Experimental Hyperreflexia: Effect of Intravesical Administration of Various Agents

Abstract

In anesthetized rabbits, we can induce a significant degree of spontaneous activity in the urinary bladder by placing a ligature around the proximal portion of the external urethra. Previous studies characterized the activity as primarily reflex in nature, since intravesical hexamethonium selectively inhibited the hyperreflexia. In this current study we determined the effect of intravesical administration of a variety of compounds to inhibit the induced hyperreflexia. The following agents were tested at concentrations of 1, 10, 100 and 500 μmol/l (intravesically): verapamil, cromakalim, nifedipine, diltiazem, and atropine; lidocaine was tested in 0.05, 0.5 and 5% solutions. The results are summarized as follows: (1) Lidocaine was the most effective agent tested, virtually eliminating both the amplitude and frequency of the spontaneous activity at the lowest concentration (0.5%). (2) Verapamil and nifedipine were somewhat more potent than cromakalim and diltiazem. Atropine sulfate was the least potent, inhibiting both the amplitude and frequency of the hyperreflexia by less than 50% at 500 μmol/l. (3) In all cases, the amplitude of the spontaneous activity was inhibited to a significantly greater degree than the frequency of the spontaneous activity. (4) In general, there was no effect of any of the agents on mean arterial pressure at 1 or 10 μmol/l. At 100 and 500 μmol/l, all agents except for lidocaine and cromakalim decreased arterial pressure. These two agents produced no consistent fall in blood pressure at any concentration. In conclusion, the acute hyperreflexic (rabbit) preparation provides a highly reproducible and consistent model for the study of the effect of drugs on hyperreflexia. The data presented in this report would indicate that the intravesical administration of antispasmodic (and other) agents might provide a useful method of treatment for this condition.

Role of the T‐type Ca2+ current on the contractile performance of guinea pig detrusor smooth muscle

“…Their presence is increased in human tissue obtained from patients with unstable bladders [Kinder and Mundy, 1987] as well as from animal models of out£ow tract obstruction [Malmgren et al, 1989;Kato et al, 1990], and it has been proposed that they contribute to overactivity of the bladder in such patients. The contractions are insensitive to tetrodotoxin but are attenuated by raised extracellular Mg and L-type Ca 2þ channel antagonists [Levin et al, 1991; and, as shown in this study, low concentrations of Ni 2þ . It is presumed that their origin is myogenic and does not originate from increased motor nerve excitability or activity, as spontaneous Ca 2þ transients can be recorded in isolated cells that are also greatly inhibited by nicardipine (Wu and Fry, unpublished data).…”

Comparative Effects of Intravesical versus Extravesical Administration of ZD6169 and Cromakalim on the Response of the in vitro Rat Whole Bladder to Field Stimulation

“…In previous studies using both isolated strips of detrusor, and an in vivo rabbit model of hyperreflexia, ZD6169 was a more potent inhibitor than cromakalim [5], These studies indicate that ZD 6169 may be clinically useful in the treatment of specific urinary bladder disorders characterized by hyperreflexia and/ or detrusor hyperactivity.…”

The effect of levcromakalim (BRL 38227) on bladder function in patients with high spinal cord lesions.

“…Cromakalim abolishes spontaneous bladder contractions in pigs [5], rats [8] and rabbits [9] with bladder instability, with little change in other urodynamic variables. Cromakalim also lowers blood pressure in pigs when administered in doses that suppress the unstable contractions [5].…”