Effects of Acute Administration of Caffeine on Vascular Function
2006; Elsevier BV; Volume: 98; Issue: 11 Linguagem: Inglês
10.1016/j.amjcard.2006.06.058
ISSN1879-1913
AutoresTakashi Umemura, Keiko Ueda, Kenji Nishioka, Takayuki Hidaka, Hiroaki Takemoto, Shuji Nakamura, Daisuke Jitsuiki, Junko Soga, Chikara Goto, Kazuaki Chayama, Masao Yoshizumi, Yukihito Higashi,
Tópico(s)Heart Rate Variability and Autonomic Control
ResumoCaffeine is the most widely used pharmacologic substance in the world. It is found in common nonessential grocery items (e.g., coffee, tea, cocoa, and chocolate). The effects of caffeine on cardiovascular diseases, including hypertension, remain controversial, and there is little information on its direct effect on vascular function. The purpose of this study was to determine the effect of caffeine on endothelial function in humans. This study was a double-blind, randomized placebo and active drug study. Forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and to sodium nitroprusside, an endothelium-independent vasodilator, were evaluated in healthy young men before and after the oral administration of caffeine 300 mg (n = 10) or placebo (n = 10). FBF was measured by using a strain-gauge plethysmograph. Caffeine significantly increased systolic and diastolic blood pressures by 6.0 ± 6.0 and 2.6 ± 3.1 mm Hg (p <0.05), respectively, but did not alter heart rate or baseline FBF. Caffeine augmented the FBF responses to ACh from 21.2 ± 7.1 to 26.6 ± 8.1 ml/min/100 ml tissue (p <0.05), whereas sodium nitroprusside–stimulated vasodilation was not altered by caffeine administration. The intra-arterial infusion of NG-monomethyl-l-arginine, a nitric oxide synthase inhibitor, abolished the caffeine-induced augmentation of FBF response to ACh. In the placebo group, the ACh- and sodium nitroprusside–stimulated vasodilation was similar before and after the follow-up period. In conclusion, these findings suggest that the acute administration of caffeine augments endothelium-dependent vasodilation in healthy young men through an increase in nitric oxide production. Caffeine is the most widely used pharmacologic substance in the world. It is found in common nonessential grocery items (e.g., coffee, tea, cocoa, and chocolate). The effects of caffeine on cardiovascular diseases, including hypertension, remain controversial, and there is little information on its direct effect on vascular function. The purpose of this study was to determine the effect of caffeine on endothelial function in humans. This study was a double-blind, randomized placebo and active drug study. Forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and to sodium nitroprusside, an endothelium-independent vasodilator, were evaluated in healthy young men before and after the oral administration of caffeine 300 mg (n = 10) or placebo (n = 10). FBF was measured by using a strain-gauge plethysmograph. Caffeine significantly increased systolic and diastolic blood pressures by 6.0 ± 6.0 and 2.6 ± 3.1 mm Hg (p <0.05), respectively, but did not alter heart rate or baseline FBF. Caffeine augmented the FBF responses to ACh from 21.2 ± 7.1 to 26.6 ± 8.1 ml/min/100 ml tissue (p <0.05), whereas sodium nitroprusside–stimulated vasodilation was not altered by caffeine administration. The intra-arterial infusion of NG-monomethyl-l-arginine, a nitric oxide synthase inhibitor, abolished the caffeine-induced augmentation of FBF response to ACh. In the placebo group, the ACh- and sodium nitroprusside–stimulated vasodilation was similar before and after the follow-up period. In conclusion, these findings suggest that the acute administration of caffeine augments endothelium-dependent vasodilation in healthy young men through an increase in nitric oxide production. This study was designed to examine the effects of the acute administration of caffeine on systemic hemodynamics and endothelial function in humans by measuring forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium-independent vasodilator.Methods and ResultsThe subjects were 20 young healthy men recruited from healthy volunteers. All were nonhabitual caffeine consumers who did not consume caffeine every day. This study was a double-blind, randomized placebo and active drug study. The 20 subjects were randomly assigned to receive caffeine (caffeine group; n = 10, mean age 26.8 ± 5.2 years) or placebo (control group; n = 10, mean age 26.1 ± 3.8 years). The study protocol was approved by the ethics committee of the Hiroshima University Graduate School of Biomedical Sciences. Informed consent was obtained from all subjects before participation.FBF was measured with the use of a mercury-filled Silastic strain-gauge plethysmograph (EC-5R, D.E. Hokanson, Inc., Bellevue, Washington), as previously described.1Panza J.A. Quyyumi A.A. Brush Jr, J.E. Epstein S.E. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension.N Engl J Med. 1990; 323: 22-27Crossref PubMed Scopus (2170) Google Scholar, 2Higashi Y. Sasaki S. Nakagawa K. Matsuura H. Oshima T. Chayama K. Endothelial function and oxidative stress in renovascular hypertension.N Engl J Med. 2002; 346: 1954-1962Crossref PubMed Scopus (431) Google Scholar Three plethysmographic measurements were averaged to determine FBF at baseline and during the administration of each drug. FBF is expressed in milliliters per minute per 100 ml of forearm tissue volume. FBF was calculated by 2 independent observers blinded to the study protocol from the linear portions of plethysmographic recordings. The intraobserver coefficient of variation was 3.0%. We confirmed the reproducibility of FBF responses to ACh and SNP on 2 separate occasions in 10 healthy men (mean age 24 ± 4 years). The coefficients of variation were 6.2% and 4.6%, respectively.All measurements were performed for subjects in the supine position in a temperature-controlled (22°C to 25°C), quiet, dark laboratory. All subjects abstained from caffeine, ethanol, and nicotine for ≥24 hours before the start of the study. After 30 minutes in the supine position, baseline FBF, heart rate, and arterial blood pressure were measured. Then the intra-arterial infusions of the endothelium-dependent vasodilator ACh (3.75, 7.5, and 15 μg/min) or the endothelium-independent vasodilator SNP (0.75, 1.5, and 3.0 μg/min) were performed randomly every 5 minutes, and FBF during the final 2 minutes of each infusion was measured.After a 30-minute rest period, caffeine 300 mg or placebo was administered orally to each subject. Baseline FBF, heart rate, and arterial blood pressure were measured 1 hour after the oral administration of caffeine or placebo. The effects of ACh and SNP were determined again by the same method as that used before caffeine and placebo administration.After a 30-minute rest period, NG-monomethyl-l-arginine (l-NMMA; Clinalfa Company, Läufelfiger, Switzerland), a nitric oxide synthase inhibitor, was infused intra-arterially at a dose of 8 μg/min for 5 minutes while baseline FBF and arterial blood pressure were recorded, and ACh (3.75, 7.5, and 15 μg/min) was administered.The results are expressed as mean ± SD. Values of p <0.05 were considered to indicate statistical significance. Baseline characteristics between 2 groups were compared using the Mann-Whitney U-statistic test. The effects of interventions on blood pressure, heart rate, and FBF were analyzed with the paired Student’s t test. Comparisons of dose-response curves of parameters during the infusion of the drugs were analyzed with repeated-measures analysis of variance. The data were processed using the software package StatView V (SAS Institute Inc., Cary, North Carolina).Baseline clinical characteristics in the caffeine group and control group are summarized in Table 1. There were no significant differences between the 2 groups in systolic blood pressure, diastolic blood pressure, heart rate, FBF, and other parameters.Table 1Clinical characteristics of the control and caffeine groupsVariableControl (n = 10)Caffeine (n = 10)Body mass index (kg/m2)22 ± 222 ± 1Systolic blood pressure (mm Hg)114 ± 7117 ± 10Diastolic blood pressure (mm Hg)64 ± 861 ± 8Heart rate (beats/min)65 ± 761 ± 9Total cholesterol (mmol/L)4.12 ± 0.594.05 ± 0.65Triglycerides (mmol/L)1.27 ± 0.671.11 ± 0.55Triglycerides (mg/dl)112 ± 5998 ± 49Low-density lipoprotein cholesterol (mmol/L)2.25 ± 0.542.12 ± 0.56Low-density lipoprotein cholesterol (mg/dl)87 ± 2182 ± 22Serum creatinine (μmol/L)80 ± 979 ± 9FBF (ml/min/100 ml tissue)6.3 ± 2.86.1 ± 3.0All results are expressed as mean ± SD. Open table in a new tab Caffeine elevated systolic blood pressure from 117 ± 10 to 123 ± 9 mm Hg (p <0.05) and elevated diastolic blood pressure from 61 ± 8 to 64 ± 8 mm Hg (p <0.05) but did not alter heart rate (Figure 1). There were no significant differences in systolic and diastolic blood pressures or heart rate after placebo ingestion.The intra-arterial infusion of ACh and SNP significantly increased FBF in a dose-dependent manner in the caffeine and control groups. FBF responses to ACh and SNP were similar in the 2 groups. Neither caffeine nor placebo altered baseline FBF. Caffeine significantly augmented FBF response to ACh (p <0.05), whereas placebo did not alter FBF response to ACh (Figure 2). Neither caffeine nor placebo altered FBF response to SNP (Figure 3). No significant change was observed in arterial blood pressure or heart rate with the intra-arterial infusion of either ACh or SNP in any of the subjects.Figure 2Effects of ACh on FBF before and after caffeine or placebo administration.View Large Image Figure ViewerDownload (PPT)Figure 3Effect of SNP on FBF before and after caffeine or placebo administration.View Large Image Figure ViewerDownload (PPT)The intra-arterial infusion of l-NMMA reduced baseline FBF and abolished the caffeine-induced augmentation of FBF response to ACh (Figure 4). No significant change was observed in arterial blood pressure or heart rate with the intra-arterial infusion of ACh in the presence of l-NMMA.Figure 