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Microcirculatory vasoconstrictor response: Relationship with vital capacity and smoking
Life Sciences, Vol. 59, No. 13, Pp. 1031-1037, 19% Copyright @19% Elsevier Science Inc. Printed in the USA. All rights rrservcd 0024-3205/% $15.00 + .oo PI1 SOO24-3205(96)00418-3
ELSEVIER
MICROCIRCULATORY WITH
VASOCONSTRICTOR RESPONSE: VITAL CAPACITY AND SMOKING
Chi-Feng Lid,
Lai-Chu
See2, Ying-Tung
RELATIONSHIP
Lad*
National Taipei College of Nursingl, Taipei; and Department of Public Health2 and Physiology3, Chang Gung College of Medicine and Technology, Taoyuan; Taiwan, Republic of China (Received
in final form July 18, 1996)
Vasoconstrictor response (VR) induced by inspiratory gasp exhibited a strong positive correlation with vital capacity (VC) which reflects the magnitude of the input stimulus for VR (Lau et al., Clin. Sci. 89:233-237,1995). Whether a stoichiometric relationship existed between VC and VR is not known. We examined this question in two studies by determining VC and microcirculatory blood flow with laser Doppler flowmetry in healthy subjects. We first studied 40 non-smokers of different gender and age and found that the variation in VR cannot be eliminated by normalization with VC. In the second study we examined 10 young male smokers as well as matched non-smokers of identical VC, we found that smokers Taking together, the present studies demonstrated that had reduced VR. vasoconstrictor response (VR) was not determined by vital capacity alone and that smoking adversely affected VR in the absence of altered VC. KV words: cutaneous cigarette
microcirculation,
inspiratory
gasp, vasocontrictory
response,
laser Doppler
flowmetry,
smoking
We have previously shown (1) that cutaneous vasoconstrictor response(VR), induced by inspiratory gasp, measured by laser Doppler flowmetry (LDF) correlates positively with the magnitude of the vital capacity(VC). Since VC may be considered as the magnitude of the stimulus for inducing the sympathetic vasoconstrictor response (1,2), our observervations are consistent with a simple and linear relationship describing the stimulus-response pattern involving inspiratory gasp-sympathetic reflex-microcirculatory response. If such a complex circuitry could be indeed quantitatively treated, the VR of the microcirculatory blood flow (MBF) could be thus standardized by a determination of VC and the normalized response (YWVC) could be utilized to assess microcirculation and the related regulatory functions. Smce cutaneous MBF determined by LDF has been examined in several physiological and pathological situations (3-8) in hoping to establish an efficient, rapid, and noninvasive method for assessing microcirculatory status, it is important to further characterize the relationship between VC and microcirculatory vasoconstrictor response. Similar approaches have generated some success in providing a quantitative test of neurovascular functions when
* Correspondence:
Dr. Ying-Tung Lau, Department of Physiology, Chang Technology, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan. FAX: (03)328-3031, E-MAIL:ytIauQcguaplo.cgu.edu.tw
Gung College of Medicine Taiwan. R.O.C.
and
1032
Microcirculatory Vasoconstrictor Response
Vol. 59, No. 13, 1996
standard stimuli of ischaemic, electrical or iontophoretical natures are applied to evaluate the dynamic changes in cutaneous MBF as determined by LDF (9-l 1). In addition to the adverse effects on respiratory functions (12,13), smoking causes a rise in plasma norepinephine and peripheral vasoconstriction in humans (14). Smoking also reduces the gastric mucosal blood volume and oxygen saturation (15). Recent findings indicate that tobacco cigarette smoke attenuates hyperemia at the ulcer margin which is associated with ulcer healing in rats (16). It is thus reasonable to assume that MBF could be influenced by Some of these actions are mediated via smoking, and skin MBF could also be involved. nicotine to stimulate the release of norepinephine (17) and thus provide other pathways to Whether this would modulate the affect the sympathetic reflex-vasoconstrictor response. response pattern in addition to its potential effect at the input level (VC) is unknown. We thus have also investigated a group of young male smokers and matched non-smokers with comparable VC in order to evaluate the potential role of smoking in determining the magnitude of the reflex-activated VR.
