Biomedical subjects
R J Krane
Publications and source records attributed to R J Krane.
The hemodynamic pathophysiology of impotence following blunt trauma to the erect penis.
A total of 19 patients provided a history of impotence following blunt trauma to the erect penis during intercourse or masturbation, or after accidents. Corporeal veno-occlusive dysfunction was the most common hemodynamic abnormality (16 of 19 patients, or 84%). A site-specific leak, which consisted of abrupt filling of the dorsal vein and/or corpus spongiosum from a focal site on the penile shaft, was demonstrated in 15 patients (79%). Cavernous artery insufficiency was found less often (7 of 19 patients, or 37%). A focal mid shaft cavernous artery occlusion was demonstrated in 5 patients (28%). It is hypothesized that the aforementioned hemodynamic abnormalities are caused by tunica and intracavernous vasculature injuries induced by the marked short-term pressure increases, which approach or exceed the tunica tensile strength during acute abrupt loading of the erect penis. This hypothesis is supported by direct recording of intracavernous pressures that exceeded 450 mm. Hg in response to angulation and manual compression of the penile shaft. Further evidence was created by a biomechanical model that was based on previously published intracavernous pressure--circumference patient data during dynamic infusion pharmacocavernosometry. Using a typical patient data set a 60% diminution of circumference at the site of abrupt loading was calculated to induce a 15% increase in circumference in the nonloaded portion of the penile shaft and an elevated intracavernous pressure exceeding 900 mm. Hg. The site-specific hemodynamic abnormalities were found to occur not only in patients with a classical penile fracture history but also in patients with injuries during masturbation or following accidents who had no acute penile swelling or ecchymosis. Thus, the erect penis is at risk for injury during any acute loading situation. It is likely that this erect trauma-induced hemodynamic pathology occurs more frequently than previously appreciated and that this type of impotence may be the underlying basis for many cases of idiopathic Peyronie's disease.
Effect of spinal cord ischemia on vesicourethral function.
We studied 9 patients with clinical evidence of spinal cord ischemia or infarction who had altered vesicourethral function. Of the patients 6 had some preservation of bladder and lower extremity sensation, a clinical pattern consistent with the anterior spinal artery syndrome. A total of 3 patients had a clinical picture more consistent with complete transverse myelopathy, since they had no preservation of bladder or lower extremity sensation. Despite sensory levels well above the sacral spinal cord segments, 6 patients had detrusor areflexia (4 with bethanechol supersensitivity and 4 with neuropathic changes in the perineal electromyograph) indicating longitudinal spinal cord involvement. Three patients had detrusor hyperreflexia with vesicosphincter dyssynergia, indicating some preservation of the sacral spinal cord. In 6 patients appreciation of pinprick in the lower extremities was absent or decreased but light touch or position sense was preserved. Bladder sensation was dissociated in 4 of these 6 patients, since they had perception of bladder distention but loss of urge to void. These findings indicate that bladder distention is a sensory modality probably mediated via the posterior spinal cord, while the sense of urgency is probably conveyed by the anterior spinal cord.
Endothelin in the urinary bladder. I. Synthesis of endothelin-1 by epithelia, muscle and fibroblasts suggests autocrine and paracrine cellular regulation.
The synthesis and localization of endothelin-1 were studied in human and rabbit bladder. In addition, the effects of endothelin-1 on smooth muscle tone and cholinergic neurotransmission were investigated in rabbit bladder. Endothelin-like immunoreactivity was localized in the transitional epithelium, serosal mesothelium, and vascular endothelium; smooth muscle of the bladder (non-vascular) and that of blood vessels; and fibroblasts. With in situ hybridization, transcripts of endothelin messenger ribonucleic acid (mRNA) were localized with the same cellular distribution as endothelin-like immunoreactivity, in bladder tissue. Northern blot analysis of bladder RNA confirmed the expression of preproendothelin-1 mRNA. Rabbit bladder strips in organ chambers contracted when exposed to endothelin-1 and this response was partially attenuated by calcium channel blockers or by removal of extracellular calcium. Transmural electrical stimulation of rabbit bladder strips elicited contractions that were greatly reduced by atropine. The remaining atropine resistant component was blocked by alpha, beta-methylene ATP, which desensitizes purinergic receptors. Endothelin-1 caused a small but consistent attenuation of the atropine sensitive component of the neurogenic contraction, while it had no effect on the atropine resistant component. The localization of endothelin synthesis in epithelia, smooth muscle, and fibroblasts suggests that endothelin may act as an autocrine hormone in the regulation of the bladder wall structure and smooth muscle tone. In addition, endothelin-1 may regulate cholinergic neurotransmission by a paracrine mechanism.
