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Abstract
Abstract Our previous studies have shown that ethanol selectively counteracts centrally mediated hypotensive responses. This study investigated the role of cardiac output and peripheral resistance in the antagonistic interaction between ethanol and antihypertensive drugs. Changes in blood pressure, heart rate, cardiac index, stroke volume, and peripheral resistance elicited by clonidine and subsequent ethanol or saline administration were evaluated in conscious rats. The aortic barodenervated rat was employed because it exhibits greater hypotensive responses to clonidine compared with the intact rat. Aortic barodenervation elicited acute rises in blood pressure, heart rate, and peripheral resistance, whereas cardiac index and stroke volume were not altered. The blood pressure of conscious aortic barodenervated rats returned to sham-operated levels by 48 hours due to concomitant reductions in cardiac index and stroke volume; the peripheral resistance, however, remained significantly elevated. Clonidine (30 μg/kg, IV) elicited greater decreases in blood pressure in aortic barodenervated compared with sham-operated rats. The hypotension was caused by decreases in cardiac index and stroke volume because peripheral resistance did not change. Ethanol (1 g/kg, IV) counteracted the hypotensive effect of clonidine and raised blood pressure to levels higher than preclonidine values. Significant (P<.05) increases in cardiac index and stroke volume and decreases in peripheral resistance accompanied the pressor effect of ethanol. Additional control groups were included in the study to determine the selectivity of the interaction. A dose of hydralazine (0.5 mg/kg, IV) was used that produced similar hypotension to that evoked by clonidine in aortic barodenervated rats. Hydralazine-evoked hypotension was similar in denervated and control rats and resulted from significant reductions in peripheral resistance. Reflex increases in heart rate and stroke volume and hence cardiac output were observed. Ethanol given after hydralazine produced a short-lived pressor effect (<5 minutes versus 40 minutes in the case of clonidine) and counteracted the sympathetically mediated increases in cardiac output, stroke volume, and heart rate. These findings support our hypothesis that ethanol selectively counteracts hypotensive responses of central origin by reversing the reduction in cardiac output elicited by clonidine.
Earlier reports from our laboratory have shown that ethanol counteracts the hypotensive effect of centrally acting antihypertensive agents such as clonidine and guanabenz.1 2 3 This deleterious effect of ethanol on centrally mediated hypotensive responses is demonstrated in conscious ABD3 and spontaneously hypertensive1 2 rats. In contrast, peripherally mediated hypotensive responses elicited by hydralazine, nitroprusside, or hexamethonium were not affected by ethanol.1 2 These findings suggest that the ability of ethanol to adversely affect centrally mediated hypotensive responses involves, at least in part, the central nervous system. This view is further supported by the observation that centrally mediated reductions in sympathetic activity that mediate the hypotensive effect of clonidine and guanabenz in conscious rats are also counteracted by ethanol.2 3 It is notable, however, that the peripheral hemodynamic effects of ethanol may influence its interaction with antihypertensive drugs. Acute ethanol administration may cause decreases,4 5 increases,1 6 or no change7 8 9 in BP. Moderate doses of ethanol dilate cutaneous blood vessels partly through a direct action on these vessels.10
The role of CO and TPR in centrally and peripherally mediated hypotensive responses has been variable. Studies in humans11 12 and experimental animals13 14 have shown that the hypotensive effect of clonidine results mainly from a reduction in CO, since TPR remained unchanged. A recent study from our laboratory15 showed that clonidine-evoked hypotension in ABD rats is mediated exclusively by a reduction in CO through a centrally mediated sympathoinhibitory action. The peripheral resistance, even though elevated in ABD rats compared with SO rats, was not influenced by clonidine.15 It is notable that the antihypertensive effect of clonidine involves activation of imidazoline receptors and α2-adrenoceptors in the lower brain stem region leading to a reduction in central sympathetic tone and subsequently a fall in BP.16 17 Contrary to clonidine, hydralazine lowers BP predominantly via a reduction in TPR; HR and CO are increased by a baroreflex-mediated increase in sympathetic outflow to the heart.18 19 It is not clear whether differences in the relative contribution of CO and TPR to the hypotensive effects of clonidine and hydralazine could explain the differential effect of ethanol on these responses in previous studies.1 3 Reports on the effect of ethanol on CO and TPR have been controversial. CO may be increased,20 21 decreased,22 23 or not affected20 24 by ethanol administration. Various effects of ethanol on TPR have also been reported.20 21 22 23 24 These discrepancies have been attributed to differences in baseline levels of measured variables, animal species and strain, dose and route of administration of ethanol and whether anesthetized or conscious animals were used.20 21 22 23 24 None of the reported studies has investigated the role of CO and TPR in the adverse hemodynamic interaction between ethanol and clonidine.