&&&&. Two separate studies involved 40 and 20 Chinese subjects, respectively, were carried out. In the first study, non-smoking students and faculty members of a medical college were enrolled. All were healthy without taking any medications, active but not regularly In the second study, 20 students from a training school for security police were exercising. enrolled. All were healthy and exercised regularly (at least 2 hr daily). Ten were heavy smokers who had smoked for 7.1M.9 yr and were currently smoking 20 or more cigarettes per day. The biological data of subjects for both studies were summarized in Table I. The vital capacity for the middle-age subjects was significantly lower than that in young subjects of Study I. There were no differences between smokers and non-smokers of Study II. However, there was significant difference in vital capacity (p ~0.025) between the young subjects of Study I and smokers of Study II (Table I). In both studies, there were no significant difference in blood pressure (MAP) or body mass index (BMI) among the groups. All subjects gave informed consent and the studies were approved by the Ethics Committee of the College.
Table I. Biological Data of Tested Subjects
Middle-age
Sex(M/F)
Age(yr)
MAP (mmHg)
BMI(kg/mz)
Vital Capaicty(1)
lO/lO lO/lO
21.5ti.2 44.8fl.l*
90.7fl .o 93.8k1.7
21.8f1.6 22.8ti.5
4.1f0.2 2.9+0.1*
10/o 10/O
23.2M.3 22.2M. 1
91.5f1.2 92.0f2.3
22.2f2.6 23.2f2.7
4.8f0.2+ 4.5rt0.2
Smdv11 Smokers Non-smokers
MAP : mean arterial pressure; BMI: body mass index *: p
Vol. 59, No. 13, 1996
Microcirculatory Vasoconstrictor Response
1033
described previously (1,18). Briefly, values of MBF in the left index fingertipe were recorded in the FLUX mode (full-scale deflection set at 1000 units and time constant at 0.1 s) and the data output were recorded and processed in a personal computer utilizing MOORSOFT (VGA Version 4.2, Moor Instrument England). The values of biological zero of the MBF measurements were not subtracted. The magnitude of the flux is linearly related to the product of the erythrocyte concentration and their mean velocities in the measuring volume. Subjects were seated comfortably with their left arm supported at heart level in air-conditioned (24fl’C) laboratory (study I) or a similar office (study II). Following a period of equilibration, MBF was determined by placing the fiberoptic probe (P4L or P5L, 0.85 mm apart between the transmitting and receiving fiber: Moor Instrument England) on the center or the left index fingertip. The baseline stable value of MBF was recorded as level A. The response was based on the rapid decrease in fingertip MBF induced by inspiratory gasp and the minimal MBF attained was defined as level B (1). The vasoconstrictor reflex (VR) was evaluated as a proportional change (%) of baseline by the following equation (19): (A) - (B) VR=
x 100% (A)
Three consecutive tests were performed and the mean value of these tests was taken as the index of the vasoconstrictor reflex for that individual. The normalized response was obtained by dividing VR by the individual’s vital capacity (VC), or VR/VC.
essment of Vital CaDacitv. Under the same laboratory setting, vital capacity following maximal inspiration of each subject was also determined with a Spiro-Analyzer (ST-250, Fukuda Sangyo Co., Tokyo, Japan) on a separate occation (within a week) or on the same day when MBFIVR were determined. The difference of separate determinations of VC was not significant. The difference between two groups was compared with Student’s t-tests. PcO.05 was considered as statistically significant. Duncan’s multiple-range test was performed for those with ~~0.05 of F-test in ANOVA (Table II). Levene median test was used to examine whether the data violated the assumption of homogeneity of variance in ANOVA and none was found in any of the variables examined. Linear regression analysis was performed using the GraphPad Inplot (version 4.0) program (GraphPad Software, CA).
