Abstract
OBJECTIVE:
The effect of chronic ethanol exposure on chemoreflexes has not been extensively studied in experimental animals. Therefore, this study tested the hypothesis that known ethanol-induced autonomic, neuroendocrine and cardiovascular changes coincide with increased chemoreflex sensitivity, as indicated by increased ventilatory responses to hypoxia and hypercapnia.
METHODS:
Male Wistar rats were subjected to increasing ethanol concentrations in their drinking water (first week: 5% v/v, second week: 10% v/v, third and fourth weeks: 20% v/v). At the end of each week of ethanol exposure, ventilatory parameters were measured under basal conditions and in response to hypoxia (evaluation of peripheral chemoreflex sensitivity) and hypercapnia (evaluation of central chemoreflex sensitivity).
RESULTS:
Decreased respiratory frequency was observed in rats exposed to ethanol from the first until the fourth week, whereas minute ventilation remained unchanged. Moreover, we observed an increased tidal volume in the second through the fourth week of exposure. The minute ventilation responses to hypoxia were attenuated in the first through the third week but remained unchanged during the last week. The respiratory frequency responses to hypoxia in ethanol-exposed rats were attenuated in the second through the third week but remained unchanged in the first and fourth weeks. There was no significant change in tidal volume responses to hypoxia. With regard to hypercapnic responses, no significant changes in ventilatory parameters were observed.
CONCLUSIONS:
Our data are consistent with the notion that chronic ethanol exposure does not increase peripheral or central chemoreflex sensitivity.
Ethanol; Chemoreflex; Hypercapnia; Hypoxia
INTRODUCTION
Evidence in the literature has shown that ethanol (ETOH) exposure stimulates changes
in the neuroendocrine and autonomic nervous systems (11. Clarck LT. Alcohol induced hypertension: mechanisms,
complications, and clinical implications. J Natl Med Assoc.
1985;77(5):385-9.
2. Resstel LB, Tirapelli CR, Lanchote VL, Uyemura AS, De Oliveira
AM, Corrêa FM. Chronic ethanol consumption alters cardiovascular functions
in conscious rats. Life Sci. 2006;78(19):2179-87,
http://dx.doi.org/10.1016/j.lfs.2005.09.021.
http://dx.doi.org/10.1016/j.lfs.2005.09....
-33. Resstel LB, Scopinho AA, Lopes da Silva A, Antunes-Rodrigues J,
Corrêa FM. Increased circulating vasopressin may account for
ethanol-induced hypertension in rats. Am J Hypertens.
2008;21(8):930-5.). The characterized autonomic
nervous system changes include an enhanced cardiac sympathetic baroreflex and a
reduced cardiac parasympathetic baroreflex (22. Resstel LB, Tirapelli CR, Lanchote VL, Uyemura AS, De Oliveira
AM, Corrêa FM. Chronic ethanol consumption alters cardiovascular functions
in conscious rats. Life Sci. 2006;78(19):2179-87,
http://dx.doi.org/10.1016/j.lfs.2005.09.021.
http://dx.doi.org/10.1016/j.lfs.2005.09....
,44. Abdel-Rahman AA, Wooles WR. Ethanol induced hypertension involves
impairment of baroreceptors. Hypertension. 1987;10(1):1965-73.). In addition, diminished
baroreflex control, which is a sympathoinhibitory reflex, may be involved in
increased arterial pressure (22. Resstel LB, Tirapelli CR, Lanchote VL, Uyemura AS, De Oliveira
AM, Corrêa FM. Chronic ethanol consumption alters cardiovascular functions
in conscious rats. Life Sci. 2006;78(19):2179-87,
http://dx.doi.org/10.1016/j.lfs.2005.09.021.
http://dx.doi.org/10.1016/j.lfs.2005.09....
), as observed
in experimental animals and humans upon ETOH exposure (22. Resstel LB, Tirapelli CR, Lanchote VL, Uyemura AS, De Oliveira
AM, Corrêa FM. Chronic ethanol consumption alters cardiovascular functions
in conscious rats. Life Sci. 2006;78(19):2179-87,
http://dx.doi.org/10.1016/j.lfs.2005.09.021.
http://dx.doi.org/10.1016/j.lfs.2005.09....
,33. Resstel LB, Scopinho AA, Lopes da Silva A, Antunes-Rodrigues J,
Corrêa FM. Increased circulating vasopressin may account for
ethanol-induced hypertension in rats. Am J Hypertens.