Endothelin in the urinary bladder. II. Characterization of endothelin receptor subtypes.
Endothelins (ET-1, ET-2, ET-3) are a family of regulatory peptides with diverse biological functions, including modulation of smooth muscle tone. To evaluate the possible role of endothelins in the control of the detrusor smooth muscle of urinary bladder, we have investigated the responses of isolated strips of bladder dome and base to endothelins, in organ chambers, and characterized the receptors for these isopeptides in bladder membranes. ET-1, ET-2 and to a lesser extent ET-3 caused sustained concentration-dependent contraction of bladder dome and base. The contraction to endothelins, unlike the short-lived contraction produced by cholinergic agents, was long lasting and difficult to wash out. Equilibrium binding studies demonstrated that endothelin isoforms bound to bladder membrane receptors specifically, with high affinity (KD of 0.4-0.6 nM) and limited capacity (60-420 fmol/mg protein). Competition analysis showed two populations of receptors: one with high affinity for ET-1 and ET-2 and low affinity for ET-3 and another with high affinity for ET-1, ET-2 and ET-3. Chemical affinity labeling of endothelins to bladder membranes demonstrated that ET-1 and ET-2 were cross-linked to three proteins (75, 52 and 34 kDa, respectively), whereas ET-3 was cross-linked mainly to a 34 kDa protein. The data obtained from equilibrium binding studies, competition analysis and cross-linking experiments suggest that at least two endothelin receptor subtypes exist in bladder tissue. These observations further suggest that bladder smooth muscle tone may be modulated by endothelin or an endothelin-like substance via interaction with specific receptor sites.
Pathophysiology of prolonged penile erection associated with trazodone use.
Treatment with the antidepressant trazodone has been associated with the occurrence of prolonged penile erection and priapism. To evaluate the effect of trazodone on erection we monitored the periodic physiological sleep-related erections in 6 healthy volunteers in a double-blind crossover study comparing the effect of trazodone, trimipramine (a tricyclic antidepressant) and placebo. In addition, to determine the effects of trazodone on the neurovascular control of penile smooth muscle we performed in vitro studies on corpus cavernosum tissue obtained from patients undergoing penile prosthesis implantation. Trazodone significantly increased the total interval of nocturnal erectile activity, while trimipramine had no effect. During the high dose treatment (nights 4 and 5) the average duration of erectile activity per night with placebo was 158 +/- 41 minutes (mean +/- standard deviation) for night 4 and 177 +/- 21 minutes for night 5. During trazodone treatment the erectile activity per night was significantly prolonged to 285 +/- 115 minutes during night 4 and 232 +/- 86 during night 5 (p less than 0.01). Analysis of the erectile activity in relation to the rapid eye movement sleep period during which erectile activity usually occurs revealed that the detumescence phase of erection, under sympathetic control, was significantly prolonged an average of 2.4 times by trazodone compared to placebo (p less than 0.05). In vitro, trazodone at concentrations comparable to those reached in plasma significantly impaired corporeal smooth muscle contractions elicited by electrical stimulation of adrenergic nerves and antagonized contractions induced by exogenous norepinephrine. We conclude that trazodone can enhance penile erection in man and propose a mechanism related to the alpha-adrenoceptor blocking properties of trazodone by interference with the sympathetic control of penile detumescence.
Disturbed sexual function in patients with spinal cord disease.
The normal neural pathways involved in erection and ejaculation and the various spinal cord and central nervous system disorders that can adversely affect these functions are reviewed in this article. Also outlined are treatment strategies currently being employed.
Effect of autolymphocyte therapy on survival and quality of life in patients with metastatic renal-cell carcinoma.
To assess the value of autolymphocyte therapy (ALT) in the treatment of metastatic renal-cell carcinoma, 90 patients were randomised to receive every month for six months oral cimetidine plus an infusion of autologous peripheral blood lymphocytes activated in vitro by a previously generated autologous lymphokine mixture, or cimetidine alone. The median follow-up was 15 months. Survival time for the autolymphocyte group was approximately 2.5 times that for the cimetidine group (p = 0.008). Patients who had greater than 500 pg interleukin-1 (IL-1) per ml autologous lymphokine mixture had a six-fold survival advantage over those with less than 500 pg/ml (p less than 0.00005). Men treated with ALT had a four-fold survival advantage (p = 0.001) over men who received cimetidine only. Infusion of the cultured autolymphocytes was accompanied by mild, self-limited fever in 11 of the 45 ALT patients, and by only one instance in which fever was accompanied by tachypnoea and hypotension.