The main objective of the present study was to investigate the role of CO and TPR in the ethanol-evoked attenuation of the hypotensive effect of clonidine. Experiments were designed to evaluate the influence of subsequent ethanol administration on hemodynamic responses elicited by clonidine in conscious freely moving rats. Changes in MAP, HR, CO, SV, and TPR evoked by clonidine and subsequently administered ethanol (1 g/kg) or an equal volume of saline were watched for 70 minutes. Because previous studies from this laboratory showed that the hypotensive effect of clonidine is significantly enhanced in rats after surgical elimination of aortic depressor nerves compared with a lesser effect in intact (SO) rats,3 15 25 the conscious ABD rat model was used in this study to allow better evaluation of ethanol-clonidine hemodynamic interaction. The reason for the enhanced hypotensive effect of clonidine in ABD rats has been investigated in recent studies from our laboratory. Upregulation of imidazoline receptors26 and α2-adrenoceptors27 in the brain stem, the main site of the hypotensive action of clonidine,16 17 28 has been suggested as a possible mechanism for the enhanced hypotensive effect of clonidine in this rat model. Further support for our hypothesis was sought by studying the effect of ethanol on the hemodynamic responses elicited by the peripherally acting drug hydralazine. A dose of hydralazine that produced hypotension similar to that produced by clonidine in ABD rats was used to facilitate data interpretation.
Methods
Preparation of the Rats
Male Sprague-Dawley rats (300 to 360 g; Charles River Laboratories, Raleigh, NC) were used in the present study. For measurement of BP, the method described in our previous studies was adopted.3 6 15 Briefly, the rats were anesthetized by methohexital (50 mg/kg IP). Catheters (polyethylene 50) were placed in the abdominal aorta and vena cava via the femoral artery and vein for measurement of BP and intravenous administration of drugs, respectively. The catheters were inserted about 5 centimeters into the femoral vessels and secured in place with sutures. The arterial catheter was connected to a Gould-Statham pressure transducer and BP was displayed on a Grass polygraph (model 7D, Grass Instrument Co). Heart rate was computed from BP waveforms by a Grass tachograph and was displayed on another channel of the polygraph. BP and HR were monitored until the sham or ABD operation was completed. Experiments were performed in strict accordance with institutional animal care and use guidelines.
Aortic Baroreceptor Denervation
Aortic barodenervation was accomplished by bilateral transection of the superior laryngeal, cervical sympathetic, and aortic depressor nerves after a midline incision in the cervical region as described in our previous studies.3 6 15 SO rats were prepared by exposing the relevant nerve trunks without sectioning. PE (4 μg/kg) was injected intravenously before and after ABD or sham operation. A smaller decrease in HR of ABD rats in response to similar PE-evoked increase in BP indicated successful denervation.3 6 15
Measurement of CO
A Cardiomax II (Columbus Instrument) interfaced with an AT-computer was used for measurement of CO by the thermodilution technique as described in previous studies,15 29 30 including our own. This arrangement allowed acquisition of data and computation of CO (mL/min) and SV (μL/beat). In addition to CO and SV measurements, the CI (CO/100 g body wt, mL · min−1 · 100 g−1) and TPR (MAP/CI, mm Hg · mL−1 · min−1 · 100 g body wt−1) were calculated.