2008;21(8):930-5.,55. Chan TC, Sutter MC. Ethanol consumption and blood pressure. Life
Sci. 1983;33(20):1965-73,
http://dx.doi.org/10.1016/0024-3205(83)90734-8.
http://dx.doi.org/10.1016/0024-3205(83)9...
6. Chan TC, Wall RA, Sutter MC. Chronic ethanol consumption, stress,
and hypertension. Hypertension. 1985;7(4):519-24,
http://dx.doi.org/10.1161/01.HYP.7.4.519.
http://dx.doi.org/10.1161/01.HYP.7.4.519...
7. Puddey IB, Beilin LJ, Vandongen R, Rouse IL, Rogers P. Evidence
for a direct effect of alcohol consumption on blood pressure in normotensive
men. A randomized controlled trial. Hypertension
1985;7(5):707-13.
8. Puddey IB, Burke V, Croft K, Beilin LJ. Increased blood pressure
and changes in membrane lipids associated with chronic ethanol treatment of
rats. Clin Exp Pharmacol Physiol. 1995;22(9):655-7,
http://dx.doi.org/10.1111/j.1440-1681.1995.tb02083.x.
http://dx.doi.org/10.1111/j.1440-1681.19...
9. Beilin LJ. Alcohol and hypertension. Clin Exp Pharmacol Physiol.
1995;22(3):185-8,
http://dx.doi.org/10.1111/j.1440-1681.1995.tb01977.x.
http://dx.doi.org/10.1111/j.1440-1681.19...
-1010. Saunders JB, Beevers DG, Paton A. Alcohol-induced hypertension.
Lancet.1981;2(8248):653-6,
http://dx.doi.org/10.1016/S0140-6736(81)90995-8.
http://dx.doi.org/10.1016/S0140-6736(81)...
).
Moreover, relationships between ETOH consumption and increased mortality have been
reported (1111. Hart CL, Smith GD, Hole DJ, Hawthorne VM. Alcohol consumption
and mortality from all causes, coronary heart disease, and stroke: results from
a prospective cohort study of scottish men with 21 years of follow up. BMJ.
1999;318(7200):1725-9,
http://dx.doi.org/10.1136/bmj.318.7200.1725.
http://dx.doi.org/10.1136/bmj.318.7200.1...
,1212. Hart CL, Smith GD. Alcohol consumption and mortality and
hospital admissions in men from the Midspan collaborative cohort study.
Addiction. 2008;103(12):1979-86,
http://dx.doi.org/10.1111/j.1360-0443.2008.02373.x.
http://dx.doi.org/10.1111/j.1360-0443.20...
).
Respiratory reflexes are related to cardiac autonomic control (1313. Feldman JL, Mitchell GS, Nattie EE. Breathing: rhythmicity,
plasticity, chemosensitivity. Annu Rev Neurosci. 2003;26:239-66,
http://dx.doi.org/10.1146/annurev.neuro.26.041002.131103.
http://dx.doi.org/10.1146/annurev.neuro....
). Therefore, the peripheral-chemoreflex (triggered by
hypoxia) and central-chemoreflex (triggered by hypercapnia), which are
sympathoexcitatory reflexes, may be increased following ETOH consumption. The effect
of acute, but not chronic, ETOH exposure on chemoreflexes has been evaluated by
several studies in humans (1414. Krol RC, Knuth SL, Bartlett DJr. Selective reduction of
genioglossal muscle activity by alcohol in normal human subjects. Am Rev Respir
Dis. 1984;129(2):247-50.,1515. van de Borne P, Mark AL, Montano N, Mion D, Somers VK. Effects
of alcohol on sympathetic activity, hemodynamics, and chemoreflex sensitivity.
Hypertension. 1997;29(6):1278-83,
http://dx.doi.org/10.1161/01.HYP.29.6.1278.
http://dx.doi.org/10.1161/01.HYP.29.6.12...
), which demonstrated that acute ETOH intake
did not alter the ventilatory response to hypoxia (1515. van de Borne P, Mark AL, Montano N, Mion D, Somers VK. Effects
of alcohol on sympathetic activity, hemodynamics, and chemoreflex sensitivity.
Hypertension. 1997;29(6):1278-83,
http://dx.doi.org/10.1161/01.HYP.29.6.1278.
http://dx.doi.org/10.1161/01.HYP.29.6.12...
) or hypercapnia (1414. Krol RC, Knuth SL, Bartlett DJr. Selective reduction of
genioglossal muscle activity by alcohol in normal human subjects. Am Rev Respir
Dis. 1984;129(2):247-50.,1515. van de Borne P, Mark AL, Montano N, Mion D, Somers VK. Effects
of alcohol on sympathetic activity, hemodynamics, and chemoreflex sensitivity.