To test whether vasoconstrictor response (VR) induced by inspiratory gasp was determined completely by the maximal stimulus, i.e., vital capacity (VC), we normalized individual value of VR with VC by dividing VR with VC from the same individual (%/liter), and calculated the average values for the groups of subjects in Study I. These results and other MBF parameters for the determination of VR are summarized in Table II. Among the four groups of healthy non-smoking subjects, the baseline values (A) of MBF were similar while the minimal values (B) were significantly different. There were no differences between the genders at the same age. Nevertheless, significant differences among the groups existed for both VR and VC. Consistent with our earlier results (l), VR decreased as VC decreased, which depended on age and gender. A strong positive correlation existed between individual VR and VC (P
Microcirculatory Vasoconstrictor Response
1034
Vol. 59, No. 13, 1996
30
*
80
--I
60
20
* g
k
40
g 20
0
VR
10
0
VR/VC
Fig. 1 Vasoconstrictor response (VR) and the normalized response (VWVC). *:p~O.OOl, between smokers (hatched bars) and non-smokers (open bars). Verticle bars indicate standard error of the mean.
30
25
20
15
10
5
0
20
Vascular
40
60
Response
Fig. 2 Correlational relationship between normalized in 60 subjects from both studies.
80
PO0
(% VW)
response (VlUVC) and the index of VR
MicrocirculatoryVasoconstrictor Response
Vol. 59, No. 13, 19%
Table II. Response and Its Normalization
Vasoconstrictor
B
VR(%)
VC
VRIVC
360127
97flO
71.4E3.6
5.chtO.2
14.4f1.4
10
306fi8
126f21
59.4f3.9
10
383f24
163f20
59.9#.
368f34
186+23
49.4f2.7
Group
n
I. Young male
10
II. Young female III. Middle-age
male
IV. Middle-age
female
10
p (ANOVA)
1035
A
0.3733
0.0117
1
O.OOOI
3.2M.2
18.7f3.5
3.3M. 1
17.9f2.1
2.4M.3
20.9f4.7
0.0006
0.0006
n=number of subjects; A: baselme MBF value (flux unit), B:mmtmal MBF value following inspiratory gasp, VR( %) : vasoconstrictor respone = (A-B) x 100/A, VC: vital capacity (I). In Study II, subjects were matched with degree of exercise, age, blood pressure, BMI, and vital capacity (Table I). We found that while both groups had similar vital capacities despite of the long smoking history of the smokers, smokers had significantly (p
The autonomic control of cutaneous blood flow mainly involves sympathetic adrenergic vasoconstrictor nerves (20-21). Prazosin, an al-adrenoceptor antagonist, significantly reduces the cutaneous vasoconstrictor reflex response (VR) induced by inspiratory gasp or contralateral hand cooling (19). Furthermore, the magnitude of vital capacity (VC) correlates positively with the magnitude of VR (1) suggesting that magnitude of the stimulus (VC) may determine the reactivity. If this were the case, VR could not be used as an index for the intactness of the reflex-vasoconstrictor response, but rather an co-variable of respiratory function. Our present findings clearly illustrated that VR was not determined by VC alone. First, if VC were the only factor determining VR, identical normalized VR (i.e., VR/VC) would be obtained for all individuals. Table II shows that among healthy non-smokers, the value of normalized VR for young male subjects was significantly lower than those of other groups, independent of gender or age. Secondly, although baseline values of MBF were not different between smokers and non-smokers, value of mean VR of smokers was significantly lower (Fig. 1). Furthermore, since the subjects examined had matched values of VC, the same difference in normalized VR between smokers and non-smokers persisted (Fig. 1). This observation indicates that the effect(s) of smoking on VR of microcirculation is independent of its potential effects on respiratory function (12,22-24), suggesting that smoking exerts adverse influence on the