Finally, the catheters and the thermistor were tunneled subcutaneously and exteriorized at the back of the neck between the scapulae. The catheters were flushed with heparin (200 U/mL) and plugged by stainless steel pins. Incisions were closed by surgical clips and swabbed with povidone-iodine solution. Each rat received an intramuscular injection of 60 000 U of penicillin G benzathine and penicillin G procaine in an aqueous suspension (Durapen) and was housed in a separate cage.
Protocols and Experimental Groups
Ethanol-Clonidine Hemodynamic Interaction
A total of 20 experiments were performed on 10 conscious rats, 5 ABD and 5 SO, to investigate the role of CO and TPR in the antagonistic hemodynamic interaction between ethanol and clonidine. Each rat was used twice on two consecutive days, ie, 48 and 72 hours after instrumentation. Treatment, ethanol or saline, was randomized as explained below. Hemodynamic variables (BP, HR, CO, SV, and TPR) were measured before and at 5 minutes (anesthetized state) and at 48 and 72 hours (conscious state) after ABD or sham operation. On the day of the experiment, the thermistor was connected to a Cardiomax II for measurement of CO and the arterial catheter was connected to a pressure transducer for measurement of blood pressure and heart rate as mentioned above. A period of 30 minutes was allowed at the beginning of the experiment for stabilization of BP and HR. Each rat received clonidine (30 μg/kg) intravenously, and 10 minutes later ethanol (1 g/kg) or an equal volume of saline (1.3 mL/kg) was infused intravenously over 1 minute. Changes in BP, HR, CO, SV, and TPR were followed for an additional 60 minutes. Ethanol (1 g/kg) was administered as 95% in a volume of 1.3 mL/kg body wt as described in our previous studies.2 3 The administration of ethanol and saline was randomized on the 2 days of the experiment. In a previous study, we have shown that ethanol-clonidine interaction is both reversible and reproducible.1
Ethanol-Hydralazine Hemodynamic Interaction
This experiment examined the effect of ethanol on peripherally mediated hemodynamic responses evoked by hydralazine. Two additional groups of rats (one ABD and one SO, n=7 to 8) instrumented for measurement of BP, HR, and CO were used in this experiment. Hydralazine (0.5 mg/kg) was administered intravenously, and 10 minutes later randomized administration of ethanol (1 g/kg) or an equal volume of saline was performed on day 1 of the study. Ethanol and saline treatments were crossed over on day 2 as described in our previous study.1 Changes in BP, HR, CO, SV, and TPR evoked by hydralazine and subsequent ethanol or saline administration were measured over a 70-minute period.
Drugs
Clonidine hydrochloride, phenylephrine hydrochloride, hydralazine hydrochloride (Sigma Chemical Co), methohexital sodium (Brevital, Eli Lilly & Co), povidone-iodine solution (Norton Co), and Durapen (Vedco, Inc) were purchased from commercial vendors.
Statistical Analysis
Values are presented as mean±SEM. Mean arterial pressure (MAP) was calculated as diastolic pressure plus one-third pulse pressure (systolic pressure minus diastolic pressures). The baroreflex sensitivity tested by PE was measured by calculation of the ratio ΔHR/ΔMAP.3 6 ANOVA followed by a Newman-Keuls post hoc analysis was used to analyze the effects of subsequent ethanol or saline administration on hemodynamic responses (BP, HR, CO, SV, and TPR) evoked by clonidine or hydralazine. Simple contrasts were made with Student’s t test. A value of P<.05 was considered significant.