4Effects of ACh on FBF in the presence of l-NMMA after caffeine administration.View Large Image Figure ViewerDownload (PPT)DiscussionTo our knowledge, this is the first study to demonstrate that the oral administration of caffeine increases FBF response to ACh, an endothelium-dependent vasodilator. In addition, l-NMMA completely abolished the caffeine-induced augmentation of FBF response to ACh. Caffeine elevated systolic and diastolic blood pressures but did not alter heart rate.Some investigators have hypothesized that caffeine is a vasoconstrictive substance.3LaCronix A.Z. Mead L.A. Liang K.Y. Thomas C.B. Pearson T.A. Coffee consumption and the incidence of coronary heart disease.N Engl J Med. 1986; 315: 977-982Crossref PubMed Scopus (169) Google Scholar, 4James J.E. Is habitual caffeine use a preventable cardiovascular risk factor?.Lancet. 1997; 349: 279-281Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 5Happonen P. Voutilainen S. Salonen J.T. Coffee drinking is dose-dependently related to the risk of acute coronary events in middle-aged men.J Nutr. 2004; 134: 2381-2386PubMed Google Scholar, 6Pincomb G.A. Lovallo W.R. Passey R.B. Passey R.B. Whitsett T.L. Silverstein S.M. Wilson M.F. Effects of caffeine on vascular resistance, cardiac output and myocardial contractility in young men.Am J Cardiol. 1985; 56: 119-122Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 7Mahmud A. Feely J. Acute effect of caffeine on arterial stiffness and aortic pressure waveform.Hypertension. 2001; 38: 227-231Crossref PubMed Scopus (139) Google Scholar, 8Corti R. Binffeli C. Sudano I. Spieker L. Hanseler E. Ruschitzka F. Chaplin W.F. Coffee acutely increases sympathetic nerve activity and blood pressure independently of caffeine content.Circulation. 2002; 106: 2935-2940Crossref PubMed Scopus (192) Google Scholar, 9Hartley T.R. Lovallo W.R. Whitsett T.L. Cardiovascular effects of caffeine in men and women.Am J Cardiol. 2004; 93: 1022-1026Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar In the present study, systolic and diastolic blood pressures were elevated after caffeine ingestion, suggesting vasoconstrictive effects of caffeine.5Happonen P. Voutilainen S. Salonen J.T. Coffee drinking is dose-dependently related to the risk of acute coronary events in middle-aged men.J Nutr. 2004; 134: 2381-2386PubMed Google Scholar Caffeine should be an antagonist of the adenosine receptor.10Fredholm B.B. Persson C.G.A. Xanthine derivatives as adenosine receptor antagonists.Eur J Pharmacol. 1982; 81: 673-676Crossref PubMed Scopus (202) Google Scholar, 11Smits P. Lenders J.W.M. Thien T. Caffeine and theophylline attenuate adenosine-induced vasodilation in humans.Clin Pharmacol Ther. 1990; 48: 410-418Crossref PubMed Scopus (117) Google Scholar It is well known that adenosine induces vasodilation. Therefore, antagonization of the adenosine receptor could induce vasoconstriction. However, although oral caffeine ingestion did not change baseline FBF, FBF response to ACh was significantly increased in the caffeine group. Hatano et al12Hatano Y. Mizumoto K. Yoshiyama T. Yamamoto M. Iranai H. Endothelial-dependent and -independent vasodilatation of isolated rat aorta induced by caffeine.Am J Physiol. 1995; 269: H1679-H1684PubMed Google Scholar reported that caffeine promotes nitric oxide synthesis in the endothelium by the release of Ca2+ from the endoplasmic reticulum through activation of the ryanodine-sensitive Ca2+ channel and the suppression of cyclic guanosine monophosphate degradation in the isolated rat aorta, resulting in the caffeine-induced augmentation of endothelium-dependent vasodilatation. In the present study, l-NMMA, a nitric oxide synthase inhibitor, completely abolished the caffeine-induced augmentation of endothelium-dependent vasodilation. These findings suggest that caffeine augments endogenous nitric oxide production by agonist stimulation. A balance of the vasodilatory effect of caffeine as an endothelium-dependent vasodilator and the vasoconstrictive effect of caffeine as an adenosine receptor antagonist may regulate vascular function.In the present study, caffeine ingestion elevated systolic and diastolic blood pressures in the brachial artery. Our results support those of previous studies showing that the acute administration of caffeine elevates peripheral blood pressure.6Pincomb G.A. Lovallo W.R. Passey R.B. Passey R.B. Whitsett T.L. Silverstein S.M. Wilson M.F. Effects of caffeine on vascular resistance, cardiac output and myocardial contractility in young men.Am J Cardiol. 1985; 56: 119-122Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 7Mahmud A. Feely J. Acute effect of caffeine on arterial stiffness and aortic pressure waveform.Hypertension. 2001; 38: 227-231Crossref PubMed Scopus (139) Google Scholar, 8Corti R. Binffeli C. Sudano I. Spieker L. Hanseler E. Ruschitzka F. Chaplin W.F. Coffee acutely increases sympathetic nerve activity and blood pressure independently of caffeine content.Circulation. 