1036
Microcirculatory
Vasoconstrictor
Response
Vol. 59, No. 13, 1996
Recent evidence revealed that cigarette smoke extracts sympathetic reflex-VR circuitry. attenuate endothelium-dependent arteriolar dilation of hamster cheek pouch preparation in vivo (25) as well as to induce degradations of endothelium-derived relaxing factor and contraction in pig coronary arterial rings in vitro (26). These findings are consistent with endothelial damage which may cause abnormal local microcirculation (27). However, in young habitual cigarette smokers, the endothelium-dependent vasodilatation in the forearm do not appear significantly altered (28). Hence whether smoking directly affect the microcirculatory blood flow remains to be resolved. Nevertheless, nicotine has been shown to stimulate sympathetic activity and epinephrine release (17,29,30), suggesting that smoking could play a role in the inspiratory gasp (VC)-sympathetic reflex-vasoconstrictor response (VR) pathway. In other words, it is likely that smoking modulates the sensitivity of the sympathetic reflex loop to alter the relationship between VC and VR, resulting in a lower normalized response (Fig. 1). It is noted that while the value of VR of smokers (Fig. 1) was reduced to the level of middle-age female non-smokers (Table II, about 50%), the magnitude of VC (4.8 1) for smokers was actually twice that of middle-age female subjects (2.4 1). Thirdly, the normalized VR (VWVC) was not an independent variable since positive correlation existed between normalized VR and VR (Fig. 2) suggesting that the relationship between the input (VC) and output (VR) of the reflexiesponse circuitry was not a simple linear one. It has been reported that a decrease in VC was a better predictor of heart failure than other symptoms in the Framingham study (31). In the present study, we found that in the absence of adverse effect on VC, smoking appeared to reduce VR at the nervous reflex-microcirculation level. Since smokers may be more likely to quit smoking if they are informed of abnormal respiratory functions (32), our results suggest that abnormal microcirculatory vasoconstrcitor response may be also used as additional information to illustrate the subtle but significant influence of smoking on circulation. In conclusion, a combined determination of VC and VR Smoking seems to provide a useful tool to examine the functional status of microcirculation. appeared to affect the microcirculation at the vascular level in the absence of altered respiratory function.
Acknow1edeemen This study was supported by Chang Gung College of Medicine and Technology (CMPR 374 and CMRP 535) and Department of Health, Executive Yuan (Research Center DOH83HR-205). The excellent assistance of Ms. Y. C. Li and Mr. C.C. Tsai in the preparation of the manuscript are gratefully acknowledged.
1. 2. 3. ;: 6. 7. 8. 9. 10.
Y.T. LAU, CF. LIU, and C.C. TSAI, Clin. Sci 8e 233-237(1995). B. BOLTON, E.A. CARMICHAEL, and G. STUPUP, 3. Physiol. (Lond) 8h 83-94 (1936). J.K. KRISTENSEN, M. ENGELHART, and T. NIELSEN, Acta Dermatovener (Stockholm)_Q 43-47 (1983). G. RAYMAN, A. HASSAN, and J.E. TOOKE, Br. Med. J. =87-90 (1986). G. RAYMAN, S.A. WILLIAMS, P.D. SPENCER, L.H. SMAJE, P.H. WISE, and J.E. TOOKE, Br. Med. J. 292 1295-1298 (1986). R.A. WESTERMAN, R.E.WIDDOP, C. HOGAN, and P. ZIMMET, Neurosci. Lett. 81 177-182 (1987). G.P. RODGERS, A.N. SCHECTER, and C.T. NOGUCHI, N. Engl. J. Med. 311 15341538 (1984). J. MICHEELS, B.ALSBJORN, and B. SORENSE, Resuscitation 1231-39 (1984). G.A. HOLLOWAY, and D.W. WATKINS, J. Investigat. Dermatol. @ 306-309 (1977). R.A. Westerman, R.E. WIDDOP, J. HANNAFORD, A. LOW, R.G.D. ROBERTS, P. KENT, K. SIDENS, T. YIP, J.R.S. HALES, and F.R.N. STEPHENS Aust. Phys. Eng. Sci.u53-65 (1988).