Hypertension. 1997;29(6):1278-83,
http://dx.doi.org/10.1161/01.HYP.29.6.1278.
http://dx.doi.org/10.1161/01.HYP.29.6.12...
). Although there is evidence that ETOH
consumption has acute effects on chemoreflexes in humans (1414. Krol RC, Knuth SL, Bartlett DJr. Selective reduction of
genioglossal muscle activity by alcohol in normal human subjects. Am Rev Respir
Dis. 1984;129(2):247-50.,1515. van de Borne P, Mark AL, Montano N, Mion D, Somers VK. Effects
of alcohol on sympathetic activity, hemodynamics, and chemoreflex sensitivity.
Hypertension. 1997;29(6):1278-83,
http://dx.doi.org/10.1161/01.HYP.29.6.1278.
http://dx.doi.org/10.1161/01.HYP.29.6.12...
), the effect of
chronic ETOH exposure on the peripheral and central chemoreflexes of experimental
animals has never been assessed.
We hypothesized that chronic ETOH exposure increases peripheral and central chemoreflex sensitivity. To test this hypothesis, we established a time course of changes in chemoreflex sensitivity during four weeks of ETOH exposure.
MATERIALS AND METHODS
ETOH exposure
Experiments were performed using male Wistar rats (250 to 300 g,
n = 24). The rats were collectively housed (4 rats per cage) in
plastic cages, had free access to food and water and were maintained with a
12:12 h light-dark cycle. All experimental procedures were performed in
accordance with the Guide for the Care and Use of Laboratory Animals [Dept.
of Health, Education and Welfare, Publication No. (NIH) 85-23, Revised 1985;
Office of Science and Health Reports, DRR/NIH, Bethesda, MD]. The
experimental protocols used in this study were approved by the Local Committee
of Ethics in Animal Research of the School of Medicine of Ribeirão Preto,
University of São Paulo (protocol 065/2009). After habituation for 7 days,
the rats were randomly divided into two groups: the first group received tap
water (control group), and the second group received an increasing concentration
(v/v) of ETOH (Labsynth, Diadema, SP, Brazil) in their drinking water for four
weeks (first week: 5%, second week: 10%, third and fourth weeks: 20%). The ETOH
doses tested in preliminary experiments were based on previously published data
(1616. Lopes da Silva A, Ruginsk SG, Uchoa ET, Crestani CC, Scopinho
AA, Correa FM, et al. Time-course of neuroendocrine changes and its correlation
with hypertension induced by ethanol consumption. Alcohol Alcohol.
2013;48(4):495-504, http://dx.doi.org/10.1093/alcalc/agt040.
http://dx.doi.org/10.1093/alcalc/agt040...
), and those that produced
consistent, repeatable responses were adopted for use in this study.
Measurement of respiratory parameters
Minute ventilation (VE) was obtained by whole-body plethysmography
(1717. Bartlett DJr, Tenney SM. Control of breathing in experimental
anemia. Respir Physiol. 1970;10(3):384-95,
http://dx.doi.org/10.1016/0034-5687(70)90056-3.
http://dx.doi.org/10.1016/0034-5687(70)9...
). Unanesthetized rats were placed
into a 5 L Plexiglas chamber at 25°C and allowed to move freely while
humidified air circulated throughout the chamber. During each VE
measurement, the airflow was interrupted for a short time (∼2 min), and
the chamber remained closed. Breathing-related oscillations in pressure were
detected by a differential transducer and amplified (MLT141 spirometer, Power
Lab, AdInstruments, NSW, Australia). The recordings were saved and analyzed
using PowerLab Chart5 software (AdInstruments, NSW, Australia). A volume
calibration was performed during each VE measurement throughout the
course of the experiments by injecting a known air volume (1 mL) inside the
chamber. The tidal volume (VT) was calculated using a previously
described formula (1717. Bartlett DJr, Tenney SM. Control of breathing in experimental
anemia. Respir Physiol. 1970;10(3):384-95,
http://dx.doi.org/10.1016/0034-5687(70)90056-3.
http://dx.doi.org/10.1016/0034-5687(70)9...
). VE was
calculated as the product of VT and respiratory frequency (f), and it
is presented at the ambient barometric pressure and at body temperature and
ambient pressure saturated with water vapor (BTPS). A gas-mixing pump (Cameron,
Canada) allowed the chamber to be ventilated with different gas mixtures.