2002; 106: 2935-2940Crossref PubMed Scopus (192) Google Scholar, 9Hartley T.R. Lovallo W.R. Whitsett T.L. Cardiovascular effects of caffeine in men and women.Am J Cardiol. 2004; 93: 1022-1026Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Karatzis et al13Karatzis E. Papaioannou T.G. Aznaouridis K. Karatzi K. Stamatelopoulos K. Zampelas A. Papamichael C. Lekakis J. Mavrikakis M. Acute effects of caffeine on blood pressure and wave reflections in healthy subjects: should we consider monitoring central blood pressure?.Int J Cardiol. 2005; 98: 425-430Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar demonstrated the augmentation of central blood pressure after the acute administration of caffeine, but peripheral systolic blood pressure did not significantly change. It has been reported that various factors, such as hypertension, exercise stress, and age, influence blood pressure response to caffeine.14Hartley T.R. Sung B.H. Pincomb G.A. Whitsett T.L. Wilson M.F. Lovallo W.R. Hypertension risk status and effect of caffeine on blood pressure.Hypertension. 2000; 36: 137-141Crossref PubMed Scopus (103) Google Scholar These observations suggest that the confounding factors should be kept fairly constant for the assessment of changes in blood pressure during caffeine administration. This study was designed to examine the effects of the acute administration of caffeine on systemic hemodynamics and endothelial function in humans by measuring forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium-independent vasodilator. Methods and ResultsThe subjects were 20 young healthy men recruited from healthy volunteers. All were nonhabitual caffeine consumers who did not consume caffeine every day. This study was a double-blind, randomized placebo and active drug study. The 20 subjects were randomly assigned to receive caffeine (caffeine group; n = 10, mean age 26.8 ± 5.2 years) or placebo (control group; n = 10, mean age 26.1 ± 3.8 years). The study protocol was approved by the ethics committee of the Hiroshima University Graduate School of Biomedical Sciences. Informed consent was obtained from all subjects before participation.FBF was measured with the use of a mercury-filled Silastic strain-gauge plethysmograph (EC-5R, D.E. Hokanson, Inc., Bellevue, Washington), as previously described.1Panza J.A. Quyyumi A.A. Brush Jr, J.E. Epstein S.E. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension.N Engl J Med. 1990; 323: 22-27Crossref PubMed Scopus (2170) Google Scholar, 2Higashi Y. Sasaki S. Nakagawa K. Matsuura H. Oshima T. Chayama K. Endothelial function and oxidative stress in renovascular hypertension.N Engl J Med. 2002; 346: 1954-1962Crossref PubMed Scopus (431) Google Scholar Three plethysmographic measurements were averaged to determine FBF at baseline and during the administration of each drug. FBF is expressed in milliliters per minute per 100 ml of forearm tissue volume. FBF was calculated by 2 independent observers blinded to the study protocol from the linear portions of plethysmographic recordings. The intraobserver coefficient of variation was 3.0%. We confirmed the reproducibility of FBF responses to ACh and SNP on 2 separate occasions in 10 healthy men (mean age 24 ± 4 years). The coefficients of variation were 6.2% and 4.6%, respectively.All measurements were performed for subjects in the supine position in a temperature-controlled (22°C to 25°C), quiet, dark laboratory. All subjects abstained from caffeine, ethanol, and nicotine for ≥24 hours before the start of the study. After 30 minutes in the supine position, baseline FBF, heart rate, and arterial blood pressure were measured. Then the intra-arterial infusions of the endothelium-dependent vasodilator ACh (3.75, 7.5, and 15 μg/min) or the endothelium-independent vasodilator SNP (0.75, 1.5, and 3.0 μg/min) were performed randomly every 5 minutes, and FBF during the final 2 minutes of each infusion was measured.After a 30-minute rest period, caffeine 300 mg or placebo was administered orally to each subject. Baseline FBF, heart rate, and arterial blood pressure were measured 1 hour after the oral administration of caffeine or placebo. The effects of ACh and SNP were determined again by the same method as that used before caffeine and placebo administration.After a 30-minute rest period, NG-monomethyl-l-arginine (l-NMMA; Clinalfa Company, Läufelfiger, Switzerland), a nitric oxide synthase inhibitor, was infused intra-arterially at a dose of 8 μg/min for 5 minutes while baseline FBF and arterial blood pressure were recorded, and ACh (3.75, 7.5, and 15 μg/min) was administered.The results are expressed as mean ± SD. Values of p <0.05 were considered to indicate statistical significance. Baseline characteristics between 2 groups were compared using the Mann-Whitney U-statistic test. The effects of interventions on blood pressure, heart rate, and FBF were analyzed with the paired Student’s t test. Comparisons of dose-response curves of parameters during the infusion of the