Three major ionic currents, Ca2+-dependent K+ current (IK-Ca), delayed rectifier type K+ current (Ikd) and Ca2+ current (ICa), were activated by depolarization under whole-cell clamp in single smooth muscle cells isolated from guinea-pig urinary bladder. Externally applied ruthenium red (RuR) reduced the amplitude of IK-Ca and ICa at 0 mV (IC50 values were 4.2 and 5.6 muM, respectively), but did not affect IKd. Spontaneous transient outward currents (STOCs) and caffeine-induced outward currents (Icaf) at -30 mV were reduced by external 10 muM RuR. When 10 muM RuR was added to the pipette solution, IK-Ca during depolarization, STOCs and Icaf significantly decreased with time. RuR did not change the unitary current amplitude of the large-conductance Ca2+-dependent K+ (BK) channels, but reduced the open probability of the channel under excised patch-clamp recording mode. RuR reduced the channel activity more effectively from the cytosolic face than from the other. This inhibition decreased when the cytosolic Ca2+ concentration was increased. These results indicate that RuR blocks BK and Ca2+ channels in urinary bladder smooth muscle cells. The decrease in IK-Ca, STOCs and Icaf by RuR is attributable to the direct inhibition of BK channel activity, probably in addition to the inhibition of Ca2+ release from storage sites. The direct inhibition of BK channel activity by RuR may be related to the interaction of RuR with the Ca2+-binding sites of the channel protein.

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The incidence of lower urinary tract symptoms (LUTS) in people consulting general practitioners (GPs) was investigated. We used a questionnaire including seven questions regarding LUTS and one question regarding bothersomeness based on the International Prostate Symptom Score (I-PSS), three questions on the Overactive Bladder Symptom Score (OABSS) and four questions on the International Consultation on Incontinence Questionnaire Short-Form (ICIQ-SF), and conducted the survey among 1120 people aged 50 or older who consulted 17 GP clinics. Of 958 persons (86%) who responded the questionnaires, we analyzed the data from 822 (73%) who completed all the above questions. There were 364 men (mean age, 67 years) and 458 women (mean age, 68 years). Moderate or severe grades in I-PSS and OABSS were indicated in 99 (27%) and 43 (12%), for men, respectively, and 55 (12%) and 39 (9%) for women, respectively. I-PSS correlated with age in men and OABSS did in both genders. Most people with moderate or severe I-PSS experienced moderate or severe bothersomeness. Fifty-five (15%) men and 185 (40%) women indicated that they had some type of urinary incontinence. There were 138 (38%) men and 165 (36%) women showing both moderate or severe I-PSS, and moderate or severe bothersomeness, and/or with an ICIQ-SF score of 1 or greater. Approximately one-third of men and women aged 50 or older consulting GPs have bothersome LUTS, including urinary incontinence. We believe that they should be carefully assessed to determine whether they need treatment.

The effects of ruthenium red (RuR) on contractility were examined in skinned fibers of guinea pig smooth muscles, where sarcoplasmic reticulum function was destroyed by treatment with A-23187. Contractions of skinned fibers of the urinary bladder were enhanced by RuR in a concentration-dependent manner (EC50 = 60 μM at pCa 6.0). The magnitude of contraction at pCa 6.0 was increased to 320% of control by 100 μM RuR. Qualitatively, the same results were obtained in skinned fibers prepared from the ileal longitudinal smooth muscle layer and mesenteric artery. The maximal contraction induced by pCa 4.5 was not affected significantly by RuR. The enhanced contraction by RuR was not reversed by the addition of guanosine 5′- O-(2-thiodiphosphate) or a peptide inhibitor of protein kinase C [PKC-(19—31)]. The application of microcystin, a potent protein phosphatase inhibitor, induced a tonic contraction of skinned smooth muscle at low Ca2+ concentration ([Ca2+]; pCa > 8.0). RuR had a dual effect on the microcystin-induced contraction-to- enhancement ratio at low concentrations and suppression at high concentrations. The relaxation following the decrease in [Ca2+] from pCa 5.0 to >8.0 was significantly slowed down by an addition of RuR. Phosphorylation of the myosin light chain at pCa 6.3 was significantly increased by RuR in skinned fibers of the guinea pig ileum. These results indicate that RuR markedly increases the Ca2+ sensitivity of the contractile system, at least in part via inhibition of myosin light chain phosphatase.