Objective: 

Vascular tone is regulated by endothelial release of vasoactive autacoids i.e. nitric oxide (NO), prostacyclin, and an endothelium-derived hyperpolarizing factor (EDHF). EDHF requires the opening of endothelial calcium-activated K⁺-channels (K_Ca), which leads to endothelial hyperpolarisation. Therefore, Ca²⁺-permeable transient receptor potential channels (TRP) may contribute.

Methods: 

In wildtype (wt) and TRPC1-deficient (TRPC1^-/-) mice vasodilations were studied in the cremaster muscle microcirculation in vivo and in carotid arteries using pressure myography in vitro. Ca²⁺ sparks and spontaneous transient outward currents (STOCs) were measured in isolated smooth muscle cells (SMC). Systolic blood pressure was determined using tail-cuff plethysmography.

Results: 

In the presence of Nitro-L-arginine and indomethacin spontaneous diameter of arterioles in vivo was significantly larger in TRPC1^-/- (14.2±0.7, wt: 11.9±0.5mm) indicating a lower spontaneous tone. ACh-induced EDHF-type dilations (presence of Nitro-L-arginine and indomethacin) were augmented in TRPC1^-/- arterioles in vivo as indicated by a shift of the EC₅₀ (from 3.25±1.29 to 0.66±0.18mmol/L, P<0.01) but nitroprusside and adenosine dilations were unchanged. Likewise, TRPC1-deficiency amplified ACh-induced EDHF-type dilations in carotid arteries in vitro (100nmol/L ACh: from 23±3 to 46±12%, P<0.05) but not ACh-induced NO-mediated dilations (presence of 32mmol/L K⁺). Vasoconstrictions to phenylephrine and 60mmol/L KCl were similar in wt and TRPC1^-/- carotid arteries. Ca²⁺-sparks and BK_Ca-mediated STOCs in isolated SMCs were equivalent in both genotypes. Systolic blood pressure was lower in TRPC1^-/- mice.

Conclusion: 

Our investigations demonstrate specifically amplified EDHF-type dilations in TRPC1-deficient mice despite preserved smooth muscle function. This suggests that TRPC1 acts as a negative regulator in the endothelial K_Ca/EDHF-type signalling complex.