Biomedical subjects

T J Bivalacqua

Publications and source records attributed to T J Bivalacqua.

At least 19 recordsLinked to original sources

PubMed2005

Gene and stem cell therapy for erectile dysfunction.

Erectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance. ED is a highly prevalent health problem with considerable impact on the quality of life of men and their partners. Although the treatment of ED with oral phosphodiesterase type V (PDE5) inhibitors is effective in a wide range of individuals, it is not efficacious in all patients. The failure of PDE5 inhibitors happens mainly in men with diabetes, non-nerve sparing radical prostatectomy, and high disease severity. Therefore, improved therapies based on a better understanding of the fundamental issues in erectile physiology and pathophysiology have recently been proposed. Here, we summarize studies on ED treatment using gene and stem cell therapies. Adenoviral-mediated intracavernosal transfer of therapeutic genes, such as endothelial nitric oxide synthase (eNOS), calcitonin gene-related peptide (CGRP), superoxide dismutase (SOD), and RhoA/Rho kinase and mesenchymal stem cell-based cell and gene therapy strategy for the treatment of age- and diabetes-related ED are the focus of this review.

Animals↗

PubMed2004

Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats.

Erectile dysfunction associated with diabetes mellitus is caused in part by disordered endothelial smooth muscle relaxation, neuropathy, and a decrease in cavernosal nitric oxide synthase (NOS) activity. The purpose of this study was to determine whether a combination of sildenafil and adenoviral gene transfer of endothelial NOS (eNOS) could enhance the erectile response in diabetic rats. Five groups of animals were utilized: (1) age-matched control rats, (2) streptozotocin (STZ)-induced diabetic rats (60 mg/kg i.p.), (3) STZ-rats + sildenafil (2 mg/kg i.v.), (4) STZ-rats transfected with AdCMVbetagal or AdCMVeNOS, and (5) STZ-rats transfected with AdCMVeNOS +sildenafil (2 mg/kg i.v.). At 2 months after i.p. injection of STZ, groups 4 and 5 were transfected with the adenoviruses and 1-2 days after transfection, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Cyclic 3',5'-guanosine monophosphate (cGMP) levels were assessed in the cavernosal tissue. STZ-diabetic rats had a significant decrease in erectile function as determined by the peak intracavernosal pressure (ICP) and total ICP (area under the erectile curve; AUC) after CNS when compared to control rats. STZ-diabetic rats+AdCMVeNOS had a peak ICP and AUC, which were similar to control animals. STZ-diabetic rats administered sildenafil demonstrated a significant increase in peak ICP at the 5 and 7.5 V settings, while the AUC was significantly increased at all voltage (V) settings. The increase in both ICP and AUC of STZ-diabetic rats transfected with AdCMVeNOS at all V settings was greater than STZ-diabetic rats transfected with AdCMVbetagal. STZ-diabetic rats transfected with AdCMVeNOS and administered sildenafil had a significant increase in total ICP that was greater than eNOS gene therapy alone. Cavernosal cGMP levels were significantly decreased in STZ-diabetic rats, but were increased after transfection with AdCMVeNOS to values greater than control animals. In conclusion, overexpression of eNOS and cGMP in combination with sildenafil significantly increased both the peak ICP and total ICP to CNS in the STZ-diabetic rat, which was similar to the response observed in control rats. Moreover, the total erectile response was greater in STZ-diabetic rats receiving eNOS gene therapy plus sildenafil than STZ-rats receiving sildenafil or eNOS gene therapy alone.

Adenoviridae↗

PubMed2004

Feline penile erection induced by topical glans penis application of combination alprostadil and SEPA (Topiglan).

