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Biomedical subjects

I Goldstein

Publications and source records attributed to I Goldstein.

At least 91 records · Page 5Linked to original sources
PubMed1999

Transforming growth factor-beta1 (TGF-beta1) is sufficient to induce fibrosis of rabbit corpus cavernosum in vivo.

PURPOSE: The pleotropic cytokine TGF-beta1 which induces connective tissue synthesis, and inhibits the growth of smooth muscle cells, has been implicated in corpus cavernosum fibrosis. The objective of this study was to determine the dose and time dependence of TGF-beta1 as an active agent in penile corporal fibrosis in an animal model. MATERIALS AND METHODS: A time release method of delivery was developed using sodium alginate microspheres containing recombinant human (rh) TGF-beta1. New Zealand White rabbits were injected intracorporally with a single alginate microsphere either with or without rh-TGF-beta1. Dosage was varied from 325 to 1500 ng./bead. Animals were sacrificed at either three or five days post injection and the penises removed en bloc, examined, and processed for quantitative histomorphometric analysis, staining the sections with Masson's trichrome. RESULTS: Alginate microspheres containing [125I]-rh-TGF-beta1 showed slow-release kinetics (t1/2 = 10.5 hours). Histomorphometric analysis of 60 sets of high powered fields/treatment/ animal showed dose dependent decreases in percentage of corporal smooth muscle with TGF-beta1 treatment (750 to 1500 ng./bead). Placebo (alginate microspheres alone) had trabecular smooth muscle content comparable to values previously reported for untreated rabbit corpus cavernosum. CONCLUSIONS: This study confirms that TGF-beta1 induces fibrosis in situ by altering connective tissue synthesis and hence the structure of the corpus cavernosum. Injection of rh-TGF-beta1 impregnated alginate microspheres into the corpus cavernosum resulted in dose-dependent decreases in percentage of corporal smooth muscle.

Animals↗
PubMed1999

Female sexual dysfunction: anatomy, physiology, evaluation and treatment options.

It has been estimated that up to 76% of women, depending upon their age, have complaints of sexual dysfunction, including decreased libido, vaginal dryness, pain with intercourse, decreased genital sensation and difficulty or inability to achieve orgasm. Female sexual dysfunction is a significant problem that affects the quality of life of many women. This review addresses the etiologies and incidence of female sexual complaints, as well as new findings in the evaluation and treatment of female sexual dysfunction.

Clitoris↗
PubMed1999

Effects of castration and androgen replacement on erectile function in a rabbit model.

We investigated, in a rabbit model, the effects of castration and testosterone replacement on: 1) the hemodynamics of the corpus cavernosum; 2) alpha-1 adrenergic receptor protein expression; 3) neural NO synthase protein expression and activity; 4) phosphodiesterase type 5 activity; and 5) trabecular smooth muscle/connective tissue balance. One week after bilateral orchiectomy, animals were treated for 7 days with vehicle alone, testosterone, or estradiol. Intact control animals received vehicle only. Systemic arterial blood and intracavernosal pressures (ICP) were measured in each animal before and after electrical stimulation of the cavernosal nerve. Alpha1-adrenergic receptor protein expression was determined by ligand binding studies. NO synthase expression and activity were determined by Western blot analyses and conversion of L-arginine to citrulline, respectively. Phosphodiesterase type 5 activity was determined by hydrolysis of guanosine 3',5'-cyclic monophosphate (cGMP) in tissue extracts in the absence or presence of 100 nM sildenafil. Smooth muscle content was assessed by Masson's trichrome staining and computer-assisted histomorphometry. Castration significantly reduced ICP, but it did not alter systemic arterial blood pressure during stimulation of the cavernosal nerve. Testosterone, but not estradiol, treatment prevented the effects of castration and restored ICP to values similar to those obtained in intact animals. Castration reduced expression of alpha1-adrenergic receptor, and this reduction was prevented or reversed by testosterone replacement. Neural NO synthase protein expression and total activity were not altered significantly by castration or after testosterone replacement. However, phosphodiesterase type 5 activity increased in castrated animals treated with testosterone. Castration significantly reduced trabecular smooth muscle content, and this reduction was restored by testosterone (but not estradiol) treatment. The results of this study demonstrate that androgen deprivation alters the functional responses and structure of erectile tissue.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1999

Histomorphometric analysis of age-related structural changes in human clitoral cavernosal tissue.