drugs were analyzed with repeated-measures analysis of variance. The data were processed using the software package StatView V (SAS Institute Inc., Cary, North Carolina).Baseline clinical characteristics in the caffeine group and control group are summarized in Table 1. There were no significant differences between the 2 groups in systolic blood pressure, diastolic blood pressure, heart rate, FBF, and other parameters.Table 1Clinical characteristics of the control and caffeine groupsVariableControl (n = 10)Caffeine (n = 10)Body mass index (kg/m2)22 ± 222 ± 1Systolic blood pressure (mm Hg)114 ± 7117 ± 10Diastolic blood pressure (mm Hg)64 ± 861 ± 8Heart rate (beats/min)65 ± 761 ± 9Total cholesterol (mmol/L)4.12 ± 0.594.05 ± 0.65Triglycerides (mmol/L)1.27 ± 0.671.11 ± 0.55Triglycerides (mg/dl)112 ± 5998 ± 49Low-density lipoprotein cholesterol (mmol/L)2.25 ± 0.542.12 ± 0.56Low-density lipoprotein cholesterol (mg/dl)87 ± 2182 ± 22Serum creatinine (μmol/L)80 ± 979 ± 9FBF (ml/min/100 ml tissue)6.3 ± 2.86.1 ± 3.0All results are expressed as mean ± SD. Open table in a new tab Caffeine elevated systolic blood pressure from 117 ± 10 to 123 ± 9 mm Hg (p <0.05) and elevated diastolic blood pressure from 61 ± 8 to 64 ± 8 mm Hg (p <0.05) but did not alter heart rate (Figure 1). There were no significant differences in systolic and diastolic blood pressures or heart rate after placebo ingestion.The intra-arterial infusion of ACh and SNP significantly increased FBF in a dose-dependent manner in the caffeine and control groups. FBF responses to ACh and SNP were similar in the 2 groups. Neither caffeine nor placebo altered baseline FBF. Caffeine significantly augmented FBF response to ACh (p <0.05), whereas placebo did not alter FBF response to ACh (Figure 2). Neither caffeine nor placebo altered FBF response to SNP (Figure 3). No significant change was observed in arterial blood pressure or heart rate with the intra-arterial infusion of either ACh or SNP in any of the subjects.Figure 3Effect of SNP on FBF before and after caffeine or placebo administration.View Large Image Figure ViewerDownload (PPT)The intra-arterial infusion of l-NMMA reduced baseline FBF and abolished the caffeine-induced augmentation of FBF response to ACh (Figure 4). No significant change was observed in arterial blood pressure or heart rate with the intra-arterial infusion of ACh in the presence of l-NMMA.Figure 4Effects of ACh on FBF in the presence of l-NMMA after caffeine administration.View Large Image Figure ViewerDownload (PPT) The subjects were 20 young healthy men recruited from healthy volunteers. All were nonhabitual caffeine consumers who did not consume caffeine every day. This study was a double-blind, randomized placebo and active drug study. The 20 subjects were randomly assigned to receive caffeine (caffeine group; n = 10, mean age 26.8 ± 5.2 years) or placebo (control group; n = 10, mean age 26.1 ± 3.8 years). The study protocol was approved by the ethics committee of the Hiroshima University Graduate School of Biomedical Sciences. Informed consent was obtained from all subjects before participation. FBF was measured with the use of a mercury-filled Silastic strain-gauge plethysmograph (EC-5R, D.E. Hokanson, Inc., Bellevue, Washington), as previously described.1Panza J.A. Quyyumi A.A. Brush Jr, J.E. Epstein S.E. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension.N Engl J Med. 1990; 323: 22-27Crossref PubMed Scopus (2170) Google Scholar, 2Higashi Y. Sasaki S. Nakagawa K. Matsuura H. Oshima T. Chayama K. Endothelial function and oxidative stress in renovascular hypertension.N Engl J Med. 2002; 346: 1954-1962Crossref PubMed Scopus (431) Google Scholar Three plethysmographic measurements were averaged to determine FBF at baseline and during the administration of each drug. FBF is expressed in milliliters per minute per 100 ml of forearm tissue volume. FBF was calculated by 2 independent observers blinded to the study protocol from the linear portions of plethysmographic recordings. The intraobserver coefficient of variation was 3.0%. We confirmed the reproducibility of FBF responses to ACh and SNP on 2 separate occasions in 10 healthy men (mean age 24 ± 4 years). The coefficients of variation were 6.2% and 4.6%, respectively. All measurements were performed for subjects in the supine position in a temperature-controlled (22°C to 25°C), quiet, dark laboratory. All subjects abstained from caffeine, ethanol, and nicotine for ≥24 hours before the start of the study. After 30 minutes in the supine position, baseline FBF, heart rate, and arterial blood pressure were measured. Then the intra-arterial infusions of the endothelium-dependent vasodilator ACh (3.75, 7.5, and 15 μg/min) or the endothelium-independent vasodilator SNP (0.75, 1.5, and 3.0 μg/min) were performed randomly every 5 minutes, and FBF during the final 2 minutes of each infusion was measured. After a 30-minute rest period, caffeine 300 mg or placebo was administered orally to each subject. Baseline