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Published in final edited form as: Microvasc Res. 2007 Dec 4;75(3):367–372. doi: 10.1016/j.mvr.2007.11.004

Influence of Chronic Alcohol Consumption on Inward Rectifier Potassium Channels in Cerebral Arterioles

Hong Sun 1, Honggang Zhao 1, Glenda M Sharpe 1, Denise M Arrick 1, William G Mayhan 1
PMCID: PMC2409969  NIHMSID: NIHMS49468  PMID: 18191159

Abstract

Inward rectifier potassium (KIR) channels appear to play an important role in the regulation of cerebral blood flow. Our goal was to examine the influence of chronic alcohol exposure on KIR channels in cerebral arterioles. Sprague-Dawley rats were fed liquid diets with or without alcohol for 8–12 weeks. Using intravital microscope, we measured diameter of pial arterioles in response to an inhibitor, BaCl2, and an activator, KCl, of KIR channels in the absence and presence of a scavenger of reactive oxygen species, tempol, or an inhibitor of NAD(P)H oxidase, apocynin. Application of BaCl2 (30 and 100 μM) produced dose-related vasoconstriction in nonalcohol-fed, but not in alcohol-fed rats. In addition, application of KCl (3, 10, and 30 mM) produced dose-related dilation in nonalcohol-fed and alcohol-fed rats, but the magnitude of vasodilatation was less in alcohol-fed rats. In contrast, nitroglycerin-induced vasodilation was similar in nonalcohol-fed and alcohol-fed rats. Superfusion of cranial window with tempol (0.1 mM) or apocynin (1 mM) did not alter baseline diameter and nitroglycerin-induced dilation of pial arterioles in nonalcohol-fed and alcohol-fed rats, but significantly improved impaired KCl-induced dilation in alcohol-fed rats. Our findings suggest that chronic alcohol consumption impairs the role of KIR channels in basal tone and KCl-induced dilation of cerebral arterioles. In addition, impaired KCl-induced dilation of cerebral arterioles during alcohol consumption may be related to enhanced release of oxygen-derived free radicals via NAD(P)H oxidase.

Keywords: Alcohol, cerebral circulation, potassium channel, oxidative stress, NAD(P)H oxidase

INTRODUCTION

Chronic alcohol consumption reduces cerebral vasoreactivity, and thus may contribute to the pathogenesis of stroke and cognitive dysfunction observed in chronic alcoholics (Brown and Tapert, 2004; Caicoya et al., 1999; Harper and Matsumoto, 2005; Hart et al., 1999; Leppala et al., 1999; Nutt, 1999). In previous studies, we reported that dilation of cerebral arterioles to agonists that stimulate either endothelial or neuronal synthesis/release of nitric oxide (NO) is profoundly impaired during chronic alcohol consumption (Mayhan, 1992; Mayhan and Didion, 1996; Sun et al., 2002). In addition to the synthesis/release of NO from the endothelium and neurons, potassium (K+) channels are present in cerebral vessels and activation of these channels may be a major mechanism of cerebral vasodilatation in response to vasoactive and physiological stimuli (Armstead, 1999a; Bolotina et al., 1994; Faraci et al., 1994; Gebramedhin et al., 1994; Toyoda et al., 1997).