The objective of this study was to evaluate the efficacy of topically applied prostaglandin E1 (PGE(1))+5% SEPA (soft enhancement of percutaneous absorption) on the glans penis in a feline erection model. Erectile response after glans penis administration of PGE(1)+5% SEPA cream (Topiglan, MacroChem Co., Lexington, MA, USA) was compared to the erectile response after intracavernosal administration of the triple-drug combination (1.65 mg papaverine, 25 microg phentolamine, and 0.5 microg PGE(1)). The placebo cream and increasing concentrations (0.25%, 2.5 mg/ml; 0.5%, 5 mg/ml; and 1%, 10 mg/ml) of PGE(1)+5% SEPA were applied in a total volume of 0.1 ml via a plastic needle-less syringe. The control triple-drug combination was administrated intracavernosally via a 30-gauge needle at the completion of each experiment to serve as a control reference. With each application of placebo, PGE(1)+SEPA, and the triple-drug combination, changes in intracavernosal pressure and systemic blood pressure were continuously monitored. Topical application of PGE(1)+SEPA induced increases in intracavernosal pressure in a dose-dependent manner, with minimal effects on systemic blood pressure. The increases obtained with 1% PGE(1) Topiglan cream were similar to the intracavernosal pressure values elicited by the standard intracavernosal triple-drug combination. These data demonstrate that topical glans penis application of PGE(1)+SEPA can induce an erectile response in cats with minimal systemic adverse effects. Oral pharmacological agents are the first-line treatment for male ED. Studies investigating the effectiveness of noninvasive modalities such as topical therapy should continue, because these agents have the potential to avoid the systemic effects commonly seen with oral therapies. Additionally, topical therapy may also benefit patients who are unresponsive to oral agents or have explicit contraindications. Topical PGE(1) application to the glans penis may become an important treatment option in selected patients suffering from erectile dysfunction.

Adjuvants, Pharmaceutic↗

PubMed2004

Peroxynitrite does not impair pulmonary and systemic vascular responses.

The effects of peroxynitrite (ONOO-) on vascular responses were investigated in the systemic and hindquarters vascular bed and in the isolated perfused rat lung. Intravenous injections of ONOO- decreased systemic arterial pressure, and injections of ONOO- into the hindquarters decreased perfusion pressure in a dose-related manner. Injections of ONOO- into the lung perfusion circuit increased pulmonary arterial perfusion pressure. Responses to ONOO- were rapid in onset, short in duration, and repeatable without exhibiting tachyphylaxis. Repeated injections of ONOO- did not alter systemic, hindquarters, or pulmonary responses to endothelium-dependent vasodilators or other vasoactive agonists and did not alter the hypoxic pulmonary vasoconstrictor response. Injections of sodium nitrate or nitrite or decomposed ONOO- had little effect on vascular pressures. Pulmonary and hindquarters responses to ONOO- were not altered by a cyclooxygenase inhibitor in a dose that attenuated responses to arachidonic acid. These results demonstrate that ONOO- has significant pulmonary vasoconstrictor, systemic vasodepressor, and vasodilator activity; that short-term repeated exposure does impair vascular responsiveness; and that responses to ONOO- are not dependent on cyclooxygenase product release.

Anesthesia↗

PubMed2003

Antimicrobial activity of antibiotic-soaked, Resist-coated Bioflex.

This study investigates whether a hydrophilic coating (Resist), designed to inhibit bacterial adherence, applied to inflatable penile prostheses can prolong the effect of intraoperative antibiotics. The activity of antibiotic-soaked Bioflex (penile prosthetic substrate material) discs with and without Resist was examined by measuring the zone of inhibition following in vivo exposure in four groups of rabbits: 1, 2, 3 and 5 days' duration of disc implantation. Coated and uncoated discs were soaked in an aqueous solution of gentamicin and bacitracin. The implanted antibiotic-soaked discs were extracted, and the zone of inhibition against four microorganisms in vitro demonstrated that the Resist coating was especially effective against Staphylococcus epidermidis, and statistically significant improvements were observed for the coated over the uncoated substrate up to 3 days following implantation. This effect, and the anti-adherence properties of Resist, may prevent adhesion and colonization of some microorganisms to penile implants and reduce chances for infection.

Animals↗

PubMed2003

Testicular-sparing surgery: a reasonable option in selected patients with testicular lesions.