Results
Ethanol-Clonidine Hemodynamic Interaction
Sectioning of the aortic depressor nerves in anesthetized rats resulted in immediate and significant (P<.05) increases in MAP (from 121±4 to 140±3 mm Hg) and HR (from 410±8 to 427±3 beats/min). The pressor response to ABD was associated with a significant (P<.05) increase in TPR (from 2.8±0.2 to 3.9±0.2 mm Hg · mL−1 · min−1 · 100 g−1). In contrast, CI (39±3 versus 38±1 mL · min−1 · 100 g−1) and SV (315±9 versus 315±11 μL/beat) were not different when measured before and 5 minutes after ABD. On the other hand, sham operation had no effect on any of the measured hemodynamic parameters (data not shown). The correlation coefficients of the thermodilution curves ranged from .92 to .99. The pressor response to a test dose of PE (4 μg/kg) before and after ABD or sham operation was not influenced by either procedure (data not shown). However, the baroreflex-mediated bradycardia was significantly (P<.05) attenuated after ABD. ABD reduced the ΔHR/ΔMAP ratio by approximately 40% (from −0.80±0.02 to −0.47±0.03 beats · min−1 · mm Hg−1) compared with no change after sham operation (from −0.84±0.05 to −0.83±0.05 beats · min−1 · mm Hg−1), which indicated successful denervation.
The hemodynamic effects evoked by clonidine and subsequent ethanol or saline administration in conscious rats 48 and 72 hours after surgery are shown in Figs 1⇓ and 2⇓. Baseline BP and HR were similar in conscious ABD and SO rats (Fig 1⇓). On the other hand, the TPR (4.0±0.1 versus 2.8±0.1 mm Hg · mL−1 · min−1 · 100 g−1; Fig 2E⇓ and 2F⇓) was significantly (P<.05) enhanced, whereas CI (27±1 versus 41±3 mL · min−1 · 100 g−1; Fig 2A⇓ and 2B⇓) and SV (210±10 versus 327±19 μL/beat; Fig 2C⇓ and 2D⇓) were significantly (P<.05) decreased in ABD compared with SO rats. Clonidine (30 μg/kg, IV) elicited significantly (P<.05) greater hypotensive responses in conscious ABD compared with SO rats (Fig 1A⇓ and 1B⇓). A maximal hypotensive response to clonidine of 18±1 and 6±1 mm Hg was obtained in ABD and SO rats, respectively. The HR of both groups of rats showed substantial decreases after clonidine (Fig 1C⇓ and 1D⇓). The initial bradycardic response was significantly (P<.05) smaller in ABD rats (47±2 versus 120±11 beats/min) and the recovery to baseline levels was slower compared with SO rats (Fig 1C⇓ and 1D⇓). The hypotensive effect of clonidine in ABD rats coincided with significant (P<.05) decreases in CI (from 29±2.8 to 18±0.9 mL · min−1 · 100 g−1; Fig 2B⇓) caused by concomitant decreases in HR (Fig 1D⇓) and SV (Fig 2D⇓). Subsequent administration of ethanol (1 g/kg) counteracted the hypotensive effect of clonidine and raised the BP to levels higher than the corresponding preclonidine levels (Fig 1B⇓). The pressor effect of ethanol in ABD rats continued for at least 40 minutes and was associated with significant increases in CI (Fig 2B⇓) and SV (Fig 2D⇓) compared with the corresponding postsaline values. In contrast, the TPR was significantly (P<.05) reduced after ethanol administration (Fig 2F⇓). In SO rats, the only effect of ethanol was the significant increase in SV (Fig 2C⇓). This response resulted in slight increases in BP (Fig 1A⇓) and CI (Fig 2A⇓), but differences were not significant when compared with the clonidine-saline group.
Effect of subsequent administration of ethanol (1 g/kg) or an equal volume of saline on hypotensive and bradycardic responses to clonidine (30 μg/kg, IV) in conscious unrestrained ABD and SO Sprague-Dawley rats. Ethanol or saline was administered intravenously 10 minutes after clonidine. Values are mean±SEM, and number of rats in each group is shown in parentheses. *P<.05 vs respective postsaline values.
