OBJECTIVE To establish the methods, feasibility and utility of evaluating the impact of diabetes on bladder and erectile function in the same rat, as more than half of diabetic patients have bladder dysfunction, and half of diabetic men have erectile dysfunction, but the severity of coincident disease has not been rigorously assessed. MATERIALS AND METHODS In all, 16 F‐344 rats had diabetes induced by streptozotocin (STZ), and were divided into insulin‐treated (five) and untreated (11), and compared with age‐matched controls (10), all assessed in parallel. All STZ rats were diabetic for 8–11 weeks. Cystometric studies were conducted on all rats, with cavernosometric studies conducted on a subset of rats. RESULTS There were insulin‐reversible increases in the following cystometric variables; bladder weight, bladder capacity, micturition volume, residual volume, micturition pressure and spontaneous activity (P < 0.05, in all, one‐way analysis of variance, anova). Cavernosometry showed a diabetes‐related, insulin‐reversible decline in the cavernosal nerve‐stimulated intracavernosal pressure (ICP) response at all levels of current stimulation (P < 0.05, in all one‐way anova). Plotting erectile capacity (i.e. ICP) against bladder capacity showed no correlation between the extent of the decline in erectile capacity and the magnitude of the increase in bladder capacity. CONCLUSIONS These studies extend previous work to indicate that the extent of diabetes‐related bladder and erectile dysfunction can vary in the same rat. As such, these findings highlight the importance of evaluating the impact of diabetes on multiple organ systems in the lower urinary tract. Future studies using this model system should lead to a better understanding of the initiation, development, progression and coincidence of these common diabetic complications.

The goal of these studies was to examine the potential utility of bladder instilled K+ channel gene therapy with hSlo cDNA (i.e., the maxi-K channel) to ameliorate bladder overactivity in a rat model of partial urinary outlet obstruction. Twenty-two female Sprague-Dawley rats were subjected to partial urethral (i.e., outlet) obstruction, with 17 sham-operated control rats run in parallel. After 6 wk of obstruction, suprapubic catheters were surgically placed in the dome of the bladder in all rats. Twelve obstructed rats received bladder instillation of 100 microg of hSlo/pcDNA in 1 ml PBS during catheterization, and another 10 obstructed rats received 1 ml PBS (7 rats) or 1 ml PBS containing pcDNA only (3 rats). Two days after surgery cystometry was performed on all animals to examine the characteristics of the micturition reflex in conscious and unrestrained rats. Obstruction was associated with a three- to fourfold increase in bladder weight and alterations in virtually every micturition parameter estimate. PBS-injected obstructed rats routinely displayed spontaneous bladder contractions between micturitions. In contrast, hSlo injection eliminated the obstruction-associated bladder hyperactivity, without detectably affecting any other cystometric parameter. Presumably, expression of hSlo in rat bladder functionally antagonizes the increased contractility normally observed in obstructed animals and thereby ameliorates bladder overactivity. These initial observations indicate a potential utility of gene therapy for urinary incontinence.

Context:Many advances have taken place in the detection of diabetic polyneuropathy with respect to examination scores, electrophysiological techniques and quantitative sensory testing.Aim:This study aims to evaluate the discriminative power of the Diabetic Neuropathy Examination Score (DNE), 10-g Semmes-Weinstein Monofilament Examination (SWME) and Quantitative Sensory Testing by Vibration Perception Threshold (VPT) in the diagnosis of diabetic polyneuropathy and seek an optimal screening method in diabetic clinic.Materials and Methods:Hundred consecutive patients with Type 2 diabetes were subjected to Diabetic Neuropathy Symptom Score, DNE score, Semmes-Weinstein monofilament examination, Vibration Perception Threshold and Nerve Conduction Studies; mean ± SD for the various characteristics were calculated. Sensitivity and specificity for the DNE, SWME and VPT were calculated, taking NCS as gold standard.Results:Seventy one of 100 subjects had evidence of neuropathy confirmed by Nerve Conduction Studies, while 29 did not have neuropathy. The DNE score gave a sensitivity of 83% and a specificity of 79%. The sensitivity of SWME was 98.5% and specificity was 55%. Vibration Perception Thresholds yielded a sensitivity of 86% and a specificity of 76%.Conclusions:A simple neurological examination score is as good as Vibration Perception threshold in evaluation of polyneuropathy in a diabetic clinic. It may be a better screening tool for diagnosis of diabetic polyneuropathy in view of the cost effectiveness and ease of applicability.