PURPOSE: To characterize age-associated histological changes of human clitoral cavernosal tissue and to determine whether age-related histological changes of clitoral cavernosal tissue correlate with vascular disease-related mortality. MATERIALS AND METHODS: Human clitorises were obtained from 15 fresh cadavers (age: 11 to 90 years) and from 3 patients undergoing clitoral surgery (age: 6 months to 15 years). Cross sections of the clitorises were stained with Masson's trichrome and utilized for computer assisted histomorphometric image analysis to determine the clitoral cavernosal content of smooth muscle and connective tissue. RESULTS: These studies revealed a strong link between increase in age and decreased clitoral cavernosal smooth muscle fibers. In histomorphometry, the percentage of clitoral cavernosal smooth muscle (mean +/- standard error) in an age group of 6 months to 15 years (n = 4) was 65+/-1.5, in 44 to 54 years (n = 7) was 50+/-1.2, and in 55 to 90 years (n = 7) was 37+/-1.3 (ANOVA, p = 0.0001). In the 18 tissues studied, decrease in the percentage of clitoral cavernosal smooth muscle significantly correlated with increase in age (simple regression, r = 0.61). In the age group of 44 to 90 years, clitoral cavernosal fibrosis was significantly greater in the presence of cardiovascular disease-related mortality compared with those without cardiovascular disease-related mortality. CONCLUSION: This study shows that aging women undergo histological changes in clitoral cavernosal erectile tissue. Vascular risk factors may adversely affect the structure of clitoral cavernosal tissue. These findings may be of importance in the pathophysiology of age-associated female sexual arousal disorders.

Adolescent↗
PubMed1999

Relative roles of cyclooxygenase and nitric oxide synthase pathways in ischemia-induced increased contraction of cavernosal smooth muscle.

PURPOSE: To study the mechanism of chronic ischemia-induced increased cavernosal smooth muscle contraction in an animal model of vasculogenic erectile dysfunction. MATERIALS AND METHODS: New Zealand White rabbits were divided into control (n = 6, fed with a regular diet), hypercholesterolemic (n = 9, fed with a diet containing 0.5% cholesterol) and chronic cavernosal ischemia (CCI, n = 10, underwent balloon de-endothelialization of iliac arteries and received a diet containing 0.5% cholesterol) groups. After 16 weeks, the relationship between iliac artery blood flow and cavernosal smooth muscle contraction was studied. The roles of cyclooxygenase and nitric oxide (NO) pathways in chronic ischemia-induced increased smooth muscle contraction were also examined. RESULTS: Iliac artery blood flow in the CCI group was significantly reduced compared with the control and hypercholesterolemic groups. Hypercholesterolemia alone did not affect cavernosal smooth muscle contraction. Atherosclerosis-induced chronic cavernosal arterial insufficiency did not affect contraction to norepinephrine while causing a significant increase in electrical field stimulation-induced neurogenic contraction. Inhibition of the cyclooxygenase pathway by indomethacin decreased electrical field stimulation-induced contraction in all animals but failed to normalize the differences between CCI and control groups. In the presence of indomethacin, L-arginine decreased electrical field stimulation-induced contraction in the control and hypercholesterolemic groups but not in the CCI group. In the presence of indomethacin, treatment with nitric oxide synthase (NOS) inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), increased electrical field stimulation-induced contraction in all groups. This effect of L-NMMA on smooth muscle contraction was significantly greater in the control and hypercholesterolemic groups compared with the CCI group. After tissue treatment with L-NMMA, the magnitude of contraction in cavernosal tissue from control and hypercholesterolemic groups was similar to those observed in the CCI group. CONCLUSIONS: Mechanism of chronic ischemia-induced increased cavernosal smooth muscle contraction involves increased output of constrictor eicosanoids and impairment of the inhibitory influence of NO pathway in cavernosal tissue.