Changes elicited by intravenous administration of clonidine (30 μg/kg) and subsequent administration of ethanol (1 g/kg) or an equal volume of saline on CI, SV, and TPR in conscious unrestrained ABD and SO Sprague-Dawley rats. Ethanol or saline was administered 10 minutes after clonidine. Values are mean±SEM, and number of rats in each group is shown in parentheses. *P<.05 vs respective postsaline values.
Ethanol-Hydralazine Hemodynamic Interaction
The hemodynamic effects of hydralazine and subsequent ethanol or saline administration in conscious unrestrained ABD and SO rats are depicted in Figs 3⇓ and 4⇓. Generally, ABD-evoked changes in TPR and CI, detailed above, did not significantly influence the hypotensive effect of hydralazine. Hydralazine (0.5 mg/kg, IV) decreased BP similarly in ABD and SO rats before ethanol or saline administration (Fig 3A⇓ and 3B⇓). Despite a significantly (P<.05) higher baseline TPR in ABD rats, the reductions in TPR from the respective baseline values elicited by hydralazine were similar in ABD and SO rats and amounted to approximately 55% (Fig 4E⇓ and 4F⇓). Similarly, the reflex increase in CI that accompanied hydralazine-evoked hypotension was approximately twofold the respective baseline values in ABD and SO rats (Fig 4A⇓ and 4B⇓). The increase in CI was associated with increases in HR (Fig 3C⇓ and 3D⇓) and SV (Fig 4C⇓ and 4D⇓). The maximal hypotensive response elicited by hydralazine was approximately 20 mm Hg (Fig 3B⇓), which was similar to that produced by clonidine in ABD rats (Fig 1B⇑). Treatment with ethanol (1 g/kg IV) during the hydralazine-evoked hypotension in ABD and SO rats elicited a brief increase in BP (Fig 3A⇓ and 3B⇓) and TPR (Fig 4E⇓ and 4F⇓) that lasted less than 5 minutes after which the MAP and TPR responses to hydralazine were similar in the treatment and control groups. The reflex elevation in CI (Fig 4A⇓) produced by hydralazine-evoked hypotension in SO rats was counteracted by ethanol administration because of significant (P<.05) decreases in HR (Fig 3C⇓) and SV (Fig 4C⇓). In ABD rats, ethanol counteracted the hydralazine-evoked increases in CI at 5 minutes only (Fig 4B⇓) and HR at 50 and 70 minutes (Fig 3D⇓) but had no effect on SV (Fig 4D⇓).
Effect of subsequent administration of ethanol (1 g/kg) or an equal volume of saline on hypotensive and tachycardic responses to hydralazine (0.5 mg/kg, IV) in conscious unrestrained ABD and SO Sprague-Dawley rats. Ethanol or saline was administered intravenously 10 minutes after clonidine. Values are mean±SEM, and number of rats in each group is shown in parentheses. *P<.05 vs respective postsaline values.
Changes elicited by intravenous administration of hydralazine (0.5 mg/kg) and subsequent administration of ethanol (1 g/kg) or an equal volume of saline on CI, SV, and TPR in conscious unrestrained ABD and SO Sprague-Dawley rats. Ethanol or saline was administered 10 minutes after hydralazine. Values are mean±SEM, and number of rats in each group is shown in parentheses. *P<.05 vs respective postsaline values.
Discussion
The findings of the present study provide evidence to support the hypothesis that the opposite effects of ethanol and clonidine on CO account for their antagonistic hemodynamic interaction. Further support for the selectivity of ethanol toward centrally mediated hypotension was the finding that ethanol failed to counteract a peripherally mediated hypotensive response similar in magnitude to that elicited by clonidine. Another pertinent finding of the study was that ethanol inhibited the sympathetically mediated increases in CO in hydralazine-treated rats, whereas it increased CO when administered after clonidine. These findings suggest that ethanol may increase or decrease CO depending on the preexisting sympathetic tone.
