(Hypertension. 1996;28:872-879.)
© 1996 American Heart Association, Inc.
Articles |
Influence of Age on the Inotropic Response to Acute Ethanol Exposure in Spontaneously Hypertensive Rats
the Department of Physiology, School of Medicine, Wayne State University, Detroit, Mich.
Correspondence to Ricardo A. Brown, PhD, Department of Physiology, School of Medicine, Wayne State University, 540 E Canfield St, Detroit, MI 48201. E-mail rbrown@med.wayne.edu.
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Abstract |
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Acute ethanol exposure depresses cardiac electromechanical function, whereas chronic ethanol consumption leads to the development of a specific myopathic state. Chronic hypertension and aging have similar effects in the impairment of myocardial function. However, little is known about the effects of ethanol on cardiac mechanical function in hypertension. We studied the effect of age on baseline mechanical properties and the inotropic response to clinically relevant concentrations of ethanol (18 to 71 mmol/L) using papillary muscles from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at 10 and 25 weeks of age. Mechanical parameters measured were peak tension developed, time to peak tension, time to 90% relaxation, and maximal velocities of tension development and tension decline. SHR exhibited elevated systolic pressure and body weight as well as cardiomegaly and hepatomegaly at 10 and 25 weeks of age. Baseline mechanical properties were similar in SHR and WKY muscles at 10 weeks, whereas at 25 weeks, SHR muscles developed less tension, and both maximal velocities of tension development and tension decline were markedly depressed. Ethanol exposure produced concentration-dependent negative inotropic effects in both groups at both ages. Ethanol (>18 mmol/L) decreased peak tension developed in both groups at 10 weeks, although higher concentrations were required at 25 weeks. The negative inotropic effect of ethanol resulted in the shortening of time to 90% relaxation in both groups at 10 weeks and was associated with a slowing of maximal velocities of both tension development and tension decline. The results suggest that aging depresses baseline mechanical properties when coupled with hypertension. In addition, the magnitude of the negative inotropic effect of ethanol was attenuated in both groups at 25 weeks of age.
Key Words: alcohol, ethyl • rats, inbred SHR • papillary muscles
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Introduction |
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It is well established that acute ethanol exposure depresses myocardial contractility in both humans and experimental animals in a concentration-dependent manner.1 2 3 4 Although the mechanism of the negative inotropic effect of ethanol remains only partially understood, recent evidence suggests that it may be the result of altered sensitivity of contractile proteins to intracellular free calcium, a reduction in the intracellular calcium transient, or a direct effect on membrane properties.5 6
Hypertension is a major risk factor for stroke and myocardial infarction, and there is also general agreement that myocardial hypertrophy is the primary adaptive response of cardiac muscle to a chronic or sustained elevation in systemic blood pressure. Hypertension is also associated with alterations in cardiac muscle function characterized by prolongations of the action potential, calcium transient, and contraction duration.7 8 More recent evidence suggests that myocardial alterations associated with advancing age are strikingly similar to those of hypertension.9 10 11
Numerous studies have shown that alcohol consumption increases the risk of hypertension in our society.12 13 For example, the risk among individuals who consume three to four drinks a day is at least 50% greater than that for nondrinkers, and the risk among individuals consuming six to seven drinks a day is 100% greater. However, only a few studies have examined the cardiovascular effects of acute ethanol exposure among hypertensive subjects. In response to a single dose of ethanol, both pressor14 and depressor15 effects have been demonstrated. The depressor effect of acute ethanol exposure was shown to be associated with reflex tachycardia and an increase in cardiac output. More recently, Abdel-Rahman,16 using normotensive rats and SHR, demonstrated that moderate doses of ethanol resulted in a sympatho-mediated enhancement of cardiac output only in normotensive animals. To our knowledge, the direct concentration-dependent effects of acute ethanol exposure on the mechanical properties of the myocardium from hypertensive animals, independent of neural, humoral, or cardiac reflex mechanisms, have not been studied. In the present investigation, we examined the inotropic response to changes in stimulation frequency, extracellular calcium concentration, and clinically relevant ethanol concentrations on the isolated SHR myocardium. We also studied the influence of age on this interaction.
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Methods |
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Experimental Animals
Experimental procedures and protocols were approved by the School of Medicine Animal Investigation Committee of Wayne State University in accordance with principles outlined in the Guide for the Care and Use of Laboratory Animals (National Institutes of Health Publication 85-23, revised 1985) and have been previously described.4 17 18 To determine whether chronic hypertension and aging alter the inotropic response to acute ethanol exposure, we obtained age-matched adult male SHR and their normotensive WKY counterparts as pairs of littermates (approximate weight, 50 g) (Harlan Sprague Dawley, Inc, Indianapolis, Ind). All rats were individually housed in a temperature-controlled room under a 12-hour light/dark illumination cycle and were allowed free access to standard rat chow and tap water ad libitum. Before death, systolic pressure was determined by the tail-cuff method with rats under mild barbiturate sedation (sodium pentobarbital, Sigma Chemical Co, 30 mg/kg IP).
