Potassium inhibits nitric oxide and adenosine arteriolar vasodilatation via K_IR and Na⁺/K⁺ATPase: implications for redundancy in active hyperaemia

Abstract

Redundancy, in active hyperaemia, where one vasodilator can compensate for another if the first is missing, would require that one vasodilator inhibits the effects of another; therefore, if the first vasodilator is inhibited, its inhibitory influence on the second vasodilator is removed and the second vasodilator exerts a greater vasodilatory effect. We aimed to determine whether vasodilators relevant to skeletal muscle contraction [potassium chloride (KCl), adenosine (ADO) and nitric oxide] inhibit one another and, in addition, to investigate the mechanisms for this interaction. We used the hamster cremaster muscle and intravital microscopy to directly visualize 2A arterioles when exposed to a range of concentrations of one vasodilator [10(-8) to 10(-5) M S-nitroso-N-acetyl penicillamine (SNAP), 10(-8) to 10(-5) M ADO, 10 and 20 mM KCl] in the absence and then in the presence of a second vasodilator (10(-7) M ADO, 10(-7) M SNAP, 10 mM KCl). We found that KCl significantly attenuated SNAP-induced vasodilatations by ∼65.8% and vasodilatations induced by 10(-8) to 10(-6) M ADO by ∼72.8%. Furthermore, we observed that inhibition of KCl vasodilatation, by antagonizing either Na(+)/K(+) ATPase using ouabain or inward rectifying potassium channels using barium chloride, could restore the SNAP-induced vasodilatation by up to ∼53.9% and 30.6%, respectively, and also restore the ADO-induced vasodilatations by up to ∼107% and 76.7%, respectively. Our data show that vasodilators relevant to muscle contraction can interact in a way that alters the effectiveness of other vasodilators. These data suggest that active hyperaemia may be the result of complex interactions between multiple vasodilators via a redundant control paradigm.

Inhibition of Na+/K+‐ATPase and KIR channels abolishes hypoxic hyperaemia in resting but not contracting skeletal muscle of humans

“…; Markwald et al . ; Joyner & Casey, ; Lamb & Murrant, ), we performed a follow‐up protocol (Protocol 2) to test the contribution of Na + /K + ‐ATPase and K IR channel activation alone. The experimental approach in Protocol 2 was identical to Protocol 1, with the exception being that only Na + /K + ‐ATPase and K IR channels were inhibited (ouabain and BaCl 2 , respectively) in the blocked condition.…”

“…In total, four experimental trials each separated by 20 min of rest were performed, and the order of normoxic and hypoxic trials before and after blockade was counterbalanced between subjects. Given the lack of an additional effect of Na + /K + -ATPase and K IR channel inhibition (see Results) compared to our previous findings with NO/PG inhibition alone (Crecelius et al 2011b) and the possibility that redundant vasodilator signalling could mask an effect of inhibiting these pathways (Schrage et al 2004;Markwald et al 2011;Joyner & Casey, 2014;Lamb & Murrant, 2015), we performed a follow-up protocol (Protocol 2) to test the contribution of Na + /K + -ATPase and K IR channel activation alone. The experimental approach in Protocol 2 was identical to Protocol 1, with the exception being that only Na + /K + -ATPase and K IR channels were inhibited (ouabain and BaCl 2 , respectively) in the blocked condition.…”

“…Second, this could suggest that NO and PGs and Na + /K + -ATPase and K IR channels operate in a redundant fashion. However, if these pathways were operating in a redundant manner, we would expect that NO/PG inhibition alone, or Na + /K + -ATPase and K IR channel inhibition alone, would not impact hypoxic vasodilatation and that the response would be abolished only when all four pathways are inhibited (Markwald et al 2011;Lamb & Murrant, 2015). Finally, it is possible that multiple pathways are involved in the regulation of vascular tone during hypoxia and perhaps, depending on the study, inhibition of a given pathway may significantly reduce or almost abolish the response.…”

Contribution of prostaglandins to exercise hyperaemia: workload, ethnicity and sex matter!

“…Accordingly, superfusion of hamster cremaster muscle with K + at 10 mM, as measured in interstitium during high workloads (Juel et al . ), attenuated arteriolar dilatation induced by graded concentrations of adenosine or NO donor, whereas neither NO donor nor adenosine affected dilatation induced by high K + (Lamb & Murrant, ). Given the mechanisms by which adenosine and NO evoke dilatation include opening of K + channels (Edwards et al .…”

Integration of vasodilatory stimuli in skeletal muscle vasculature: subtraction by addition?

“…In the 1 December 2015 issue of The Journal of Physiology , Lamb and colleagues attempt to directly test assumptions surrounding the redundant dilator hypothesis. Specifically, they aimed to identify inhibitory interactions between vasodilators where the presence of an interacting vasodilator can limit the action of others (Lamb & Murrant, ). If this scenario were to exist, blocking the action of the interacting vasodilator would remove inhibition of the secondary vasodilatory pathways thus allowing for compensatory vasodilatation.…”