Role of Ca
            <sup>2+</sup>
            -Dependent K
            <sup>+</sup>
            Channels in Cerebral Vasodilatation Induced by Increases in Cyclic GMP and Cyclic AMP in the Rat

Paternò, Roberto; Faraci, Frank M.; Heistad, D D

doi:10.1161/01.str.27.9.1603

Cited by 97 publications

(73 citation statements)

References 29 publications

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“…An influence of K Ca channel activity on the resting tone of gracilis muscle arterioles has also been reported by this laboratory and others (5,44), but these findings do not extend to arterioles in all skeletal muscles or in some other vascular beds. For example, arteriolar smooth muscle K Ca channel activity appears to be silent under resting conditions in rat and hamster cremaster muscle (23,31) and rat cerebral cortex (39). These vessel-tovessel differences in the steady-state activity of K Ca channels at normal vascular tone could be due to differences in the Ca 2ϩ set point of these channels, as suggested by Jackson and Blair (23).…”

Section: Discussionmentioning

confidence: 84%

High dietary salt reduces the contribution of 20-HETE to arteriolar oxygen responsiveness in skeletal muscle

Marvar

Falck²,

Boegehold

2007

American Journal of Physiology-Heart and Circulatory Physiology

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coupling of tissue blood flow to cellular metabolic demand involves oxygen-dependent adjustments in arteriolar tone, and arteriolar responses to oxygen can be mediated, in part, by changes in local production of 20-HETE. In this study, we examined the long-term effect of dietary salt on arteriolar oxygen responsiveness in the exteriorized, superfused rat spinotrapezius muscle and the role of 20-HETE in this responsiveness. Rats were fed either a normal-salt (NS, 0.45%) or high-salt (HS, 4%) diet for 4 -5 wk. There was no difference in steady-state tissue PO 2 between NS and HS rats, and elevation of superfusate oxygen content from 0% to 10% caused tissue PO 2 to increase by the same amount in both groups. However, the resulting reductions in arteriolar diameter and blood flow were less in HS rats than NS rats. Inhibition of 20-HETE formation with or 17-octadecynoic acid (17-ODYA) attenuated oxygen-induced constriction in NS rats but not HS rats. Exogenous 20-HETE elicited arteriolar constriction that was greatly reduced by the large-conductance Ca 2ϩ -activated potassium (K Ca) channel inhibitors tetraethylammonium chloride (TEA) and iberiotoxin (IbTx) in NS rats and a smaller constriction that was less sensitive to TEA or IbTx in HS rats. Arteriolar responses to exogenous angiotensin II were similar in both groups but more sensitive to inhibition with DDMS in NS rats. Norepinephrine-induced arteriolar constriction was similar and insensitive to DDMS in both groups. We conclude that 20-HETE contributes to oxygen-induced constriction of skeletal muscle arterioles via inhibition of K Ca channels and that a high-salt diet impairs arteriolar responses to increased oxygen availability due to a reduction in vascular smooth muscle responsiveness to 20-HETE. 20-hydroxyeicosatetraenoic acid; vascular control; blood flow; NaCl LOCAL OXYGEN AVAILABILITY is an important determinant of microvascular resistance and tissue blood flow (10,17,22,41), and consumption of a high-salt diet can lead to changes in resistance vessel function that alter the relationship between oxygen and vascular tone. For example, small gracilis muscle feed arteries from rats fed high salt for as little as 3 days consistently show an impaired dilator response to reduced oxygen levels (47, 48). However, the effect of oxygen on the tone of smaller arterioles in rat cremaster muscle is unchanged after 3 days on a high-salt diet (13). This suggests that either a longer period of high-salt intake is required to alter the oxygen responsiveness of these more distal resistance vessels or that there is a fundamental difference between extraparenchymal arteries and intramuscular arterioles in the susceptibility of oxygen-sensitive tone to dietary salt. The first aim of this study was to distinguish between these possibilities by determining whether a prolonged period of high-salt intake can change the relationship between oxygen and vascular tone in the arteriolar network of skeletal muscle.The mechanisms through which oxygen can influence resistance vessel to...

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Section: Discussionmentioning

confidence: 84%

High dietary salt reduces the contribution of 20-HETE to arteriolar oxygen responsiveness in skeletal muscle

Marvar

Falck²,

Boegehold

2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…As both cAMP and cGMP are known vasodilators (Dundore et al, 1993;Dundore et al, 1992;Fertel and Weiss 1976;Paterno et al, 1996), it is possible that the cognitive enhancement evident in our studies following treatment with PDE inhibitors could be explained by increased delivery of energy substrates to the brain as a consequence of decrease cerebrovascular resistance. Certainly, rolipram did increase blood flow in the perirhinal cortex, although it had no effect in hippocampus.…”

Section: Discussionmentioning

confidence: 90%

“…However, PDE4 and PDE5 inhibitors also cause peripheral vasodilatation by elevating cAMP and cGMP, respectively (Dundore et al, 1993;Dundore et al, 1992;Paterno et al, 1996). Therefore, an alternative explanation could be that these drugs improve memory performance by enhancing cerebral blood flow and the delivery of glucose and oxygen to the brain, although such a mechanism is more likely to be important when the cognitive impairment arises from vascular insufficiency in the first place (eg, vascular dementia).…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats

Rutten

Donkelaar

Ferrington

et al. 2009

Neuropsychopharmacol

111

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Phosphodiesterase (PDE) inhibitors prevent the breakdown of the second messengers, cyclic AMP (cAMP) and cyclic GMP (cGMP), and are currently studied as possible targets for cognitive enhancement. Earlier studies indicated beneficial effects of PDE inhibitors in object recognition. In this study we tested the effects of three PDE inhibitors on spatial memory as assessed in a place and object recognition task. Furthermore, as both cAMP and cGMP are known vasodilators, the effects of PDE inhibition on cognitive functions could be explained by enhancement of cerebrovascular function. We examined this possibility by measuring the effects of PDE5 and PDE4 inhibitor treatment on local cerebral blood flow and glucose utilization in rats using [ 14 C]-iodoantipyrine and [ 14 C]-2-deoxyglucose quantitative autoradiography, respectively. In the spatial location task, PDE5 inhibition (cGMP) with vardenafil enhanced only early phase consolidation, PDE4 inhibition (cAMP) with rolipram enhanced only late phase consolidation, and PDE2 inhibition (cAMP and cGMP) with Bay 60-7550 enhanced both consolidation processes. Furthermore, PDE5 inhibition had no cerebrovascular effects in hippocampal or rhinal areas. PDE4 inhibition increased rhinal, but not hippocampal blood flow, whereas it decreased glucose utilization in both areas. In general, PDE5 inhibition decreased the ratio between blood flow and glucose utilization, indicative of general oligaemia; whereas PDE4 inhibition increased this ratio, indicative of general hyperemia. Both oligaemic and hyperemic conditions are detrimental for brain function and do not explain memory enhancement. These results underscore the specific effects of cAMP and cGMP on memory consolidation (object and spatial memory) and provide evidence that the underlying mechanisms of PDE inhibition on cognition are independent of cerebrovascular effects.

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“…In cardiovascular disease, K + channels functionally change [22][23][24] . Hypertension develops, with functional downregulation of K V channels but up-regulation of BK Ca in smooth muscle [25] .…”

Section: Discussionmentioning

confidence: 99%

Magnesium lithospermate B dilates mesenteric arteries by activating BKCa currents and contracts arteries by inhibiting KV currents

Zhang

Chen

et al. 2010

Acta Pharmacol Sin

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Aim: To examine the involvement of K + channels and endothelium in the vascular effects of magnesium lithospermate B (MLB), a hydrophilic active component of Salviae miltiorrhiza Radix. Methods: Isolated rat mesenteric artery rings were employed to investigate the effects of MLB on KCl-or norepinephrine-induced contractions. Conventional whole-cell patch-clamp technique was used to study the effects of MLB on K + currents in single isolated mesenteric artery myocytes. Results: MLB produced a concentration-dependent relaxation in mesenteric artery rings precontracted by norepinephrine (1 μmol/L) with an EC 50 of 111.3 μmol/L. MLB-induced relaxation was reduced in denuded artery rings with an EC 50 of 224.4 μmol/L. MLB caused contractions in KCl-precontracted artery rings in the presence of N-nitro-L-arginine methyl ester (L-NAME) with a maximal value of 130.3%. The vasodilatory effect of MLB was inhibited by tetraethylammonium (TEA) in both intact and denuded artery rings. In single smooth muscle cells, MLB activated BK Ca currents (EC 50 156.3 μmol/L) but inhibited K V currents (IC 50 26.1 μmol/L) in a voltageand concentration-dependent manner. Conclusion: MLB dilated arteries by activating BK Ca channels in smooth muscle cells and increasing NO release from endothelium, but it also contracted arteries precontracted with KCl in the presence of L-NAME.

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Role of Ca ²⁺ -Dependent K ⁺ Channels in Cerebral Vasodilatation Induced by Increases in Cyclic GMP and Cyclic AMP in the Rat

Abstract: These findings suggest that dilatation of cerebral arterioles by receptor-mediated activation of adenylate cyclase and by direct activation of guanylate cyclase in the rat is mediated in large part by activation of Ca(2+)-dependent K+ channels.

Cited by 97 publications

References 29 publications

High dietary salt reduces the contribution of 20-HETE to arteriolar oxygen responsiveness in skeletal muscle

High dietary salt reduces the contribution of 20-HETE to arteriolar oxygen responsiveness in skeletal muscle

Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats

Magnesium lithospermate B dilates mesenteric arteries by activating BKCa currents and contracts arteries by inhibiting KV currents

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Role of Ca 2+ -Dependent K + Channels in Cerebral Vasodilatation Induced by Increases in Cyclic GMP and Cyclic AMP in the Rat

Abstract: These findings suggest that dilatation of cerebral arterioles by receptor-mediated activation of adenylate cyclase and by direct activation of guanylate cyclase in the rat is mediated in large part by activation of Ca(2+)-dependent K+ channels.

Cited by 97 publications

References 29 publications

High dietary salt reduces the contribution of 20-HETE to arteriolar oxygen responsiveness in skeletal muscle

High dietary salt reduces the contribution of 20-HETE to arteriolar oxygen responsiveness in skeletal muscle

Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats

Magnesium lithospermate B dilates mesenteric arteries by activating BKCa currents and contracts arteries by inhibiting KV currents

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Role of Ca ²⁺ -Dependent K ⁺ Channels in Cerebral Vasodilatation Induced by Increases in Cyclic GMP and Cyclic AMP in the Rat