At the end of the experimental period, rats were killed under barbiturate sedation (60 mg/kg IP), and the hearts were rapidly excised and immersed in oxygenated (95% O2/5% CO2) Tyrode's solution at 37°C. Left ventricular papillary muscles were dissected and mounted vertically in a temperature-controlled bath superfused with oxygenated Tyrode's solution (mmol/L: KCl 5.4, NaCl 136.9, NaHCO3 11.9, MgCl2 0.50, CaCl2 2.70, NaH2PO4 0.45, and glucose 5.6, pH 7.4) flowing at 10 mL/min at 30°C.
Recording Equipment
Preparations were allowed to equilibrate in Tyrode's solution for 90 minutes while electrically driven by a stimulator (S-88, Grass Instrument Co) at a frequency of 0.5 Hz for establishment of baseline isometric peak tension development. Square-wave pulses of 2 milliseconds' duration and 50% suprathreshold were delivered through a pair of platinum electrodes in close contact with one end of the muscle. Length-tension curves were constructed for each preparation, and isometric tension was recorded at approximately 90% of Lmax with a force transducer (F-30, Hugo Sachs). Signals were amplified, differentiated, and displayed on a chart recorder (Grass 79). The output of the chart recorder was coupled to the input stage of a digital storage oscilloscope (Nicolet 310).
Acute Ethanol Exposure
After equilibration, preparations were exposed to various ethanol concentrations (Aaper Chemical Co) for 10 minutes at a time when the maximal effects on developed tension were apparent. The addition of ethanol to the superfusion solution did not modify pH or alter osmolarity. The following parameters were measured: developed tension, TPT, RT90, +VT, and -VT. Recovery was continuously monitored up to 20 minutes after the drug was removed from the superfusate.
Data Analysis
For each experimental series, data are reported as mean±SE. Differences between means within groups for each variable were calculated by repeated measures ANOVA. When an overall significance was determined, Dunnett's post hoc analysis was used for comparison of conditions with control. Differences between groups were assessed with two-way ANOVA. A value of P<.05 was considered statistically significant.
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Results |
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General Features of Control and Experimental Rats
The effects of hypertension and age on blood pressure and body, heart, liver, and kidney weights are shown in Table 1
. As expected, SHR exhibited a significantly greater systolic pressure than WKY at both 10 and 25 weeks of age. The hypertensive state was also associated with a greater body weight gain, cardiomegaly, and hepatomegaly at both 10 and 25 weeks of age. Interestingly, 25-week-old SHR developed hypoglycemia compared with age-matched WKY and their hypertensive counterparts at 10 weeks of age.
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Baseline Mechanical Properties
The hypertensive state did not modify peak tension developed at 10 weeks of age (Fig 1A). However, isolated papillary muscles from 25-week-old SHR developed less tension than their age-matched WKY counterparts (1.38±0.16 versus 2.10±0.15 g, P<.05) and muscles from SHR at 10 weeks of age (1.38±0.16 versus 1.72±0.14 g, P<.05; Fig 1B). When developed tension was normalized for muscle cross-sectional area, preparations from SHR at 25 weeks developed considerably less tension than muscles from age-matched WKY but not from 10-week-old SHR (data not shown). The associated baseline myocardial mechanical properties of isolated papillary muscles from WKY and SHR are shown in Table 2. The reduced ability of muscles from 25-week-old SHR was not associated with any change in contraction or relaxation duration, represented as TPT and RT90. However, +VT and -VT in muscles from 25-week-old SHR were significantly slower than values obtained in preparations from age-matched WKY. In addition, +VT values obtained from 25-week-old SHR were also significantly slower than values obtained in muscles from 10-week-old SHR. Also, age had no effect on either contraction or relaxation duration or +VT and -VT in WKY preparations.
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significantly different from respective WKY control responses, P<.05.
