M. Hassouna

The Effect of Diabetes on Sexual Behavior and Reproductive Tract Function in Male Rats

The effect of streptozotocin induced diabetes and sabeluzole (SBZ) on sexual function was evaluated in male rats. SBZ is a benzothiazole derivative with antihypoxic and antiischaemic activities. Rats were rendered diabetic by intraperitoneal injection of streptozotocin, 60 mg./kg. body weight, and either left untreated or treated with 1.0 mg./kg. of SBZ. Two groups of control rats treated with or without SBZ were also evaluated. Seven weeks after the induction of diabetes, all rats were studied in vivo for mating behavior. Animals were sacrificed one week later, and detrusor strip response in vitro was evaluated. The reproductive organ weight, sperm content and motility as well as in vitro testosterone secretion and serum levels of LH and testosterone were determined. Diabetes induced significant reduction in mating behavior. The diabetic rats that received SBZ showed a significant improvement in mating behavior. The percentage of animals that exhibited ejaculation was 0% in the diabetic group compared to 70% in the controls and 38% in diabetic plus SBZ group. The strips of the detrusor muscle of the diabetic group showed a marked hypersensitivity to bethanechol HCL. In the diabetic plus SBZ group, the strips of the detrusor muscle showed a response similar to that of the control. The diabetic rats had significantly diminished reproductive organ weight, testicular sperm content, epididymal sperm content and sperm motility relative to the control. In addition, marked decrease in the serum level of testosterone and in vitro testosterone secretion was observed in diabetic rats. In the diabetic plus SBZ group, the reproductive organ weight, sperm content and motility as well as serum testosterone and in vitro testosterone secretion showed an improvement compared to diabetic rats. In summary, our data suggest that sex behavior and reproductive tract functions are markedly affected by streptozotocin induced diabetes. Sabeluzole treatment could be beneficial in reducing the deleterious effect of diabetes on sexual functions.

Electrical Stimulation Induced Sphincter Fatigue During Voiding

The stimulation of the sacral nerves to induce voiding is often associated with simultaneous contraction of the striated sphincter rendering micturition difficult or impossible. Rhizotomy of some sacral nerves was found to be necessary to facilitate voiding with stimulation. An main objective in the present experiment was to evaluate the feasibility of achieving the same result using electrical stimulation to fatigue the sphincter. In order to compare the effect of rhizotomy and fatiguing striated sphincter, the bladder outlet resistance was measured. S2 nerves were stimulated with 3 V, 35 Hz and 100 microseconds duration for 5 to 10 sec. Following S2 nerves stimulation the pudendal nerve was stimulated till we obtained sphincteric fatigue. The optimal parameter to induce sphincter fatigue were 3 V, 100-500 Hz and 100 microseconds. for 15-20 sec. The combined pressure-flow studies showed that fatiguing the sphincter via the pudendal nerve using these parameters was as good as cutting it in achieving bladder emptying with stimulation.

The Mode of Action of Prostaglandin E2, F2α and Prostacyclin on Vesicourethral Smooth Muscle

Abstract Interactions of prostaglandin E 2 (PGE 2 ), F 2α (PGF 2α ) and prostacyclin (PGI 2 ) with Ca 2+ on the isometric contraction of rabbit detrusor muscle strips were studied using two types of Ca 2+ antagonists of different mechanisms of action: verapamil and sodium nitroprusside (NP). The effects of PGI 2 on vesicourethral smooth muscle and their relationship with cholinergic, adrenergic receptors and nervous activity were also investigated. PGE 2 and F 2α (3 X 10 −8 to 3 X 10 −5 M) caused dose-dependent contraction of the strips. Pretreatment of the strips with verapamil (10 −7 to 10 −5 M) significantly inhibited PGs-induced contraction in a dose-dependent manner, whereas NP(10 −7 to 10 −5 M) failed to suppress the contraction. Relaxation of the preparations once contracted by PGE 2 and F 2a (3 X 10 −6 M) was induced completely by addition of verapamil (10 −5 M), and incompletely by NP(10 −5 to 10 −3 M). Washing of the strips with Ca 2+ -free solution containing 0.01xa0mM EGTA completely eliminated spontaneous activity and diminished basal tension, but replenishment of Ca 2+ (0.5 to 10xa0mM) to the medium caused dose-related contraction and spontaneous activity of the strips. Addition of PGE 2 and F 2α to the Ca 2+ -free medium enhanced Ca 2+ -induced contraction and spontaneous activity during Ca 2+ replenishment, which were significantly inhibited by pretreatment with verapamil (10 −7 to 10 −5 M) in a dose-dependent manner, but not affected by NP (10 −7 to 10 −5 M). In Ca 2+ -free medium containing 0.1xa0mM EGTA, PGE 2 and F 2ft , caused a slight degree of tension increase of the strips dose-dependently at the higher concentration exceeding 3 × 10 −6 M. PGI 2 (10 −9 to 3 × 10 −4 M) caused dose-dependent contraction of the strips from the bladder body, base and the urethra. The contractile action of PGI 2 was greatest on the bladder body, less on the base and minimal on the urethra. The effect of PGI 2 was less potent than those of PGE 2 and F 2α . The PGI 2 -induced contraction was slow in onset, short lasting, and not affected by pretreatment with phentolamine, propranolol, atropine, hexamethonium, hemicholinium-3 and tetrodotoxin. The interactions of PGI 2 with Ca 2+ were similar to those of PGE 2 and F 2 «. These results suggest that PGE 2 , F 2α and I 2 -induced detrusor muscle contraction is greatly dependent on transmembrane extracellular Ca 2+ influx, not only in its initiation but also in its maintenance, and that these PGs act at sarcolemmal level of detrusor smooth muscle cells in a manner that allows extracellular Ca 2+ to enter the cells at an accelerated pace. It is also suggested, however, that some intracellular Ca 2+ fractions might participate in the contractile effects of these PGs. PGI 2 was shown to exert the contractile effect directly on the smooth muscle independent of nervous activity and not mediated through adrenergic or cholinergic receptors.

