(Hypertension. 1995;25:201-206.)
© 1995 American Heart Association, Inc.
Articles |
Impaired Endothelium-Dependent Vasodilation of Large Epicardial and Resistance Coronary Arteries in Patients With Essential Hypertension
Different Responses to Acetylcholine and Substance P
From the Research Institute of Angiocardiology and Cardiovascular Clinic, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Correspondence to Kensuke Egashira, MD, PhD, Research Institute of Angiocardiology, Kyushu University School of Medicine, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812, Japan.
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Abstract |
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Abstract Hypertensive patients have impaired endothelium-dependent coronary vasodilation evoked with acetylcholine. The aim of this study was to examine whether the impaired endothelium-dependent dilation of coronary arteries is related to a specific abnormality of the muscarinic receptor that mediates the effects of acetylcholine. Responses of the large epicardial and resistance coronary arteries were assessed in seven hypertensive patients (mean arterial pressure, 106±14 mm Hg) and seven control subjects (83±6 mm Hg, P<.01) during cardiac catheterization. To assess coronary endothelial function, we infused acetylcholine and substance P (endothelium-dependent agents that act on different receptors) and papaverine and nitrate (direct vascular smooth muscle dilators) into the left anterior descending coronary artery and determined coronary artery diameter by arteriography and coronary blood flow with an intracoronary Doppler catheter technique. In control subjects, 3 µg/min acetylcholine increased (P<.05) and 30 µg/min acetylcholine decreased (P<.05) arterial diameter, and in hypertensive patients, 1, 3, 10, and 30 µg/min acetylcholine decreased arterial diameter in a dose-dependent manner. Substance P at 3, 10, and 30 ng/min caused comparable increases in diameter in both groups. Increases in coronary blood flow with both acetylcholine and substance P were significantly (P<.01) blunted in hypertensive patients compared with control subjects. No significant differences were noted between the groups in the responses of large epicardial coronary artery diameter and coronary blood flow to papaverine and nitrate. Vasodilation of the large coronary artery with acetylcholine was impaired, but the response to substance P was preserved in hypertensive patients, indicating that diminished vasodilation of the large epicardial coronary artery in hypertensive patients may be related to a specific abnormality in the endothelial muscarinic receptor. Blunted coronary blood flow responses to both acetylcholine and substance P in hypertensive patients suggest that endothelial dysfunction in the resistance coronary artery in this condition is related to a more generalized endothelial abnormality but is not confined to the muscarinic receptor.
Key Words: vasodilation • hypertension, essential • coronary circulation • acetylcholine • substance P • endothelium-derived relaxing factor
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Introduction |
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Essential hypertension is associated with many structural and functional abnormalities in the coronary arteries.1 2 3 Structural abnormalities include hypertrophy and hyperplasia of vascular smooth muscle and accumulation of collagen in the perivascular space, leading to a decrease in lumen size.1 2 3 Functional abnormalities include defective endothelium-mediated control of vascular tone.4 5 6
The vascular endothelium plays an important role in the control of vascular tone by releasing various endothelium-derived vasoactive substances.7 8 9 10 11 12 Recently, it was shown in humans that endothelium-dependent coronary and forearm vasodilation evoked with acetylcholine is defective in several pathophysiological conditions,13 14 15 16 17 including hypertension.4 5 6 18 19 20 More recently, Panza et al21 have reported that an inhibitory effect of NG-monomethyl-L-arginine (an inhibitor of endothelium-derived nitric oxide) on acetylcholine-induced forearm vasodilation is significantly less in hypertensive patients than control subjects, indicating that a decreased release of endothelium-derived nitric oxide evoked with acetylcholine is involved in the mechanism responsible for impaired endothelium-dependent forearm vasodilation in hypertensive patients. In these previous studies, however, endothelial function in hypertensive patients was assessed exclusively by examination of vasomotor responses to acetylcholine, which stimulates the release of nitric oxide through the endothelial muscarinic receptor.7 8 9 10 11 12
Substance P, another endothelium-dependent vasodilator, is know to act on an endothelial tachykinin receptor that is different from the muscarinic receptor.22 23 Recent studies24 25 suggest that large epicardial coronary artery segments that show an abnormal response to acetylcholine may have preserved vasodilator responses to substance P in patients with coronary atherosclerosis or vasospasm. The concomitant use of acetylcholine and substance P in a certain condition may help test the hypothesis of whether endothelial dysfunction is related to a specific abnormality of the endothelial muscarinic receptor. However, this hypothesis has not been tested in hypertensive patients. Investigation of this hypothesis in essential hypertension appears to be important because it could provide a more precise knowledge concerning the mechanisms responsible for impaired endothelium-dependent coronary vasodilation in this condition.
