AJP - Heart Calcium Transients and Cell-Sarcomere
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 293: H1745-H1749, 2007. First published June 8, 2007; doi:10.1152/ajpheart.00329.2007
0363-6135/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/3/H1745    most recent
00329.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Boesen, E. I.
Right arrow Articles by Pollock, D. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Boesen, E. I.
Right arrow Articles by Pollock, D. M.

Effect of chronic IL-6 infusion on acute pressor responses to vasoconstrictors in mice

Erika I. Boesen and David M. Pollock

Vascular Biology Center, Medical College of Georgia, Augusta, Georgia

Submitted 15 March 2007 ; accepted in final form 8 June 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Interleukin (IL)-6 has been implicated as a contributing factor in the pathogenesis of hypertension, although the mechanisms involved are unclear. Studies conducted in vitro suggest that IL-6 may have a direct effect on vascular tone and may modulate constrictor responses to agonists. Whether this effect can be observed in vivo is unknown. Therefore, mice were treated with either IL-6 (16 ng/h sc) or vehicle for 14 days, and the acute blood pressure and heart rate responses to endothelin (ET)-1, angiotensin II (ANG II), and phenylephrine (PE) were assessed under isoflurane anesthesia. Blood pressure responses to ET-1 were identical in vehicle- and IL-6-infused mice, both in the presence and the absence of ganglion blockade with chlorisondamine. The fall in heart rate during ET-1 responses was significantly attenuated in IL-6-infused mice with autonomic reflexes intact (vehicle vs. IL-6, P < 0.05 at 1 and 3 nmol/kg of ET-1), but this difference was not observed after ganglionic blockade. Both blood pressure and heart rate responses to ANG II were indistinguishable between IL-6- and vehicle-infused mice, as were responses to PE except for a significant increase in the blood pressure response and decrease in the heart rate response in IL-6-infused mice observed only at the highest dose of PE (300 µg/kg; P < 0.05). These findings show that, despite what might be predicted from studies conducted in vitro, chronic exposure to elevated plasma IL-6 concentrations in itself does not predispose the mouse to enhanced responsiveness to vasoconstrictors in vivo.

cytokines; endothelin; angiotensin II

INCREASED CIRCULATING LEVELS of the proinflammatory cytokine interleukin (IL)-6 are associated with increased risk of cardiovascular disease and all-cause mortality, particularly in older individuals (10, 26, 27, 29). Currently, a potential role for IL-6 in hypertension is emerging. Epidemiologic studies have demonstrated a positive association between plasma IL-6 and blood pressure in apparently healthy men and women (2, 5). Chronic infusion of IL-6 increases blood pressure in pregnant but not nonpregnant rats (9, 24). In addition, angiotensin II (ANG II)-induced hypertension is attenuated, and acute pressor responses to psychosocial stress reduced, in male IL-6-knockout mice (15, 16).

Despite the growing evidence implicating IL-6 in hypertension, the mechanisms involved are poorly understood. One possibility is that IL-6 may affect vascular tone and responsiveness to vasoconstrictors. Several studies have reported acute vasoconstrictor effects of IL-6 on arterial tissue (1, 11, 25). In addition, preincubation of aortic strips with IL-6 enhances contraction to phenylephrine (PE) (23), although organ culture of rat basilar artery or human temporal artery with IL-6 does not alter contraction to endothelin (ET)B receptor activation (17, 32). Chronic IL-6 infusion in mice was reported to increase ANG II type 1 (AT1) receptor expression, enhance constriction to ANG II, increase oxidative stress, and impair endothelium-dependent vasodilation, all measured in aortic tissue in vitro (30). Impaired endothelial nitric oxide (NO)-cGMP-mediated relaxation and enhanced constriction to PE have also been reported in aortic strips isolated from IL-6-infused pregnant rats (24). While these changes noted in aortic tissue raise the possibility of similar changes occurring in resistance vessels and may well have implications for blood pressure control, effects of chronic IL-6 infusion on pressor responsiveness in vivo have not been studied. We therefore tested the hypothesis that chronic exposure to elevated levels of IL-6 would enhance pressor responses to vasoactive agents in mice.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Male mice obtained from Jackson Laboratories (Bar Harbor, ME) were used in these experiments, and all procedures were approved in advance by the Medical College of Georgia Institutional Animal Care and Use Committee. One experiment utilized wild-type (C57BL/6) and IL-6-knockout mice (B6.129S2-Il6m1Kopf/J). In all other experiments, C57BL/6 mice received 14-day subcutaneous infusions of either mouse recombinant IL-6 (R & D Systems, Minneapolis, MN) at a rate published previously (16 ng/h; Ref. 14) or vehicle [0.1% bovine serum albumin (BSA) in phosphate-buffered saline]. The solutions were delivered by microosmotic pumps (Alzet model 1002, Alza, Palo Alto, CA) implanted subcutaneously at the back of the neck under brief anesthesia (2% isoflurane; Baxter Pharmaceutical Products, Deerfield, IL).