Animals↗
PubMed1999

The causes of patient dropout from penile self-injection therapy for impotence.

PURPOSE: Penile self-injection therapy, a second line treatment for erectile dysfunction, is the most efficacious means of reestablishing functional erections when first line therapies fail and the patient wants to avoid penile prosthesis implantation. Despite high efficacy rates, injection therapy has high dropout rates. To our knowledge studies to date analyzing patient attrition have reviewed small numbers of patients followed for only short periods. We elucidate the main reasons for patient dropout in a large penile self-injection program with long-term followup. MATERIALS AND METHODS: A questionnaire was mailed to 1,424 patients who completed the office training and home use phases of a penile self-injection program. RESULTS: The overall attrition rate was 31% of the 720 men who completed the questionnaire, with a mean followup of 38 months. The main reasons for dropout were cost of therapy, patient and partner problems with the concept of penile injection, lack of partner availability and spontaneous improvement in erections. Lack of efficacy of therapy was the primary reason for only 1 of 7 dropouts. Furthermore, adverse effects of penile injections (priapism, penile nodules, pain) appeared to be only minor contributors to dropout. CONCLUSIONS: To our knowledge this study is the largest published, single center cohort of patients treated with injection and followed for an analysis of dropout rates. Based on study data a reduction in dropout rates may be achieved by keeping the cost of therapy low, and ensuring patient and partner education as well as continued support throughout treatment.

Adult↗
PubMed1998

Sildenafil inhibits phosphodiesterase type 5 in human clitoral corpus cavernosum smooth muscle.

Phosphodiesterases play an important physiological role by regulating the intracellular levels of cyclic nucleotides. In this study, we investigated the kinetic parameters of inhibition of phosphodiesterase (PDE) type 5 (EC 3.1.4.35, 3',5'-cyclic GMP phosphodiesterase) by a novel, high-affinity, selective PDE type 5 inhibitor, sildenafil, in intact cells and in soluble extracts of human clitoral corpus cavernosum smooth muscle cells. Sildenafil inhibited cGMP hydrolysis in the crude extract (Ki = 7.2 +/- 2.7) and in partially purified preparations (Ki = 9 nM) in a competitive manner, as determined by Dixon plots. Sildenafil was a more effective PDE type 5 inhibitor than zaprinast (Ki = 400.0 +/- 76.4 nM, crude extracts; 250 nM, partially purified). Stimulation of intracellular cGMP synthesis by the nitric oxide donor sodium nitroprusside resulted in a 3.3- and 2.9-fold increase in cGMP concentration in the presence of sildenafil or zaprinast, respectively, compared to sodium nitroprusside treatment alone in intact cells at physiological temperatures. These observations suggest that human clitoral corpus cavernosum smooth muscle tone may be regulated by the synthesis and release of nitric oxide and that this pathway is dependent on PDE type 5 activity.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1998

Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group.

