Effects of chronic smoke exposure on the cardiovascular responses to acute nicotine infusion in the rat

European Journal of Pharmacology, 146 (1988) 237-245

237

Elsevier EJP 50118

Effects of chronic smoke exposure on the cardiovascular responses to acute nicotine infusion in the rat K i r k W. B a r t o n *, C h e r y l M. H e e s c h , B e r n a r d P. F l e m i n g , C h e n - Y i e C h i e n a n d J o h n N . D i a n a Department of Physiology and Biophysics, University of Kentucky, Tobacco and Health Research Institute, Cooper and A lumni Drive, Lexington, K Y 40546-0236, U.S.A.

Received 22 July 1987, revised MS received 23 October 1987, accepted 10 November 1987

Rats were exposed daily to cigarette smoke for 17-22 weeks in order to characterize mean arterial pressure and regional hemodynamic effects of chronic smoke exposure and to determine if cardiovascular reactivity to acute nicotine infusions is altered by chronic smoke exposure. Urethane-anesthetized animals were instrumented with miniaturized pulsed-Doppler flow probes on the iliac and mesenteric vascular beds. Under resting conditions sham-smoked and smoke-exposed animals had similar levels of mean arterial pressure and mesenteric blood flow; however, resting heart rate was lower in the smoke-exposed group, while iliac blood flow was elevated in the smoke-exposed group. Acute nicotine infusion (6.25, 12.5 and 25/~g/kg per min) produced equivalent, dose-dependent pressor effects as well as increases in iliac and mesenteric resistance in sham and smoke-e;~posed groups. Thus, chronic cigarette smoke-exposure in rats may exert significant cardiovascular effects other than on arterial pressure such as lowered heart rate and elevated blood flow to skeletal muscle beds, while cardiovascular responses to nicotine are not altered by chronic smoke-exposure. Nicotine; Hemodynamics; Cigarette smoke; Heart rate; Blood pressure

1. Introduction The effects of acute administration of nicotine on the cardiovascular system have been well documented in man and experimental animals and result in eleyation of arterial pressure (Sutton and Isaac, 1973; Cryer et al., 1976; Su, 1984; Armitage, 1965; D o w n e y et al. 1981; Comroe, 1960). These pressor effects have been primarily associated with an increase in sympathetic nervous system outflow mediated by a variety of mechanisms such as facilitation of ganglionic transmission (Gebber,

* To whom all correspondence should be addressed: Dept. of Physiology and Biophysics, University of Kentucky, Tobacco and Health Research Institute, Cooper and Alumni Drive, Lexington, KY 40546-0236, U.S.A.

1969), activation of arterial chemoreceptors (Cornroe, 1960), and a u g m e n t a t i o n of norepinephrine release f r o m sympathetic nerve terminals (Bevan and Haeusler, 1975; Fewings et al., 1966; L/3ffelholz, 1970). Additionally, nicotine has been reported to cause vasopressin release ( H a y w a r d and Pavasuthipaisit, 1976; Reaves et al., 1981) and renin secretion (Slaven et al., 1973), both of which m a y contribute to the pressor action of nicotine. While the acute effects of nicotine are pressor in nature, it is n o t e w o r t h y that there is equivocal evidence concerning whether chronic administration of nicotine or chronic exposure to cigarette smoke is associated with an elevation in arterial pressure. In h u m a n subjects there is little evidence of chronic elevation in arterial pressure due to long-term smoking, and, in fact, smokers tend to have a slightly lower arterial pressure as c o m p a r e d

0014-2999/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)