Responses to ET-1. For wild-type and IL-6-knockout mice, or after 14 days of vehicle or IL-6 infusion, mice were anesthetized (isoflurane) and placed on a servo-controlled heating table to maintain body temperature. Catheters were inserted into 1) the carotid artery to measure arterial pressure and heart rate, with care taken not to damage the vagus nerve, and 2) the jugular vein for infusion of 1% BSA in phosphate-buffered saline at 6 µl/min. After a 30-min stabilization period, blood pressure and heart rate responses to rapid intravenous infusions of ET-1 (0.1–3 nmol/kg; American Peptide, Sunnyvale, CA) were recorded (Powerlab data acquisition system). ET-1 doses were administered at 10-min intervals in ascending order in volumes of 50 µl, which were flushed in intravenously at a rate of 100 µl/min by infusion pump. In separate groups of similarly prepared mice a blood sample of ~100 µl was taken from the carotid artery catheter immediately before commencement of the stabilization period and replaced with an equivalent volume of 1% BSA, and the effects of ET-1 (0.03–3 nmol/kg) were studied after ganglionic blockade with chlorisondamine (10 mg/kg iv; Tocris Bioscience, Ellisville, MO).

Responses to ANG II and PE. In separate groups of mice, a blood sample of ~100 µl was taken immediately after completion of surgery and replaced with an equivalent volume of 1% BSA. After the 30-min stabilization period, blood pressure and heart rate responses to rapid intravenous infusions of ANG II (0.1–3 µg/kg; Phoenix Pharmaceuticals, Belmont, CA) and PE (10–300 µg/kg; Sigma-Aldrich, St. Louis, MO) were measured. For each agent, doses were administered in volumes of 50 µl delivered at 200 µl/min and given in random order, with either the ANG II or the PE dose-response curve constructed first, this being alternated between mice.

Plasma IL-6 concentrations. Blood samples were centrifuged in heparinized capillary tubes, and the plasma was collected and stored at –80°C until analysis. Plasma IL-6 concentrations were measured with a commercially available kit according to the manufacturer's directions (Quantikine Mouse IL-6 Immunoassay; R & D Systems).

Data analysis. Basal arterial pressures and heart rates were calculated by averaging values recorded during the 5 min before administration of the first dose of ET-1 or from the average values obtained over 30-s intervals immediately before administration of each dose of ANG II or PE. Representative traces of responses to agonists are shown in Fig. 1. Responses to all agonists were calculated as the area under the curve from preinfusion values for either the 10-min period following each ET-1 dose or the duration of the response to ANG II or PE.


Figure 1
View larger version (20K):
[in this window]
[in a new window]

  		Fig. 1. Representative traces of acute responses to vasoconstrictors in vehicle-infused mice. Data shown are mean arterial pressure (solid line) and heart rate (dotted line) responses to acute intravenous bolus administration of endothelin (ET)-1 (A), ET-1 following ganglionic blockade with chlorisondamine (B), angiotensin II (ANG II; C), and phenylephrine (PE; D). Doses indicated are in nanomoles per kilogram (ET-1) or micrograms per kilogram (ANG II and PE). bpm, Beats per minute.