BACKGROUND: Sildenafil is a potent inhibitor of cyclic guanosine monophosphate hydrolysis [corrected] in the corpus cavernosum and therefore increases the penile response to sexual stimulation. We evaluated the efficacy and safety of sildenafil, administered as needed in two sequential double-blind studies of men with erectile dysfunction of organic, psychogenic, and mixed causes. METHODS: In a 24-week dose-response study, 532 men were treated with oral sildenafil (25, 50, or 100 mg) or placebo. In a 12-week, flexible dose-escalation study, 329 different men were treated with sildenafil or placebo, with dose escalation to 100 mg based on efficacy and tolerance. After this dose-escalation study, 225 of the 329 men entered a 32-week, open-label extension study. We assessed efficacy according to the International Index of Erectile Function, a patient log, and a global-efficacy question. RESULTS: In the dose-response study, increasing doses of sildenafil were associated with improved erectile function (P values for increases in scores for questions about achieving and maintaining erections were <0.001). For the men receiving 100 mg of sildenafil, the mean score for the question about achieving erections was 100 percent higher after treatment than at base line (4.0 vs. 2.0 of a possible score of 5). In the last four weeks of treatment in the dose-escalation study, 69 percent of all attempts at sexual intercourse were successful for the men receiving sildenafil, as compared with 22 percent for those receiving placebo (P<0.001). The mean numbers of successful attempts per month were 5.9 for the men receiving sildenafil and 1.5 for those receiving placebo (P<0.001). Headache, flushing, and dyspepsia were the most common adverse effects in the dose-escalation study, occurring in 6 percent to 18 percent of the men. Ninety-two percent of the men completed the 32-week extension study. CONCLUSIONS: Oral sildenafil is an effective, well-tolerated treatment for men with erectile dysfunction.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1998

Cavernosal expandability is an erectile tissue mechanical property which predicts trabecular histology in an animal model of vasculogenic erectile dysfunction.

PURPOSE: Reliable, clinically available, non-invasive measurements able to predict trabecular histology without the need for erectile tissue biopsy would improve impotence management, since the percentage of trabecular smooth muscle content has been shown to be associated with corporal veno-occlusive dysfunction. The purpose was to identify whether the erectile tissue mechanical property, cavernosal expandability, correlated with the percentage of trabecular smooth muscle content in an animal model of hypercholesterolemia and ischemic-induced corporal fibrosis. MATERIALS AND METHODS: New Zealand White rabbits (6 to 7 months old, 3 to 3.5 kg.), were divided into control (n = 7), hypercholesterolemic (n = 5, 0.5% cholesterol diet) and atherosclerotic groups (n = 8, 0.5% cholesterol diet with balloon de-endothelialization). At 16 weeks, the corpora cavernosa were removed en bloc and submerged in physiologic salt solution, and volume-pressure data were plotted at 20 mm. Hg pressure intervals under trabecular smooth muscle relaxation. Cavernosal expandability, X, (the measure of the ability to achieve high corporal expansion at relatively low intracavernosal pressure) and tunical distensibility, V(E)/V(F), (relative volume of fully erect to flaccid penis) were calculated. Erectile tissue was assessed by computer-assisted color histomorphometry with Masson's trichrome stained sections (30 to 45 high power fields/animal) to assess percentage of trabecular smooth muscle content. RESULTS: The overall mean percentage of trabecular smooth muscle content and mean cavernosal expandability values were 45.4 +/- 1.6, 39.2 +/- 0.9, 33.9 +/- 0.6 and 0.0165 +/- 3.04 x 10(-3), 0.0116 +/- 1.63 x 10(-3), 0.0118 +/- 1.26 x 10(-3) mm. Hg(-1) for the control, hypercholesterolemic and atherosclerotic groups, respectively (r = 0.87). Significant differences in trabecular smooth muscle content were observed among all 3 groups, and in cavernosal expandability, between control and atherosclerotic groups, as well as between control and hypercholesterolemic groups but not between atherosclerotic and hypercholesterolemic groups. CONCLUSIONS: The erectile tissue mechanical property, cavernosal expandability, correlated with erectile tissue structural quality. Since cavernosal histology has been shown to predict corporal veno-occlusive function, it is hypothesized that the measurement of cavernosal expandability may become a valuable functional clinical parameter in the diagnosis and treatment of men with erectile dysfunction.

Animals↗
PubMed1998

Sildenafil, a novel inhibitor of phosphodiesterase type 5 in human corpus cavernosum smooth muscle cells.