Four types of K+ channel, including ATP-sensitive (KATP), calcium-activated (KCa), voltage-dependent (KV), and KIR channels, are present in cerebral arterioles (Horiuchi et al., 2002; Sobey et al., 1998). Recent evidence indicates that KCa, KV, and KIR channels are active under basal conditions in cerebral arterioles (Gokina et al., 1996; Horiuchi et al., 2002; Horiuchi et al., 2001). In addition, KIR channels have been suggested to be involved in the regional coupling of cerebral blood flow to changes in cerebral metabolism (Zaritsky et al., 2000). Studies have reported that acute exposure of cultured rat aortic smooth muscle cells to alcohol inhibits KV and KCa channels (Dopico, 2003; Walter et al., 2000; Wu and Chao, 1995). In our previous study, we found that chronic alcohol consumption impairs dilation of cerebral arterioles in response to activation of KATP (Mayhan and Didion, 1996). No studies, however, have examined the effects of chronic alcohol consumption on KIR channels under basal conditions, or during stimulation of KIR channels in cerebral arterioles. Thus, our first goal was to examine whether in vivo reactivity of pial arterioles to an inhibitor and an activator of KIR channels is altered during chronic alcohol consumption. Our second goal was to examine a possible mechanism that may contribute to impaired reactivity of pial arterioles during alcohol consumption. Recent studies indicated that oxidative stress contributes to impairment of K+ channel function in cerebral vasculature, coronary vasculature, and cerebral artery smooth muscle cells (Armstead, 1999b; Armstead, 2001; Bari et al., 1996; Brzezinska et al., 2000; Liu et al., 2001). Previous studies, including ours, have suggested that alcohol consumption induces oxidative stress via NAD(P)H oxidase (Kono et al., 2000; Polikandriotis et al., 2005; Sun et al., 2006a; Sun et al., 2006b). Thus, we measured the effects of oxygen radical scavenger (tempol) and NAD(P)H oxidase inhibitor (apocynin) on alcohol consumption induced inhibition of KIR channel function in cerebral arterioles.

METHODS

Experimental diets

All procedures were in accordance with the “Principle of Laboratory Animal Care” (NIH publication No. 86-23, revised 1985) and were approved by the Institutional Animal Care and Use Committee. Male Sprague-Dawley rats were purchased from Harlan. At 2 months of age (body weight 200 to 220 g), the rats were singly housed and divided into two groups, a nonalcohol-fed group (n=17) and an alcohol-fed group (n=18). We fed rats liquid diets (Dyets, Bethlehem, PA) for 8–12 weeks. These diets have been used extensively to study the chronic effects of alcohol in rats (Lieber et al., 1989; Mayhan, 1992; McMartin et al., 1989). The nonalcohol rats were given a liquid diet that contained 1.0 kcal/ml, of which 35% were derived from fat, 47% were derived from carbohydrates, and 18% were derived from protein. Rats in the alcohol fed groups were given a liquid diet that contained 1.0 kcal/ml, of which 35% were derived from fat, 11% were derived from carbohydrates, 18% were derived from protein, and 36% were derived from ethanol. The concentration of full dose ethanol in the diet was 6.4%. We gradually introduced full dose ethanol into the diet over a 5-day period. Ethanol was given at 1.6% during first two days, at 3.2% during next three days, and at full dose (6.4%) from the 6th day. The total daily volume of diet fed to the nonalcohol-fed rats was based on the consumption of diet by the alcohol-fed rats, and thus the daily consumption of diet was similar in the nonalcohol-fed and alcohol-fed rats.

Preparation of animals

Before the experiment, we removed liquid diet for 12 hours. The rats were anesthetized with thiobutabarbital sodium (Inactin) (100 mg/kg body weight, ip), and a tracheotomy was performed. The rats were ventilated mechanically with room air and supplemental oxygen. A catheter was placed into a femoral vein for injection of supplemental anesthesia, and a femoral artery was cannulated for measurement of arterial blood pressure and to obtain a blood sample for the measurement of arterial blood gas.

To visualize the microcirculation of the cerebrum, a craniectomy was prepared over the left parietal cortex. The cranial window was suffused with artificial cerebrospinal fluid (2 ml/min) that was bubbled with 95% nitrogen and 5% carbon dioxide. Temperature of the suffusate was maintained at 37±1°C. The cranial window was connected via a three-way valve to a pump, which was allowed for infusion of agonists and antagonists into the suffusate. This method maintained a constant temperature, pH, PCO2 and PO2 of the suffusate during infusion of drugs. Diameter of pial arteriolar was measured using a video image-shearing device.