 
Unpaired t-tests or Mann-Whitney U-tests were used to compare basal data between vehicle- and IL-6-infused mice within each experiment. Responses to vasoconstrictors were analyzed by repeated-measures analysis of variance testing whether responses to vasoconstrictors were dose-dependent (Pdose) and whether IL-6 infusion or genotype affected the responses in a manner independent of the dose of vasoconstrictor (Pgroup) or dependent on the dose of vasoconstrictor (Pdose*group). Post hoc contrasts were used to compare between groups where Pdose*group < 0.05. P ≤ 0.05 was considered statistically significant. Data are presented as means ± SE except where indicated.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Infusion of IL-6 for 14 days significantly increased plasma IL-6 concentration, but basal mean arterial pressures and heart rates were similar between vehicle- and IL-6-infused mice (Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1. Baseline characteristics in anesthetized mice

 
Responses to ET-1. Both vehicle- and IL-6-infused mice demonstrated dose-dependent increases in mean arterial pressure and decreases in heart rate in response to ET-1 (Pdose = 0.0001; Fig. 2, A and B). Although mean arterial pressure responses were similar in magnitude in vehicle- and IL-6-infused mice, IL-6-infused mice displayed significantly smaller reductions in heart rate, particularly at the higher doses of ET-1 (P < 0.05 for 1 and 3 nmol/kg; Fig. 2B). This resulted in maximal reductions in heart rate of 112 ± 29 vs. 54 ± 19 beats/min at 3 nmol/kg in vehicle- and IL-6-infused mice, respectively. To determine whether the absence of endogenous IL-6 affected the responses to ET-1, dose-response curves to ET-1 were also constructed in wild-type and IL-6-knockout mice. Both genotypes demonstrated dose-dependent changes in mean arterial pressure and heart rate in response to ET-1, but there were no significant differences in the responses between the two genotypes (Fig. 3).


Figure 2
View larger version (26K):
[in this window]
[in a new window]

  		Fig. 2. Acute responses to ET-1 in anesthetized mice. Data shown are mean arterial pressure (A and C) and heart rate (B and D) responses to acute intravenous bolus administration of ET-1 in vehicle ({blacksquare})- and interleukin (IL)-6 ({square})-infused mice, expressed as means ± SE for area under the curve (AUC) from baseline. Responses were obtained in separate groups of mice either with autonomic reflexes intact (A and B; n = 8 and 6 for vehicle and IL-6 groups, respectively) or after ganglionic blockade with chlorisondamine (C and D; n = 4 and 5 for vehicle and IL-6 groups, respectively). Repeated-measures ANOVA was used to test whether responses to ET-1 were dose-dependent (Pdose) and whether IL-6 infusion affected the responses in a manner independent of the dose of ET-1 (Pgroup) or dependent on the dose of ET-1 (Pdose*group). *P < 0.05 for IL-6 vs. vehicle at the given dose. NS, nonsignificant.

 

Figure 3
View larger version (13K):
[in this window]
[in a new window]

  		Fig. 3. Acute responses to ET-1 in anesthetized wild-type ({blacksquare}, n = 8) and IL-6-knockout ({square}, n = 8) mice. Data shown are mean arterial pressure (A) and heart rate (B) responses to acute intravenous bolus administration of ET-1, expressed as means ± SE for AUC from baseline. Statistics are as in Fig. 2.

 
Responses to ET-1 during ganglion blockade. To determine whether baroreflexes were masking an alteration in the direct effects of ET-1 on the heart rate of IL-6-infused mice, responses to ET-1 were recorded in separate groups of vehicle- and IL-6-infused mice after ganglion blockade with chlorisondamine. Treatment with chlorisondamine significantly reduced basal mean arterial pressure and heart rate in both IL-6- and vehicle-infused mice; however, the magnitudes of the reductions were not significantly different between the two groups (Table 1). After ganglion blockade, ET-1 produced dose-dependent increases in both mean arterial pressure and heart rate, but the responses were indistinguishable between the two groups (Fig. 2, C and D).