Therefore, the aim of this study was to determine whether impaired endothelium-dependent dilation of large epicardial and resistance coronary arteries is caused by a specific abnormality of the muscarinic receptor or by a more generalized abnormality of the endothelium. For this purpose, we assessed responses of the large epicardial coronary artery diameter and coronary blood flow to acetylcholine and substance P in patients with essential hypertension and normotensive control subjects.
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Methods |
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Patients
The study was done in seven patients with essential arterial hypertension and seven normotensive control subjects undergoing diagnostic cardiac catheterization for evaluation of chest pain. All patients and subjects had atypical chest pain, normal exercise stress test results, angiographically normal coronary arteries, and normal left ventricular function. To assess the isolated effects of hypertension on coronary endothelial function, we excluded patients with diabetes mellitus, hypercholesterolemia (total cholesterol level >6.2 mmol/L [240 mg/dL] at the time of study), a history of myocardial infarction, variant angina, valvular heart diseases, or heart failure. Individuals with evidence of left ventricular hypertrophy as assessed by electrocardiogram and echocardiogram were also excluded. A history of hypertension was defined as a blood pressure elevation greater than 160/95 mm Hg requiring the use of antihypertensive drugs. No patients or subjects were on cholesterol-lowering drugs before study. Hypertensive patients were being treated with various antihypertensive drugs.
The research protocol of this study was approved by the institutional committee for clinical research. Written informed consent was obtained from each participant.
Quantitative Coronary Angiography
Coronary cineangiograms were recorded with a cineangiographic
system (Siemens Inc). An appropriate view that allowed the best
visualization of the left anterior descending coronary artery (the
study artery) was selected.
We determined changes in the luminal diameter of the left anterior descending coronary artery, a segment 2 to 3 mm distal to the tip of the Doppler catheter, as described previously.15 16 17 The end-diastolic frame was selected on a cine projector. The images of interest were taken into a videodensitometric analyzer (Kontron Instruments) and digitized. The diameter of the segment of interest was measured for later analysis. A Judkins catheter was used to calibrate the arterial diameter in millimeters. Arterial diameter measurements were done blindly without knowledge of the clinical characteristics of the patients or subjects.
Measurement of Coronary Blood Flow Velocity and Estimation of
Coronary Blood Flow
An 8F angioplasty-guiding catheter was introduced into the left
main coronary artery through a femoral approach. A 3F Doppler
flow-velocity catheter (model DC-201, Millar Instruments) was
introduced into the left anterior descending coronary artery. The
Doppler catheter then was connected to a DC-101 Velocimeter (Millar
Instruments) to obtain mean and phasic velocity signals. Increases in
coronary blood flow were estimated from the product of the mean
coronary blood flow velocity and the cross-sectional area of the
arterial segment at the tip of the Doppler catheter and were expressed
as percent increases from baseline as described
previously.15 16 17
Study Protocol
Cardiac catheterization was performed with patients and subjects
in the fasting state after premedication with 5 mg oral diazepam.
Control subjects were not receiving antianginal or antihypertensive
drugs before the study. All hypertensive patients were receiving drugs
such as nitrates, calcium channel blockers, ß-blockers, and
angiotensin-converting enzyme inhibitors. These drugs were discontinued
3 days before the study; during this period, patients were monitored
for blood pressure elevation.