238 with the non-smoking population (Surgeon General, 1979; Stamler et al., 1975; Seltzer, 1974). Similarly, chronic administration of nicotine in experimental animals has been reported to have minimal effect, if any effect, on arterial pressure in dogs with osmotic p u m p infusion of nicotine (Holtz et al., 1984) and in rats with nicotine chronically administered in drinking water (H~iggendal and Henning, 1980). Other studies have indicated that a 3 month exposure to nicotine reduces blood pressure in normotensive animals and can even reverse renal hypertension (Wenzel et al., 1964; Wenzel and Azmeh, 1970). On the other hand, Ahmed et al. (1976) and Loscutoff et al. (1982) have reported that chronic smoke exposure in dogs and rats, respectively, can result in chronic elevation in arterial pressure, Since the acute effects of cigarette smoking are primarily associated with the effects of nicotine (Kilburn, 1974; Lefkowitz, 1976), it is interesting that this acute stimulus of sympathoadrenal outflow does not necessarily increase arterial pressure when applied on a long-term basis through either tobacco smoke or nicotine administration. In the study by Holtz et al. (1984), it was found that chronic infusions of nicotine led to the developmerit of tolerance to the acute effects of nicotine on sympathoadrenal activation in dogs. Thus, the primary purpose of this study was to examine the effects of acute nicotine administration in chronically smoked rats in order to determine if tolerance develops to the pressor effects of nicotine in smoked rats. To accomplish this purpose, we have examined steady state responses in nicotine through continuous infusions of nicotine and have also examined regional blood flow to the mesenteric and iliac vascular beds because these vascular beds have been shown to be sensitive to the acute and chronic effects of nicotine administration (Downey et al., 1981; Richardson and Morton, 1979).

2. Materials and methods

2.1. Animals Male Sprague-Dawley rats (150-174 g) were obtained from Harlan/Sprague-Dawley, Indi-

anapolis, and observed under quarantine for 10 days. Animals were then randomly selected for either sham-smoking or smoking protocols. All animals were housed in hanging stainless steel wire cages, maintained in a controlled environment, and allowed free access to food and water in the animal care facility at the University of Kentucky Tobacco and Health Research Institute.

2.2. Smoking procedures Animals were randomly divided into two groups: (1) smoke-exposed, which were exposed daily to fresh tobacco smoke from a University of Kentucky 2R1 reference cigarette, and (2) sham control, which received the same handling but were exposed to puffs of room air. After a 1 week acclimatization period, the smoke-exposed group was exposed to 10 p u f f s / d a y , 7 d a y s / w e e k throughout the entire exposure period (17-22 weeks). The smoke generation and exposure equipment has been previously described in detail (Griffith and Hancock, 1985; Griffith and Standarer, 1985). Briefly, each minute a 2 s, 35 ml puff from a 2R1 cigarette is drawn into a recycle reservoir for dilution with air with the animal receiving smoke for the first 16-20 s of each 1 rain exposure period. Daily assessment of total particulate matter exposure was performed, as previously described (Griffith and Hancock, 1985; Griffith and Standafer, 1985). The procedure assesses removal by the animals of the total particulate matter in the smoke from the smoke chambers during each exposure period. The daily smoke exposure was assessed by monitoring the total particulate matter exposure for the smoked rats, which was 4.1 _+ 0.3 m g / k g per day.

2.3. Animal surgical procedures Twenty-four to 30 h after the last smoke or sham smoke exposure period, animals were anesthetized with 1.25 g / k g (i.p.) of urethane. The trachea was cannulated with PE205 tubing to maintain a patent airway. The right femoral artery was cannulated with a 28-gauge teflon tubing tipped cannula to assess arterial blood pressure, and the right femoral vein was cannulated with a

239 PE50 catheter for i.v. administration of drugs. To assess regional blood flow in splanchnic and skeletal muscle vascular beds, the superior mesenteric artery and iliac artery, respectively, were selected and implanted with miniaturized pulsed-Doppler flow probes, Briefly, this procedure entails a midline laparotomy and careful surgical exposure under a stereomicroscope of the superior mesenteric and left iliac arteries. A miniaturized pulsed-Doppler probe of appropriate lumen size is placed around each vessel (Haywood et al., 1981). After closure of the incision, the exteriorized-Doppler probe leads are connected to a pulsed-Doppler flowmeter (University of Iowa Bioengineering Department). This technique measures changes in blood velocity which are recorded as Doppler shift in kHz. Assessment of blood velocity with this technique has been shown to be directly and linearly related to absolute blood flow (Haywood et al., 1981). With this information, relative vascular resistance is determined from the following formula: relative vascular resistance (RVR) in mm H g / k H z = mean arterial pressure (mm H g ) / D o p p l e r shift (kHz). This relative resistance value is then used to determine percentage change in vascular resistance from the equation, RVR E - R V R c / R V R c × 100%, where RVRc and RVRE are the control and experimental relative vascular resistance val-

2.5. Statistical analysis For statistical analysis, a three-way repeated measures analysis of variance was employed with the three factors: treatment, dose and time. Significance was set at the P < 0.05 level. Values are presented asmeans_+S.E.