Responses to ANG II. ANG II induced dose-dependent increases in mean arterial pressure and reductions in heart rate (Fig. 4, A and B). These responses were not significantly different between vehicle- and IL-6-infused mice.


Figure 4
View larger version (24K):
[in this window]
[in a new window]

  		Fig. 4. Acute responses to ANG II and PE in anesthetized mice. Data shown are mean arterial pressure (A and C) and heart rate (B and D) responses to acute intravenous bolus administration of ANG II (A and B) and PE (C and D) in vehicle ({blacksquare}, n = 10)- and IL-6 ({square}, n = 8 for ANG II and 9 for PE) -infused mice, expressed as means ± SE for AUC from baseline. Statistics are as in Fig. 2.

 
Responses to PE. PE induced dose-dependent increases in mean arterial pressure and reductions in heart rate in both groups (Fig. 4, C and D). Responses were similar in the groups at the lower doses, but at the highest dose of PE (300 µg/kg) the rise in mean arterial pressure and fall in heart rate were significantly greater in IL-6-infused mice (P < 0.05).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
A number of studies have investigated whether inflammatory cytokines, including IL-6, TNF-{alpha}, and IL-1beta, might modulate vascular responsiveness to vasoconstrictors. Most such studies to date have examined responsiveness of isolated vessels (7, 17, 23, 24, 30, 32) or of specific vascular beds in situ (1, 8) after either acute or chronic exposure to the cytokine of interest. To our knowledge, the present study represents the first to examine the effects of chronic exposure to IL-6 on whole animal cardiovascular responses to vasoconstrictors.

It was somewhat surprising that, despite previous reports of enhanced constrictor responses to ANG II and PE in rats and mice chronically infused with IL-6 (24, 30), we saw no effect of IL-6 treatment on pressor responses to these agents, except for a small enhancement of the response to PE at the highest dose used. The functional significance of this effect is not clear, since the absolute peak increase in arterial pressure in response to PE at 300 µg/kg was not significantly different between vehicle- and IL-6-infused mice (39 ± 1 vs. 42 ± 2 mmHg). Although there were differences between the present study and the previous studies in terms of the treatment protocol and species used, the fold increase in plasma IL-6 concentration measured at day 14 in our study was at least as large as, if not larger than, those reported by the other studies (24, 30). Our findings strongly suggest that chronic exposure to increased circulating IL-6 concentrations does not alter pressor responsiveness to ANG II, PE, or ET-1, therefore suggesting that the effects noted previously in aortic tissue may not carry over to include effects on the resistance vasculature.

It was of interest to examine the effects of chronic IL-6 infusion on responses to ET-1 since ET-1, and perhaps IL-6, may be involved in hypertension in humans (2, 5, 28) and both have been implicated in experimental ANG II-induced hypertension (16, 21). Neither the absence of endogenous IL-6 nor chronic IL-6 infusion had any significant effect on blood pressure responses to ET-1. However, unexpectedly, the reflex-mediated fall in heart rate observed in response to ET-1 was significantly diminished in mice infused with IL-6. This reduced effect on heart rate in IL-6-infused mice does not appear to be due either to a difference in the concurrent pressor response, as the rise in blood pressure was not different with or without ganglion blockade, or to an enhanced direct chronotropic effect of ET-1. A generalized change in baroreflex sensitivity also appears an unlikely explanation since heart rate fell during ANG II and PE responses to a similar extent in both IL-6 and vehicle groups. One possibility is that IL-6 produces a change in heart rate control that can only be observed during the more sustained changes in blood pressure elicited by ET-1 and does not come into play during the more transient pressor responses to PE and ANG II. Rapid (minutes), although incomplete, resetting of baroreflexes has been described (4, 22). Thus it may be possible that IL-6-infused mice display more rapid resetting of baroreflex control of heart rate than vehicle-infused mice. Determining whether this is the case would require a distinct set of experiments and is beyond the scope of the present study.