FBF, heart rate, and arterial blood pressure were measured 1 hour after the oral administration of caffeine or placebo. The effects of ACh and SNP were determined again by the same method as that used before caffeine and placebo administration. After a 30-minute rest period, NG-monomethyl-l-arginine (l-NMMA; Clinalfa Company, Läufelfiger, Switzerland), a nitric oxide synthase inhibitor, was infused intra-arterially at a dose of 8 μg/min for 5 minutes while baseline FBF and arterial blood pressure were recorded, and ACh (3.75, 7.5, and 15 μg/min) was administered. The results are expressed as mean ± SD. Values of p <0.05 were considered to indicate statistical significance. Baseline characteristics between 2 groups were compared using the Mann-Whitney U-statistic test. The effects of interventions on blood pressure, heart rate, and FBF were analyzed with the paired Student’s t test. Comparisons of dose-response curves of parameters during the infusion of the drugs were analyzed with repeated-measures analysis of variance. The data were processed using the software package StatView V (SAS Institute Inc., Cary, North Carolina). Baseline clinical characteristics in the caffeine group and control group are summarized in Table 1. There were no significant differences between the 2 groups in systolic blood pressure, diastolic blood pressure, heart rate, FBF, and other parameters. All results are expressed as mean ± SD. Caffeine elevated systolic blood pressure from 117 ± 10 to 123 ± 9 mm Hg (p <0.05) and elevated diastolic blood pressure from 61 ± 8 to 64 ± 8 mm Hg (p <0.05) but did not alter heart rate (Figure 1). There were no significant differences in systolic and diastolic blood pressures or heart rate after placebo ingestion. The intra-arterial infusion of ACh and SNP significantly increased FBF in a dose-dependent manner in the caffeine and control groups. FBF responses to ACh and SNP were similar in the 2 groups. Neither caffeine nor placebo altered baseline FBF. Caffeine significantly augmented FBF response to ACh (p <0.05), whereas placebo did not alter FBF response to ACh (Figure 2). Neither caffeine nor placebo altered FBF response to SNP (Figure 3). No significant change was observed in arterial blood pressure or heart rate with the intra-arterial infusion of either ACh or SNP in any of the subjects. The intra-arterial infusion of l-NMMA reduced baseline FBF and abolished the caffeine-induced augmentation of FBF response to ACh (Figure 4). No significant change was observed in arterial blood pressure or heart rate with the intra-arterial infusion of ACh in the presence of l-NMMA. DiscussionTo our knowledge, this is the first study to demonstrate that the oral administration of caffeine increases FBF response to ACh, an endothelium-dependent vasodilator. In addition, l-NMMA completely abolished the caffeine-induced augmentation of FBF response to ACh. Caffeine elevated systolic and diastolic blood pressures but did not alter heart rate.Some investigators have hypothesized that caffeine is a vasoconstrictive substance.3LaCronix A.Z. Mead L.A. Liang K.Y. Thomas C.B. Pearson T.A. Coffee consumption and the incidence of coronary heart disease.N Engl J Med. 1986; 315: 977-982Crossref PubMed Scopus (169) Google Scholar, 4James J.E. Is habitual caffeine use a preventable cardiovascular risk factor?.Lancet. 1997; 349: 279-281Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 5Happonen P. Voutilainen S. Salonen J.T. Coffee drinking is dose-dependently related to the risk of acute coronary events in middle-aged men.J Nutr. 2004; 134: 2381-2386PubMed Google Scholar, 6Pincomb G.A. Lovallo W.R. Passey R.B. Passey R.B. Whitsett T.L. Silverstein S.M. Wilson M.F. Effects of caffeine on vascular resistance, cardiac output and myocardial contractility in young men.Am J Cardiol. 1985; 56: 119-122Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 7Mahmud A. Feely J. Acute effect of caffeine on arterial stiffness and aortic pressure waveform.Hypertension. 2001; 38: 227-231Crossref PubMed Scopus (139) Google Scholar, 8Corti R. Binffeli C. Sudano I. Spieker L. Hanseler E. Ruschitzka F. Chaplin W.F. Coffee acutely increases sympathetic nerve activity and blood pressure independently of caffeine content.Circulation. 2002; 106: 2935-2940Crossref PubMed Scopus (192) Google Scholar, 9Hartley T.R. Lovallo W.R. Whitsett T.L. Cardiovascular effects of caffeine in men and women.Am J Cardiol. 2004; 93: 1022-1026Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar In the present study, systolic and diastolic blood pressures were elevated after caffeine ingestion, suggesting vasoconstrictive effects of caffeine.5Happonen P. Voutilainen S. Salonen J.T. Coffee drinking is dose-dependently related to the risk of acute coronary events in middle-aged men.J Nutr. 2004; 134: 2381-2386PubMed Google Scholar Caffeine should be an antagonist of the adenosine receptor.10Fredholm B.B. Persson C.G.A. Xanthine derivatives as adenosine receptor antagonists.Eur J Pharmacol. 