OBJECTIVE: To describe our experience of inguinal exploration in patients who had a reasonable chance of having a benign testicular lesion. PATIENTS AND METHODS: From 1995 to 2002, 11 patients (mean age 43 years, range 27-63) with testicular masses that were suspected to be benign underwent inguinal exploration. RESULTS: In nine of the 11 patients, frozen-section analysis and the final pathological results were similar, and two underwent inguinal orchidectomy. In seven patients the testicle was spared. Finally, because of an uncertain pathological diagnosis and patient age, two patients underwent orchidectomy. CONCLUSIONS: Inguinal exploration and testicular-sparing surgery are reasonable options in patients with peripheral intratesticular lesions, on the basis of preoperative ultrasonographic characteristics, and if there is a possibility of the mass being benign because of age, race, physical examination and tumour markers.

Adult↗

PubMed2003

Comparison of cadaveric pericardial, dermal, vein, and synthetic grafts for tunica albuginea substitution using a rat model.

OBJECTIVE: To evaluate in an animal model the intermediate and long-term efficacy of cadaveric pericardium, dermis, vein and Gore-Tex per thousand as grafting materials for tunica albuginea substitution after plaque excision for Peyronie's disease. MATERIALS AND METHODS: The study comprised 100 male Sprague-Dawley rats (300-325 g) divided into five equal groups: group 1, sham-operated controls; and groups 2-5 which underwent wedge excision of the tunica albuginea and replacement with either cadaveric pericardium, dermis, vein or Gore-Tex grafts. Ten rats in each group had the cavernosal nerve stimulated electrically to assess erectile function at 4 months, and the remaining 10 rats at 6 months. After death the sampled tissues were fixed in 10% formalin, paraffin-embedded, and stained with Masson's trichrome and Verhoff's van Giesen for collagen and elastic fibres. RESULTS: Erectile function, assessed by cavernosal nerve stimulation, did not differ significantly in any of the groups (P > 0.05). The histological assessment of penile cross-sections showed minimal fibrosis surrounding the patch in the dermal and vein grafts, and moderate to severe fibrosis in the Gore-Tex graft at 4 and 6 months. In the pericardial graft there was a moderate degree of fibrosis at 4 months with only minimal fibrosis at 6 months. CONCLUSIONS: These results show that cadaveric pericardium allows complete penile expansion and is strong enough to withstand normal intracorporal pressures. There was minimal fibrosis in the pericardial, dermal and vein grafts, and moderate fibrosis in the Gore-Tex graft at 6 months. The pericardial graft is a satisfactory grafting material when used for tunica albuginea substitution, including the surgical management of Peyronie's disease.

Animals↗

PubMed2002

Implications of nitric oxide synthase isoforms in the pathophysiology of Peyronie's disease.

Peyronie's disease is an idiopathic, localized connective tissue disorder of the penis which involves the tunica albuginea of the corpus cavernosum and the adjacent areolar space. Peyronie's disease is characterized by local changes in the collagen and elastic fiber composition of the tunica albuginea. The formation of fibrotic plaques alters penile anatomy and can cause different degrees of bending and narrowing, as well as penile pain and erectile dysfunction. Though long recognized as an important clinical entity of the male genitalia, the etiology of this disease has remained poorly understood. Until recently there have been no studies to examine the role nitric oxide (NO) and nitric oxide synthase (NOS) isoforms may play in the onset and progression of Peyronie's disease. NO is a potent biological mediator with diverse physiological and pathophysiological roles. The purpose of this review is to describe each of the NOS isoforms and their potential roles in the pathophysiology of Peyronie's disease, with particular emphasis on the regulation of endothelial and inducible NOS isoforms.

Animals↗

PubMed2002

Localization of peripheral dopamine D1 and D2 receptors in rat corpus cavernosum.