In human corpus cavernosum, release of nitric oxide from the non-adrenergic, non-cholinergic nerves and/or the endothelium activates guanylyl cyclase and increases intracellular cGMP levels. The increase in intracellular cGMP modulates intracellular calcium and in turn regulates smooth muscle contractility and erectile function. Phosphodiesterases play an important physiological role by regulating the intracellular levels of cyclic nucleotides. In this study, we investigated the kinetic parameters of inhibition of phosphodiesterase (PDE) type 5 (E.C. 3.1.4.35 3',5'-cyclic GMP phosphodiesterase) by a novel, high affinity, selective PDE type 5 inhibitor, sildenafil, in soluble extracts of human corpus cavernosum smooth muscle cells. Sildenafil inhibited PDE type 5 cGMP-hydrolytic activity, in the crude extract (Ki=4-6 nM) and in partially purified preparations (Ki=2 nM) in a competitive manner, as determined by Dixon plots. Sildenafil (Ki=2-4 nM) was a more effective PDE type 5 inhibitor than zaprinast (Ki=250 nM). Stimulation of intracellular cGMP synthesis by the nitric oxide donor, sodium nitroprusside, resulted in less than a 5% increase in cGMP levels in the absence of sildenafil and a 35% increase in cGMP levels in the presence of sildenafil, in intact cells at physiological temperatures. These results are in accord with the clinical observations that sildenafil, taken orally, promotes penile erection through increased intracellular cGMP in response to sexual stimulation, potentiating smooth muscle relaxation.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1998

The expression of functional postsynaptic alpha2-adrenoceptors in the corpus cavernosum smooth muscle.

1. The purpose of this study was to determine if corpus cavernosum smooth muscle expresses functional postsynaptic alpha2-adrenoceptors (AR). 2. The alpha2-adrenoceptor agonist UK 14,304 elicited concentration-dependent contractions in rabbit corpus cavernosum smooth muscle (CCSM). The half-maximal response occurred at 0.32+/-0.03 microM and the maximum contraction at 10 microM UK 14,304. 3. Pretreatment of CCSM strips with selective alpha2-adrenoceptor antagonists, rauwolscine and RS-15385, produced rightward shifts in the dose-response curves to UK 14,304 (pA2 values 7.1 and 8.5, respectively). In contrast, these antagonists did not alter contraction induced by the alpha1-adrenoceptor agonist phenylephrine (PE) or oxymetazoline. UK 14,304-induced contractions were also inhibited by prazosin (pA2 = 9.08). 4. UK 14,304-induced contractions, unlike those to PE, were highly dependent on the presence of extracellular Ca2+. 5. [3H]-rauwolscine bound to CCSM membranes with high affinity (Kd = 1.5 nM). [3H]-rauwolscine binding was displaced by unlabelled rauwolscine, RS-15385, UK 14,304 and prazosin, but not by PE. 6. UK 14,304 inhibited forskolin and prostaglandin E1 (PGE1)-induced increases in intracellular cyclic AMP concentration in primary cultures of rabbit CCSM cells. 7. These results demonstrate that CCSM expresses Gi-coupled postsynaptic alpha2-adrenoceptors, and activation of these receptors causes contraction of trabecular smooth muscle.

Adrenergic alpha-Agonists↗
PubMed1998

Percutaneous core biopsy of the penis.

To describe the efficacy of percutaneous core biopsy of penile corporal tissue, on ten impotent men, the biopsy was performed with a 19 and a 20 gauge core biopsy co-axial system using an automatic biopsy device. All biopsies were performed on an outpatient basis under local anesthesia. Adequate biopsy specimens were obtained in all. Percutaneous core biopsy of the penis is a safe procedure that is technically easy to perform.

Anesthesia, Local↗
PubMed1998

Engineering analysis of penile hemodynamic and structural-dynamic relationships: Part I--Clinical implications of penile tissue mechanical properties.