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Acute Inotropic Effects of Ethanol
The acute inotropic effects of clinically relevant ethanol concentrations (18 to 71 mmol/L) on myocardium from WKY and SHR at 10 and 25 weeks of age are shown in Fig 1
. Acute exposure to ethanol elicited dose-dependent negative inotropic effects on peak tension developed in all groups. At 10 and 25 weeks of age, a relatively low concentration of ethanol (18 mmol/L) significantly reduced peak tension developed in muscles from both groups (Fig 1A and 1B). When preparations were normalized for muscle cross-sectional area, the threshold of the negative inotropic effects elicited by acute ethanol exposure at 10 weeks was shifted to a higher concentration (data not shown). By contrast, at 25 weeks of age, the threshold of the negative inotropic effect of ethanol was not altered when expressed as a function of muscle area. The magnitude of the negative inotropic effect of ethanol on myocardium from WKY and SHR at 10 and 25 weeks of age is shown in Fig 1C and 1D, respectively. The extent to which acute ethanol exposure reduced developed tension was nearly identical in WKY and SHR muscles at both 10 and 25 weeks of age. However, in response to the highest dose tested (71 mmol/L), the magnitude of the negative inotropic effect of ethanol was considerably less in muscles from 25-week-old WKY and SHR compared with their 10-week-old counterparts. Interestingly, muscles from both groups at 10 weeks of age failed to completely recover from the negative inotropic effect of acute ethanol exposure, whereas at 25 weeks, removal of ethanol from the superfusate resulted in a complete reversal of negative inotropic effect.
Acute Effects of Ethanol on TPT and RT90
The acute effects of ethanol on TPT and RT90 in muscles from 10- and 25-week-old WKY and SHR are shown in Table 2. Acute ethanol exposure produced a dose-dependent shortening of contraction duration that was significant at concentrations greater than 27 mmol/L in muscles from 10- and 25-week-old WKY. By contrast, in preparations from SHR at 10 weeks, acute ethanol exposure decreased TPT only at 71 mmol/L and failed to alter TPT in muscles from 25-week-old SHR at any of the concentrations tested. Similarly, acute ethanol exposure exerted a dose-dependent shortening of RT90 in muscles from 10- and 25-week-old WKY, whereas only the highest concentration tested shortened relaxation duration in SHR at both 10 and 25 weeks.
Acute Effects of Ethanol on +VT and -VT
Acute exposure to ethanol caused a dose-dependent slowing of both +VT and -VT in preparations from 10-week-old SHR and WKY (Table 2). Interestingly, muscles from 10- and 25-week-old WKY were more sensitive to the ethanol-induced slowing of contraction velocity, given that the threshold of this response was lower (<27 mmol/L) than that required to reduce +VT in preparations from age-matched WKY. Similarly, with respect to relaxation velocity, acute ethanol exposure caused a significant slowing; however, only muscles from 10-week-old WKY exhibited sensitivity to this action of ethanol.
Inotropic Effects of Changes in Stimulation Frequency
The inotropic effects of changes in stimulation frequency (0.01 to 5 Hz) are illustrated in Fig 2. The maximal contractile response generated at the lowest stimulation frequency was defined as the rested-state contraction, which in this study occurred at 0.01 Hz. At the rested-state contraction, the amount of tension developed by muscles from 10-week-old SHR and WKY was almost identical (Fig 2A). However, at 25 weeks, SHR preparations developed considerably less tension than age-matched WKY muscles (Fig 2B) even when normalized for muscle cross-sectional area (data not shown). As expected, increasing the frequency of stimulation resulted in a negative staircase effect in preparations from all groups. Despite the decreased ability of muscles from SHR at 25 weeks to develop tension at the rested-state contraction, their response to increases in stimulation frequency was virtually identical to that in their age-matched counterparts when expressed as a percentage of rested-state contraction (Fig 2D). The magnitude of change in developed tension was also similar between groups at 10 weeks of age (Fig 2C).
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Inotropic Effects of Changes in Extracellular Calcium Concentration
The inotropic responses to changes in the calcium concentration of the bath medium (0.5 to 10 mmol/L) in WKY and SHR preparations at 10 and 25 weeks of age are shown in Fig 3. When the calcium concentration of the bath medium was lowered from 2.7 to 0.5 mmol/L, the amount of tension developed by all muscles was similar regardless of age or hypertension (Fig 3A and 3B). At 25 weeks, SHR preparations developed considerably less tension between 0.75 and 4 mmol/L than age-matched WKY muscles (Fig 3B) even when normalized for muscle cross-sectional area (data not shown). Despite the decreased ability of SHR muscles at 25 weeks to develop tension, their response to changes in extracellular calcium concentration was slightly greater than that in their age-matched counterparts when expressed as a percentage of developed tension in normal-calcium Tyrode's solution (Fig 3D). The magnitude of change in developed tension was similar between groups at 10 weeks of age (Fig 3C). A decrease in the force-generating capacity of both SHR and WKY preparations was seen at a higher calcium concentration (10 mmol/L).