After completion of the diagnostic catheterization, the following interventions were performed: (1) a bolus injection of papaverine (10 mg/5 mL) through the guiding catheter; (2) infusion of saline (0.5 to 1.0 mL/min for 2 minutes) through the Doppler catheter; (3) infusions of acetylcholine (0.5 to 1.0 mL/min) at 1, 3, 10, and 30 µg/min (for 2 minutes at each dose) through the Doppler catheter; (4) infusions of substance P at 3, 10, and 30 ng/min through the Doppler catheter; and (5) bolus injection of 2 mg isosorbide dinitrate. After completion of the study with one drug, we waited for at least 5 minutes before beginning infusion of the next drug, by which time the coronary diameter and coronary blood flow velocity returned to baseline values. Coronary arteriography was performed before and 2 minutes after each drug. Mean and phasic coronary blood flow velocities, arterial pressure, heart rate, and standard 12-lead electrocardiograms were monitored continuously and recorded on a multichannel recorder (Nihon Kohden Polygraph System). Steady-state values were used for later analysis.
Statistical Analysis
Data are expressed as mean±SD or SEM. When serial changes in
hemodynamic variables to the graded doses of drugs were compared,
one-way ANOVA was used. When the responses were compared between study
groups, two-way ANOVA for repeated measures followed by Bonferroni's
multiple comparison test was used. A value of P<.05 was
considered statistically significant.
Clinical characteristics such as age, sex, arterial pressure, and serum
cholesterol levels were compared between hypertensive patients and
control subjects by Student's t tests or
2 tests. The effects of these clinical factors on
coronary vasomotion in response to acetylcholine were examined by
multiple linear regression analysis.
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Results |
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Clinical Characteristics and Hemodynamic Data
The clinical characteristics of hypertensive patients and control subjects were comparable with regard to age, male sex, total serum cholesterol level, and history of cigarette smoking (Table). Left ventricular diastolic and systolic dimensions and left ventricular posterior wall thickness as determined by echocardiogram did not differ between the two groups.
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Systolic, diastolic, and mean arterial pressures at the time of study were significantly higher in hypertensive patients than control subjects. Heart rate and left ventricular end-diastolic pressure were similar between the two groups. The diameter of the proximal segments of the left anterior descending coronary artery at baseline was similar in the two groups. Baseline mean arterial pressure and heart rate before drugs did not significantly change during the study in either hypertensive patients or control subjects (data not shown). Mean arterial pressure and heart rate were not significantly altered by intracoronary administration of either acetylcholine, substance P, papaverine, or nitrate, as described previously.15 16 17 24 25
Responses of the Large Epicardial Coronary Artery
Intracoronary infusion of saline did not change the diameter of
the large epicardial coronary artery. In control subjects,
acetylcholine at the low dose (3 µg/min) increased (P<.05
by one-way ANOVA and multiple comparison tests) and at the high dose
(30 µg/min) decreased (P<.05) arterial diameter (Fig 1). In hypertensive patients, acetylcholine
significantly decreased (P<.01 by one-way ANOVA) arterial
diameter in a dose-dependent manner. No significant vasodilation of the
large epicardial coronary artery was noted in hypertensive patients.
The vasoconstrictor responses of the large epicardial coronary artery
to acetylcholine in hypertensive patients were significantly greater
(P<.01 by two-way ANOVA and multiple comparison tests) than
the responses in control subjects. The effects of clinical
characteristics (Table) on the vasoconstrictor response to 30 µg/min
acetylcholine were assessed by multiple regression analysis;
arterial pressure but not the other factors significantly
(P<.01) correlated with the response to acetylcholine.
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) and control subjects
(
). Percent changes in large epicardial coronary artery diameter
in response to drugs are presented. **P<.01 vs control
by two-way ANOVA and multiple comparison tests. Values are mean±SEM.Substance P significantly increased (P<.01 by one-way ANOVA) arterial diameter in hypertensive patients and control subjects. The vasodilator responses of the large epicardial coronary artery to substance P were comparable between the two groups (Fig 1).
The vasodilator responses to papaverine (4±3% and 4±4% in hypertensive patients and control subjects, respectively) and nitrate (15±2% and 11±1%) were comparable between the two groups.
Responses of Coronary Blood Flow
Intracoronary infusion of saline did not change coronary blood
flow. A real-time tracing of coronary blood flow velocity during drug
infusion in a control subject is presented in Fig 2.
Both acetylcholine and substance P increased coronary blood flow in a
dose-dependent manner in hypertensive patients and control subjects.