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R.G. KARANFILIAN, T.G., LYNCH, B.C. LEE, and R.W. HOBSON, Am. Surg. a 641-644 (1984). 12. C. FLETCHER, R. PETO, C. TINKER and F.E. SPEIZER, The natural history of chronic bronchitis and emphysema: an eight-year study of early chronic obstructive lung disease in working men in London. Oxford, England: Oxford University Press, 1976. M.D. EVANS, and W.A. PRYOR, Am. J. Physiol. 266 L593-L611(1994). R.J. LUSBY, B. BAUMINGER, G. WALTERS, P.W. DAVIES, J. WOODCOCK, R. SKIDMORE, and R.N. BAIRD, Baird, R. N. In Srnokiw and Arerial Disease. R. M. Greenhalgh (ed.) ~~218-225. Pitman Medical, Bath,(1981). F. IWATA, and F.W. LEUNG, Am. J. Physiol. 268 G153-G160 (1995). ::: T. KAMADA, S. KAWANO, N. SATO, M. FUKUDA, H. FUSAMOTO, and H. ABE, Gastroenterology & 1541-1546 (1983). Z. LI, and S.P. DUCKLES, 3. Pharmacol. Exp. Ther. 264 1305-1310 (1993). :;: G.E. NILLSON, T. TENLAND, and P.A. OBERG, IEEE Trans. Biomed. Eng., BME-a 597-603 (1980). 19. F. KHAN, A.D. STRUTHERS, and V.A. SPENCE, Br. J. Clin. Pharmac. a 267-272, (1988). 20. I.C. RODDI, Circulation to skin and adipose tissue. Handbook of Physiology Section 3, Washington DC: American Society of Physiology, 3 285-317(1983). 21. J.M. JOHNSON, Circulation to rhe skiq. H.D. PATTON, A.F., FUCHS, B, HILLE, A.M. SCHER, and R. STEINER (ed) Textbook of Physiology, 21st end, Philadelphia: W.B. Saunders, 898-910 (1989). 22. US Department of Health and Human Services, Public Health Service, National Institutes Smoking and health: A report of the of Health, Heart, Lung, and Blood Institute. surgeon general. Rockville, MD: US department of health and human service, p.15-135, (1979). 23. US Department of Health and Human Services, Public Health Service, National Institutes of Health, Heart, Lung, and Blood Institute. Tobacco smoking and emphysema. In: The Health Consequences of Smoking: Chronic Obstructive Lung Disease. A Report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, p.238244 (1984). 24. US Department of Health and Human Services, Public Health Service,.National Institutes of Health, Heart, Lung, and Blood Institute. Cigarette smoke deposition in the lung. In: The Health Consequences of Smoking: Chronic Obstructive Lung Disease. A Report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, p.417-425(1984). 25. I. RUBINSTEIN, T. YONG, S.I. RENNARD, and W.G. MAYHAN, Am. J. Physiol. 26p H1913-H1918(1991). 26. T. MUROHARA, K. KUGIYAMA, M. OHGUSHI, S. SUGIYAMA, and H. YASUE Am. J. Physiol. a H874-H880 (1994). R.M. PITTILO, Adv. Exp. Med. Biol. 273 61-78 (1985). ;;(: M.C. JACOBS, J.W.M. LENDERS, J.A. KAPMA, P. SMITS, and T. THIEN, Clin. Sci. 85 51-55 (1993). 29. G. MANCIA, A. GROPPELLI, R. CASADEI, S. OMBONI, E. MUTTI, and G. PARATI, Clin. Exp. Hypertens. 12 917-929 (1990). 31 W.B. KANNEL, J.M. SEIDMAN, W. FERCHO, and W.P. CASTELLI, Circulation & 1160-1166 (1974). 31. S. IKUSHIMA, I. MURAMATSU, and M. FUJIWARA, J. Pharmcol. Exp. Ther. 219 792-797 (1981). 32. R.O. CRAPO, N. Engl. J. Med. 33125-30 (1994). 11.