OBJECTIVE: To detect and locate anatomically peripheral dopamine D1 and D2 receptors in rat cavernosa, as dopamine is important in sexual drive and penile erection through receptors located in the central nervous system. MATERIALS AND METHODS: Corpora cavernosa were obtained from Sprague-Dawley rats; total RNA and membrane proteins were extracted and cryostat sections prepared. The rat brain hypothalamus was used as a control for dopamine D1 and D2 receptors. The presence and expression of peripheral dopamine D1 and D2 receptor mRNAs in rat corpus cavernosa was assessed using reverse transcription and polymerase chain reaction (RT-PCR), and Northern blot hybridization using (32)P-UTP-labelled RNA probes. Concurrently, corresponding proteins from D1 and D2 receptors were assayed and detected by a Western blotting technique. The anatomical location of dopamine D1 and D2 receptor mRNAs in rat penile tissues was identified by in situ hybridization using (35)S-UTP-labelled RNA probes in cryostat sections. Immunohistochemical staining was used to locate peripheral dopamine D1 and D2 receptor proteins in rat corpora cavernosa. RESULTS: Dopamine D1 and D2 receptor gene expression was detected in rat corpora cavernosa. In situ hybridization signals for dopamine D1 and D2 receptor mRNAs were localized to corpus cavernosal tissues and dorsal vessels in the rat penis. Western blot analyses showed peripheral dopamine D1 and D2 receptor proteins in rat corpora cavernosa. Immunohistochemically, peripheral dopamine D1 and D2 receptor proteins were detected in dorsal nerves, dorsal vessels and corpus cavernosal smooth muscle of the rat penile tissues. CONCLUSIONS: Peripheral dopamine D1 and D2 receptors are present in the corpora cavernosa of rats. The functional significance of these receptors and signal transduction pathways in modulating the vascular tone of the penis warrants further investigation.

Animals↗

PubMed2002

Cardioprotection with sildenafil, a selective inhibitor of cyclic 3',5'-monophosphate-specific phosphodiesterase 5.

The effects of sildenafil (Viagra), a specific inhibitor of phosphodiesterase 5, on ischemic myocardium was examined using an isolated rat heart model. Rats were pretreated with sildenafil at doses ranging from 0.001 mg to 0.5 mg/kg body weight. After 60 min, isolated hearts were subjected to ischemia for 30 min followed by 2 h of reperfusion. The results demonstrated that at 0.05 mg/kg (and to some extent at 0.01 mg/kg), sildenafil provided significant cardioprotection as evidenced by improved ventricular recovery, a reduced incidence of ventricular fibrillation and decreased myocardial infarction. At higher doses, it caused a significant increase in the incidence of ventricular fibrillation while at very low doses it had no effect on cardiac function. As expected, sildenafil increased cyclic 3',5'-monophosphate (cGMP) content in the heart. The results demonstrate for the first time that within a narrow dose range, sildenafil can protect the heart from ischemia/reperfusion injury, probably through a cGMP-signaling pathway.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2001

Differential responses to ATPgammaS in the mesenteric and hindlimb vascular bed of the cat.

The mechanism by which the purinergic agonist adenosine 5'-O-(3 thiotriphosphate) (ATPgammaS) decreases vascular resistance was investigated in the mesenteric and hindlimb vascular beds of the cat. Injections of ATPgammaS into the hindlimb perfusion circuit elicited dose-dependent decreases in perfusion pressure while injections into the mesenteric circuit produced a biphasic response with an initial vasopressor response followed by a vasodepressor response. In the mesenteric vascular bed the pressor response to ATPgammaS was blocked by a P2X1 receptor antagonist. Also an inhibitor of nitric oxide synthase enhanced the vasoconstrictive responses to ATPgammaS. However, the vasodepressor response in the mesenteric bed was not altered by the adminstration of an alpha adrenergic receptor antagonist, a cyclooxygenase inhibitor, a P2Y1 receptor antagonist, or a K+ATP channel blocking agent. These data suggest that the vasopressor response to ATPgammaS in the mesenteric vascular bed of the cat is mediated via P2X1 receptor activation. The differential responses to ATPgammaS in the hindlimb and mesentery suggest differences in purinergic receptor distribution in the vascular system of the cat. In addition, the results suggest that prostaglandin synthesis, P2Y1 receptor activation, alpha receptor inhibition, and K+ATP channels activation play little to no role in mediating the vascular response to ATPgammaS in the mesentery of the cat.

Adamantane↗

PubMed2001

Increased expression of arginase II in human diabetic corpus cavernosum: in diabetic-associated erectile dysfunction.

