Histamine causes endothelium‐independent dilation of mouse bladder feeder arterioles

In addition to being highly vascularized, the urinary bladder vasculature has unique properties that help to maintain blood flow during voiding and filling. Unlike other vessels of similar size, however, bladder arterioles do not contract to increases in intraluminal pressure. Prolonged decreases in bladder blood flow are linked to many types of bladder dysfunction, including painful bladder syndrome and interstitial cystitis. Although the vasculature has an important role in bladder dysfunction, the mechanisms regulating vasculature diameter in the bladder are still widely unknown. We tested the hypothesis that histamine, an important pro‐inflammatory compound released from mast cells in the bladder wall, also alters bladder arteriolar diameter. Using pressure myography with isolated bladder feed arterioles, concentration‐response curves to histamine (1 nM – 10 µM) were performed in vessels constricted with the thromboxane mimetic U‐46619 (10 nM). Histamine caused a concentration‐dependent vasodilation that was inhibited by the histamine H2 receptor antagonist cimetidine (10 µM) but not the H1 receptor antagonist fexofenadine (10 µM). Histamine‐dependent vasodilation was not inhibited by the NOS inhibitor L‐NAME (200 µM), the inward rectifier K+ channel blocker BaCl2 (100 µM), or endothelial denudation, suggesting the dilation was endothelium‐independent. Alternatively, increasing extracellular K+ (35 mM) or exposure to the KV channel blocker XE‐991 (10 µM) attenuated dilations to histamine. These findings suggest the H2 receptors in bladder vascular smooth muscle, and not the endothelium, mediate histamine‐induced dilation in bladder arterioles. Since H2 receptors are coupled to GaS, these findings also suggest that histamine dilation results from an increase in cAMP that may hyperpolarize smooth muscle cells via protein kinase A‐mediated activation of smooth muscle KV channels.