Another possible explanation for the apparently reduced heart rate sensitivity of IL-6 mice with regard to ET-1 is that IL-6 somehow specifically modulates the effects of ET-1 on the baroreflex. Unfortunately, little appears to be known regarding the effects of peripheral ET-1 on the baroreflex control of the cardiovascular system. One study reported that exposure of the endothelium-denuded carotid sinus to high concentrations (100 nM) of ET-1 reduced baroreceptor activity at high carotid pressures, whereas lower concentrations (0.01–1 nM) appeared to enhance activity (6). The net effect of endogenously produced ET-1 in an intact carotid sinus, however, may depend both on these apparently concentration-dependent direct effects of ET-1 on the neurons or vascular wall and on indirect effects mediated by ETB receptor-endothelium-derived factors such as NO, which has been shown to inhibit baroreceptor activity (19), or prostaglandins, which enhance baroreceptor activity (20). Further studies are needed to increase our understanding of this complex and seemingly underinvestigated area of cardiovascular control.

A number of limitations exist regarding the ability to assess the effects of IL-6 infusion on vascular responsiveness in vivo. It is possible that chronic infusion of IL-6 may have had additional effects that masked changes in vascular reactivity to the agonists used in this study. One such possible effect is changes to the baroreflex mechanism as discussed above. An additional possibility is that if IL-6 infusion increased endogenous levels of ANG II, ET-1, or circulating catecholamines, this might alter responsiveness to exogenous administration of these or other agents. Reports of plasma norepinephrine concentrations in IL-6-knockout mice are conflicting (15, 31), and the effect of chronic IL-6 infusion on plasma catecholamines is currently unknown. Plasma ET-1 concentration is not altered by the IL-6 infusion protocol used in this study (unpublished data); however, we cannot rule out an effect of IL-6 infusion on local production of ET-1, or on plasma or tissue ANG II concentrations.

The basal blood pressures of the mice in our study, while no doubt slightly lower than those of conscious mice, are comparable to or greater than values reported by others in anesthetized mice (3, 12). Importantly, care was taken to maintain body temperature, and our mice displayed basal heart rates in the physiological range. As expected, blood pressure and heart rate fell during ganglionic blockade. While it is possible that the low blood pressure following ganglionic blockade in itself may have affected responses to ET-1, we did not attempt to restore basal blood pressures by infusion of another pressor agent as this could have also affected responses to ET-1 in some way.

The dose of IL-6 chosen for infusion in this study was based on that used in a previous study also conducted in mice (14) and yielded similar plasma IL-6 concentrations. The IL-6 infusion rate used in the previous study was designed to generate a rise in plasma IL-6 concentration to approximate the roughly fourfold elevation of plasma IL-6 seen in obesity (13). The plasma concentrations of IL-6 observed in the present study were somewhat higher than the concentration (~30 pg/ml) previously reported during ANG II-induced hypertension in mice (16) but were much lower than those observed in sepsis (18).

Although the findings of our study do not preclude a potential for differential effects on vascular resistance of specific vascular beds, the results of the present study strongly suggest that chronic elevation of plasma IL-6 concentrations in normotensive mice does not lead to a generalized increase in vascular responsiveness. Whether IL-6 enhances pressor responsiveness in the setting of hypertension remains an open question; however, our data indicate that a chronically elevated plasma IL-6 concentration in itself is insufficient to alter whole animal cardiovascular responses to pressor agents. Moreover, our data caution against using effects observed on responsiveness of the aorta in vitro to predict cardiovascular responses at the whole animal level.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Heart, Lung, and Blood Institute Grants HL-64776 and HL-74167, an Established Investigator Award from the American Heart Association (D. M. Pollock), and an American Heart Association Postdoctoral Fellowship (E. I. Boesen).