Nitric oxide (NO) is the principal mediator of penile erection. NO is synthesized by nitric oxide synthase (NOS). It has been well documented that the major causative factor contributing to erectile dysfunction in diabetic patients is the reduction in the amount of NO synthesis in the corpora cavernosa of the penis resulting in alterations of normal penile homeostasis. Arginase is an enzyme that shares a common substrate with NOS, thus arginase may downregulate NO production by competing with NOS for this substrate, l-arginine. The purpose of the present study was to compare arginase gene expression, protein levels, and enzyme activity in diabetic human cavernosal tissue. When compared to normal human cavernosal tissue, diabetic corpus cavernosum from humans with erectile dysfunction had higher levels of arginase II protein, gene expression, and enzyme activity. In contrast, gene expression and protein levels of arginase I were not significantly different in diabetic cavernosal tissue when compared to control tissue. The reduced ability of diabetic tissue to convert l-arginine to l-citrulline via nitric oxide synthase was reversed by the selective inhibition of arginase by 2(S)-amino-6-boronohexanoic acid (ABH). These data suggest that the increased expression of arginase II in diabetic cavernosal tissue may contribute to the erectile dysfunction associated with this common disease process and may play a role in other manifestations of diabetic disease in which nitric oxide production is decreased.

Arginase↗

PubMed2001

Analysis of responses to hAmylin, hCGRP, and hADM in isolated resistance arteries from the mesenteric vascular bed of the rat.

Responses to human calcitonin gene-related peptide (hCGRP) and human adrenomedullin (hADM) hAmylin were investigated in isolated mesenteric resistance arteries from the rat. The results of the present investigation show that hCGRP, hAmylin, and hADM induce dose-related vasodilator responses in isolated resistance arteries from the rat mesenteric vascular bed. Vasodilator responses to hCGRP and hAmylin were not altered after denuding the vascular endothelium, after administration of the nitric oxide synthase inhibitor L-NA, or after administration of the soluble guanylate cyclase inhibitor ODQ, suggesting that vasodilator responses to hCGRP and hAmylin are not mediated by the release of nitric oxide from the vascular endothelium and the subsequent increase in cGMP. Vasodilator responses to hCGRP, hAmylin, and hADM were not altered by the vascular selective K+(ATP) channel antagonist U-37883A. The role of the CGRP1 receptor was investigated and responses to hCGRP and hAmylin, but not hADM, were significantly reduced following administration of hCGRP-(8-37). Moreover, vasodilator responses to hCGRP and hAmylin, but not hADM, were significantly reduced by hAmylin-(8-37), suggesting that an hAmylin-(8-37)-sensitive receptor mediates responses to hCGRP and hAmylin in the rat mesenteric artery. These data suggest that hCGRP and hAmylin have direct vasodilator effects in the isolated mesenteric resistance artery that are mediated by hAmylin-(8-37)- and hCGRP-(8-37)-sensitive receptors.

Acetylcholine↗

PubMed2001

Evaluation of oral ro70-0004/003, an alpha1A-adrenoceptor antagonist, in the treatment of male erectile dysfunction.

Alpha-adrenoceptor antagonists have been used for the treatment of male erectile dysfunction (MED). Ro70-0004/003 (Ro70-0004) is a selective and orally active alpha1A-adrenoceptor antagonist. The objective of this study was to: (1) pharmacologically elucidate the alpha1-adrenoceptor subtype mediating norepinephrine-induced contraction of human isolated corpus cavernosal tissue and (2) conduct a clinical proof-of-concept study with Ro70-0004 to test the hypothesis that selective alpha1A-adrenoceptor blockade would improve erectile function in patients with MED. In vitro organ bath studies were conducted with strips of human isolated corpus cavernosal tissue obtained from patients undergoing penile prosthesis implantation. Prazosin, cyclazosin, RS-100329 and Ro70-0004/003 antagonized norepinephrine-induced contractile responses with affinity estimates (pK(B) or pA2) of 8.4, 7.3, 9.2 and 8.8, respectively, consistent with the singular involvement of alpha1A-adrenoceptor subtype. A clinical study (single center, observer-blind, randomized, placebo-controlled, extended period Latin-Square crossover design) was conducted in 24 male patients (mean age 44 y) with MED of no established organic cause to evaluate the efficacy of a 5-mg oral dose of Ro70-0004. The primary efficacy endpoint was the duration of rigidity > 60% at the base of the penis measured between 0.5 and 2.5 h post-dose. Rigidity was assessed by penile plethysmography using the RigiScan Plus device during visual sexual stimulation. The safety and efficacy of Ro70-0004 was also assessed. A 50-mg dose of sildenafil was included as a positive control. For the primary efficacy endpoint, the mean duration of erection was 9.69 min following administration of placebo, 8.28 min following Ro70-0004, and 22.64 min following sildenafil. Only the difference between sildenafil and placebo reached statistical significance (P < 0.05). A similar pattern was observed when measuring a duration of rigidity > 80% at the base of the penis (secondary endpoint). Ro70-0004 was safe and generally well tolerated (only two out of 20 patients reported at least one adverse event). The highly selective alpha1A-adrenoceptor antagonist, Ro70-0004, given at a single dose of 5 mg, did not improve erectile function when compared to placebo.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2001