The increases in coronary blood flow evoked with acetylcholine were
markedly less (P<.01 by two-way ANOVA) in hypertensive
patients than control subjects (Fig 2). The percent increases in
coronary blood flow with acetylcholine at 1, 3, 10, and 30 µg/min
were 13±9%, 37±17%, 67±16%, and 184±76%, respectively, in
hypertensive patients and 49±17%, 179±42%, 289±36%, and
372±23%, respectively, in control subjects. Multiple regression
analysis showed that there was a significant negative correlation
between arterial pressure and the percent increase in coronary blood
flow evoked with 30 µg/min acetylcholine.
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The percent increases in coronary blood flow evoked with substance P were also significantly less (P<.01 by two-way ANOVA) in hypertensive patients than control subjects (Fig 3). The percent increases in coronary blood flow evoked with substance P at 3, 10, and 30 ng/min were 10±5%, 20±6%, and 32±10% in hypertensive patients and 11±3%, 70±7%, and 143±28% in control subjects.
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The percent increase in coronary blood flow in response to papaverine was similar between hypertensive patients (426±35%) and control subjects (394±34%, P=NS). The coronary blood flow response to nitrate was also similar between the groups (122±14% and 98±13%, hypertensive patients and control subjects, respectively, P=NS).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We have made two new observations in the present study. First, vasodilator responses of the large epicardial coronary artery to substance P were preserved in hypertensive patients in whom acetylcholine produced significant vasoconstrictor responses, suggesting that endothelial dysfunction of the large epicardial coronary artery in hypertensive patients may be related to a specific abnormality of the muscarinic receptors that mediate the effect of acetylcholine. Second, the increases in coronary blood flow evoked with both acetylcholine and substance P were attenuated in hypertensive patients compared with control subjects. The latter finding suggests that defective endothelium-dependent vasodilation of the resistance coronary artery in hypertensive patients may not be related to a specific abnormality of the muscarinic receptor.
Endothelial Dysfunction in the Large Epicardial Coronary Artery in
Hypertensive Patients
Our results that vasoconstrictor responses of the large epicardial
coronary artery to acetylcholine in hypertensive patients were greater
than those in control subjects are consistent with previous findings in
animals and humans suggesting that hypertension is associated with
diminished endothelium-dependent dilation of the large
coronary artery.4 6 7 8 Previous studies have noted that
atherosclerosis and various risk factors augment vasoconstrictor
responses of angiographically normal-looking epicardial coronary
arteries to acetylcholine.13 Our hypertensive patients had
angiographically normal coronary arteries and no hypercholesterolemia
or diabetes mellitus. Age, sex, and incidence of smoking were
comparable between the two study groups. Furthermore, multiple linear
regression analysis revealed that the levels of arterial pressure
but not other clinical factors were significantly correlated with the
responses of the large epicardial coronary artery and coronary blood
flow to acetylcholine. Thus, as reported in previous
studies,4 5 6 7 8 it is likely that augmented vasoconstrictor
responses of the large epicardial coronary artery to acetylcholine were
related to hypertension. However, we cannot exclude the possibility
that the presence of angiographically undetected atherosclerosis was
responsible for these findings.
It has been shown that acetylcholine and substance P dilate the large epicardial coronary artery by the release of endothelium-derived nitric oxide.26 27 28 29 However, acetylcholine and substance P act on different receptors to evoke the release of nitric oxide: muscarinic and tachykinin receptors, respectively.22 23 A new finding of the present study is that endothelium-dependent vasodilation of the large epicardial coronary artery evoked with substance P was preserved in hypertensive patients who had diminished endothelium-dependent vasodilation with acetylcholine. Endothelium-independent vasodilation with papaverine and nitrate was comparable in hypertensive patients and control subjects. These results suggest that diminished endothelium-dependent vasodilation of the large epicardial coronary artery with acetylcholine in hypertensive patients was related to a selective abnormality in the endothelial muscarinic receptor of the large epicardial coronary artery.