Our previous studies showed that ethanol counteracts hypotensive responses to clonidine after both acute1 3 and chronic31 administration. However, these previous studies were based on changes in BP, and no measurement of CI or TPR was made. The present study evaluated the relative contribution of CO and TPR to the pressor effect of ethanol observed when administered during clonidine-evoked hypotension. To facilitate data interpretation, the effect of ethanol was also investigated on the hypotensive response elicited by hydralazine and on the associated CO and TPR responses. A dose of hydralazine that produced hypotension similar to that produced by clonidine was used in the present study.
The findings of the present study that ethanol counteracted clonidine- but not hydralazine-evoked hypotension confirm our previous findings in ABD and spontaneously hypertensive rats.1 2 3 Furthermore, the present investigation showed that the differential effect of ethanol on hypotensive responses produced by clonidine and hydralazine may relate, at least in part, to the relative contribution of peripheral hemodynamics (CO and TPR) to these responses. Results of this study and previous studies13 15 18 19 demonstrated that the hypotensive effects of clonidine and hydralazine involve reductions in CO and TPR, respectively. The reduction in CO produced by clonidine seems to result from the inhibition of central sympathetic tone. This view is supported by a recent study from our laboratory15 that showed that the hypotensive and sympathoinhibitory responses to intracisternally administered clonidine in ABD rats are associated with significant reductions in CO. The ability of clonidine-evoked sympathoinhibition to reduce CO but not TPR may be explained by the nonuniformity in the central control of sympathetic outflows to peripheral tissues32 and therefore the responsiveness of these tissues to the sympathoinhibitory action of clonidine.33 Furthermore, clonidine-evoked sympathoinhibition may have affected the capacitance vessels (venodilatation), which consequently leads to a reduction in venous return and CO.34
The ability of ethanol to counteract clonidine-evoked hypotension may be explained by its ability to enhance the sympathetic neural activity.35 36 37 Also, we have shown that microinjection of ethanol into the anterior hypothalamus and rostral ventrolateral medulla increased sympathetic neural activity in rats.38 The latter is the major site of action of clonidine.28 It is notable that ethanol acutely administered to humans8 39 and rats6 40 elicits a modest and short-lived pressor effect despite its sympathoexcitatory action.35 36 37 38 In a recent study we demonstrated in intact Sprague-Dawley rats that the hemodynamic effects of ethanol administered alone depended on the dose used.20 At a dose of 0.5 g/kg, ethanol increased CO that was sympathetically mediated and resulted, at least in part, from ethanol-evoked reduction in TPR.20 At a higher dose (1 g/kg), it seems that the centrally mediated sympathoexcitatory action of ethanol38 counteracted its peripheral vasodilatory effect7 10 because TPR was modestly reduced while CO remained unchanged.20 Therefore, the dose of ethanol used in the present study (1 g/kg) does not significantly change CO when administered to Sprague Dawley rats in the absence of clonidine. Nonetheless, the current study demonstrates for the first time that this dose of ethanol significantly increased CO when basal sympathetic tone was inhibited by previous clonidine administration. The increase in CO seems to outweigh the modest inhibitory effect of ethanol on TPR and to have resulted in an enhanced and longer-lasting pressor effect of ethanol. In effect, a previous study from our laboratory3 showed that the ability of ethanol to enhance sympathetic tone depends on the magnitude of the preexisting activity of the sympathetic nervous system. A larger fall in sympathetic activity developed by clonidine in ABD, compared with SO, rats has been associated with a greater sympathoexcitatory response to subsequently administered ethanol.3 Taken together, these findings suggest that the sympathetically mediated changes in CO play an important role in mediating the adverse hemodynamic interaction between ethanol and clonidine.
