Systemic and topical drug administration in the pig ureter: Effect of phosphodiesterase inhibitors alpha 1, beta and beta 2-adrenergic receptor agonists and antagonists on the frequency and amplitude of ureteral contractions

Purpose: We searched for compounds that are pharmacologically active on ure teral motility for treating ureteral colic to ease retrograde access into t he ureter and improve the clearance of stones or stone particles from the u reter. The effects of the 1 alpha -adrenergic receptor agonist phenylephrin e, the nonselective beta and beta2-adrenergic receptor agonists isoproteren ol and fenoterol, and the phosphodiesterase inhibitors papaverine (nonspeci fic) and rolipram (type IV) on the frequency and amplitude of ureteral cont ractions when administered intravenously or topically were investigated in pigs. Materials and Methods: A total of 52 pigs were anesthetized. A double lumen 6Fr catheter was inserted through each renal pelvis and into the ureter, a llowing perfusion of saline or drug solution into the renal pelvis and the recording of contractions from the mid portion of the ureter. Results: The alpha1 and beta -adrenergic receptors of the ureter are not to nically activated by endogenous epinephrine or norepinephrine. Phenylephrin e administered intravenously at a dose of 0.01 to 3 mg./kg. and topically a t 0.1 to 3 mg./ml. per minute increased contraction frequency 10 and 4-fold , respectively, and contraction amplitude 2-fold each in a dose dependent m anner. Arterial blood pressure increased markedly during intravenous admini stration of phenylephrine but was minimally affected during topical applica tion. The phenylephrine effects were reversed by the antagonist prazosin. I soproterenol administered intravenously at a dose of 0.01 to 10 mg./kg. and topically at 0.1 to 200 mug./ml. per minute decreased contraction frequenc y to 13% and 31% of controls, respectively. Contraction amplitude was not a ffected by intravenous administration but decreased to 59% of controls when applied topically. These effects were also observed with a slight delay in the saline perfused contralateral ureter. The heart rate also increased, s uggesting absorption of the drug by the urothelium. The isoproterenol effec ts were blocked by the antagonist propranolol. Fenoterol administered intra venously at a dose of 0.1 to 30 mug./kg. and topically at 0.003 to 1 mg./ml . per minute decreased contraction frequency to 14% and 10% of controls, an d contraction amplitude to 84% and 65%, respectively. These effects on the drug perfused ureter were also observed on the contralateral saline perfuse d ureter but to a lesser extent. The fenoterol effects were blocked by the antagonist propranolol. Papaverine administered intravenously at a dose of 0.001 to 3 mg./kg, decreased contraction frequency to 33% of controls. Topi cally administered papaverine as well as intravenous and topically administ ered rolipram had no relevant effect on ureteral motility. Conclusions: Intravenous phenylephrine increases, and isoproterenol and fen oterol decrease the frequency and amplitude of ureteral contractions in the pig. The same effects are observed with the topical administration of phen ylephrine, which causes a significant local but not systemic side effect. T opical administration of isoproterenol and fenoterol produced local as well as systemic effects, suggesting absorption by the urothelium. However, to our knowledge a drug that relaxes ureteral peristalsis in pigs without caus ing systemic side effects has not yet been identified.