It has been shown that the increase in flow produces mechanical shear stress on the endothelial cell surface and thus causes endothelium-dependent vasodilation of large conduit vessels including the human epicardial coronary artery.30 31 Therefore, we do not exclude the possibility that diminished vasodilation of the large epicardial coronary artery in response to acetylcholine in hypertensive patients might have resulted from altered flow-induced endothelium-dependent vasodilation and not be related to an abnormality in the endothelial muscarinic receptor, since coronary blood flow could not be controlled in our patients. However, we consider it plausible that diminished endothelium-dependent vasodilation of the large epicardial coronary artery with acetylcholine in hypertensive patients may not totally be explained by attenuated flow-induced vasodilation. This hypothesis is based on the following findings. First, vasodilation of the large epicardial coronary artery with substance P in hypertensive patients was equivalent to that in control subjects, whereas the increases in coronary blood flow in response to substance P were markedly blunted in the hypertensive patients (Figs 1 and 3). Second, 1 µg/min acetylcholine, which did not significantly increase coronary blood flow in either group, produced a significant difference in the response of the large epicardial coronary artery between hypertensive patients and control subjects. Acetylcholine at high doses (10 to 30 µg/min), which markedly increased coronary blood flow, caused progressive vasoconstriction of the large epicardial coronary artery in both groups.
Endothelial Dysfunction in the Resistance Coronary Artery in
Hypertensive Patients
It is reasonable to assume that the increases in coronary blood
flow evoked with the drugs used in this study reflected vasodilation of
the resistance coronary artery, because these drugs increased coronary
blood flow without altering arterial pressure and heart rate. Although
acetylcholine caused a modest vasoconstriction of the large epicardial
coronary artery, we15 16 17 and other
investigators32 have previously shown that this degree of
vasoconstriction of the large epicardial coronary artery does not
attenuate the coronary blood flow responses to vasodilator stimuli.
Thus, it is unlikely that the acetylcholine-induced vasoconstriction of
the large coronary artery might have limited the coronary blood flow
responses to acetylcholine.
Previous studies have indicated that endothelium-dependent vasodilation of the resistance coronary artery evoked with acetylcholine is impaired in hypertensive patients,5 6 which agrees with the data presented in the present study. However, the coronary blood flow response to another endothelium-dependent vasodilator such as substance P has not been studied in hypertensive patients. We found in the present study that the coronary blood flow responses to both acetylcholine and substance P were attenuated in hypertensive patients, indicating that endothelium-dependent dilation of the resistance coronary artery in response to both drugs was impaired in our hypertensive patients. We also demonstrated that the endothelium-independent responses to papaverine and nitrate were similar between hypertensive patients and control subjects, indicating that altered endothelium-dependent responses in hypertensive patients did not result from a nonspecific abnormality in the response of vascular smooth muscle. These findings indicate that defective endothelium-dependent vasodilation of the resistance coronary artery in hypertensive patients is related to a more generalized abnormality of endothelial cells in response to diverse stimuli but not confined to a local endothelial abnormality at the muscarinic receptor level.
Recently, Panza et al,21 using a specific inhibitor of endothelium-derived nitric oxide (NG-monomethyl-L-arginine), have suggested that impaired endothelium-dependent forearm vasodilation in hypertensive patients is related to a decreased release of nitric oxide. However, we could not determine the degree to which endothelium-derived nitric oxide might be involved in the mechanisms responsible for impaired endothelium-dependent vasodilation of the resistance coronary artery in hypertensive patients because responses of the resistance coronary artery to acetylcholine and substance P were not assessed before and after an inhibitor of endothelium-derived nitric oxide. Therefore, we do not know whether endothelial dysfunction in the resistance coronary artery in hypertensive patients is related to reduced release of endothelium-derived nitric oxide or hyperpolarizing factor,33 inactivation of endothelium-derived relaxing factors,34 or augmented release of endothelium-derived constricting factors.35 Further studies are needed to determine the relative contributions of these possibilities in impaired endothelium-dependent coronary vasodilation in this condition.
Conclusion
The results of this study suggest that diminished
endothelium-dependent dilation of the large epicardial
coronary artery in hypertensive patients may be related to a selective
abnormality in the muscarinic receptor of the endothelium and that
blunted endothelium-dependent dilation of the
resistance coronary artery in this condition may be related to a more
generalized endothelial abnormality but not confined to the muscarinic
receptor. These findings may contribute to our understanding of the
pathophysiology of altered endothelial function of the coronary
arteries in hypertensive patients.