1982; 81: 673-676Crossref PubMed Scopus (202) Google Scholar, 11Smits P. Lenders J.W.M. Thien T. Caffeine and theophylline attenuate adenosine-induced vasodilation in humans.Clin Pharmacol Ther. 1990; 48: 410-418Crossref PubMed Scopus (117) Google Scholar It is well known that adenosine induces vasodilation. Therefore, antagonization of the adenosine receptor could induce vasoconstriction. However, although oral caffeine ingestion did not change baseline FBF, FBF response to ACh was significantly increased in the caffeine group. Hatano et al12Hatano Y. Mizumoto K. Yoshiyama T. Yamamoto M. Iranai H. Endothelial-dependent and -independent vasodilatation of isolated rat aorta induced by caffeine.Am J Physiol. 1995; 269: H1679-H1684PubMed Google Scholar reported that caffeine promotes nitric oxide synthesis in the endothelium by the release of Ca2+ from the endoplasmic reticulum through activation of the ryanodine-sensitive Ca2+ channel and the suppression of cyclic guanosine monophosphate degradation in the isolated rat aorta, resulting in the caffeine-induced augmentation of endothelium-dependent vasodilatation. In the present study, l-NMMA, a nitric oxide synthase inhibitor, completely abolished the caffeine-induced augmentation of endothelium-dependent vasodilation. These findings suggest that caffeine augments endogenous nitric oxide production by agonist stimulation. A balance of the vasodilatory effect of caffeine as an endothelium-dependent vasodilator and the vasoconstrictive effect of caffeine as an adenosine receptor antagonist may regulate vascular function.In the present study, caffeine ingestion elevated systolic and diastolic blood pressures in the brachial artery. Our results support those of previous studies showing that the acute administration of caffeine elevates peripheral blood pressure.6Pincomb G.A. Lovallo W.R. Passey R.B. Passey R.B. Whitsett T.L. Silverstein S.M. Wilson M.F. Effects of caffeine on vascular resistance, cardiac output and myocardial contractility in young men.Am J Cardiol. 1985; 56: 119-122Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 7Mahmud A. Feely J. Acute effect of caffeine on arterial stiffness and aortic pressure waveform.Hypertension. 2001; 38: 227-231Crossref PubMed Scopus (139) Google Scholar, 8Corti R. Binffeli C. Sudano I. Spieker L. Hanseler E. Ruschitzka F. Chaplin W.F. Coffee acutely increases sympathetic nerve activity and blood pressure independently of caffeine content.Circulation. 2002; 106: 2935-2940Crossref PubMed Scopus (192) Google Scholar, 9Hartley T.R. Lovallo W.R. Whitsett T.L. Cardiovascular effects of caffeine in men and women.Am J Cardiol. 2004; 93: 1022-1026Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Karatzis et al13Karatzis E. Papaioannou T.G. Aznaouridis K. Karatzi K. Stamatelopoulos K. Zampelas A. Papamichael C. Lekakis J. Mavrikakis M. Acute effects of caffeine on blood pressure and wave reflections in healthy subjects: should we consider monitoring central blood pressure?.Int J Cardiol. 2005; 98: 425-430Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar demonstrated the augmentation of central blood pressure after the acute administration of caffeine, but peripheral systolic blood pressure did not significantly change. It has been reported that various factors, such as hypertension, exercise stress, and age, influence blood pressure response to caffeine.14Hartley T.R. Sung B.H. Pincomb G.A. Whitsett T.L. Wilson M.F. Lovallo W.R. Hypertension risk status and effect of caffeine on blood pressure.Hypertension. 2000; 36: 137-141Crossref PubMed Scopus (103) Google Scholar These observations suggest that the confounding factors should be kept fairly constant for the assessment of changes in blood pressure during caffeine administration. To our knowledge, this is the first study to demonstrate that the oral administration of caffeine increases FBF response to ACh, an endothelium-dependent vasodilator. In addition, l-NMMA completely abolished the caffeine-induced augmentation of FBF response to ACh. Caffeine elevated systolic and diastolic blood pressures but did not alter heart rate. Some investigators have hypothesized that caffeine is a vasoconstrictive substance.3LaCronix A.Z. Mead L.A. Liang K.Y. Thomas C.B. Pearson T.A. Coffee consumption and the incidence of coronary heart disease.N Engl J Med. 1986; 315: 977-982Crossref PubMed Scopus (169) Google Scholar, 4James J.E. Is habitual caffeine use a preventable cardiovascular risk factor?.Lancet. 1997; 349: 279-281Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 5Happonen P. Voutilainen S. Salonen J.T. Coffee drinking is dose-dependently related to the risk of acute coronary events in middle-aged men.J Nutr. 2004; 134: 2381-2386PubMed Google Scholar, 6Pincomb G.A. Lovallo W.R. Passey R.B. Passey R.B. Whitsett T.L. Silverstein S.M. Wilson M.F. Effects of caffeine on vascular resistance, cardiac output and myocardial contractility in young men.Am J Cardiol. 