Effects of verapamil, prostaglandin F2α, phenylephrine, and noradrenaline on upper urinary tract dynamics

OBJECTIVESnThe effects of verapamil (VRP), prostaglandin F2 alpha (PGF2 alpha), phenylephrine, and noradrenaline on upper urinary tract dynamics were studied in vivo, using a pig model involving 12 miniswine which were subjected to acute pharmacologic perfusion studies of the upper urinary tract.nnnMETHODnChanges in renal pelvic pressure (Ppvs) and ureteral peristalsis frequency were recorded at 2 mL/min perfusion rate premedication, and then during perfusion with different concentrations of each drug tested in three experiments.nnnRESULTSnPpvs showed no significant variations with VRP perfusion when compared with premedication readings, whereas ureteral peristalsis frequency was decreased significantly by 10(-3) mol/L of VRP. PGF2 alpha perfusion caused no statistically significant changes in Ppvs when compared with premedication values, but increased ureteral peristalsis frequency from 3 to 6.5/min at a concentration of 2 x 10(-1) mg (200 micrograms). Phenylephrine HCl and noradrenaline perfusion increased Ppvs from 8 +/- 1.1 to 11.9 +/- 1.6 cm water at a concentration of 100 micrograms. They augmented the frequency of ureteral peristalsis from about 2.5 +/- 1.2 to 4.1 +/- 1.3/min. No systemic effects were recorded since pulse, respiration, and left ureteral activity were unchanged during pharmacologic perfusion of the right side.nnnCONCLUSIONnPharmacologic manipulation of ureteral activity can be achieved via direct perfusion with no significant modulation of Ppvs or systemic impact. VRP-induced smooth muscle relaxation of the upper urinary tract may be useful in percutaneous surgery for stones.

HYPERREFLEXIA OF THE URINARY BLADDER: POSSIBLE ROLE OF THE EFFERENT FUNCTION OF THE CAPSAICIN SENSITIVE PRIMARY AFFERENTS

PURPOSEnCapsaicin sensitive primary afferents (CSPA) have been implicated in the pathogenesis of hyperreflexia after spinalization. In this study we investigated the role of the efferent function of these fibers in detrusor hyperreflexia and its effect on detrusor physiology and pharmacology.nnnMATERIALS AND METHODSnFour groups of female Sprague Dawley rats were included in our study. These groups were normal controls, capsaicin treated normal rats, spinalized rats and capsaicin treated spinalized rats. Six weeks following spinalization, animals were subjected to cystometric study, and bladders were obtained for either in vitro detrusor contractility study or substance P (SP), neurokinin A (NKA) and calcitonin gene related peptide (CGRP) quantification by radioimmunoassay.nnnRESULTSnSpinalized animals consistently developed hyperreflexia after spinalization in the form of uninhibited contractions more than 15 cm. water in amplitude. This was accompanied by increased urinary bladder total content of the neuropeptides but without any change in the detrusor contractility or neurokinin receptor pharmacology as shown by responses to KCl, electric field stimulation and neurokinin receptor selective agonists in the in vitro study. In the control group, urinary bladder total content of SP, NKA and CGRP was 0.19+/-0.03, 0.15+/-0.01 and 0.84+/-0.1 pmol/bladder respectively. In contrast, in the spinalized animals, these were 0.44+/-0.07, 0.21+/-0.03 and 2.28+/-0.34 pmol/bladder for the same peptides, respectively. Capsaicin treatment abolished hyperreflexia, which corresponded with the decrease in the neuropeptide content of the urinary bladder. The number and amplitude of the uninhibited contractions decreased dramatically. SP, NKA and CGRP reached 0.06+/-0.01, 0.07+/-0.01 and 0.44+/-0.18 pmol/bladder 2 weeks after capsaicin treatment in spinalized animals. This was associated with the occurrence of detrusor super-sensitivity to both neurokinin receptor selective agonists.nnnCONCLUSIONnThis study demonstrates the importance of the efferent function of the CSPA in the pathogenesis of hyperreflexia. On the other hand, detrusor changes were shown to be a noncrucial factor in the development of hyperreflexia.