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Acknowledgments |
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This study was supported by grants-in-aid for scientific research (Nos. 05670617 and 05857085) from the Ministry of Education, Science and Culture, Tokyo, Japan; by a Japan Cardiovascular Research Foundation research grant, Osaka, Japan; and by a Japan Heart Foundation research grant, Tokyo, Japan.
Received September 6, 1994; first decision October 19, 1994; accepted October 19, 1994.
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C. H. Pullin, P. A. L. Ashfield-Watt, M. L. Burr, Z. E. Clark, M. J. Lewis, S. J. Moat, R. G. Newcombe, H. J. Powers, J. M. Whiting, and I. F. W. McDowell Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1799 - 1805. [Abstract] [Full Text] [PDF]
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 M.P. Pellegrini, D. E Newby, S. Maxwell, and D. J Webb Short-term effects of transdermal nicotine on acute tissue plasminogen activator release in vivo in man Cardiovasc Res, November 1, 2001; 52(2): 321 - 327. [Abstract] [Full Text] [PDF]
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S. Sasaki, Y. Higashi, K. Nakagawa, H. Matsuura, G. Kajiyama, and T. Oshima Effects of Angiotensin-(1-7) on Forearm Circulation in Normotensive Subjects and Patients With Essential Hypertension Hypertension, July 1, 2001; 38(1): 90 - 94. [Abstract] [Full Text] [PDF]
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Y. Higashi, S. Sasaki, K. Nakagawa, H. Matsuura, G. Kajiyama, and T. Oshima Effect of the angiotensin-converting enzyme inhibitor imidapril on reactive hyperemia in patients with essential hypertension: relationship between treatment periods and resistance artery endothelial function J. Am. Coll. Cardiol., March 1, 2001; 37(3): 863 - 870. [Abstract] [Full Text] [PDF]
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K. M. Gauthier and N. J. Rusch Rat Coronary Endothelial Cell Membrane Potential Responses During Hypertension Hypertension, January 1, 2001; 37(1): 66 - 71. [Abstract] [Full Text] [PDF]
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 G. Nickenig, A. Stablein, S. Wassmann, C. Wyen, C. Muller, and M. Bohm Acute effects of ACE inhibition on coronary endothelial dysfunction Journal of Renin-Angiotensin-Aldosterone System, December 1, 2000; 1(4): 361 - 364. [Abstract] [PDF]
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J. E. Graves, I. A. Greenwood, and W. A. Large Tonic regulation of vascular tone by nitric oxide and chloride ions in rat isolated small coronary arteries Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2604 - H2611. [Abstract] [Full Text] [PDF]
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 G.Y.H Lip, D.C Felmeden, F.L Li-Saw-Hee, and D.G Beevers Hypertensive heart disease. A complex syndrome or a hypertensive 'cardiomyopathy'? Eur. Heart J., October 2, 2000; 21(20): 1653 - 1665. [PDF]
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 J. A. Vita, A. C. Yeung, M. Winniford, J. M. Hodgson, C. B. Treasure, J. L. Klein, S. Werns, M. Kern, D. Plotkin, W. J. Shih, et al. Effect of Cholesterol-Lowering Therapy on Coronary Endothelial Vasomotor Function in Patients With Coronary Artery Disease Circulation, August 22, 2000; 102(8): 846 - 851. [Abstract] [Full Text] [PDF]
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 E. S. G. Stroes, E. E. van Faassen, M. Yo, P. Martasek, P. Boer, R. Govers, and T. J. Rabelink Folic Acid Reverts Dysfunction of Endothelial Nitric Oxide Synthase Circ. Res., June 9, 2000; 86(11): 1129 - 1134. [Abstract] [Full Text] [PDF]
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 H. Laine, P. Nuutila, M. Luotolahti, C. Meyer, T. Elomaa, P. Koskinen, T. Rönnemaa, and J. Knuuti Insulin-Induced Increment of Coronary Flow Reserve Is Not Abolished by Dexamethasone in Healthy Young Men J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 1868 - 1873. [Abstract] [Full Text]