Experimental protocol
During the four weeks of exposure to ETOH or tap water, each animal was exposed
to hypercapnia or hypoxia once at the end of each week according to an
experimental protocol adapted from Sabino et al. (1818. Sabino JPJ, de Oliveira M, Giusti H, Glass ML, Fazan Junior R,
Salgado HC. Hemodynamic and ventilatory response to different levels of hypoxia
and hypercapnia in carotid body-denervated rats. Clinics. 2013;68(3):395-9,
http://dx.doi.org/10.6061/clinics/2013(03)OA18.
http://dx.doi.org/10.6061/clinics/2013(0...
). The animals were placed into a plethysmographic
chamber and allowed to move freely for 40-50 min for acclimatization while the
chamber was flushed with humidified air (21% O2, 79% N2,
1.2 L/min). After the baseline measurement of ventilatory parameters, each
animal was subjected (30 min) to hypoxia (10% inspired O2) or
hypercapnia (7% inspired CO2), and the ventilatory parameters were
measured at 10, 20 and 30 minutes after each exposure.
Statistical analysis
The results are expressed as the mean ± standard error of the mean (SEM). The basal values and changes in f, VT and VE in response to hypoxia and hypercapnia were evaluated using two-way ANOVA followed by Tukey’s post-hoc test. Differences were considered statistically significant at p<0.05.
RESULTS
Baseline ventilatory parameters
Figure 1 shows the baseline ventilatory parameters before hypoxia and hypercapnia. During the four weeks of the study, rats administered ETOH showed lower baseline values for f compared with the control tap water group (F1.63 = 29.55, p<0.05). After the first week, experimental rats showed a higher VT (F1.63 = 8.03, p<0.05), whereas VE remained unchanged during the experimental period (F1.63 = 0.46, p>0.05) (Figure 1).
Baseline values of respiratory frequency (f, top), tidal volume (VT, middle) and minute ventilation (VE, bottom) in rats receiving water (control group) or ethanol (ETOH) in increasing concentrations (first week: 5% v/v, second week: 10% v/v, third and fourth weeks: 20% v/v). Values are expressed as the mean±SEM. *, p<0.05 (two-way ANOVA) compared to control rats.
Ventilatory response to hypoxia
In general, during the four-week period, hypoxia caused a sharp (1.8-fold) increase in VE that was maintained during the 30 minutes of hypoxia exposure. This increased VE was due to increases in f and VT.
Figure 2 shows the changes in ventilatory parameters in response to hypoxia during the first and second weeks. Rats that received ETOH exhibited a similar increase in f (F1.30 = 1.42, p>0.05) and VT (F1.30 = 0.24, p>0.05). However, the increase in VE was attenuated in the ETOH group (F1.30 = 7.81, p<0.05) compared with the control group (Figure 2). In the second week, the hypoxia-induced increase in VT was similar in both groups (F1.30 = 0, p>0.05); however, hypoxia-induced tachypnea (F1.30 = 13.63, p<0.05) and the response of VE to hypoxia (F1.30 = 8.49, p<0.05) were lower in rats that received ETOH (Figure 2).
Changes during the first (left panel) and second (right panel) weeks in respiratory frequency (f, top), tidal volume (VT, middle) and minute ventilation (VE, bottom) in response to 10% O2-mediated hypoxia in rats receiving water (control group) or ethanol (ETOH) in increasing concentrations (first week: 5% v/v, second week: 10% v/v, third and fourth weeks: 20% v/v). Values are expressed as the mean±SEM. *, p<0.05 (two-way ANOVA) compared to control rats.
Figure 3 shows the changes in the ventilatory parameters in response to hypoxia during the third and fourth weeks of ETOH exposure. In the third week, the ETOH group showed attenuated increases in f (F1.30 = 19.08, p<0.05) and VE (F1.30 = 9.51, p<0.05). In contrast, the changes in VT (F1.30 = 0.05, p>0.05) were similar in the ETOH and control groups (Figure 3). In the final week, hypoxia caused similar increases in f (F1.30 = 0.14, p>0.05), VT (F1.30 = 1.23, p>0.05) and VE (F1.30 = 0.28, p>0.05) in both groups.
Changes during the third (left panel) and fourth (right panel) weeks in respiratory frequency (f, top), tidal volume (VT, middle) and minute ventilation (VE, bottom) in response to 10% O2-mediated hypoxia in rats receiving water (control group) or ethanol (ETOH) in increasing concentrations (first week: 5% v/v, second week: 10% v/v, third and fourth weeks: 20% v/v). Values are expressed as the mean±SEM. *, p<0.05 (two-way ANOVA) compared to control rats.