3. Results

3.1. Baseline variables Table 1 demonstrates the comparison of baseline variables between the smoke-exposed and sham-exposed groups. The smoke-exposed group weighed significantly less than the sham group. While mean arterial pressure was equivalent in the two groups, resting heart rate was reduced in the smoked group. Iliac artery blood velocity was elevated in the s~noke-exposed group and, consequently, the calculated iliac vascular resistance was diminished. Mesenteric artery blood velocity and vascular resistance were equivalent in the sham and the smoked groups,

ues, respectively.

TABLE 1

2.4. Experimental protocol

Comparison of baseline variables: sham-smoked versus smoke-exposed rats. Values represent means_+S.E.; blood vel. = blood velocity; vas. resist. = vascular resistance; a significantly different groups (P < 0.05).

After a 15-20 rain stabilization period a 15 min i.v. nicotine infusion was initiated using each of the following infusion rates: 6.25, 12.5 and 25.0 /~g/kg per min. A minimum 30 min interval was allowed between each of the infusions. Nicotine solutions were prepared daily from nicotine free base (Sigma) and the pH was adjusted to 7.3-7.4. The maximum infusion volume at the highest dose (25/~g/kg per rain) was 10 ~ l / m i n . Arterial pressure was monitored with a Century Technologies CP-01 pressure transducer, and heart rate responses were derived from the arterial pulse interval by a Beckman 9857B cardiotachometer. Signals were recorded on a Beckman R612 Dynograph.

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324 _+ 9 ~

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240

3.2. Effects of nicotine

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a greater elevation in arterial pressure in both groups than at the 6.25 /~g/kg per rain infusion level (fig. 1). The pressor effects of nicotine in the s h a m - s m o k e d and smoke-exposed groups were not different. C o n c o m i t a n t with the pressor response there was also an elevated heart rate in both groups during the 1 2 . 5 / ~ g / k g per min infusion of nicotine (fig. 2). While there was an apparent divergence in the degree of tachycardia between the two groups, this difference was not significant (P =0.15). Similar to the responses observed at the lower infusion levels of nicotine, the pressor effects of 25 /~g/kg per min infusion of nicotine were not different between the two groups (fig. 1). However, at the 25 /~g/kg per min infusion (fig.

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241

0.05). Interestingly, the h e a r t rate r e s p o n s e to nicotine in the s h a m - s m o k e d g r o u p at this elevated infusion rate was reversed f r o m an initial positive to a negative c h r o n o t r o p i c response b y the e n d of the 15 min infusion period. T h e effects of n i c o t i n e on the iliac a n d mesenteric vascular resistance responses in the s h a m a n d s m o k e d g r o u p are d e m o n s t r a t e d in figs. 3 a n d 4, respectively. It should be n o t e d that there was an increase in iliac vascular resistance in b o t h g r o u p s at the 6.25 f f g / k g p e r rain (P < 0.05) infusion rate b u t n o t in the mesenteric vascular bed. A t the 12.5 a n d 25 ~ g / k g p e r m i n infusion rates n i c o t i n e infusion i n c r e a s e d resistance in b o t h the iliac (P < 0.05) a n d mesenteric vascular beds (P < 0.05), but there was n o difference b e t w e e n the v a s c u l a r resistance responses in the s h a m versus

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s m o k e - e x p o s e d g r o u p in either b e d or for either the 12.5 or 2 5 / ~ g / k g p e r m i n infusion rate. W h i l e c o m p a r i s o n of the r e s p o n s e s of the two b e d s suggested that there was a greater v a s o c o n s t r i c t i o n in the iliac t h a n m e s e n t e r i c bed, this difference was n o t significant.