Long-term follow-up on use of pericardial graft in the surgical management of Peyronie's disease.

We have previously reported on the use of Tutoplast cadaveric pericardium as an alternative material for grafting the tunica albugineal defect after Peyronie's plaque excision with satisfactory results in 11 patients. We now review long-term outcomes in this cohort of men. Eleven patients with significant penile curvature interfering with sexual intercourse were evaluated after at least 12 months of conservative therapy. All patients underwent pre-operative evaluation, including penile duplex Doppler ultrasound studies. Chemically processed and gamma-irradiated pericardium (Biodynamics International, Parsippany, NJ) was used to graft the cavernosal defect after surgical excision of the penile plaque. Three patients simultaneously underwent placement of penile prostheses secondary to documented erection problems identified at duplex Doppler ultrasound evaluation. The long-term postoperative complications and erectile function were evaluated with a mean follow-up of 30 months (range 25-35 months). All patients reported resolution of penile curvature allowing for normal sexual function after a mean follow-up of the first 14 months. Thirty months after placement of cadaveric pericardium, the three prosthetic patients still reported excellent sexual function. For the eight patients who did not undergo placement of a prosthesis, three with small to medium plaque size (<2 x 5 cm) continued to do well. The remaining five patients with a large plaque size (>2 x 5 cm) did well initially, but later reported difficulty maintaining erection due to venous leakage, thus they are currently using either a vacuum constriction device or an Actis ring. Three out of these five venous leakage patients had ventral plaques; two had dorsal plaques, one of significant size (4 x 5 cm). We conclude that for those patients who do not undergo placement of a prosthesis, a better long-term outcome is observed when the plaque is small to medium in size (<2 x 5 cm) and dorsally located. Patients with ventral plaque, extreme curvature, or plaque size >4 x 5 cm were more likely to have venoocclusive dysfunction, necessitating further intervention.

Aged↗

PubMed2001

Role of genitourinary inflammation in infertility: synergistic effect of lipopolysaccharide and interferon-gamma on human spermatozoa.

Pro-inflammatory cytokines are elevated in the semen of patients with genitourinary inflammation (GUI). Whether this increase in cytokines in GUI patients plays any critical role in male factor infertility is not clear. The present study investigated the in vitro effects of two important pro-inflammatory cytokines, lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma), on sperm motility, viability, membrane integrity and motion parameters. Washed spermatozoa from healthy donors were incubated with LPS (0.1 mg/mL) or IFN-gamma (0.1 mg/mL) alone or in combination. Sperm motility, viability, membrane integrity and computer-assisted motion were evaluated at various time intervals (0, 30, 60 and 180 min) after treatment. Sperm membrane integrity was analysed using the hypo-osmotic swelling test (HOST). LPS and IFN-gamma individually did not alter sperm viability or motility, but their combination showed a significant time-dependent decrease (p < 0.05) in sperm motility, viability and membrane integrity. Sperm motion parameters (straight-line velocity, curvilinear velocity, mean linearity, or amplitude of lateral head displacement) were not affected by LPS or IFN-gamma at the concentrations used in this study. These data suggest that the combination of LPS and IFN-gamma is detrimental to human spermatozoa and may contribute to male factor infertility in patients with chronic GUI.