Unlike the case with clonidine, results of this study showed that the hypotensive effect of hydralazine in ABD and SO rats resulted exclusively from a peripherally mediated reduction in TPR. The increases in HR, CO, and SV that accompanied the vasodilatory effect of hydralazine result from compensatory baroreflex-mediated increases in sympathetic outflow to the heart.19 41 It is conceivable to assume that the presence of a high sympathetic tone in hydralazine-treated rats may have masked the sympathoexcitatory action of ethanol and hence its ability to counteract the hydralazine-evoked hypotension. With this in mind, the present finding that ethanol significantly lowered CO in hydralazine-treated SO rats may be accounted for by a predominant myocardial depressant effect of ethanol. It is notable that the net cardiac response to ethanol is the algebraic sum of two opposite effects, a direct cardiac depressant action and an indirect sympathetically mediated cardiac stimulatory action.42 Further support for this notion is the enhanced bradycardic effect of ethanol in the spontaneously hypertensive rat40 in which an enhanced sympathetic activity is exhibited.43
It is noteworthy that the present study investigated the role of CO and TPR in the interaction of ethanol with antihypertensive agents. However, the possibility must be considered that the myocardial and metabolic effects of ethanol may have contributed to its interaction with antihypertensive drugs. Reported findings have shown that ethanol decreases myocardial contractility (dP/dt) and left ventricular work.44 45 These effects of ethanol may relate to its ability to inhibit the attachment of calcium to contractile proteins or to significantly alter mitochondrial function.46 Whether pretreatment with clonidine or hydralazine, which elicit opposite effects on cardiac sympathetic activity, influenced the cardiac effects of ethanol needs to be investigated.
As discussed above, the direct cardiac depressant action of ethanol42 may not manifest because of its direct sympathoexcitatory action.35 36 37 Therefore, factors that influence the sympathetic activity are expected to modify the latter action of ethanol and hence the net effect on cardiac function. The ABD rat model, chosen because it unmasks the hypotensive action of clonidine,3 15 exhibits elevated sympathetic activity even when BP is restored to normal levels.15 25 The elevated sympathetic activity in this animal model in conjunction with hypotensive drugs that modified such activity may be an important factor in determining the net effect of ethanol on CO. For example, ethanol significantly decreased hydralazine-evoked increases in CO in SO rats but not in ABD rats. This differential effect of ethanol appears to involve differences in its effects on SV in SO (decrease) and ABD (no change) rats, since HR was significantly reduced by ethanol in the two preparations. Given that hydralazine elicited similar increases in CO in ABD and SO rats, the presence of a significantly lower CO in ABD rats compared with SO rats before hydralazine administration may have limited the capacity of ethanol to decrease CO in ABD rats. Furthermore, the ability of ethanol to counteract clonidine-evoked decreases in CO in ABD rats but not in SO rats coincided with a markedly lower CO in ABD rats. That ABD enhances the sympathetic nervous system activity, which is known to play a key role in the interaction between ethanol and antihypertensive agents,2 3 may explain, at least in part, the different effects of ethanol on CO when sympathetic activity is increased (hydralazine) or decreased (clonidine).
In summary, the present findings suggest that ethanol counteracts the hypotensive response to clonidine via a mechanism that involves, at least in part, reversal of clonidine-evoked decreases in CO and SV. In contrast, ethanol had no effect on the peripherally mediated hypotensive response to hydralazine. Interestingly, ethanol also counteracted the compensatory increases in CO, which resulted from hydralazine-evoked hypotension. These findings suggest that the preexisting sympathetic tone determines the final effect of ethanol on CO and TPR and hence on blood pressure.
Selected Abbreviations and Acronyms
| ABD | = | aortic barodenervated, aortic barodenervation |
| BP | = | blood pressure |
| CI | = | cardiac index |
| CO | = | cardiac output |
| HR | = | heart rate |
| MAP | = | mean arterial pressure |
| PE | = | phenylephrine |
| SO | = | sham-operated |
| SV | = | stroke volume |
| TPR | = | total peripheral resistance |
Acknowledgments
This study was supported by grant AA07839 from the National Institute on Alcohol Abuse and Alcoholism, Bethesda, Md.
- Received December 2, 1996.
- Revision received January 2, 1997.
- Accepted January 24, 1997.
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- Role of Cardiac Output in Ethanol-Evoked Attenuation of Centrally Mediated Hypotension in Conscious Rats