PURPOSE: The least investigated physical determinant of penile rigidity has been penile tissue material properties. The goals in this study (Part I) were to define two penile mechanical parameters, cavernosal expandability X and tunical distensibility VE/VF, determine their magnitudes in humans and develop an analytical expression for penile volume as a function of these two tissue characteristics and intracavernosal pressure. METHODS: Dynamic infusion pharmacocavernosometry was performed in 21 impotent patients (age 43 +/- 19 y) to provide human geometric, hemodynamic and structural data. A mathematically derived model of hemodynamic and structural-dynamic characteristics of penile erection was developed (Parts I, II, III) incorporating penile tissue mechanical qualities. RESULTS: Cavernosal expandability X provided a measure of the ability to approach maximum volume at relatively low intracavernosal pressures. Tunical distensibility VE/VF denoted the maximal erect to flaccid penile volume ratio. The magnitudes of X and VE/VF in the study population were 0.04-0.17 mmHg-1 and 1.7-5.0 respectively. CONCLUSIONS: Enabling penile volume to be derived as a function of tissue mechanical characteristics and pressure, allows for penile rigidity to be expressed (in Part II) as a function of pressure, geometry and tissue qualities.

Adult↗
PubMed1998

Engineering analysis of penile hemodynamic and structural-dynamic relationships: Part II--Clinical implications of penile buckling.

PURPOSE: Penile buckling force was analytically described in terms of its constituents. In addition, theoretically-derived buckling force data were compared to clinically measured data and the influence of each constituent on penile buckling force data was assessed. METHODS: Using engineering buckling theory for a column, a mathematically-derived penile buckling model was developed which incorporated geometric and hemodynamic data obtained by dynamic infusion pharmacocavernosometry studies in 21 impotent patients (age 43, range 24-62 y) as well as penile tissue mechanical characteristics previously developed (Part I). RESULTS: In 17 of 21 patients the mean difference between theoretically derived and clinically measured buckling force data was 0.33 +/- 0.25 kg (r = 0.96). Factors which increased penile buckling forces were: (1) high intracavernosal pressure values (rigidity was related to pressure in an exponential-like fashion); (2) high penile aspect ratio (D/L) values (relatively large diameter/short length penile geometry) and high flaccid diameter; and (3) high cavernosal expandability values (a measure of the ability of the corpora to approach its erect volume with relatively low intracavernosal pressures). CONCLUSIONS: Pressure-volume data (pressure, geometry and tissue characteristics) obtained during erectile function testing have been shown, for the first time, to theoretically predict the magnitude of clinically-measured penile buckling forces.

Adult↗
PubMed1998

Engineering analysis of penile hemodynamic and structural-dynamic relationships: Part III--Clinical considerations of penile hemodynamic and rigidity erectile responses.

PURPOSE: The extent to which hemodynamic erectile responses predict penile buckling forces has not previously been analytically investigated. An engineering study was performed to compare hemodynamic data with penile buckling force values. METHODS: Dynamic infusion pharmacocavernosometry studies in 21 impotent patients (age 43, range 24-62 y) were accomplished to obtain information during penile erection concerning hemodynamic values, penile buckling forces and their determinants: intracavernosal pressure, erectile tissue mechanical properties and penile geometry. RESULTS: In the 21 patients, discrepancies existed in several patients who demonstrated normal hemodynamic values (low flow-to-maintain and high equilibrium intracavernosal pressures) but elevated cavernosal compliance values and diminished penile buckling forces. There was poor correlation between cavernosal compliance and equilibrium intracavernosal pressure (r = -0.36); better correlation between compliance and expandability (r = -0.72) and best correlation between dimensionless compliance and the dimensionless product of expandability with equilibrium pressure (r = -0.88). These data implied that cavernosal compliance was dependent on multiple factors, not only equilibrium intracavernosal pressure. CONCLUSIONS: Hemodynamic indices which correlate with intracavernosal pressure alone do not predict penile buckling forces since the latter are dependent not only on intracavernosal pressure but also on penile geometry and erectile tissue properties. The most relevant tissue property in predicting adequate penile buckling forces is cavernosal expandability. A new impotence classification system and diagnostic algorithm based on the determinants of penile rigidity and not exclusively on hemodynamic responses in proposed.

Adult↗