Ventilatory response to hypercapnia
Similar to hypoxia, the typical hypercapnia-induced hyperventilation response was generally observed in all groups. Hypercapnia caused a sharp (2.5-fold) increase in VE that was maintained during the 30 minutes of hypercapnia. This increase in VE was due to increases in f and VT.
Figure 4 shows the changes in ventilatory parameters in response to hypercapnia during the first and second weeks. In the control and ETOH groups, hypercapnia caused similar increases in f (F1.30 = 3.85, p>0.05 and F1.30 = 2.38, p>0.05, respectively), VT (F1.30 = 3.96, p>0.05 and F1.30 = 0.05, p>0.05, respectively) and VE (F1.30 = 0.12, p>0.05 and F1.30 = 0.48, p>0.05, respectively) (Figure 4). Figure 5 shows the ventilatory parameters in response to hypercapnia during the third and fourth weeks. In the control and ETOH groups, hypercapnia caused similar increases in f (F1.30 = 1.90, p>0.05 and F1.21 = 0.83, p>0.05, respectively), VT (F1.30 = 1.32, p>0.05 and F1.21 = 0.16, p>0.05, respectively) and VE (F1.30 = 1.45, p>0.05 and F1.30 = 0.28, p>0.05, respectively).
Changes during the first (left panel) and second (right panel) weeks in respiratory frequency (f, top), tidal volume (VT, middle) and minute ventilation (VE, bottom) in response to 7% CO2-mediated hypercapnia in rats receiving water (control group) or ethanol (ETOH) in increasing concentrations (first week: 5% v/v, second week: 10% v/v, third and fourth weeks: 20% v/v). Values are expressed as the mean±SEM.
Changes during the third (left panel) and fourth (right panel) weeks in respiratory frequency (f, top), tidal volume (VT, middle) and minute ventilation (VE, bottom) in response to 7% CO2-mediated hypercapnia in rats receiving water (control group) or ethanol (ETOH) in increasing concentrations (first week: 5% v/v, second week: 10% v/v, third and fourth weeks: 20% v/v). Values are expressed as the mean±SEM.
DISCUSSION
In this study, we tested the hypothesis that chronic ETOH exposure increases peripheral and central chemoreflex sensitivity. Surprisingly, the obtained data do not support our hypothesis because a reduced ventilatory response to hypoxia was observed, indicating decreased peripheral chemoreflex sensitivity. In addition, we found an unaltered ventilatory response to hypercapnia in rats administered ETOH, indicating unchanged central chemoreflex sensitivity. Such findings indicate that the autonomic control changes observed during chronic ETOH intake are complex and that the well-documented elevation in sympathetic tonus (responsible for ETOH-induced hypertension) may not involve increased chemoreflexes.
Moreover, this study also provides evidence indicating that chronic ETOH intake
reduces f, with little effect on VE, due to a higher VT.
Similarly, VE has been observed to be normal in subjects who were acutely
exposed to ETOH (1414. Krol RC, Knuth SL, Bartlett DJr. Selective reduction of
genioglossal muscle activity by alcohol in normal human subjects. Am Rev Respir
Dis. 1984;129(2):247-50.,1515. van de Borne P, Mark AL, Montano N, Mion D, Somers VK. Effects
of alcohol on sympathetic activity, hemodynamics, and chemoreflex sensitivity.
Hypertension. 1997;29(6):1278-83,
http://dx.doi.org/10.1161/01.HYP.29.6.1278.
http://dx.doi.org/10.1161/01.HYP.29.6.12...
). Therefore, the results indicate that pulmonary ventilation
remains unchanged in both humans and experimental animals following exposure to
ETOH.
Conversely, when ETOH is administered during the perinatal period, a marked decrease in spontaneous respiratory frequency and VE can be observed in 3- to 4-week-old rats, whereas VT remains unchanged (1919. Dubois C, Naassila M, Daoust M, Pierrefiche O. Early chronic ethanol exposure in rats disturbs respiratory network activity and increases sensitivity to ethanol. J Physiol. 2006;576(Pt 1):297-307.). The differences between our results and those of Dubois and colleagues (1919. Dubois C, Naassila M, Daoust M, Pierrefiche O. Early chronic ethanol exposure in rats disturbs respiratory network activity and increases sensitivity to ethanol. J Physiol. 2006;576(Pt 1):297-307.) may be due to the periods of ETOH exposure examined, the concentration of ETOH or the age of the animals. Nevertheless, it is worth noting that both studies showed a decrease in spontaneous f after ETOH exposure.