Cell Membrane↗

PubMed2001

Gene transfer of prepro-calcitonin gene-related peptide restores erectile function in the aged rat.

Erectile dysfunction in the aging male is caused, in part, by inadequate relaxation of the corpora cavernosal smooth musculature. Calcitonin gene-related peptide (CGRP), a peptide neurotrasmitter localized in the corpora cavernosa, is down-regulated in the aging rat penis. We examined the hypothesis that this reduction in CGRP may contribute to decreased cavernosal smooth muscle relaxation. Therefore, we sought to determine whether adenoviral-mediated gene transfer of prepro-CGRP (AdRSVCGRP) could enhance erectile responses in aged rats. We found a significant decrease in CGRP concentrations and in cAMP and cGMP levels in aged rat cavernosal tissue compared to younger rats. Aged rats also had significantly lower erectile function as determined by cavernosal nerve stimulation compared to younger rats. Five days after transfection with AdRSVCGRP, these aged rats had an approximately threefold increase in cavernosal CGRP levels compared to animals transfected with adenoviruses encoding nuclear-targeted beta-galactosidase (AdRSV beta gal). The AdRSVCGRP-transfected animals also demonstrated an increase in CGRP mRNA and immunohistochemical localization of CGRP in the smooth muscle of the corpora cavernosa. In addition, cAMP levels in the corpora cavernosa were significantly increased, whereas cGMP levels remained unchanged. Adenoviral transduction efficiency of beta-galactosidase reporter gene was measured by chemiluminescence and was observed in cavernosal tissue 5 days after transfection with AdRSV beta gal. More importantly, 5 days after administration of AdRSVCGRP, a significant increase was observed in the erectile response to cavernosal nerve stimulation in the aged rat, similar to the response observed in younger rats. These data suggest that in vivo adenoviral gene transfer of CGRP can physiologically improve erectile function in the aged rat.

Adenoviridae↗

PubMed2001

Analysis of vasodilator responses to novel nitric oxide donors in the hindquarters vascular bed of the cat.

Controlled release of nitric oxide (NO*) may be useful in the treatment of a variety of vascular disorders. NO* donors of the diazeniumdiolate family with different rates of spontaneous NO* release have been synthesized. In the current study responses to seven diazeniumdiolate NO* donors (DEA/NO*, DETA/NO*, OXI/NO*, PIPERAZI/NO*, PROLI/NO*, SPER/NO*, and SULFI/NO*) were investigated in the hindquarters vascular bed of the cat. Intravenous injections of all NO* donors caused dose-dependent decreases in systemic arterial pressure and the rank order of potency was SNP > DEA/NO* > PIPERAZI/NO* > SPER/NO* > PROLI/NO* > OXI/NO*. Injections of all NO* donors into the hindlimb perfusion circuit caused dose-related decreases in hindquarters perfusion pressure that were similar to the order of potency in decreasing systemic arterial pressure. The rank order of the time required for the response to return to 50% of the maximal decrease in pressure (T(1/2)) and total duration of action of the NO* donors was SPER/NO* > PIPERAZI/NO* > DEA/NO* > OXI/NO* > DETA/NO* > PROLI/NO* > SULFI/NO*. After treatment with the NO* synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (100 mg/kg, i.v.), hindlimb vasodilator responses to the NO* donors were not significantly different, but vasodilator responses to acetylcholine were significantly reduced. After treatment with zaprinast (2 mg/kg, i.v.), a type V cyclic 3',5'-guanosine monophosphate-specific phosphodiesterase inhibitor, the duration of vasodilator responses to the NO* donors, as measured by T(1/2), was increased significantly, whereas the duration of the response to the beta2-adrenergic receptor agonist albuterol was unchanged. These data suggest that diazeniumdiolate NO* donors are endothelium-independent, directly stimulate soluble guanylate cyclase, and decrease vascular resistance by increasing cyclic 3',5'-guanosine monophosphate levels in the hindquarters vascular bed of the cat.

Animals↗