Experimental Protocol

Rats from each group were divided into three experimental conditions, BaCl2, KCl before and during tempol, and KCl before and during apocynin. Cerebral vessels were superfused with artificial cerebral spinal fluid for one hour before testing responses of arterioles. To examine the basal activity of KIR channels and KIR channel activation-induced cerebral vasodilation, we measured responses of pial arterioles to BaCl2 (30 and 100 μM; an inhibitor of KIR channels) and KCl (3, 10, and 30 mM; an activator of KIR channels), respectively. We also examined responses to nitroglycerin (0.1 and 1 μM) in the absence and presence of tempol and apocynin. BaCl2, KCl, and nitroglycerin were mixed in artificial cerebral spinal fluid, and then superfused over the cranial window. Diameter of pial arterioles was measured immediately before application of antagonist and agonists and every minute for 5 minutes during application of antagonist and agonists. Steady-state responses to the antagonist and agonists were reached within 2–3 minutes after starting application and the diameter of pial arterioles returned to baseline within 5 minutes after application of antagonist and agonists was stopped. To examine the potential mechanism underlying impaired KIR channel activation-mediated dilation during alcohol consumption, we suffused the cranial window preparation with cerebrospinal fluid containing tempol (0.1 mM) or apocynin (1 mM) after the initial measurements. One hour after starting the suffusion of tempol or apocynin, and continuing for the duration of the experiment, we again examined responses of pial arterioles to KCl and nitroglycerin.

Statistical analysis

For comparison of the various treatments, results were compared using a two-way repeated measure ANOVA with Tukey’s post hoc test. Student t tests were used to compare responses to KCl and nitroglycerin before and following application of tempol or apocynin. Values are means ± SEM. A p value of 0.05 or less was considered to be significant.

RESULTS

Control conditions

Body weight (nonalcohol-fed: 426 ± 12 g; alcohol-fed: 417 ± 7 g) and mean arterial pressure (nonalcohol-fed: 85 ± 7 mmHg; alcohol-fed: 85 ± 6 mmHg) were similar in both groups of rats.

Effects of alcohol consumption on basal activation of KIR channels

Baseline diameter of pial arterioles was 39 ± 1 μm in non-alcohol-fed and 38 ± 2 μm in alcohol-fed rats (P > 0.05). BaCl2 (30 and 100 μM) produced a significant vasoconstriction in nonalcohol-fed (n=5), but not in alcohol-fed rats (n=5) (Figure 1).

Figure 1.

Figure 1

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Response of parietal pial arterioles to BaCl2 in 2–3 months nonalcohol-fed (Control) (n=5) and alcohol-fed (Alcohol) (n=5) rats. Values are means ± SEM. * p < 0.05 vs. baseline diameter.

Effect of alcohol consumption on KCl-induced activation of KIR channels

Baseline diameter of pial arterioles was 38 ± 1 μm in nonalcohol-fed and 39 ± 2 μm in alcohol-fed rats (P > 0.05). Topical application of KCl (3, 10, and 30 mM) produced a dose-related dilation of pial arterioles in nonalcohol-fed (n=12) and alcohol-fed rats (n=13). However, the magnitude of vasodilatation to KCl was significantly less in the alcohol-fed rats (Figures 2 and 3). In addition, no difference was observed in nitroglycerin-induced dilation of pial arterioles between nonalcohol-fed and alcohol-fed rats (Figure 4).

Figure 2.

Figure 2

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Response of parietal pial arterioles to KCl in 2–3 months nonalcohol-fed (Control) (n=6) and alcohol-fed (Alcohol) (n=6) rats before and after suffusion with tempol (0.1 mM). Values are means ± SEM. * P< 0.05 vs. nonalcohol-fed rats. † P < 0.05 vs. response before suffusion with tempol.

Figure 3.

Figure 3

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Response of parietal pial arterioles to KCl in 2–3 months nonalcohol-fed (Control) (n=6) and alcohol-fed (Alcohol) (n=7) rats before and after suffusion with apocynin (1 mM). Values are means ± SEM. * P< 0.05 vs. nonalcohol-fed rats. † P < 0.05 vs. response before suffusion with apocynin.

Figure 4.

Figure 4

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Response of parietal pial arterioles to nitroglycerin in 2–3 months nonalcohol-fed (Control) (n=12) and alcohol-fed (Alcohol) (n=13) rats before and after suffusion with tempol (0.1 mM) or apocynin (1 mM). Values are means ± SEM.