Apomorphine versus mating behavior in testing erectile capabilities of diabetic rats

OBJECTIVESnDiabetes mellitus (DM) is an important cause of organic impotence. It is estimated that 35% to 75% of diabetic patients are impotent. In the present study we investigated the effect of experimentally induced diabetes (streptozocin 60 mg/kg, intraperitoneally, for 9 weeks) on sexual behavior and compared it to the apomorphine (APO) bioassay test.nnnMETHODSnLibido, genital reflex excitability, and penile competence as measured by different parameters of mating behavior were reduced with DM (P < 0.05 versus control for each parameter).nnnRESULTSnOf 17 diabetic rats, 53% (9 rats) experienced positive mating behavior (either intromission or ejaculation) compared with 82.4% (14 rats) positive response to the APO bioassay test. Moreover, combined apomorphine injection and mating sexual testing in diabetic rats that achieved intromission but not ejaculation or those that did not achieve intromission in the initial mating, considerably improved the performance of these rats.nnnCONCLUSIONSnWe suggest that the APO test alone or, even better, combined APO injection and sexual testing are superior in eliciting maximum erectile capabilities of the diabetic rats than mating testing alone.

Priapism: An Avoidable Complication of Pharmacologically Induced Erection

Priapism is an alarming complication during treatment of erectile dysfunction with vasoactive drugs, particularly papaverine alone or in combination with phentolamine mesylate. An investigational protocol was designed to identify patients who are more susceptible to priapism after intracavernous injection of papaverine alone or with phentolamine. The protocol was applied in 331 men with impotence of various etiology. The association of a positive response to visual sexual stimulation and penile brachial index of more than 0.8 represented a higher risk for post-injection priapism. We were able to reduce the incidence of this compliance to 1% in the last 101 patients.

The effect of early bladder stimulation on spinal shock: a preliminary report.

The period of spinal shock which frequently follows spinal cord injury is associated with bladder areflexia and urinary retention. We studied the effect of early bladder electric stimulation on detrusor activity during the spinal shock phase in the dog. The animals had a spinal cord section at T10 vertebra and their bladder management was assigned to one of the three following groups: intermittent catheterization, indwelling catheterization and electric bladder stimulation. The parameters for evaluating each treatment included: blood chemistry, radiographic and urodynamic tests. The salient feature was the early return of detrusor activity in the group of animals treated by early electric stimulation of the bladder.

Role of calcium ion antagonists of the bladder detrusor muscle: in vitro and in vivo study.

Calcium (Ca2+) ions play an important role in the contractility of the detrusor. Most of the neurotransmitters and modulators act on the detrusor through altering the final intracellular concentration of Ca2+. We studied three commonly used Ca2+ antagonists on their effect of detrusor contractility in vitro: verapamil, nifedipine and segontin. All three inhibited the detrusor-induced contraction in a dose-dependent fashion. Verapamil showed noncompetitive inhibition. Segontin showed a competitive inhibition on both phasic and tonic contractions of the detrusor strips. Nifedipine selectively inhibited the phasic contraction noncompetitively but competitively suppressed the tonic contraction. The in vivo application of verapamil on the bladder of rabbits with multiple-sclerosis-like disease showed a significant increase in bladder capacity. The study shows the possibility of the potential use of Ca2+-antagonist to suppress the problem of bladder instability.

Intravesical Instillation of a Calcium Entry Blocker and its Effects on Detrusor Contractility: In Vitro and Vivo Experiments

The effects of intravesical instillation of a Ca2+ entry blocker (verapamil) on the contractility of the bladder detrusor muscle of the rabbit were investigated in vitro and in vivo. In in vitro experiments, using whole bladder preparations, spontaneous contractile activity and contraction induced by direct electric stimulation or acetylcholine were monitored. Both activities were inhibited in a time-dependent manner after the intravesical instillation of 7.5 mg. verapamil. The amplitude of spontaneous contraction 90 minutes after the instillation, was reduced to 10 per cent of control (before the instillation), and the response to electric stimulation and acetylcholine were inhibited to 16 per cent and 38 per cent of controls respectively. The detrusor contractility was still inhibited two hours after the removal of verapamil from the bladder. This inhibition of the detrusor contractility after removal of verapamil was completely reversed by adding four mM Ca2+ intravesically. During in vivo experiments, the changes of intravesical pressure elicited by pelvic nerve stimulation and the systemic arterial pressure were monitored. Sixty minutes after the intravesical instillation of 10 mg. verapamil, the rise of the intravesical pressure following the pelvic nerve stimulation was inhibited to 18 per cent of control, while the systemic arterial pressure was not affected. It is suggested that the intravesical instillation of verapamil can inhibit detrusor contractility without affecting cardiovascular status.