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T h e results of this s t u d y i n d i c a t e that the pressor r e s p o n s e to i.v. infusion of n i c o t i n e is not altered in rats c h r o n i c a l l y e x p o s e d (4-5 m o n t h s ) to cigarette smoke. Similarly, the regional v a s o c o n s t r i c t o r effects of n i c o t i n e in the iliac a n d m e s e n t e r i c v a s c u l a r b e d s also a p p e a r to be unaffected b y c h r o n i c s m o k e exposure. T h e one dif-

242 ference in the effects of nicotine in the smoke-exposed group was an augmented positive chronotropic effect at the highest infusion rate of nicotine. These results also offer relevant information concerning the effects of chronic smoke exposure on resting cardiovascular variables. We have observed that chronic smoke exposure has no effect on resting mean arterial pressure with the smoking protocol employed in this study. However, in the smoke-exposed animals two observations are notable. First, there is a decrease in resting heart rate, and second, there is a significant increase in resting iliac but not mesenteric blood flow. Two points concerning the design of this study should be noted. First, regional blood flow was assessed in the mesenteric and iliac vascular beds in order to better examine the peripheral circulatory mechanism of the pressor action of nicotine, This technique allows a more detailed examination of the peripheral circulation than is possible with only measurement of arterial blood pressure by allowing assessment of changes in regional blood flow distribution. Mesenteric and iliac blood flows were examined because the mesenteric blood flow is representative of the splanchnic circulation which receives about 25% of the total cardiac output (Donald, 1983), while iliac blood flow offers an assessment of skeletal muscle circulation, which plays an important role in arterial baroreceptor reflex control of arterial pressure (Donald and Shepherd, 1978; Kendrick et al., 1972). The second point to be noted is that the effects of nicotine were examined during continuous infusion of nicotine. This design was employed in order to study the effects of nicotine approaching steady state conditions and to avoid the transient changes resulting from bolus administration of nicotine,

4.1. Effect of smoke exposure on resting cardiovascular variables While chronic smoke exposure did not alter resting arterial pressure, two differences were noted in resting cardiovascular variables between the smoke-exposed and sham groups. First, the resting heart rate in the smoked group was significantly lower than in the sham group. Interestingly, similar observations have been made from chroni-

cally smoked mice (Marks et al., 1983) and rats (Loscutoff et al., 1982). One possible explanation for the decreased resting heart rate in the smokeexposed group comes from the finding that chronic tobacco smoke administration to laboratory rats has been found to increase the sensitivity of arterial baroreflex control of the cardiovascular system (Bennett and Richardson, 1984). Oiven similar resting arterial pressures in the two groups, a greater sensitivity in baroreflex control of heart rate could lead to lower resting heart rate in the smoke-exposed group. The second difference between the sham and smoked groups is that the resting iliac blood flow was elevated in the smoke-exposed group. This observation did not reflect a general decrease in vascular resistance in all beds since resting mesenteric resistance was not altered. The increase of blood flow to the iliac bed, when coupled with a lack of change in arterial pressure in the smoked group, demonstrated that, under resting conditions, the vascular resistance in the iliac bed was lower in the smoke-exposed group. A somewhat similar observation has been reported by Richardson and Morton (1979) where chronic administration of nicotine, but not tobacco smoke, also produced a decreased vascular resistance in the iliac circulation of the rat. The results of Richardson and Morton (1979) serve to indicate that the alteration in iliac vascular resistance in our smoke-exposed group may be due to the chronic effect of nicotine. It is also possible that other stimuli may have contributed to the decrease in iliac vascular resistance. For instance, Koehler et al. (1985) have reported that acute exposure to carbon monoxide, one of the constituents of tobacco smoke, may reduce skeletal muscle vascular resistance.

4.2. Effects of nicotine in chronically smoke-exposed rats As previously described, the acute effects of nicotine and smoking are hypertensive in nature (Comroe, 1960; Armitage, 1965; Sutton and Isaac, 1973; Cryer et al., 1976; Downey et al., 1981; Su, 1984; Aronow, 1974; Tachmes et al., 1978). Based on these acute effects, it is interesting that there is