Treatment of metastatic renal cell carcinoma with autolymphocyte therapy. Low toxicity outpatient approach to adoptive immunotherapy without use of in vivo interleukin-2.
Thirty-six patients with Stage IV renal cell carcinoma were treated with autolymphocyte therapy (ALT). This new form of adoptive immunotherapy is based on the infusion of relatively small numbers of autologous lymphocytes that are depleted of suppressor cells and immunized in vitro by a method designed for antigen-specific activation using a 3M KCl extract of autologous tumor and an autologous lymphokine mixture. Patients received six monthly infusions of immunized lymphocytes, all on an outpatient basis. The majority of patients experienced no toxicity. The few reactions that occurred were minor and self-limiting; none required any medical intervention or subsequent delay in therapy. Patients also received oral cimetidine to reduce in vivo suppressor cell function. Survival at twenty-four months is 36 percent. Median survival is fifteen months, a significant improvement over the natural history of this disease. A multi-site, randomized, controlled trial of ALT in renal cell carcinoma has been initiated to confirm that this treatment causes a significant prolongation of survival with virtually no toxicity in these patients.
Prognostic assessment in nonseminomatous testicular cancer: implications for therapy.
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Dysfunctional penile cholinergic nerves in diabetic impotent men.
Impotence in the diabetic man may be secondary to a neuropathic condition of the autonomic penile nerves. The relationship between autonomic neuropathy and impotence in diabetes was studied in human corporeal tissue obtained during implantation of a penile prosthesis in 19 impotent diabetic and 15 nondiabetic patients. The functional status of penile cholinergic nerves was assessed by determining their ability to accumulate tritiated choline (34), and synthesize (34) and release (19) tritiated-acetylcholine after incubation of corporeal tissue with tritiated-choline (34). Tritiated-choline accumulation, and tritiated-acetylcholine synthesis and release were significantly reduced in the corporeal tissue from diabetic patients compared to that from nondiabetic patients (p less than 0.05). The impairment in acetylcholine synthesis worsened with the duration of diabetes (p less than 0.025). No differences in the parameters measured were found between insulin-dependent (11) and noninsulin-dependent (8) diabetic patients. The ability of the cholinergic nerves to synthesize acetylcholine could not be predicted clinically with sensory vibration perception threshold testing. It is concluded that there is a functional penile neuropathic condition of the cholinergic nerves in the corpus cavernosum of diabetic impotent patients that may be responsible for the erectile dysfunction.
Effects of intracavernosal trazodone hydrochloride: animal and human studies.
Trazodone hydrochloride is an oral antidepressant agent which has been associated with the improvement of erections in impotent men and the development of prolonged erections or priapism in potent men. An in vivo study in animal and human subjects was performed to gain experience with the effect of intracavernosal trazodone. In the anesthetized New Zealand White rabbit, intracavernosal trazodone or its major metabolite m-chlorophenylpiperazine (m-CPP) produced full penile erection in 76% and 84% of animals studied respectively with doses ranging from one to 15 mg. On the other hand, intracavernosal administration of five mg. papaverine resulted in a prolonged erection in 90% of animals studied. In 13 selected volunteer patients, intracavernosal trazodone caused tumescence but not full penile erection with corporal body pressures of 28.2 +/- 5.8 mm. Hg. Intracavernosal papaverine or papaverine and phentolamine in these subjects resulted in significantly higher corporal body pressures of 58 +/- 18 mm. Hg (p less than .05). Intracavernosal administration of alpha adrenoceptor agonists but not normal saline resulted in complete detumescence of trazodone- or m-CPP-induced prolonged erection in the animal studies. Intracavernosal trazodone results in erectile activity that appears in part based on its local alpha blocking activity but like other intracavernosal alpha-blocking agents is not as effective in initiating penile erections as are intracavernosal agents that directly induce smooth muscle relaxation.
Traumatic laceration of intracavernosal arteries: the pathophysiology of nonischemic, high flow, arterial priapism.
Two forms of priapism are known to occur. The more common type, veno-occlusive priapism, presents with a prolonged painful erection, and it is characterized by ischemia and pooling of blood within the corpora cavernosa. The less common form, high flow priapism, is characterized by lack of pain and ischemia. The pathophysiology of this disorder is poorly understood and the treatment is unclear. We report 2 cases of nonischemic priapism, one of which occurred after blunt perineal trauma and the other after intracavernosal self-injection with papaverine and phentolamine. Based on our 2 cases as well as a review of the literature (5 cases), we propose that the pathophysiological mechanism of this disorder is unregulated arterial inflow into the corpora, classify it as arterial priapism, and describe a diagnostic and therapeutic algorithm for its management.