ELSEVIER
MICROCIRCULATORY WITH
VASOCONSTRICTOR RESPONSE: VITAL CAPACITY AND SMOKING
Chi-Feng Lid,
Lai-Chu
See2, Ying-Tung
RELATIONSHIP
Lad*
National Taipei College of Nursingl, Taipei; and Department of Public Health2 and Physiology3, Chang Gung College of Medicine and Technology, Taoyuan; Taiwan, Republic of China (Received
in final form July 18, 1996)
Vasoconstrictor response (VR) induced by inspiratory gasp exhibited a strong positive correlation with vital capacity (VC) which reflects the magnitude of the input stimulus for VR (Lau et al., Clin. Sci. 89:233-237,1995). Whether a stoichiometric relationship existed between VC and VR is not known. We examined this question in two studies by determining VC and microcirculatory blood flow with laser Doppler flowmetry in healthy subjects. We first studied 40 non-smokers of different gender and age and found that the variation in VR cannot be eliminated by normalization with VC. In the second study we examined 10 young male smokers as well as matched non-smokers of identical VC, we found that smokers Taking together, the present studies demonstrated that had reduced VR. vasoconstrictor response (VR) was not determined by vital capacity alone and that smoking adversely affected VR in the absence of altered VC. KV words: cutaneous cigarette
microcirculation,
inspiratory
gasp, vasocontrictory
response,
laser Doppler
flowmetry,
smoking
We have previously shown (1) that cutaneous vasoconstrictor response(VR), induced by inspiratory gasp, measured by laser Doppler flowmetry (LDF) correlates positively with the magnitude of the vital capacity(VC). Since VC may be considered as the magnitude of the stimulus for inducing the sympathetic vasoconstrictor response (1,2), our observervations are consistent with a simple and linear relationship describing the stimulus-response pattern involving inspiratory gasp-sympathetic reflex-microcirculatory response. If such a complex circuitry could be indeed quantitatively treated, the VR of the microcirculatory blood flow (MBF) could be thus standardized by a determination of VC and the normalized response (YWVC) could be utilized to assess microcirculation and the related regulatory functions. Smce cutaneous MBF determined by LDF has been examined in several physiological and pathological situations (3-8) in hoping to establish an efficient, rapid, and noninvasive method for assessing microcirculatory status, it is important to further characterize the relationship between VC and microcirculatory vasoconstrictor response. Similar approaches have generated some success in providing a quantitative test of neurovascular functions when
* Correspondence:
Dr. Ying-Tung Lau, Department of Physiology, Chang Technology, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan. FAX: (03)328-3031, E-MAIL:ytIauQcguaplo.cgu.edu.tw
Gung College of Medicine Taiwan. R.O.C.
and
1032
Microcirculatory Vasoconstrictor Response
Vol. 59, No. 13, 1996
standard stimuli of ischaemic, electrical or iontophoretical natures are applied to evaluate the dynamic changes in cutaneous MBF as determined by LDF (9-l 1). In addition to the adverse effects on respiratory functions (12,13), smoking causes a rise in plasma norepinephine and peripheral vasoconstriction in humans (14). Smoking also reduces the gastric mucosal blood volume and oxygen saturation (15). Recent findings indicate that tobacco cigarette smoke attenuates hyperemia at the ulcer margin which is associated with ulcer healing in rats (16). It is thus reasonable to assume that MBF could be influenced by Some of these actions are mediated via smoking, and skin MBF could also be involved. nicotine to stimulate the release of norepinephine (17) and thus provide other pathways to Whether this would modulate the affect the sympathetic reflex-vasoconstrictor response. response pattern in addition to its potential effect at the input level (VC) is unknown. We thus have also investigated a group of young male smokers and matched non-smokers with comparable VC in order to evaluate the potential role of smoking in determining the magnitude of the reflex-activated VR.
&&&&. Two separate studies involved 40 and 20 Chinese subjects, respectively, were carried out. In the first study, non-smoking students and faculty members of a medical college were enrolled. All were healthy without taking any medications, active but not regularly In the second study, 20 students from a training school for security police were exercising. enrolled. All were healthy and exercised regularly (at least 2 hr daily). Ten were heavy smokers who had smoked for 7.1M.9 yr and were currently smoking 20 or more cigarettes per day. The biological data of subjects for both studies were summarized in Table I. The vital capacity for the middle-age subjects was significantly lower than that in young subjects of Study I. There were no differences between smokers and non-smokers of Study II. However, there was significant difference in vital capacity (p ~0.025) between the young subjects of Study I and smokers of Study II (Table I). In both studies, there were no significant difference in blood pressure (MAP) or body mass index (BMI) among the groups. All subjects gave informed consent and the studies were approved by the Ethics Committee of the College.