Responses following acute application of tempol and apocynin

A 1-hour topical application of tempol or apocynin did not alter baseline diameter of pial arterioles in nonalcohol-fed and alcohol-fed rats. In addition, tempol or apocynin did not alter dilation of pial arterioles in response to KCl (Figures 2 and 3) in nonalcohol-fed rats, and nitroglycerin (Figure 4) in both nonalcohol-fed and alcohol-fed rats. In contrast, topical application of tempol or apocynin significantly improved dilation of pial arterioles to KCl in alcohol-fed rats (Figures 2 and 3). However, tempol did not improve the response of pial arterioles to BaCl2 in alcohol-fed rats (data not shown).

DISCUSSION

There are three new findings from this study. First, chronic alcohol consumption inhibits the influence of KIR channels on basal diameter of parietal pial arterioles. Second, alcohol consumption impairs dilation of parietal pial arterioles in response to KCl. Third, topical application of tempol and apocynin can significantly improve alcohol consumption-induced impairment of KCl-induced dilation in parietal pial arterioles. Since activation of KIR channels may contribute to the regulation of cerebral blood flow, we suggest that our findings may have implications for the control of cerebral blood flow and the pathogenesis of cerebrovascular abnormalities observed in binge drinkers and chronic alcoholics.

Many studies have shown that K+ channels are involved in cerebral vasodilatation in response to NO, endothelium-dependent hyperpolarizing factor (EDHF), cAMP, reactive oxygen species, physiological stimuli (hypoxia and hypercapnia), and K+ ion (Kitazono et al., 1995). Thus, K+ channels play a major role as a mediator of cerebral vasodilatation. An increase in extracellular K+ ion is a potent signal for the coupling of regional blood flow to the metabolic needs in the brain and many other tissue, such as heart and skeletal muscle (Haddy et al., 2006; Knot et al., 1996; Zaritsky et al., 2000). In addition, it has been reported that extracellular K+ ion can increase to >10 mM during cerebral hypoxia and ischemia (Somjen, 1979). A modest increase in extracellular K+ ion produces vasodilation in large and small cerebral arteries. Previously, we found that KCl (1–3 mM)-induced dilation of the basilar artery was significantly inhibited in chronic alcohol-fed rats (Sun et al., 2004). In the present study, KCl (3–30 mM)-induced dilation was similarly significantly attenuated in pial arterioles of alcohol-fed rats. KCl-induced cerebral vasodilatation is generally thought to relate to activation of vascular smooth muscle KIR channels (Knot et al., 1996; Zaritsky et al., 2000). However, previous studies have reported that NO, smooth muscle KATP channel, and smooth muscle Na+-K+ ATPase may be partially involved in KCl-induced cerebral vasodilatation (Dreier et al., 1995; Horiuchi et al., 2002; Knot et al., 1996). Although we did not determine the contribution of NO, smooth muscle KATP channel, and smooth muscle Na+-K+ ATPase in KCl-induced vasodilatation during chronic alcohol consumption, our previous studies found that alcohol consumption impairs NO-dependent and KATP channel activation-mediated dilation of cerebral arterioles (Mayhan, 1992; Mayhan and Didion, 1996; Sun et al., 2002). In addition, no studies have examined the influence of chronic alcohol consumption on cerebral vascular smooth muscle Na+-K+ ATPase. Thus, reduced NO availability, smooth muscle KATP channel activity, and/or smooth muscle Na+-K+ ATPase activity during chronic alcohol consumption cannot be excluded from impaired KCl-induced dilation of cerebral arterioles.

