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We sought to determine the physiological relevance of pannexin/purinergic‐dependent signaling in mediating conducted vasodilation elicited by capillary stimulation through skeletal muscle contraction. Using hamster cremaster muscle and intravital microscopy we stimulated capillaries through local muscle contraction while observing the associated upstream arteriole. Capillaries were stimulated with muscle contraction at low and high contraction (6 and 60CPM) and stimulus frequencies (4 and 40 Hz) in the absence and presence of pannexin blocker mefloquine (MEF; 10−5 M), purinergic receptor antagonist suramin (SUR 10−5 M) and gap‐junction uncoupler halothane (HALO, 0.07%) applied between the capillary stimulation site and the upstream arteriolar observation site. Conducted vasodilations elicited at 6CPM were inhibited by HALO while vasodilations at 60CPM were inhibited by MEF and SUR. The conducted response elicited at 4 Hz was inhibited by MEF while the vasodilation at 40 Hz was unaffected by any blocker. Therefore, upstream vasodilations resulting from capillary stimulation via muscle contraction are dependent upon a pannexin/purinergic‐dependent pathway that appears to be stimulation parameter‐dependent. Our data highlight a physiological importance of the pannexin/purinergic pathway in facilitating communication between capillaries and upstream arteriolar microvasculature and, consequently, indicating that this pathway may play a crucial role in regulating blood flow in response to skeletal muscle contraction. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We hypothesized that CO2 and H+ stimulate capillaries and arterioles to produce local and conducted vasodilations required to coordinate the distribution of blood flow to contracting skeletal muscle fibers. Methods: CO2 and H+ independently and in combination were applied to 2A arterioles (first branch order from the 1A feed arteriole) and capillaries of the in situ, blood‐perfused hamster cremaster muscle. The resulting local and conducted vasodilations were measured. Results: H+ (pH: 7.2‐6.6) and CO2 (5% and 10%) applied to the vascular network induced 2A arteriolar vasodilations, while 15% CO2 produced vasoconstriction. Localized application of H+ produced 2A arteriolar vasodilation, while 15% CO2 resulted in a variable response. Simultaneous application of CO2 and H+ did not result in the predicted additive effects. Application of CO2 and H+ alone or combined on arterioles or capillaries did not induce a conducted response. Conclusions: CO2 and H+ produce arteriolar vasodilation but, critically, cannot stimulate the spread of vasodilation throughout the network, thus limiting their ability to coordinating blood flow to contracting skeletal muscle fibers. Given their potential for interaction, the importance of CO2 and H+ may lie in their ability to modify the effects of other vasodilators. [ABSTRACT FROM AUTHOR]

Key points Multiple vasodilators have been identified as being important in matching blood flow to the metabolism of contracting skeletal muscle and it has been hypothesized that this process is governed by redundancy between vasodilators, where one vasodilator can compensate for the loss of another., In the present study, we aimed to determine whether redundancy between vasodilators exists by investigating whether vasodilators relevant to skeletal muscle contraction can inhibit the effects of other vasodilators., We show that potassium can inhibit vasodilatations induced by adenosine and nitric oxide, and also that adenosine and nitric oxide can interact in a way that changes over time., Furthermore, we show that inward rectifying potassium channels and Na+/K+ATPase are partially mechanistically responsible for the interaction between potassium and adenosine and nitric oxide., Our data provide proof of principle that vasodilators relevant to muscle contraction interact and also that redundancy may govern the processes of 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 m m KCl] in the absence and then in the presence of a second vasodilator (10−7 m ADO, 10−7 m SNAP, 10 m m 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. [ABSTRACT FROM AUTHOR]

We sought to determine if a pannexin/purinergic-dependent intravascular communication pathway exists in skeletal muscle microvasculature that facilitates capillary communication with upstream arterioles that control their perfusion. Using the hamster cremaster muscle and intravital microscopy, we locally stimulated capillaries and observed the vasodilatory response in the associated upstream 4A arteriole. We stimulated capillaries with vasodilators relevant to muscle contraction: 10 -6 M S -nitroso- N -acetyl-dl-penicillamine (SNAP; nitric oxide donor), 10 -6 M adenosine, 10 mM potassium chloride, 10 -5 M pinacidil, as well as a known initiator of gap-junction-dependent intravascular communication, acetylcholine (10 -5 M), in the absence and the presence of the purinergic membrane receptor blocker suramin (10 -5 M), pannexin blocker mefloquine (2 × 10 -5 M), or probenecid (5 × 10 -6 M) and gap-junction inhibitor halothane (0.07%) applied in the transmission pathway, between the capillary stimulation site and the upstream 4A observation site. Potassium chloride, SNAP, and adenosine-induced upstream vasodilations were significantly inhibited by suramin, mefloquine, and probenecid but not halothane, indicating the involvement of a pannexin/purinergic-dependent signaling pathway. Conversely, SNAP-induced upstream vasodilation was only inhibited by halothane indicating that communication was facilitated by gap junctions. Both pinacidil and acetylcholine were inhibited by suramin but only acetylcholine was inhibited by halothane. These data demonstrate the presence of a pannexin/purinergic-dependent communication pathway between capillaries and upstream arterioles controlling their perfusion. This pathway adds to the gap-junction-dependent pathway that exists at this vascular level as well. Given that vasodilators relevant to muscle contraction can use both of these pathways, our data implicate the involvement of both pathways in the coordination of skeletal muscle blood flow. NEW & NOTEWORTHY Blood flow control during increased metabolic demand in skeletal muscle is not fully understood. Capillaries have been implicated in controlling blood flow to active skeletal muscle, but how capillaries communicate to the arteriolar vascular network is not clear. Our study uncovers a novel pathway through which capillaries can communicate to upstream arterioles to cause vasodilation and therefore control perfusion. This work implicates a new vascular communication pathway in blood flow control in skeletal muscle.

Objective: We hypothesized that CO 2 and H + stimulate capillaries and arterioles to produce local and conducted vasodilations required to coordinate the distribution of blood flow to contracting skeletal muscle fibers., Methods: CO 2 and H + independently and in combination were applied to 2A arterioles (first branch order from the 1A feed arteriole) and capillaries of the in situ, blood-perfused hamster cremaster muscle. The resulting local and conducted vasodilations were measured., Results: H + (pH: 7.2-6.6) and CO 2 (5% and 10%) applied to the vascular network induced 2A arteriolar vasodilations, while 15% CO 2 produced vasoconstriction. Localized application of H + produced 2A arteriolar vasodilation, while 15% CO 2 resulted in a variable response. Simultaneous application of CO 2 and H + did not result in the predicted additive effects. Application of CO 2 and H + alone or combined on arterioles or capillaries did not induce a conducted response., Conclusions: CO 2 and H + produce arteriolar vasodilation but, critically, cannot stimulate the spread of vasodilation throughout the network, thus limiting their ability to coordinating blood flow to contracting skeletal muscle fibers. Given their potential for interaction, the importance of CO 2 and H + may lie in their ability to modify the effects of other vasodilators., (© 2018 John Wiley & Sons Ltd.)