, and nitric-oxide synthase activation. Conversely, the increase in perfusion pressure induced by micromolar concentrations of phenylephrine is attributable to the stimulation of alpha(1A)-adrenoceptors.

Adrenergic alpha-1 Receptor Agonists↗

PubMed2000

Functional adenosine receptors in human corpora cavernosa.

We have demonstrated that adenosine has potent relaxant activity on the rabbit corpus cavernosum, acting through the A2a subtype receptor for adenosine. We now report studies on the identification and functional characterization of adenosine receptors in human penile vessels. To identify A2 receptors in human corpora cavernosa (HCC) we performed binding studies using the selective radioligand [125I]PAPA-APEC in membranes from HCC. We found the presence of a single class of high affinity (Kd= 0.23 +/- 0.06 nM), low capacity (Bmax=134 +/- 37 fmoles/mg protein) binding sites. Adenosine and CGS 21680 completely displaced [125I]PAPA-APEC binding (Kd= 146.7 +/- 64 microM and 51.52 +/- 27 nM, respectively). Accordingly, in functional studies adenosine relaxed phenylephrine precontracted HCC with an IC50=2.28 +/- 0.17 mM. The effect of adenosine was independent from nitric oxide (NO), and was counteracted by the A2 antagonist CGS 15943. In order to evaluate the in vivo effect of adenosine, increasing concentrations (6, 60, 600 microg) of adenosine or prostaglandin E1 (PGE1) (10 microg) were injected into the corpora cavernosa of four healthy volunteers. Blood flow and erectile response were evaluated at different times by duplex sonography and visual inspection, respectively. It was found that adenosine increased cavernosal peak blood flow velocity in a time- and dose-dependent manner. The highest concentrations of injected adenosine elicited a response that was not statistically different from that of PGE1 (10 microg). However, in contrast to PGE1, a full or partial erection was never obtained. To further investigate the lack of effect of adenosine on penile tumescence (despite the substantial increase in cavernosal blood flow), in vitro experiments were performed on human deep dorsal penile veins (DDPV) obtained from surgical ligation for impotence. Adenosine did not affect basal tone, but it induced almost complete relaxation in noradrenaline-precontracted vein strips with an IC50=1.6 +/- 0.22 mM. Conversely, PGE1 stimulated a sustained increase in basal tone. Therefore, the lack of effect of adenosine on penile tumescence could be due to a simultaneous relaxing activity on penile corpora cavernosa and veins. In conclusion, our study indicates that adenosine relaxes HCC as well as penile veins without affecting erection, at least at the concentrations we have used. Conversely, PGE1 relaxes corpora cavernosa as well as adenosine but strongly stimulates vein contraction, allowing penile tumescence.

Adenosine↗

PubMed2000

Erectile dysfunction: from biochemical pharmacology to advances in medical therapy.

Research on penile smooth muscle physiology has increased the number of drugs available for treating erectile dysfunction (ED). Penile erection involves the relaxation of smooth muscle in the corpus cavernosum. The key mediator of smooth muscle relaxation is nitric oxide (NO), which acts by increasing the cellular level of cGMP. Another cyclic nucleotide, cAMP, is involved in smooth muscle cell relaxation; cAMP formation is stimulated by a number of compounds, such as alprostadil. An increase in cAMP and/or cGMP levels can also be induced by inhibition of phosphodiesterases (PDEs), the enzymes involved in cyclic nucleotide breakdown. Both papaverine and sildenafil are PDE inhibitors. Papaverine is a non-specific inhibitor of these enzymes; sildenafil is an orally active, potent and selective inhibitor of GMP-specific PDE5, the predominant isoenzyme metabolizing cGMP in the cells of the corpus cavernosum. Penile smooth muscle contraction, induced by adrenergic fibers through alpha(1) adrenoceptors, produces detumescence, thus making alpha adrenoceptor antagonists suitable for maintenance of penile erection. The orally active drug yohimbine is a mixed alpha(1)-alpha(2) adrenoceptor antagonist that works by a dual mechanism; it facilitates sexual arousal by acting on alpha(2) adrenoceptors in the central nervous system and blocks adrenergic influences at peripheral level.

Adrenergic alpha-Antagonists↗

PubMed2000

Inositol phosphate metabolism and nitric-oxide synthase activity in endothelial cells are involved in the vasorelaxant activity of nebivolol.

Nebivolol is a recently developed beta-blocker provided with vasodilator properties. Because the mechanism of the putative endothelium-dependent effect of this beta-adrenoceptor blocker has not been completely elucidated, the aim of this study was to investigate the effects of nebivolol on an isolated resistance vascular bed and on cell messengers and constitutive nitric-oxide synthase activity (cNOS) in endothelial cells. Experiments were carried out using the rat mesenteric vascular bed and cultured bovine coronary postcapillary venular endothelial cells from bovine heart (CVEC). In mesenteric vascular bed preconstricted by 30 microM noradrenaline and 0.3 microM U46619, dl-nebivolol induced a concentration-dependent relaxing effect at concentrations between 3 and 30 microM; this effect was changed to a concentration-dependent vasoconstrictor response either in endothelium-denuded preparations or in intact preparations pretreated with 100 microM N(omega)-nitro-L-arginine methyl ester plus 3 microM indomethacin. The vasorelaxant effect of dl-nebivolol in preconstricted preparations was completely blocked by pretreatment either with the phospholipase C inhibitor U73122 (1 microM) or with the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin (1 microM) for 30 min. The cellular level of the inositol trisphosphate metabolite inositol monophosphate in coronary postcapillary venular endothelial cells was not affected by dl-nebivolol in the concentration range 100 nM to 1 microM, but it was concentration dependently increased after exposure for 15 min to 10 and 30 microM dl-nebivolol. The activity of cNOS was almost doubled after a 5-min exposure to 10 microM dl-nebivolol and was significantly impaired by thapsigargin and N(omega)-nitro-L-arginine methyl ester treatment, although it was unaffected by N(omega)-nitro-D-arginine methyl ester. These findings demonstrate that nebivolol, in micromolar concentrations, induces vasorelaxation through activation of inositol phosphate metabolism and stimulation of cNOS activity in endothelial cells.

Animals↗