Various pathological processes decrease the functionality of vascular KIR channels, such as hypertension, diabetes, and ischemia-reperfusion (Goto et al., 2004; Marrelli et al., 1998; Mayhan et al., 2004). Several mechanisms could account for impaired KIR channel-mediated dilation of pial arterioles during chronic alcohol consumption. First, chronic alcohol consumption may alter the function of KIR channels via activation of other cellular enzyme pathways, such as protein kinase C (PKC) and angiotensin II. Although the mechanisms leading the process are not understood, chronic alcohol consumption has been demonstrated to up-regulate PKC (Stubbs and Slater, 1999). In addition, alcohol consumption robustly activates the renin-angiotensin system, and increases plasma concentration of angiotensin II (Fitts and Hoon, 1993; Linkola and Ylikahri, 1979; Puddey et al., 1987; Wright et al., 1986). Recent studies found that angiotensin II inhibit the activity of KIR channels through PKC in rabbit coronary arterial smooth muscle cells (Park et al., 2005; Park et al., 2006). In addition, Chrissobolis et al found that PKC inhibits K+-induced dilation in rat basilar artery (Chrissobolis and Sobey, 2002). Second, alcohol consumption may alter the function of KIR channels via an increase in oxidative stress. Recent studies reported that tempol restored KCa function of arterial smooth muscle cells in hypertensive rats (Xu et al., 2006) and apocynin improved KV function of small coronary arteries during oxidative stress (Bubolz et al., 2005). In addition, oxidative stress has been indicated to contribute to post-ischemic impairment of smooth muscle Kir2.x current density and function (Petrault et al., 2004). Previous studies, including ours (Sun and Mayhan, 2001), suggested that alcohol consumption induces oxidative stress (Agar et al., 1999; Montoliu et al., 1994; Omodeo-Sale et al., 1997; Sun et al., 2001; Yin et al., 2001). Increased production of oxygen free radicals was found in brain, liver, and plasma of alcohol-fed rodents. Recently, we found that NAD(P)H oxidase may play an important role in alcohol consumption-induced oxidative stress in cerebral artery and cerebral cortex tissue (Sun et al., 2006a; Sun et al., 2006b). In the present study, we found that topical application with tempol or apocynin significantly improved dilation of pial arterioles in response to KCl. Thus, impaired KCl-induced dilation of cerebral arterioles during alcohol consumption may be related to increased production/release of oxygen radicals via NAD(P)H oxidase.

KIR channels have been suggested to be active under basal conditions in cerebral arterioles (Horiuchi et al., 2002; Horiuchi et al., 2001). We found that topical application of BaCl2 produced dose-related constriction of pial arterioles under basal conditions in nonalcohol-fed rats. However, BaCl2 did not alter baseline diameter of pial arterioles in alcohol-fed rats. This finding suggests that KIR channels may not be active in pial arterioles under basal condition during alcohol consumption. In general, the basal tone of pial arterioles is influenced by many regulatory systems, including endothelium-derived relaxing factors, endothelium-derived contracting factors, and K+ channels. In our previous studies and in the present study, we did not find the difference in baseline diameter of pial arterioles between nonalcohol-fed and alcohol-fed rats (Mayhan, 1992; Mayhan and Didion, 1996; Sun et al., 2002). The explanation for this finding remains unclear but may be due to compensatory actions of other regulatory networks. In addition, topical application with tempol failed to improve the response of cerebral arterioles to BaCl2 and both tempol and apocynin did not influence the baseline diameter of pial arterioles in alcohol-fed rats. Thus, it is possible that different KIR channel subtype(s) may be involved in regulation of basal tone in cerebral arterioles, and it seems that inhibition of basal activation of KIR channels during alcohol consumption is not related to enhanced oxidative stress and/or NAD(P)H oxidase.

In summary, alterations in reactivity of pial arterioles observed during chronic alcohol consumption may be important for the regulation of local cerebral blood flow and altered responses of pial arterioles during chronic alcohol consumption may produce detrimental effects on the brain. Studies have shown that alcohol consumption is a risk factor for the pathogenesis of stroke and cognitive dysfunction. In the present study, we found that chronic alcohol consumption inhibits basal activation of KIR channels and KCl-induced dilation in cerebral arterioles. We speculate that impaired responses of cerebral vessels during alcohol consumption to activation of an important vasodilator pathway, i.e., KIR channels, may have important implications for the pathogenesis of cererovascular abnormalities observed in chronic alcoholics.

Acknowledgments

This study was supported by National Institutes of Health Grants DA 14258, HL79587, AA 11288, a Scientist Development Grant from the American Heart Association (0635052N), and funds from the University of Nebraska Medical Center.

Footnotes

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