tetrodotoxin and Urinary-Incontinence

To evaluate the effect of St. John's wort (SJW), an effective and safe herbal antidepressant, on rat bladder contractility. Recent data have suggested a strong association between depression and urinary incontinence.. Strips were cut from the bladder body and placed in organ baths containing Krebs solution. Contractions were induced by electrical field stimulation (EFS) and, in some experiments, by exogenous alpha,beta (alpha,beta)-methylene adenosine triphosphate.. St. John's wort was significantly more active in inhibiting the EFS-induced contractions than the alpha,beta-methylene adenosine triphosphate-induced contractions, suggesting both a presynaptic site of action and a direct inhibition of bladder smooth muscle. The inhibitory effect of SJW on EFS-induced contractions was unaffected by methysergide, haloperidol, phentolamine plus propranolol (antagonists that block the action of the neurotransmitters 5-hydroxytriptamine, dopamine, and noradrenaline on their own receptors), the L-type calcium channel antagonist verapamil, capsazepine (which blocks the vanilloid receptor), or cannabinoid CB1 receptor antagonist SR141716A. However, the opioid receptor antagonist naloxone significantly reduced the inhibitory effect of SJW on EFS-induced contractions. Among the chemical constituents of SJW tested, hyperforin and, to a lesser extent, the flavonoid kaempferol showed inhibitory effects.. The results of our study demonstrated that SJW inhibits excitatory transmission of the rat urinary bladder and also directly inhibits smooth muscle contractility. The inhibitory effect on excitatory transmission could involve, at least in part, opioid receptors. SJW may be evaluated for its possible use in treating urinary incontinence in depressed patients.

Topics: Acetylcholine; Adenosine Triphosphate; Animals; Anthracenes; Antidepressive Agents; Atropine; Bridged Bicyclo Compounds; Capsaicin; Depression; Electric Stimulation; Female; Haloperidol; Hypericum; Kaempferols; Male; Methysergide; Muscle Contraction; Muscle, Smooth; Naloxone; Perylene; Phentolamine; Phloroglucinol; Piperidines; Plant Extracts; Propranolol; Pyrazoles; Quercetin; Rats; Rats, Wistar; Rimonabant; Rutin; Terpenes; Tetrodotoxin; Urinary Bladder; Urinary Incontinence; Verapamil

Bladder overactivity associated with outflow obstruction is a common human condition recapitulated in the female rat by narrowing the diameter of the urethra. The goal of these studies was to evaluate the role of intercellular communication through connexin43 (Cx43)-derived gap junction channels to bladder overactivity following partial urethral outflow obstruction of 3-day to 6-wk duration. Cx43 mRNA and protein expression were barely detectable by Northern or Western blots, respectively, in the detrusor layer of normal bladders, but bands were found with both techniques after 6 wk of obstruction. Linear regression analysis of the RT-PCR data revealed a statistically significant positive correlation between the duration of obstruction (again, ranging from 3-day to 6-wk duration) and Cx43 mRNA transcript levels, such that after 6 wk of obstruction, Cx43 transcript levels were approximately 15-fold greater than initial control values. When taking into account the approximately fivefold increase in bladder weight over this same time frame, the absolute amount of Cx43 mRNA in the bladder apparently increased by approximately 75-fold. In that regard, as anticipated, and consistent with previous observations, 6 wk of obstruction was also associated with a significant increase in spontaneous bladder contractions between micturitions. The amplitude of these contractions was significantly reduced by heptanol given intravesically. Furthermore, carbachol-precontracted bladder strips from obstructed animals were more sensitive to heptanol-induced relaxation (100 microM) than their unobstructed counterparts (n = 6; P < 0.01). When bladder strips were equivalently precontracted via electrical field stimulation (EFS; 20 Hz), similar heptanol-induced relaxation responses were observed. However, the tetrodotoxin-resistant portion of the EFS-induced contraction was greater in the obstructed than in the unobstructed animals, and this portion of the contractile response was more sensitive to heptanol-induced relaxation in obstructed than unobstructed bladders (n = 7; P < 0.01). Taken together, these observations indicate that partial outlet obstruction produces an overactive bladder that may be more dependent on intercellular communication through gap junctions for modulation of contractile responses than its normal counterpart.

Topics: Animals; Carbachol; Cell Communication; Connexin 43; Disease Models, Animal; Female; Gap Junctions; Gene Expression; Heptanol; Muscle Contraction; Muscle Relaxation; Organ Size; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tetrodotoxin; Time Factors; Urinary Bladder; Urinary Incontinence