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 Y. Zhang and D. B. Hoover Signaling Mechanisms for Muscarinic Receptor-Mediated Coronary Vasoconstriction in Isolated Rat Hearts J. Pharmacol. Exp. Ther., April 1, 2000; 293(1): 96 - 106. [Abstract] [Full Text]
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Y. Higashi, S. Sasaki, K. Nakagawa, T. Ueda, A. Yoshimizu, S. Kurisu, H. Matsuura, G. Kajiyama, and T. Oshima A comparison of angiotensin-converting enzyme inhibitors, calcium antagonists, beta-blockers and diuretic agents on reactive hyperemia in patients with essential hypertension: a multicenter study J. Am. Coll. Cardiol., February 1, 2000; 35(2): 284 - 291. [Abstract] [Full Text] [PDF]
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 E G Zouridakis, I D Cox, X Garcia-Moll, S Brown, P Nihoyannopoulos, and J C Kaski Negative stress echocardiographic responses in normotensive and hypertensive patients with angina pectoris, positive exercise stress testing, and normal coronary arteriograms Heart, February 1, 2000; 83(2): 141 - 146. [Abstract] [Full Text]
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M. Usui, K. Egashira, H. Tomita, M. Koyanagi, M. Katoh, H. Shimokawa, M. Takeya, T. Yoshimura, K. Matsushima, and A. Takeshita Important Role of Local Angiotensin II Activity Mediated via Type 1 Receptor in the Pathogenesis of Cardiovascular Inflammatory Changes Induced by Chronic Blockade of Nitric Oxide Synthesis in Rats Circulation, January 25, 2000; 101(3): 305 - 310. [Abstract] [Full Text] [PDF]
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M. Koyanagi, K. Egashira, M. Kubo-Inoue, M. Usui, S. Kitamoto, H. Tomita, H. Shimokawa, and A. Takeshita Role of Transforming Growth Factor-{beta}1 in Cardiovascular Inflammatory Changes Induced by Chronic Inhibition of Nitric Oxide Synthesis Hypertension, January 1, 2000; 35(1): 86 - 90. [Abstract] [Full Text] [PDF]
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M. Usui, K. Egashira, S. Kitamoto, M. Koyanagi, M. Katoh, C. Kataoka, H. Shimokawa, and A. Takeshita Pathogenic Role of Oxidative Stress in Vascular Angiotensin-Converting Enzyme Activation in Long-Term Blockade of Nitric Oxide Synthesis in Rats Hypertension, October 1, 1999; 34(4): 546 - 551. [Abstract] [Full Text] [PDF]
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Y. Higashi, S. Sasaki, S. Kurisu, A. Yoshimizu, N. Sasaki, H. Matsuura, G. Kajiyama, and T. Oshima Regular Aerobic Exercise Augments Endothelium-Dependent Vascular Relaxation in Normotensive As Well As Hypertensive Subjects : Role of Endothelium-Derived Nitric Oxide Circulation, September 14, 1999; 100(11): 1194 - 1202. [Abstract] [Full Text] [PDF]
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 C. Thalhammer, B. Balzuweit, A. Busjahn, C. Walter, F. C. Luft, and H. Haller Endothelial Cell Dysfunction and Arterial Wall Hypertrophy Are Associated With Disturbed Carbohydrate Metabolism in Patients at Risk for Cardiovascular Disease Arterioscler Thromb Vasc Biol, May 1, 1999; 19(5): 1173 - 1179. [Abstract] [Full Text] [PDF]
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Y. Higashi, S. Sasaki, N. Sasaki, K. Nakagawa, T. Ueda, A. Yoshimizu, S. Kurisu, H. Matsuura, G. Kajiyama, and T. Oshima Daily Aerobic Exercise Improves Reactive Hyperemia in Patients With Essential Hypertension Hypertension, January 1, 1999; 33(1): 591 - 597. [Abstract] [Full Text] [PDF]
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M. Katoh, K. Egashira, M. Usui, T. Ichiki, H. Tomita, H. Shimokawa, H. Rakugi, and A. Takeshita Cardiac Angiotensin II Receptors Are Upregulated by Long-Term Inhibition of Nitric Oxide Synthesis in Rats Circ. Res., October 5, 1998; 83(7): 743 - 751. [Abstract] [Full Text] [PDF]