   ACKNOWLEDGMENTS
 
The authors thank C. Rhoden and A. Dukes for expert technical assistance with plasma IL-6 measurements.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. M. Pollock, Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta GA 30912 (e-mail: dpollock{at}mail.mcg.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Baudry N, Rasetti C, Vicaut E. Differences between cytokine effects in the microcirculation of the rat. Am J Physiol Heart Circ Physiol 271: H1186–H1192, 1996.[Abstract/Free Full Text]
  2. Bermudez EA, Rifai N, Buring J, Manson JE, Ridker PM. Interrelationships among circulating interleukin-6, C-reactive protein, and traditional cardiovascular risk factors in women. Arterioscler Thromb Vasc Biol 22: 1668–1673, 2002.[Abstract/Free Full Text]
  3. Berthiaume N, Yanagisawa M, Labonte J, D'Orleans-Juste P. Heterozygous knock-out of ETB receptors induces BQ-123-sensitive hypertension in the mouse. Hypertension 36: 1002–1007, 2000.[Abstract/Free Full Text]
  4. Burke SL, Dorward PK, Korner PI. Rapid resetting of rabbit aortic baroreceptors and reflex heart rate responses by directional changes in blood pressure. J Physiol 378: 391–402, 1986.[Abstract/Free Full Text]
  5. Chae CU, Lee RT, Rifai N, Ridker PM. Blood pressure and inflammation in apparently healthy men. Hypertension 38: 399–403, 2001.[Abstract/Free Full Text]
  6. Chapleau MW, Hajduczok G, Abboud FM. Suppression of baroreceptor discharge by endothelin at high carotid sinus pressure. Am J Physiol Regul Integr Comp Physiol 263: R103–R108, 1992.[Abstract/Free Full Text]
  7. Davis JR, Giardina JB, Green GM, Alexander BT, Granger JP, Khalil RA. Reduced endothelial NO-cGMP vascular relaxation pathway during TNF-{alpha}-induced hypertension in pregnant rats. Am J Physiol Regul Integr Comp Physiol 282: R390–R399, 2002.[Abstract/Free Full Text]
  8. Fukumoto Y, Shimokawa H, Ito A, Kadokami T, Yonemitsu Y, Aikawa M, Owada MK, Egashira K, Sueishi K, Nagai R, Yazaki Y, Takeshita A. Inflammatory cytokines cause coronary arteriosclerosis-like changes and alterations in the smooth-muscle phenotypes in pigs. J Cardiovasc Pharmacol 29: 222–231, 1997.[CrossRef][ISI][Medline]
  9. Gadonski G, LaMarca BB, Sullivan E, Bennett W, Chandler D, Granger JP. Hypertension produced by reductions in uterine perfusion in the pregnant rat: role of interleukin 6. Hypertension 48: 711–716, 2006.[Abstract/Free Full Text]
  10. Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr, Heimovitz H, Cohen HJ, Wallace R. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 106: 506–512, 1999.[CrossRef][ISI][Medline]
  11. Iversen PO, Nicolaysen A, Kvernebo K, Benestad HB, Nicolaysen G. Human cytokines modulate arterial vascular tone via endothelial receptors. Pflügers Arch 439: 93–100, 1999.[CrossRef][ISI][Medline]
  12. Janssen BJ, De Celle T, Debets JJ, Brouns AE, Callahan MF, Smith TL. Effects of anesthetics on systemic hemodynamics in mice. Am J Physiol Heart Circ Physiol 287: H1618–H1624, 2004.[Abstract/Free Full Text]
  13. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 280: E745–E751, 2001.[Abstract/Free Full Text]
  14. Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 52: 2784–2789, 2003.[Abstract/Free Full Text]
  15. Lee DL, Leite R, Fleming C, Pollock JS, Webb RC, Brands MW. Hypertensive response to acute stress is attenuated in interleukin-6 knockout mice. Hypertension 44: 259–263, 2004.[Abstract/Free Full Text]
  16. Lee DL, Sturgis LC, Labazi H, Osborne JB Jr, Fleming C, Pollock JS, Manhiani M, Imig JD, Brands MW. Angiotensin II hypertension is attenuated in interleukin-6 knockout mice. Am J Physiol Heart Circ Physiol 290: H935–H940, 2006.[Abstract/Free Full Text]