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Discussion |
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Previous studies have shown that acute ethanol exposure elicits concentration-dependent negative inotropic effects on isolated myocardium.3 This action has been attributed in part to a depletion of high-energy phosphates and/or inhibition of excitation-contraction coupling due to a depletion of Ca2+ from the sarcoplasmic reticulum.5 6 19 It has also been suggested that ethanol may reduce myofilament Ca2+ sensitivity, leading to a reduction in contractile responses. Epidemiological evidence has long suggested that there is a significant interaction between ethanol ingestion, blood pressure, and the development of hypertension.20 21 However, to our knowledge, the acute inotropic effects of ethanol on myocardial tissue from a hypertensive animal model have not been studied. Therefore, our goal in the present study was to characterize the inotropic effects of clinically relevant ethanol concentrations on isolated SHR myocardium and the influence of age on this interaction.
In the genetically inbred SHR model of essential hypertension, blood pressure is significantly greater than in normotensive controls, as expected. Moreover, it is also known that blood pressure increases with advancing age, particularly as senescence is approached.22 In the present study, systolic pressure was elevated in SHR and continued to increase with age. However, our mean values are somewhat lower than those previously reported at similar ages.23 This small difference may be the result of common variations in blood pressure phenotype within rat colonies among vendors. The development of myocardial hypertrophy is the primary adaptive response of cardiac muscle to a chronic or sustained elevation in systemic blood pressure and may be attributed to an increase in myocyte size, the number of fibrotic foci, or both.24 25 This increase in heart size, primarily in the left ventricle, allows for the normalization of myocardial wall stress, end-systolic volume, and ejection fraction.11 In our study, myocardium from hypertensive compared with normotensive rats exhibited hypertrophic growth at both 10 and 25 weeks of age when expressed as a function of body weight. Among SHR, although heart size was increased in both age groups, only 25-week-old rats exhibited alterations in myocardial mechanical properties. These results imply that factors in addition to the increase in individual myocyte size may play a role in the development of altered mechanical properties in long-term hypertension.
Alterations in the force-generating capacity of cardiac muscle in chronic hypertension are characterized by a reduction in developed tension, a significant prolongation of contraction duration, and a depression in force-velocity relations.23 25 26 27 By contrast, the hypertrophied myocardium of the young SHR has been shown to possess an increased ability to develop force.28 The increased ability of hypertrophied myocardium from young SHR was attributed to an increase in the intracellular calcium transient compared with normotensive rats. In the present study, age alone did not alter the baseline force-generating capacity of isolated myocardium nor was it modified in hypertrophied cardiac muscle from 10-week-old SHR. However, developed tension in muscles from 25-week-old SHR was significantly reduced compared with preparations from age-matched WKY even when normalized for cross-sectional area. Additionally, at this age, the velocity of contraction and relaxation was significantly reduced, which essentially paralleled the combined effect of age and hypertension on developed tension. The age-induced reduced force-generating capacity of myocardium from hypertensive rats may be the result of ultrastructural changes, reduced Ca2+ entry through sarcolemmal calcium channels, and/or Ca2+ release from intracellular stores or alterations in the calcium sensitivity of contractile proteins. Ultrastructural changes in myocardial tissue after chronic pressure overload include myocyte hypertrophy, hyperplasia of cellular organelles, swollen mitochondria, and myofibrillar and intercalated disc irregularities.24 Moreover, the reduced force-generating capacity of myocardium from hypertensive rats could also be attributed to changes in the connective tissue matrix that surrounds heart cells, such as myocardial fibrosis and increased synthesis of type V collagen, which results in an increase in ventricular stiffness.25 29 The change in collagen content reported to occur at 25 weeks of age is thought to result in a decrease in the force-generating capacity of the heart. In SHR myocardium, it has also been suggested that the intracellular calcium concentration, 
1-adrenergic receptor density, and number of functional calcium channels increase.11 30 31 32 The increased intracellular calcium concentration in hypertensive myocytes was thought to be the result of inhibition of Na+,K+-ATPase activity. Additionally, in SHR, there is a shift in myosin isoenzyme from the faster V1 to the slower V3 isoform.11 Thus, the reduction in developed tension in muscles from 25-week-old SHR may be due to alterations in intrinsic and/or extrinsic factors not related to cardiac muscle.