1985; 56: 119-122Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 7Mahmud A. Feely J. Acute effect of caffeine on arterial stiffness and aortic pressure waveform.Hypertension. 2001; 38: 227-231Crossref PubMed Scopus (139) Google Scholar, 8Corti R. Binffeli C. Sudano I. Spieker L. Hanseler E. Ruschitzka F. Chaplin W.F. Coffee acutely increases sympathetic nerve activity and blood pressure independently of caffeine content.Circulation. 2002; 106: 2935-2940Crossref PubMed Scopus (192) Google Scholar, 9Hartley T.R. Lovallo W.R. Whitsett T.L. Cardiovascular effects of caffeine in men and women.Am J Cardiol. 2004; 93: 1022-1026Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar In the present study, systolic and diastolic blood pressures were elevated after caffeine ingestion, suggesting vasoconstrictive effects of caffeine.5Happonen P. Voutilainen S. Salonen J.T. Coffee drinking is dose-dependently related to the risk of acute coronary events in middle-aged men.J Nutr. 2004; 134: 2381-2386PubMed Google Scholar Caffeine should be an antagonist of the adenosine receptor.10Fredholm B.B. Persson C.G.A. Xanthine derivatives as adenosine receptor antagonists.Eur J Pharmacol. 1982; 81: 673-676Crossref PubMed Scopus (202) Google Scholar, 11Smits P. Lenders J.W.M. Thien T. Caffeine and theophylline attenuate adenosine-induced vasodilation in humans.Clin Pharmacol Ther. 1990; 48: 410-418Crossref PubMed Scopus (117) Google Scholar It is well known that adenosine induces vasodilation. Therefore, antagonization of the adenosine receptor could induce vasoconstriction. However, although oral caffeine ingestion did not change baseline FBF, FBF response to ACh was significantly increased in the caffeine group. Hatano et al12Hatano Y. Mizumoto K. Yoshiyama T. Yamamoto M. Iranai H. Endothelial-dependent and -independent vasodilatation of isolated rat aorta induced by caffeine.Am J Physiol. 1995; 269: H1679-H1684PubMed Google Scholar reported that caffeine promotes nitric oxide synthesis in the endothelium by the release of Ca2+ from the endoplasmic reticulum through activation of the ryanodine-sensitive Ca2+ channel and the suppression of cyclic guanosine monophosphate degradation in the isolated rat aorta, resulting in the caffeine-induced augmentation of endothelium-dependent vasodilatation. In the present study, l-NMMA, a nitric oxide synthase inhibitor, completely abolished the caffeine-induced augmentation of endothelium-dependent vasodilation. These findings suggest that caffeine augments endogenous nitric oxide production by agonist stimulation. A balance of the vasodilatory effect of caffeine as an endothelium-dependent vasodilator and the vasoconstrictive effect of caffeine as an adenosine receptor antagonist may regulate vascular function. In the present study, caffeine ingestion elevated systolic and diastolic blood pressures in the brachial artery. Our results support those of previous studies showing that the acute administration of caffeine elevates peripheral blood pressure.6Pincomb G.A. Lovallo W.R. Passey R.B. Passey R.B. Whitsett T.L. Silverstein S.M. Wilson M.F. Effects of caffeine on vascular resistance, cardiac output and myocardial contractility in young men.Am J Cardiol. 1985; 56: 119-122Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 7Mahmud A. Feely J. Acute effect of caffeine on arterial stiffness and aortic pressure waveform.Hypertension. 2001; 38: 227-231Crossref PubMed Scopus (139) Google Scholar, 8Corti R. Binffeli C. Sudano I. Spieker L. Hanseler E. Ruschitzka F. Chaplin W.F. Coffee acutely increases sympathetic nerve activity and blood pressure independently of caffeine content.Circulation. 2002; 106: 2935-2940Crossref PubMed Scopus (192) Google Scholar, 9Hartley T.R. Lovallo W.R. Whitsett T.L. Cardiovascular effects of caffeine in men and women.Am J Cardiol. 2004; 93: 1022-1026Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Karatzis et al13Karatzis E. Papaioannou T.G. Aznaouridis K. Karatzi K. Stamatelopoulos K. Zampelas A. Papamichael C. Lekakis J. Mavrikakis M. Acute effects of caffeine on blood pressure and wave reflections in healthy subjects: should we consider monitoring central blood pressure?.Int J Cardiol. 2005; 98: 425-430Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar demonstrated the augmentation of central blood pressure after the acute administration of caffeine, but peripheral systolic blood pressure did not significantly change. It has been reported that various factors, such as hypertension, exercise stress, and age, influence blood pressure response to caffeine.14Hartley T.R. Sung B.H. Pincomb G.A. Whitsett T.L. Wilson M.F. Lovallo W.R. Hypertension risk status and effect of caffeine on blood pressure.Hypertension. 2000; 36: 137-141Crossref PubMed Scopus (103) Google Scholar These observations suggest that the confounding factors should be kept fairly constant for the assessment of changes in blood pressure during caffeine administration.
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