Table I. Biological Data of Tested Subjects
Middle-age
Sex(M/F)
Age(yr)
MAP (mmHg)
BMI(kg/mz)
Vital Capaicty(1)
lO/lO lO/lO
21.5ti.2 44.8fl.l*
90.7fl .o 93.8k1.7
21.8f1.6 22.8ti.5
4.1f0.2 2.9+0.1*
10/o 10/O
23.2M.3 22.2M. 1
91.5f1.2 92.0f2.3
22.2f2.6 23.2f2.7
4.8f0.2+ 4.5rt0.2
Smdv11 Smokers Non-smokers
MAP : mean arterial pressure; BMI: body mass index *: p
Vol. 59, No. 13, 1996
Microcirculatory Vasoconstrictor Response
1033
described previously (1,18). Briefly, values of MBF in the left index fingertipe were recorded in the FLUX mode (full-scale deflection set at 1000 units and time constant at 0.1 s) and the data output were recorded and processed in a personal computer utilizing MOORSOFT (VGA Version 4.2, Moor Instrument England). The values of biological zero of the MBF measurements were not subtracted. The magnitude of the flux is linearly related to the product of the erythrocyte concentration and their mean velocities in the measuring volume. Subjects were seated comfortably with their left arm supported at heart level in air-conditioned (24fl’C) laboratory (study I) or a similar office (study II). Following a period of equilibration, MBF was determined by placing the fiberoptic probe (P4L or P5L, 0.85 mm apart between the transmitting and receiving fiber: Moor Instrument England) on the center or the left index fingertip. The baseline stable value of MBF was recorded as level A. The response was based on the rapid decrease in fingertip MBF induced by inspiratory gasp and the minimal MBF attained was defined as level B (1). The vasoconstrictor reflex (VR) was evaluated as a proportional change (%) of baseline by the following equation (19): (A) - (B) VR=
x 100% (A)
Three consecutive tests were performed and the mean value of these tests was taken as the index of the vasoconstrictor reflex for that individual. The normalized response was obtained by dividing VR by the individual’s vital capacity (VC), or VR/VC.
essment of Vital CaDacitv. Under the same laboratory setting, vital capacity following maximal inspiration of each subject was also determined with a Spiro-Analyzer (ST-250, Fukuda Sangyo Co., Tokyo, Japan) on a separate occation (within a week) or on the same day when MBFIVR were determined. The difference of separate determinations of VC was not significant. The difference between two groups was compared with Student’s t-tests. PcO.05 was considered as statistically significant. Duncan’s multiple-range test was performed for those with ~~0.05 of F-test in ANOVA (Table II). Levene median test was used to examine whether the data violated the assumption of homogeneity of variance in ANOVA and none was found in any of the variables examined. Linear regression analysis was performed using the GraphPad Inplot (version 4.0) program (GraphPad Software, CA).
To test whether vasoconstrictor response (VR) induced by inspiratory gasp was determined completely by the maximal stimulus, i.e., vital capacity (VC), we normalized individual value of VR with VC by dividing VR with VC from the same individual (%/liter), and calculated the average values for the groups of subjects in Study I. These results and other MBF parameters for the determination of VR are summarized in Table II. Among the four groups of healthy non-smoking subjects, the baseline values (A) of MBF were similar while the minimal values (B) were significantly different. There were no differences between the genders at the same age. Nevertheless, significant differences among the groups existed for both VR and VC. Consistent with our earlier results (l), VR decreased as VC decreased, which depended on age and gender. A strong positive correlation existed between individual VR and VC (P
Microcirculatory Vasoconstrictor Response
1034
Vol. 59, No. 13, 1996
30
*
80
--I
60
20
* g
k
40
g 20
0
VR
10
0
VR/VC
Fig. 1 Vasoconstrictor response (VR) and the normalized response (VWVC). *:p~O.OOl, between smokers (hatched bars) and non-smokers (open bars). Verticle bars indicate standard error of the mean.
30
25
20
15
10
5
0
20
Vascular
40
60
Response
Fig. 2 Correlational relationship between normalized in 60 subjects from both studies.
80
PO0
(% VW)
response (VlUVC) and the index of VR
MicrocirculatoryVasoconstrictor Response
Vol. 59, No. 13, 19%
Table II. Response and Its Normalization
Vasoconstrictor
B
VR(%)
VC
VRIVC
360127
97flO
71.4E3.6
5.chtO.2
14.4f1.4
10
306fi8
126f21
59.4f3.9
10
383f24
163f20
59.9#.