As previously mentioned, this study showed that chemoreflex sensitivity was
attenuated in response to hypoxia until the third week of ETOH exposure. These
results indicate that the chemoreflex, which is a sympathoexcitatory reflex, may not
be involved in the increased sympathetic or decreased parasympathetic activities and
consequent hypertension observed in rats after ETOH exposure (22. Resstel LB, Tirapelli CR, Lanchote VL, Uyemura AS, De Oliveira
AM, Corrêa FM. Chronic ethanol consumption alters cardiovascular functions
in conscious rats. Life Sci. 2006;78(19):2179-87,
http://dx.doi.org/10.1016/j.lfs.2005.09.021.
http://dx.doi.org/10.1016/j.lfs.2005.09....
,33. Resstel LB, Scopinho AA, Lopes da Silva A, Antunes-Rodrigues J,
Corrêa FM. Increased circulating vasopressin may account for
ethanol-induced hypertension in rats. Am J Hypertens.
2008;21(8):930-5.). In agreement with
this notion, ETOH was reported to have an inhibitory effect on chemoreflexes by Sun
and Reis (2020. Sun MK, Reis DJ. Ethanol inhibits chemoreflex excitation of
reticulospinal vasomotor neurons. Brain Res. 1996;730(1-2):182-92,
http://dx.doi.org/10.1016/0006-8993(96)00445-3.
http://dx.doi.org/10.1016/0006-8993(96)0...
), who showed that the increased
blood pressure and vasomotor neuronal activity (located in the rostroventrolateral
area of the medulla oblongata) in response to intracarotid cyanide administration
were markedly attenuated following acute ETOH exposure.
Another reflex evaluated in this study was the central chemoreflex, which has been
evaluated based on the ventilatory response to hypercapnia (1515. van de Borne P, Mark AL, Montano N, Mion D, Somers VK. Effects
of alcohol on sympathetic activity, hemodynamics, and chemoreflex sensitivity.
Hypertension. 1997;29(6):1278-83,
http://dx.doi.org/10.1161/01.HYP.29.6.1278.
http://dx.doi.org/10.1161/01.HYP.29.6.12...
,2121. Narkiewicz K, Pesek CA, van de Borne PJ, Kato M, Somers VK.
Enhanced sympathetic and ventilatory responses to central chemoreflex activation
in heart failure. Circulation. 1999;100(3):262-7,
http://dx.doi.org/10.1161/01.CIR.100.3.262.
http://dx.doi.org/10.1161/01.CIR.100.3.2...
22. Kristen AV, Just A, Haass M, Seller H. Central hypercapnic
chemoreflex modulation of renal sympathetic nerve activity in experimental heart
failure. Basic Res Cardiol. 2002;97(2):177-86,
http://dx.doi.org/10.1007/s003950200009.
http://dx.doi.org/10.1007/s003950200009...
23. Sun SY, Wang W, Zucker IH, Schultz HD. Enhanced peripheral
chemoreflex function in conscious rabbits with pacing-induced heart failure.
J Appl Physiol. 1999;86(4):1264-72.-2424. Ueno H, Asanoi H, Yamada K, Oda Y, Takagawa J, Kameyama T, et
al. Attenuated respiratory modulation of chemoreflex-mediated sympathoexcitation
in patients with chronic heart failure. J Card Fail. 2004;10(3):236-43,
http://dx.doi.org/10.1016/j.cardfail.2003.09.005.
http://dx.doi.org/10.1016/j.cardfail.200...
). We found that chronic ETOH exposure did
not alter the increases in f, VT or VE induced by hypercapnia.
Similarly, previous studies performed in humans have also shown that
hypercapnia-induced hyperventilation is not affected by acute ETOH exposure (1414. Krol RC, Knuth SL, Bartlett DJr. Selective reduction of
genioglossal muscle activity by alcohol in normal human subjects. Am Rev Respir
Dis. 1984;129(2):247-50.,1515. van de Borne P, Mark AL, Montano N, Mion D, Somers VK. Effects
of alcohol on sympathetic activity, hemodynamics, and chemoreflex sensitivity.
Hypertension. 1997;29(6):1278-83,
http://dx.doi.org/10.1161/01.HYP.29.6.1278.
http://dx.doi.org/10.1161/01.HYP.29.6.12...