Lagaud, Guy, Venkateswarlu Karicheti, Harm. J. Knot, George J. Christ, and Ismail Laher. Inhibitors of gap junctions attenuate myogenic tone in cerebral arteries. Am J Physiol Heart Circ Physiol 283: H2177-H2186, 2002; 10.1152/ajpheart. 00605.2001.-The effects of two structurally distinct inhibitors of gap junction communication were studied by using three different forms of vasoconstriction in pressurized rat middle cerebral arteries. The sensitivity of myogenic tone (at 60 mmHg), vasopressin-induced tone (10 nM, at 20 mmHg), and depolarizing solution-induced tone (80 mM K ϩ , at 20 mmHg) to inhibition by heptanol (1.0 M to 3.0 mM) or 18␣-glycyrrhetinic acid (18␣-GA, 1.0 to 50 M) were determined. Pressure-induced myogenic tone was inhibited by heptanol (IC50 ϭ 0.75 Ϯ 0.09 mM) and 18␣-GA (ϳ30 M). Vasopressin-induced vasoconstriction was also inhibited by heptanol (IC 50 ϭ 0.4 Ϯ 0.3 mM) and 18␣-GA (Ͼ1 M). Depolarizing solution-induced vasoconstriction was less sensitive to inhibition by heptanol compared to vasopressin (P Ͻ 0.01) or pressure-induced constriction (P Ͻ 0.05). However, 18␣-GA did not inhibit depolarization-induced constriction. Sharp microelectrode experiments on isolated arteries revealed stable membrane potentials, with no detectable effect of heptanol (1 mM) or 18␣-GA (20-30 M) on the average membrane potential at 20 mmHg. However, Ϸ20% of impaled cells (5 of 28) exhibited uncharacteristic oscillations in membrane potential after pharmacological uncoupling. At 60 mmHg a Ϸ7-to 9-mV hyperpolarization and corresponding vasodilation (Ϸ50%) was observed, and the frequency of membrane potential oscillations doubled (9 of 23 cells). These data indicate that gap junctions play an important role in the maintenance and modulation of membrane potential and tone in cerebral resistance arteries.heptanol; glycyrrhetinic acid; vascular smooth muscle; resistance arteries; vasopressin and depolarization RESISTANCE ARTERIES react to increases and decreases in transmural pressure by constriction and dilation, respectively. This ability to respond to pressure in a manner independent of neurohormonal modulation (15) resides in vascular smooth muscle cells and was therefore termed a "myogenic response" (22). Currently, the mechanisms producing pressure-induced constriction are complex and not fully understood. However, elevations in pressure produce smooth muscle depolarization, which coincides with arterial constriction, and in some studies the production of spontaneous action potentials (20)(21)24). This in turn results in an inward movement of Ca 2ϩ via voltageoperated Ca 2ϩ channels. The net result of Ca 2ϩ influx (associated with membrane depolarization), coupled with enhanced myofilament calcium sensitivity, is an increase in vascular tone (15,24,28). Despite the stable arterial diameter commonly observed in small pressurized cerebral arteries, recent studies in resistance arteries demonstrate great individual variability in Ca 2ϩ -signaling modalities in individual myocytes within the vascular wall, suggesting...

1 The eects of the putative intercellular uncoupling agent 1-heptanol on electrical activity in the guinea-pig vas deferens were studied by use of intracellular and extracellular recording techniques. 2 At concentrations of 0.5, 1 and 2 mM, heptanol rapidly, monotonically and reversibly attenuated intracellularly recorded excitatory junction potential (e.j.p.) amplitude without aecting its time course, while spontaneous excitatory junction potentials (s.e.j.ps) were left unaected.

Urine storage is facilitated by somatic (pudendal nerve) and sympathetic [hypogastric nerve (HgN)] reflexes to the urethral rhabdosphincter (URS) and urethral smooth muscle, respectively, initiated by primary afferent fibers in the pelvic nerve (PelN). Inhibition of storage reflexes is required for normal voiding. This study characterizes a urine storage reflex inhibitory network that can be activated by PelN afferent fibers concurrently with the reflexes themselves. Electrical stimulation of PelN produced evoked potentials recorded by URS EMG electrodes (10-ms latency) or HgN electrodes (60-ms latency) in chloralose-anesthetized cats. When a second (i.e., paired) pulse of the same stimulus intensity was applied to the PelN 50-500 ms after the first, the reflexes evoked by the second stimulus were inhibited. The inhibition was maximal at paired-pulse intervals of 50-100 ms and remained after acute spinal transection at T10, confirming that the inhibitory center is located in the spinal cord. The 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tertralin (8-OH-DPAT; 3-300 mug/kg iv) consistently reduced the paired-pulse inhibition from 20% to 60% of control in spinal-intact animals but had no effect in acute spinal animals (i.e., supraspinal site of action). N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-2-pyridinylcyclohexanecarboxamide maleate (300 mug/kg iv) completely reversed 8-OH-DPAT's effects. The PelN-HgN reflex paired-pulse inhibition was not affected by 8-OH-DPAT. These results indicate the presence of a spinal, urine storage reflex, inhibitory center (SUSRIC) that is activated within 50 ms after activation of the reflexes themselves. SUSRIC is inhibited (disfacilitated) by supraspinal 5-HT(1A) receptors.

Smooth muscle cells constitute a heterogeneous collection of effector cells that, by virtue of both their constituency in blood vessels and presence as primary parenchymal cells in diverse tissues, affect the function of all organs. Thus, perhaps it is not surprising that alterations in, and/or dysfunction of, smooth muscle cells are quite common, and responsible, at least in part, for the morbidity and mortality associated with a very wide range of human diseases. These facts point to the necessity for improved understanding of the mechanism(s) governing the control of myocyte contractility (i.e., tone). Such understanding has been rapidly forthcoming in recent years, and has indicated that in many smooth muscle cell types intercellular communication through gap junctions acts in concert with nonjunctional (K+) ion channels to make important contributions to the control of myocyte tone and tissue homeostasis in physiologically diverse organs. Intercellular communication through connexin43-derived gap junction channels and K+ flux through the KCa and KATP channel subtypes, in particular, appear to play prominent roles in this process. The goal of this report, therefore, is to review the data concerning junctional and nonjunctional ion channels on the detrusor myocytes of the urinary bladder, as well as on the specialized vascular myocytes of the corpus cavernosum. The choice of an excitable (i.e., bladder detrusor myocytes) and nonexcitable (i.e., corporal smooth muscle) smooth muscle cell type ensures that the discussion will at least encompass consideration of a large portion of the spectrum of physiological possibilities for the participation of junctional and nonjunctional ion channels in the initiation, maintenance and modulation of smooth muscle tone. A central thesis of this communication is that detailed knowledge of the myocyte- and tissue-specific properties of K+ channels and gap junctions will likely lead to the improved understanding and treatment of human smooth muscle diseases/disorders.

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