Acute ethanol exposure is known to exert a concentration-dependent depression of myocardial contractile function.5 6 19 33 In our study, acute ethanol exposure caused a concentration-dependent negative inotropic response in all muscles. However, at 25 weeks of age, the magnitude of reduction in developed tension was markedly reduced in myocardium from both normotensive and hypertensive rats. This decreased sensitivity exhibited by 25-week-old preparations was also associated with a decrease in the magnitude of the negative inotropic effect of ethanol. Additionally, 10-week-old rats from both groups failed to fully recover from acute ethanol exposure. Contraction duration measured as TPT was not attenuated in the myocardium of 25-week-old SHR. Moreover, relaxation duration measured as RT90 was not significantly depressed in either WKY or SHR myocardium at 25 weeks of age. However, this response was effected at doses higher than those needed to elicit a significant response in tension development. Interestingly, when expressed as a percent change from respective baseline values of developed tension, WKY myocardium was more sensitive to ethanol than SHR preparations at 10 weeks. At 25 weeks, WKY myocardium was less sensitive to ethanol than SHR myocardium.
Although the exact mechanism underlying the negative inotropic effect of ethanol remains only partially understood, it has been shown that low doses of ethanol depress myofilament responsiveness to Ca2+ and at higher doses, excitation-contraction coupling is impaired at the level of both the sarcoplasmic reticulum and contractile proteins.19 Acute ethanol has also been shown to result in a net efflux of Ca2+, with a reduction in sarcoplasmic reticular Ca2+ stores.6 33 The net efflux of Ca2+ has been attributed to an inhibition of Ca2+ influx through L-type Ca2+ channels and/or an enhanced efflux of Ca2+. Evidence also suggests that the ethanol-induced shortening of the action potential is possibly due to alterations at the calcium or sodium channel level.5 6 19 The inotropic response to ethanol in SHR myocardium at both 10 and 25 weeks of age was similar to that in myocardium of age-matched normotensive counterparts. However, at 25 weeks of age, SHR myocardium was less responsive than such preparations from 10-week-old SHR to the negative inotropic effects of acute ethanol exposure. This leads us to believe that alterations associated with age may be responsible for the decreased sensitivity to ethanol observed at 25 weeks of age.
Myocardial contraction in response to rhythmic depolarizations largely depends on the extent of intracellular free calcium elevation. The calcium concentration available to the contractile proteins is derived from both extracellular and intracellular compartments, where extracellular calcium entry through voltage-dependent calcium channels promotes intracellular calcium release from the sarcoplasmic reticulum.34 In most mammals, increases in the frequency of stimulation results in a positive inotropic effect.35 However, in rat myocardium, increases in stimulation frequency result in a negative staircase effect, given that contraction in this species depends more on intracellular calcium release than on sarcolemmal calcium entry.36 Few studies have examined the rate-staircase phenomenon in SHR over a wide range of stimulation frequencies. In the present investigation, the negative staircase response obtained in SHR preparations was virtually identical to that in the normotensive WKY and was uninfluenced even at 25 weeks of age. This particular finding suggests in part that the hypertensive state does not impair the sarcoplasmic reticular calcium uptake at the frequencies tested and at least up to this stage of a rat's life. However, Perez et al31 demonstrated that after 15 minutes of rest, the potentiated contraction of papillary muscles from normotensive animals was significantly greater than the previous steady-state values, whereas in SHR preparations, this value was not different from the steady-state control value. In the present investigation, we also found no qualitative difference in the magnitude of responsiveness of SHR compared with WKY myocardium to a wide range of extracellular calcium concentrations. Our findings are similar to the results of Perez et al and Kondo and Shibata,37 who used skinned trabeculae from hypertensive and normotensive rats and isolated papillary muscles, respectively, over a similar range of bath calcium concentrations. By contrast, Mertens et al38 demonstrated that the contractile response of isolated papillary muscles from hypertensive rats to extracellular calcium and Bay K8644 was significantly greater than that obtained in preparations from normotensive WKY.
The myocardial adaptations that occur with advancing age are essentially similar to those found in hypertensive humans.30 These cardiovascular changes include myocardial hypertrophy, reduced ventricular filling velocity, increased aortic impedance, and decreased baroreceptor reflex control as well as a diminished response to adrenergic stimulation. It is therefore possible that these changes over time may alter baseline mechanical function and the inotropic response of cardiac muscle to acute ethanol exposure. The results of our findings may be important clinically as they relate to myocardial mechanical changes that might occur in individuals with a history of hypertension who consume alcoholic beverages.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported in part by the National Institutes of Health (NIMH-MH17153). The authors gratefully acknowledge the technical assistance of Jawana M. Lawhorn and Pauline Filipovich. Special thanks are also extended to Dr Mary F. Walsh for her critical review of this manuscript.
Received January 22, 1996;
first decision February 21, 1996; first decision June 25, 1996;
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