).
Reconciling the available data, it appears that the central chemoreflex is not
involved in the autonomic changes (including hypertension) induced by ETOH during
acute or chronic ETOH exposure.
Thus, clinical evaluations of alcoholics should focus on the autonomic (including
blood pressure) and endocrine changes caused by ETOH consumption but may not
necessarily need to examine chemoreflex sensitivity. In fact, it has been documented
that abstinent alcoholic subjects may show abnormal respiratory events during sleep;
however, such changes are unlikely to be related to changes in chemoreflex
sensitivity (2525. Lambie DG, Tan ET, Johnson RH. Respiratory responsiveness in
male alcoholics after withdrawal. Alcohol Clin Exp Res. 1987;11(1):49-51,
http://dx.doi.org/10.1111/j.1530-0277.1987.tb01262.x.
http://dx.doi.org/10.1111/j.1530-0277.19...
).
In conclusion, our results indicate that the chronic administration of ETOH to rats does not increase peripheral or central chemoreflex sensitivity. Therefore, chemoreflex sensitivity may not be related to the autonomic, neuroendocrine and cardiovascular changes observed following chronic ETOH exposure.
Acknowledgments
Funding for the present study was provided by Fundação de Amparo è Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq) and Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
REFERENCES
-
1Clarck LT. Alcohol induced hypertension: mechanisms, complications, and clinical implications. J Natl Med Assoc. 1985;77(5):385-9.
-
2Resstel LB, Tirapelli CR, Lanchote VL, Uyemura AS, De Oliveira AM, Corrêa FM. Chronic ethanol consumption alters cardiovascular functions in conscious rats. Life Sci. 2006;78(19):2179-87, http://dx.doi.org/10.1016/j.lfs.2005.09.021.
» http://dx.doi.org/10.1016/j.lfs.2005.09.021 -
3Resstel LB, Scopinho AA, Lopes da Silva A, Antunes-Rodrigues J, Corrêa FM. Increased circulating vasopressin may account for ethanol-induced hypertension in rats. Am J Hypertens. 2008;21(8):930-5.
-
4Abdel-Rahman AA, Wooles WR. Ethanol induced hypertension involves impairment of baroreceptors. Hypertension. 1987;10(1):1965-73.
-
5Chan TC, Sutter MC. Ethanol consumption and blood pressure. Life Sci. 1983;33(20):1965-73, http://dx.doi.org/10.1016/0024-3205(83)90734-8.
» http://dx.doi.org/10.1016/0024-3205(83)90734-8 -
6Chan TC, Wall RA, Sutter MC. Chronic ethanol consumption, stress, and hypertension. Hypertension. 1985;7(4):519-24, http://dx.doi.org/10.1161/01.HYP.7.4.519.
» http://dx.doi.org/10.1161/01.HYP.7.4.519 -
7Puddey IB, Beilin LJ, Vandongen R, Rouse IL, Rogers P. Evidence for a direct effect of alcohol consumption on blood pressure in normotensive men. A randomized controlled trial. Hypertension 1985;7(5):707-13.
-
8Puddey IB, Burke V, Croft K, Beilin LJ. Increased blood pressure and changes in membrane lipids associated with chronic ethanol treatment of rats. Clin Exp Pharmacol Physiol. 1995;22(9):655-7, http://dx.doi.org/10.1111/j.1440-1681.1995.tb02083.x.
» http://dx.doi.org/10.1111/j.1440-1681.1995.tb02083.x -
9Beilin LJ. Alcohol and hypertension. Clin Exp Pharmacol Physiol. 1995;22(3):185-8, http://dx.doi.org/10.1111/j.1440-1681.1995.tb01977.x.
» http://dx.doi.org/10.1111/j.1440-1681.1995.tb01977.x -
10Saunders JB, Beevers DG, Paton A. Alcohol-induced hypertension. Lancet.1981;2(8248):653-6, http://dx.doi.org/10.1016/S0140-6736(81)90995-8.
» http://dx.doi.org/10.1016/S0140-6736(81)90995-8 -
11Hart CL, Smith GD, Hole DJ, Hawthorne VM. Alcohol consumption and mortality from all causes, coronary heart disease, and stroke: results from a prospective cohort study of scottish men with 21 years of follow up. BMJ. 1999;318(7200):1725-9, http://dx.doi.org/10.1136/bmj.318.7200.1725.
