Phloroglucinol inhibits human ureteral contractions via activation of cAMP‐PKA pathway

Abstract Background and Purpose Phloroglucinol is used to treat renal colic, especially when non‐steroidal anti‐inflammatory drugs are contraindicated. This study aimed to clarify its mechanism by examining effects on human ureteral contractility and underlying signalling pathways. Experimental Approach Urinary levels of neurokinin A (NKA), substance P (SP), 5‐hydroxytryptamine (5‐HT) and PGE 2 were measured in patients after acute renal colic. Human ureteral tissues from organ donors were studied in organ baths and myosin light chain (MLC) phosphorylation in human ureteral smooth muscle cells (hUSMCs) was assessed as a marker of contractile activity. Key Results Urinary NKA, SP and 5‐HT but not PGE 2 were significantly increased in patients with colic. Phloroglucinol concentration‐dependently inhibited rises in the basal tone during spasmic contractions evoked by high concentrations of KCl, NKA and 5‐HT. Phloroglucinol also attenuated the frequency of spontaneous or low concentrations of NKA‐evoked (30–100 nM) and 5‐HT‐evoked (3–10 μM) phasic contractions. The above inhibitory effects of phloroglucinol were significantly attenuated in the presence of SQ22536 (adenylate cyclase inhibitor) or H89 (PKA inhibitor). Although phloroglucinol attenuated EFS‐evoked (neurogenic) contractions, this effect was markedly weaker than that observed for myogenic contractions. Phloroglucinol increased intracellular levels of cAMP and PKA in hUSMCs, and reduced the enhanced MLC phosphorylation evoked by NKA (10 μM) and 5‐HT (100 μM). Conclusions and Implications These findings support the clinical use of phloroglucinol in treating renal colic, inhibiting ureteral spasm contractions via the activation of cAMP‐PKA signalling and provides a rationale for its potential utility in facilitating stone expulsion.