The stimulatory action of carbachol and acetylcholine (ACh) on phosphoinositide turnover, as well as their contractile effects, were investigated in human isolated detrusor muscle. Carbachol, and ACh in combination with 10(-7) M physostigmine, induced increases in phosphoinositide turnover. However, at all the concentrations tested, carbachol was more effective than ACh (plus physostigmine), and at the highest concentration used (10(-4) M), the difference was significant (p less than 0.05). Also in a Ca(2+)-free medium containing the chelator EGTA (10(-4) M), both agonists (10(-4) M) induced small but distinct increases in phosphoinositide breakdown. Carbachol and ACh contracted the detrusor preparations concentration-dependently, and the responses were almost identical when ACh was combined with 10(-7) M physostigmine. In Ca(2+)-free medium the agonists elicited a moderate but concentration-dependent contractile response at high concentrations. The results show that muscarinic receptor agonists stimulate phosphoinositide turnover in the human bladder. Possibly, this effect is coupled to multiple muscarinic receptor subtypes. More studies are required to elucidate to what extent phosphoinositide breakdown participates in the contractile activation of this tissue.

A previously unrecognized non-adrenergic, non-nitrergic, non-prostanoid inhibitory mediator is released from the rat urinary bladder by muscarinic receptor stimulation. The physiological importance of such a factor remains to be established.

The effects of the calcium channel blockers (CCBs) verapamil, nifedipine and diltiazem on contractile activation of isolated human penile erectile tissues were investigated. Specimens of the corpus spongiosum (CS) and corpora cavernosa (CC) were obtained from men with a history of normal penile erection undergoing cystourethrectomy because of bladder malignancy. Preparations were mounted in organ baths and isometric tension was recorded. Deprivation of extracellular calcium abolished electrically induced contractions in both CS and CC preparations within 15 min.; norepinephrine (NE)-induced contractions were reduced by 90% (CS) and 83% (CC) after 30 min. All the CCBs reduced electrically induced contractions concentration-dependently, nifedipine being the most potent agent. Contractions induced by exogenous NE were depressed by about 50%, whereas high K+ (124 mM) induced responses were abolished. It is concluded that contraction in penile erectile tissues is mediated mainly by neuronally released NE stimulating postjunctional alpha-adrenoceptors. The contraction is highly dependent on extracellular calcium and can partly be inhibited by CCBs. It cannot be excluded that some CCBs injected intracavernosally may be useful for diagnosis and even treatment of erectile dysfunction. However, calcium channel blockade may not be as effective as a therapeutic principle as blockade of alpha-adrenoceptors.

In isolated bladder smooth muscle from both rabbit and man, carbachol-induced contractions were reduced by the calcium channel blocker nifedipine, whereas the calcium channel promotor Bay K 8644 had no effect. In nominally calcium-free medium containing 10(-4) M EGTA, carbachol-induced contractions were reduced by 69% (rabbit) and 87% (man). These contractions were abolished by nifedipine, whereas Bay K 8644 significantly increased their amplitude, in rabbit preparations almost to control level. Electrical field stimulation produced contractions which could be suppressed by scopolamine by about 50% (rabbit) and more than 90% (man). These contractions were abolished by calcium-free medium (10(-4) M EGTA), suppressed by nifedipine, but significantly enhanced by Bay K 8644. The depressant effects of nifedipine, verapamil and diltiazem were reversed by Bay K 8644. The calcium channel blockers relaxed K+-induced contractions to base line, and this action was counteracted by Bay K 8644, less effectively when relaxations were induced by diltiazem. It is concluded that contractions produced by muscarinic receptor stimulation are primarily dependent on calcium bound to the outside of the membrane of the smooth muscle, and/or coming from the extracellular medium. Electrically evoked, scopolamine sensitive contractions seem to be mediated by a mechanism different from that of contractions produced by exogenously added muscarinic receptor agonist. The present data support the view that combined blockade of muscarinic receptors and calcium channels is an effective way of inhibiting bladder contractions in both rabbit and man.