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. 2015 Dec 1;593(23):5111-26.
doi: 10.1113/JP270613. Epub 2015 Nov 15.

Potassium Inhibits Nitric Oxide and Adenosine Arteriolar Vasodilatation via K(IR) and Na(+)/K(+) ATPase: Implications for Redundancy in Active Hyperaemia

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Potassium Inhibits Nitric Oxide and Adenosine Arteriolar Vasodilatation via K(IR) and Na(+)/K(+) ATPase: Implications for Redundancy in Active Hyperaemia

Iain R Lamb et al. J Physiol. .
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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.

Figures

Figure 1
Figure 1. KCl attenuated the magnitude of vasodilatation produced by SNAP but SNAP did not affect the magnitude of KCl‐induced vasodilatation
A, change in diameter in response to incremental concentrations of SNAP in the absence (■) and presence (▲) of 10 mm KCl. B, change in diameter in response to incremental doses of KCl in the absence (■) and presence (▲) of 10−7  m SNAP. *SNAP + KCl differs significantly from SNAP alone.
Figure 2
Figure 2. KCl attenuated the magnitude of vasodilatation produced by ADO but ADO did not affect the magnitude of KCl‐induced vasodilatation
A, change in diameter in response to incremental doses of ADO in the absence (■) and presence (▲) of 10 mm KCl. B, change in diameter in response to incremental doses of KCl in the absence (■) and presence (▲) of 10−7  m ADO. *ADO + KCl differs significantly from ADO alone.
Figure 3
Figure 3. SNAP did not affect the vasodilator response of ADO and ADO did not affect the magnitude of SNAP‐induced vasodilatation
A, change in diameter in response to incremental doses of SNAP in the absence (■) and presence (▲) of 10−7  m ADO. B,change in diameter in response to incremental doses of ADO in the absence (■) and presence (▲) of 10−7  m SNAP.
Figure 4
Figure 4. KCl attenuated the vasodilatations induced by ADO and SNAP when added simultaneously, and the simultaneous addition of SNAP and ADO showed complex interactions over time
A, change in diameter in response to 10−7  m SNAP alone (■), 10 mm KCl alone (▲) and 10−7  m SNAP + 10 mm KCl added together simultaneously (▼). * SNAP alone differed significantly from SNAP + KCl. B, change in diameter in response to 10−7  m ADO alone (■), 10 mm KCl alone (▲) and 10−7  m ADO + 10 mm KCl added together simultaneously (▼). * ADO alone differed significantly from ADO + KCl. C, change in diameter in response to 10−7  m ADO alone (■),10−7  m SNAP alone (▲) and 10−7  m ADO + 10−7  m SNAP added together simultaneously (▼). * SNAP alone differed significantly from ADO + SNAP.
Figure 5
Figure 5. KCl attenuation of SNAP vasodilatation is reversed through the inhibition of KIR channels and Na+/K+ATPase
A, change in diameter in response to KCl + SNAP in the absence (■) and presence (▲) of BaCl. * SNAP + KCl differed significantly from SNAP + KCl + BaCl. For comparison, the diameter change in response to SNAP only (▼) is shown (data from Fig. 1). B, change in diameter in response to KCl + SNAP in the absence (■) and presence (▲) of 10−4  m Oua. *SNAP + KCl differed significantly from SNAP + KCl + Oua. For comparison, the diameter change in response to SNAP only (▼) is shown (data from Fig. 1).
Figure 6
Figure 6. KCl inhibition of ADO vasodilatation is reversed through the inhibition of KIR channels and Na+/K+ATPase
A, change in diameter in response to ADO + KCl in the absence (■) and presence (▲) of BaCl. *ADO + KCl differed significantly from ADO + KCl + BaCl. For comparison, the diameter change in response to ADO only (▼) is shown (data from Fig. 2). B, change in diameter in response to ADO + KCl in the absence (■) and presence (▲) of 10−4  m Oua. *ADO + KCl differed significantly from ADO + KCl + Oua. For comparison, the diameter in response to ADO only (▼) is shown (data from Figure 2).
Figure 7
Figure 7. Potential vasodilator interactions to describe different redundancy paradigms
Different paradigms represented in (i) to (iv) show different ways in which vasodilators can inhibit each other to create redundancy. i), a more singular relationship between vasodilator interactions where (A) inhibits (B), which can inhibit (C), which can inhibit (D). (D) is shown to be able to inhibit a vasodilator (C) because, if it did not, then inhibiting (D) alone should show a significant decrease in vasodilatation because there would be no redundant system to fill in for (D) if it was inhibited. ii), shows a scenario where one vasodilator can inhibit more than one vasodilator: (A) can inhibit both (B) and (C). (B) and (C) are shown to interact as well. If they did not, there would be no redundant system to replace the effects of (B) or (C) and inhibiting either (B) or (C) would result in a significant decrease in vasodilatation. iii), a slightly more integrated system of inhibition that is a variation of (A) where each vasodilator interacts with another vasodilator. iv), a more integrated network of vasodilator interactions where one group of interacting vasodilators can also interact with another group of interacting vasodilators. These are just a few potential relationships out of many, depending on how many vasodilators are involved and also on the complexity of the redundant networks.

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