» http://dx.doi.org/10.1136/bmj.318.7200.1725 -
12Hart CL, Smith GD. Alcohol consumption and mortality and hospital admissions in men from the Midspan collaborative cohort study. Addiction. 2008;103(12):1979-86, http://dx.doi.org/10.1111/j.1360-0443.2008.02373.x.
» http://dx.doi.org/10.1111/j.1360-0443.2008.02373.x -
13Feldman JL, Mitchell GS, Nattie EE. Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci. 2003;26:239-66, http://dx.doi.org/10.1146/annurev.neuro.26.041002.131103.
» http://dx.doi.org/10.1146/annurev.neuro.26.041002.131103 -
14Krol RC, Knuth SL, Bartlett DJr. Selective reduction of genioglossal muscle activity by alcohol in normal human subjects. Am Rev Respir Dis. 1984;129(2):247-50.
-
15van de Borne P, Mark AL, Montano N, Mion D, Somers VK. Effects of alcohol on sympathetic activity, hemodynamics, and chemoreflex sensitivity. Hypertension. 1997;29(6):1278-83, http://dx.doi.org/10.1161/01.HYP.29.6.1278.
» http://dx.doi.org/10.1161/01.HYP.29.6.1278 -
16Lopes da Silva A, Ruginsk SG, Uchoa ET, Crestani CC, Scopinho AA, Correa FM, et al. Time-course of neuroendocrine changes and its correlation with hypertension induced by ethanol consumption. Alcohol Alcohol. 2013;48(4):495-504, http://dx.doi.org/10.1093/alcalc/agt040.
» http://dx.doi.org/10.1093/alcalc/agt040 -
17Bartlett DJr, Tenney SM. Control of breathing in experimental anemia. Respir Physiol. 1970;10(3):384-95, http://dx.doi.org/10.1016/0034-5687(70)90056-3.
» http://dx.doi.org/10.1016/0034-5687(70)90056-3 -
18Sabino JPJ, de Oliveira M, Giusti H, Glass ML, Fazan Junior R, Salgado HC. Hemodynamic and ventilatory response to different levels of hypoxia and hypercapnia in carotid body-denervated rats. Clinics. 2013;68(3):395-9, http://dx.doi.org/10.6061/clinics/2013(03)OA18.
» http://dx.doi.org/10.6061/clinics/2013(03)OA18 -
19Dubois C, Naassila M, Daoust M, Pierrefiche O. Early chronic ethanol exposure in rats disturbs respiratory network activity and increases sensitivity to ethanol. J Physiol. 2006;576(Pt 1):297-307.
-
20Sun MK, Reis DJ. Ethanol inhibits chemoreflex excitation of reticulospinal vasomotor neurons. Brain Res. 1996;730(1-2):182-92, http://dx.doi.org/10.1016/0006-8993(96)00445-3.
» http://dx.doi.org/10.1016/0006-8993(96)00445-3 -
21Narkiewicz K, Pesek CA, van de Borne PJ, Kato M, Somers VK. Enhanced sympathetic and ventilatory responses to central chemoreflex activation in heart failure. Circulation. 1999;100(3):262-7, http://dx.doi.org/10.1161/01.CIR.100.3.262.
» http://dx.doi.org/10.1161/01.CIR.100.3.262 -
22Kristen AV, Just A, Haass M, Seller H. Central hypercapnic chemoreflex modulation of renal sympathetic nerve activity in experimental heart failure. Basic Res Cardiol. 2002;97(2):177-86, http://dx.doi.org/10.1007/s003950200009.
» http://dx.doi.org/10.1007/s003950200009 -
23Sun SY, Wang W, Zucker IH, Schultz HD. Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure. J Appl Physiol. 1999;86(4):1264-72.
-
24Ueno H, Asanoi H, Yamada K, Oda Y, Takagawa J, Kameyama T, et al. Attenuated respiratory modulation of chemoreflex-mediated sympathoexcitation in patients with chronic heart failure. J Card Fail. 2004;10(3):236-43, http://dx.doi.org/10.1016/j.cardfail.2003.09.005.
» http://dx.doi.org/10.1016/j.cardfail.2003.09.005 -
25Lambie DG, Tan ET, Johnson RH. Respiratory responsiveness in male alcoholics after withdrawal. Alcohol Clin Exp Res. 1987;11(1):49-51, http://dx.doi.org/10.1111/j.1530-0277.1987.tb01262.x.
» http://dx.doi.org/10.1111/j.1530-0277.1987.tb01262.x
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No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
2014
History
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Received
2 July 2013 -
Reviewed
13 Aug 2013 -
Accepted
24 Sept 2013