Duraphase penile prosthesis--results of clinical trials in 63 patients.
The Duraphase penile prosthesis was implanted in 63 patients at 4 investigative sites during clinical trials. This device is a semirigid rod that is bendable and provides good support to the erection. Mechanical complications included 4 instances of cable breakage rendering the device nonfunctional. Of 57 patients questioned 55 were pleased with the results after 4 months. Ease of insertion and exceptional bendability are other features that make this device attractive.
"High-flow" priapism: treatment with superselective transcatheter embolization.
Hemodynamically, most cases of priapism occur as a result of venous outflow obstruction producing engorgement of the corpora cavernosa. In a small number of patients, however, the cause is uncontrolled arterial inflow, often from direct arterial trauma. The authors report two cases of arterial or "high-flow" priapism that were successfully treated with selective transcatheter embolization with autologous clot.
Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence.
Relaxation of the smooth muscle of the corpora cavernosa of the penis is necessary for penile erection. To determine the relation of impaired relaxation to impotence in diabetic patients, we performed an in vitro examination of corpus cavernosum tissue obtained at the time of implantation of a penile prosthesis in 21 diabetic and 42 nondiabetic men with impotence. Contraction was induced in isolated strips of corporal smooth muscle by norepinephrine; then relaxation was assessed with electrical stimulation of autonomic nerves and with the administration of three agents: acetylcholine, which is known to be mediated by endothelium-derived relaxing factor; papaverine; and sodium nitroprusside. The latter two act directly on smooth muscle (i.e., they are endothelium-independent). Autonomically mediated relaxation with electrical stimulation was less pronounced in the smooth muscle from diabetic men (n = 18) than in the smooth muscle from nondiabetic men (n = 24; P = 0.001). The degree of impairment increased with the duration of diabetes (r = 0.61, P = 0.007). Endothelium-dependent relaxation was also impaired, as evidenced by a lower degree of muscle relaxation after the administration of acetylcholine in the tissue from diabetic men (n = 16) than in that from nondiabetic men (n = 22; P = 0.001). The adverse effects of diabetes persisted after we controlled for smoking and hypertension. Endothelium-independent relaxation after the administration of nitroprusside and papaverine was similar in tissue from the diabetic and nondiabetic men. We conclude that diabetic men with impotence have impairment in both the autonomic and the endothelium-dependent mechanisms that mediate the relaxation of the smooth muscle of the corpora cavernosa. These findings may provide a rationale for the treatment of diabetic men with impotence by intracavernosal injection of vasodilators to induce endothelium-independent relaxation of the smooth muscle.
Regulation of adrenergic activity in penile corpus cavernosum.
The regulation of adrenergic activity in the penis was investigated by studying human and rabbit corpus cavernosum strips in organ chambers and measuring the release of norepinephrine from adrenergic nerve terminals. Electrical field stimulation of corporal strips caused frequency-dependent contractions which were potentiated by cocaine and attenuated by the alpha 1 adrenoceptor antagonist prazosin (10(-7) M), but not by the alpha 2 adrenoceptor antagonist rauwolscine (10(-7) M). Norepinephrine caused concentration-dependent contractions of corporal strips, which were attenuated by prazosin and rauwolscine. Acetylcholine and physostigmine attenuated adrenergic nerve mediated contractions and also significantly reduced electrically-induced norepinephrine release. These effects were reversed by atropine. Atropine alone enhanced electrically-induced norepinephrine release. Rauwolscine inconsistently enhanced adrenergic nerve mediated contractions but augmented norepinephrine release caused by electrical stimulation. The alpha 2 adrenoceptor agonist clonidine inhibited electrically-induced norepinephrine release. Vasoactive intestinal polypeptide (VIP) attenuated adrenergically-mediated contractions, but had no effect on electrically-induced release of norepinephrine. It is concluded that: 1) contraction of corporal smooth muscle is mediated by postjunctional alpha 1 adrenoceptors; 2) adrenergic activity is modulated by prejunctional alpha 2 adrenoceptors and cholinergic nerves via prejunctional muscarinic receptors; and 3) the putative nonadrenergic noncholinergic neurotransmitter, VIP, has no apparent role in the regulation of adrenergic nerves.