368f34
186+23
49.4f2.7
Group
n
I. Young male
10
II. Young female III. Middle-age
male
IV. Middle-age
female
10
p (ANOVA)
1035
A
0.3733
0.0117
1
O.OOOI
3.2M.2
18.7f3.5
3.3M. 1
17.9f2.1
2.4M.3
20.9f4.7
0.0006
0.0006
n=number of subjects; A: baselme MBF value (flux unit), B:mmtmal MBF value following inspiratory gasp, VR( %) : vasoconstrictor respone = (A-B) x 100/A, VC: vital capacity (I). In Study II, subjects were matched with degree of exercise, age, blood pressure, BMI, and vital capacity (Table I). We found that while both groups had similar vital capacities despite of the long smoking history of the smokers, smokers had significantly (p
The autonomic control of cutaneous blood flow mainly involves sympathetic adrenergic vasoconstrictor nerves (20-21). Prazosin, an al-adrenoceptor antagonist, significantly reduces the cutaneous vasoconstrictor reflex response (VR) induced by inspiratory gasp or contralateral hand cooling (19). Furthermore, the magnitude of vital capacity (VC) correlates positively with the magnitude of VR (1) suggesting that magnitude of the stimulus (VC) may determine the reactivity. If this were the case, VR could not be used as an index for the intactness of the reflex-vasoconstrictor response, but rather an co-variable of respiratory function. Our present findings clearly illustrated that VR was not determined by VC alone. First, if VC were the only factor determining VR, identical normalized VR (i.e., VR/VC) would be obtained for all individuals. Table II shows that among healthy non-smokers, the value of normalized VR for young male subjects was significantly lower than those of other groups, independent of gender or age. Secondly, although baseline values of MBF were not different between smokers and non-smokers, value of mean VR of smokers was significantly lower (Fig. 1). Furthermore, since the subjects examined had matched values of VC, the same difference in normalized VR between smokers and non-smokers persisted (Fig. 1). This observation indicates that the effect(s) of smoking on VR of microcirculation is independent of its potential effects on respiratory function (12,22-24), suggesting that smoking exerts adverse influence on the
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Recent evidence revealed that cigarette smoke extracts sympathetic reflex-VR circuitry. attenuate endothelium-dependent arteriolar dilation of hamster cheek pouch preparation in vivo (25) as well as to induce degradations of endothelium-derived relaxing factor and contraction in pig coronary arterial rings in vitro (26). These findings are consistent with endothelial damage which may cause abnormal local microcirculation (27). However, in young habitual cigarette smokers, the endothelium-dependent vasodilatation in the forearm do not appear significantly altered (28). Hence whether smoking directly affect the microcirculatory blood flow remains to be resolved. Nevertheless, nicotine has been shown to stimulate sympathetic activity and epinephrine release (17,29,30), suggesting that smoking could play a role in the inspiratory gasp (VC)-sympathetic reflex-vasoconstrictor response (VR) pathway. In other words, it is likely that smoking modulates the sensitivity of the sympathetic reflex loop to alter the relationship between VC and VR, resulting in a lower normalized response (Fig. 1). It is noted that while the value of VR of smokers (Fig. 1) was reduced to the level of middle-age female non-smokers (Table II, about 50%), the magnitude of VC (4.8 1) for smokers was actually twice that of middle-age female subjects (2.4 1). Thirdly, the normalized VR (VWVC) was not an independent variable since positive correlation existed between normalized VR and VR (Fig. 2) suggesting that the relationship between the input (VC) and output (VR) of the reflexiesponse circuitry was not a simple linear one. It has been reported that a decrease in VC was a better predictor of heart failure than other symptoms in the Framingham study (31). In the present study, we found that in the absence of adverse effect on VC, smoking appeared to reduce VR at the nervous reflex-microcirculation level. Since smokers may be more likely to quit smoking if they are informed of abnormal respiratory functions (32), our results suggest that abnormal microcirculatory vasoconstrcitor response may be also used as additional information to illustrate the subtle but significant influence of smoking on circulation. In conclusion, a combined determination of VC and VR Smoking seems to provide a useful tool to examine the functional status of microcirculation. appeared to affect the microcirculation at the vascular level in the absence of altered respiratory function.
Acknow1edeemen This study was supported by Chang Gung College of Medicine and Technology (CMPR 374 and CMRP 535) and Department of Health, Executive Yuan (Research Center DOH83HR-205). The excellent assistance of Ms. Y. C. Li and Mr. C.C. Tsai in the preparation of the manuscript are gratefully acknowledged.
1. 2. 3. ;: 6. 7. 8. 9. 10.
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