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H. Tomita, K. Egashira, Y. Ohara, M. Takemoto, M. Koyanagi, M. Katoh, H. Yamamoto, K. Tamaki, H. Shimokawa, and A. Takeshita Early Induction of Transforming Growth Factor-ß via Angiotensin II Type 1 Receptors Contributes to Cardiac Fibrosis Induced by Long-term Blockade of Nitric Oxide Synthesis in Rats Hypertension, August 1, 1998; 32(2): 273 - 279. [Abstract] [Full Text] [PDF]
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H. Laine, O. T. Raitakari, H. Niinikoski, O.-P. Pitkanen, H. Iida, J. Viikari, P. Nuutila, and J. Knuuti Early impairment of coronary flow reserve in young men with borderline hypertension J. Am. Coll. Cardiol., July 1, 1998; 32(1): 147 - 153. [Abstract] [Full Text] [PDF]
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H. C. McGill Jr, C. A. McMahan, R. E. Tracy, M. C. Oalmann, J. F. Cornhill, E. E. Herderick, and J. P. Strong Relation of a Postmortem Renal Index of Hypertension to Atherosclerosis and Coronary Artery Size in Young Men and Women Arterioscler Thromb Vasc Biol, July 1, 1998; 18(7): 1108 - 1118. [Abstract] [Full Text] [PDF]
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Y. Higashi, T. Oshima, S. Sasaki, Y. Nakano, M. Kambe, H. Matsuura, and G. Kajiyama Angiotensin-Converting Enzyme Inhibition, But Not Calcium Antagonism, Improves a Response of the Renal Vasculature to L-Arginine in Patients With Essential Hypertension Hypertension, July 1, 1998; 32(1): 16 - 24. [Abstract] [Full Text] [PDF]
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U. C. Kopp, M. Z. Cicha, D. M. Farley, L. A. Smith, and B. S. Dixon Renal Substance P–Containing Neurons and Substance P Receptors Impaired in Hypertension Hypertension, March 1, 1998; 31(3): 815 - 822. [Abstract] [Full Text] [PDF]
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B. Ghaleh, L. Hittinger, S.-J. Kim, R. K. Kudej, M. Iwase, M. Uechi, A. Berdeaux, S. P. Bishop, and S. F. Vatner Selective large coronary endothelial dysfunction in conscious dogs with chronic coronary pressure overload Am J Physiol Heart Circ Physiol, February 1, 1998; 274(2): H539 - H551. [Abstract] [Full Text] [PDF]
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K. M. Gauthier-Rein and N. J. Rusch Distinct Endothelial Impairment in Coronary Microvessels from Hypertensive Dahl Rats Hypertension, January 1, 1998; 31(1): 328 - 334. [Abstract] [Full Text] [PDF]
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M. Takemoto, K. Egashira, H. Tomita, M. Usui, H. Okamoto, A. Kitabatake, H. Shimokawa, K. Sueishi, and A. Takeshita Chronic Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade : Effects on Cardiovascular Remodeling in Rats Induced by the Long-term Blockade of Nitric Oxide Synthesis Hypertension, December 1, 1997; 30(6): 1621 - 1627. [Abstract] [Full Text]
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U. Solzbach, B. Hornig, M. Jeserich, and H. Just Vitamin C Improves Endothelial Dysfunction of Epicardial Coronary Arteries in Hypertensive Patients Circulation, September 2, 1997; 96(5): 1513 - 1519. [Abstract] [Full Text]
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D. B. Hoover and D. A. Neely Differentiation of Muscarinic Receptors Mediating Negative Chronotropic and Vasoconstrictor Responses to Acetylcholine in Isolated Rat Hearts J. Pharmacol. Exp. Ther., September 1, 1997; 282(3): 1337 - 1344. [Abstract] [Full Text]
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A. A. Quyyumi, D. Mulcahy, N. P. Andrews, S. Husain, J. A. Panza, and R. O. Cannon III Coronary Vascular Nitric Oxide Activity in Hypertension and Hypercholesterolemia: Comparison of Acetylcholine and Substance P Circulation, January 7, 1997; 95(1): 104 - 110. [Abstract] [Full Text]
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K. Numaguchi, K. Egashira, M. Takemoto, T. Kadokami, H. Shimokawa, K. Sueishi, and A. Takeshita Chronic Inhibition of Nitric Oxide Synthesis Causes Coronary Microvascular Remodeling in Rats Hypertension, December 1, 1995; 26(6): 957 - 962. [Abstract] [Full Text]
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