243 no evidence of a sustained elevation in blood pressure after chronic smoke exposure in humans (Stamler et al., 1975; Surgeon General, 1979; Seltzer, 1974). In experimental animals, the effect of chronic smoke exposure has been varied in that smoking has been reported (1) to have no effect on arterial pressure in rats exposed 34 months to cigarette smoke (Haag et al., 1960), (2) to elicit an 11 mm Hg increase in arterial pressure after a 24 month smoke exposure in rats (Loscutoff et al., 1982), and (3) to produce an elevation in arterial pressure in dogs exposed 22 months to cigarette smoke (Ahmed et al., 1976). Chronic administration of nicotine in dogs has been reported to have no effect on arterial pressure (Holtz et al., 1984) or to increase arterial pressure (Ahmed et al., 1976), while in rats, chronic nicotine administration either produces no effect on arterial pressure (Hiiggendal and Henning, 1980) or elicits a hypotensive effect (Wenzel and Azmeh, 1970). When taken as a whole, this information demonstrates that there is conflicting evidence, at best, concerning the effects of chronic smoke exposure and nicotine on arterial pressure, and, in fact, the majority of the evidence would argue against a change in blood pressure, One explanation for the lack of elevated arterial pressure with chronic smoking or nicotine administration is that tolerance could develop due to the effects of nicotine. Holtz et al. (1984) have noted that tolerance develops to nicotine-induced activation of the sympathoadrenal system during chronic administration of nicotine and that this tolerance may contribute to the lack of development of hypertension. However, the results of our study indicate that in chronically smoke-exposed rats there is no change in the response to nicotine, Thus, it would appear that tolerance to cardiovascular effects of nicotine does not develop. It could be argued that other mechanisms could mask a change in the response to nicotine, such as an increase in vascular reactivity coupled with a net decrease in sympathetic release of catecholamines. While vascular reactivity was not specifically examined in this study, other studies have examined this possibility after chronic nicotine administration (Holtz et al., 1984) and after chronic smoke exposure (Loscutoff et al., 1982)

and have found no change in vascular reactivity to sympathomimetic agents. The one notable difference in the effect of nicotine in the smoke-exposed group is the tachycardia which occurred at the 25 /~g/kg per min dose of nicotine. Comroe and Mortimer (1964) showed that nicotine could elicit either tachycardia or bradycardia through stimulation of aortic chemoreceptors or carotid bodies, respectively. While differential chemoreceptor activation in sham versus smoked animals could conceivably account for the different heart rate response at the 25 /~g/kg per min infusion level this explanation seems unlikely since femoral venous infusion of nicotine would have equal access to both aortic and carotid chemoreceptors. Another possible explanation is that tolerance to the bradycardic effects of nicotine may have occurred in the smoked group. Marks et al. (1985) have reported that tolerance develops to nicotine induced bradycardia during chronic i.v. nicotine infusion in mice. A third possible factor that may have contributed to the tachycardia is the marked reduction in resting heart rate in the smoked group. In other words, the lower baseline heart rate, which was approximately 90 b e a t s / m i n less in the smoke-exposed group, is likely to have contributed to the tachycardia.

4.3. Effect of nicotine on regional blood flow The results of this study clearly demonstrate that there is an increase in peripheral vascular resistance in the iliac and mesenteric circulations. These findings are in agreement with results obtained in dogs by Downey et al. (1981; 1982) and in cats by Rubenstein and Sonnenschein (1971), which have demonstrated increased vascular resistance in iliac and splanchnic beds during nicotine infusion. Similar constrictor effects have also been observed in skin and muscle of the human forearm by Fewings et al. (1966). However, to the best of our knowledge, the results of the present study are the first demonstration of these findings in the rat. The mechanism of the increased vascular re~ sistance would appear to derive at least partially from an increase in sympathetic vasoconstrictor tone since ~-adrenoceptor blockade has been

244

shown t o a t t e n u a t e the pressor effects of nicotine (S~tton and Isaac, 1973; Downey et al. 1981). As described previously the increased sympathetic constrictor tone may be attributable to actions of nicotine at the CNS (Armitage et al., 1967; Feldberg and Guertenstein, 1976), on ganglionic t r a n s m i s s i o n (Gebber, 1969), at chemoreceptors (Cornroe, 1960; Comroe and Mortimer, 1967), at sympathetic nerve terminals (Bevan and Haeusler, 1975; Fewings et al., 1966; L~Sffelholz, 1970) and o n hormonal release of vasopressin (Hayward and Pavasuthipaisit, 1976; Reaves et al., 1981) or renin (Slaven et al., 1973). Acknowledgements The authors wish to acknowledge Ruth A. Oremus for her technical assistance, Martha Butts for her secretarial assistance in preparing this manuscript, and John Turbek for his assistance with the statistical analyses. This work was supported by grants from the Tobacco and Health Research Institute, University of Kentucky 5-41075, and NIH-HLBI Grant HL 36552.

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