  17. Leseth KH, Adner M, Berg HK, White LR, Aasly J, Edvinsson L. Cytokines increase endothelin ETB receptor contractile activity in rat cerebral artery. Neuroreport 10: 2355–2359, 1999.[ISI][Medline]
  18. Liu J, Mankani G, Shi X, Meyer M, Cunningham-Runddles S, Ma X, Sun ZS. The circadian clock Period 2 gene regulates gamma interferon production of NK cells in host response to lipopolysaccharide-induced endotoxic shock. Infect Immun 74: 4750–4756, 2006.[Abstract/Free Full Text]
  19. Matsuda T, Bates JN, Lewis SJ, Abboud FM, Chapleau MW. Modulation of baroreceptor activity by nitric oxide and S-nitrosocysteine. Circ Res 76: 426–433, 1995.[Abstract/Free Full Text]
  20. McDowell TS, Axtelle TS, Chapleau MW, Abboud FM. Prostaglandins in carotid sinus enhance baroreflex in rabbits. Am J Physiol Regul Integr Comp Physiol 257: R445–R450, 1989.[Abstract/Free Full Text]
  21. Moreau P, d'Uscio LV, Shaw S, Takase H, Barton M, Luscher TF. Angiotensin II increases tissue endothelin and induces vascular hypertrophy: reversal by ETA-receptor antagonist. Circulation 96: 1593–1597, 1997.[Abstract/Free Full Text]
  22. Munch PA, Andresen MC, Brown AM. Rapid resetting of aortic baroreceptors in vitro. Am J Physiol Heart Circ Physiol 244: H672–H680, 1983.[Abstract/Free Full Text]
  23. Orshal JM, Khalil RA. Interleukin-6 impairs endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of pregnant rats. Am J Physiol Regul Integr Comp Physiol 286: R1013–R1023, 2004.[Abstract/Free Full Text]
  24. Orshal JM, Khalil RA. Reduced endothelial NO-cGMP-mediated vascular relaxation and hypertension in IL-6-infused pregnant rats.Hypertension 43: 434–444, 2004.[Abstract/Free Full Text]
  25. Osuka K, Suzuki Y, Tanazawa T, Hattori K, Yamamoto N, Takayasu M, Shibuya M, Yoshida J. Interleukin-6 and development of vasospasm after subarachnoid haemorrhage. Acta Neurochir (Wien) 140: 943–951, 1998.[CrossRef][Medline]
  26. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342: 836–843, 2000.[Abstract/Free Full Text]
  27. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101: 1767–1772, 2000.[Abstract/Free Full Text]
  28. Touyz RM, Schiffrin EL. Role of endothelin in human hypertension. Can J Physiol Pharmacol 81: 533–541, 2003.[CrossRef][ISI][Medline]
  29. Volpato S, Guralnik JM, Ferrucci L, Balfour J, Chaves P, Fried LP, Harris TB. Cardiovascular disease, interleukin-6, and risk of mortality in older women: the Women's Health and Aging Study. Circulation 103: 947–953, 2001.[Abstract/Free Full Text]
  30. Wassmann S, Stumpf M, Strehlow K, Schmid A, Schieffer B, Bohm M, Nickenig G. Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor. Circ Res 94: 534–541, 2004.[Abstract/Free Full Text]
  31. Wernstedt I, Edgley A, Berndtsson A, Faldt J, Bergstrom G, Wallenius V, Jansson JO. Reduced stress- and cold-induced increase in energy expenditure in interleukin-6-deficient mice. Am J Physiol Regul Integr Comp Physiol 291: R551–R557, 2006.[Abstract/Free Full Text]
  32. White LR, Juul R, Skaanes KO, Aasly J. Cytokine enhancement of endothelin ETB receptor-mediated contraction in human temporal artery. Eur J Pharmacol 406: 117–122, 2000.[CrossRef][ISI][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/3/H1745    most recent
00329.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Boesen, E. I.
Right arrow Articles by Pollock, D. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Boesen, E. I.
Right arrow Articles by Pollock, D. M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.