Substance P is a member of vasoactive neuropeptides and is present in the myocardium and perivascular regions (1,2). Substance P causes endothelium-dependent vasodilation in coronary artery (3-5) and forearm vessels (6), and its receptors have been demonstrated on endothelial cells of canine carotid and porcine coronary arteries (7,8). Recent studies have shown that endothelial cells release substance P in response to increased shear stress and hypoxia (9-12), and it is possible that substance P acts as a local hormone to cause endothelium-dependent vasodilation. Therefore substance P may add a greater contribution to the endothelium-dependent control of vascular tone than we have expected from the circulating concentration of substance P. However, the precise mechanism(s) whereby substance P causes vasodilation in humans is(are) not fully understood.
We demonstrated that L-arginine increases acetylcholine-induced forearm vasodilation but did not increase substance P-induced vasodilation (6). These results may suggest that the role of nitric oxide in substance P-induced forearm vasodilation is minor. However, the role of nitric oxide in substance P-induced vasodilation in the coronary circulation remains unclear in humans. It has been demonstrated in humans that acetylcholine-induced vasodilation is significantly attenuated by NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthesis, in the forearm (13,14) and coronary arteries (15). These results suggest a significant role of nitric oxide in acetylcholine-induced vasodilation. In our study, we examined the effects of L-NMMA on substance P-induced vasodilation in the coronary and forearm arteries in humans to determine whether substance P-induced vasodilation is mediated by nitric oxide in the human coronary and forearm arteries.
Eight patients undergoing diagnostic cardiac catheterization for evaluation of coronary artery diseases (two men and six women) were studied. Ages of subjects were 57-73 years with a mean of 64 ± 6 years. All patients had angiographically normal coronary arteries. Hypercholesterolemia was noted in two patients and hypertension in two. Five patients had no risk factor. Overt congestive heart failure was not recognized in any patient.
Coronary and forearm blood-flow responses to acetylcholine and substance P were determined in each patient. Antianginal and antihypertensive medications were discontinued ≥24 h before the coronary and forearm blood-flow study. Cardiac catheterization was performed in the fasting state after administration of 5 mg of oral diazepam. After completion of diagnostic coronary arteriography, the coronary blood-flow study was carried out with use of the intracoronary Doppler guide wire and quantitative coronary arteriography techniques (15). On a different day, after the coronary blood-flow study, the forearm blood-flow study was performed with use of a strain-gauge plethysmograph. The study protocol was approved by the Human Research Committee of the Research Institute of Angiocardiology, Faculty of Medicine. Written informed consent was obtained from each patient before the study.
Measurements of coronary blood-flow velocity and blood flow
Continuous measurement of coronary blood flow was achieved by using a 0.014-inch intracoronary Doppler-tipped guide wire (FloWire; Cardiometrics Inc.) and an FFT-based, on-line spectral analyzer (FloMap; Cardiometrics). The Doppler guide wire was advanced through the Judkins catheter, and the tip was placed at the proximal segment of the left anterior descending coronary artery. Average peak blood-flow velocity signals were continuously obtained, and time-averaged volumetric coronary flow was calculated according to the following formula: coronary blood flow (ml/min) = 0.5 × average peak velocity (cm/min) × cross-sectional area (cm2) (15,16).
Systemic arterial blood pressure was recorded via the Judkins catheter. Heart rate was obtained from standard 12-lead electrocardiogram that was monitored continuously throughout the study.
Quantitative coronary arteriography
Coronary cineangiograms were recorded by using a cineangiographic system (Siemens Bicor & Hicor, Erlangen, FRG). Nonionic contrast medium (Ioversol; Yamanouchi Pharmaceutical Co., Tokyo, Japan) was used. An appropriate view was selected to permit clear visualization of the coronary segment under study without overlapping branches. An angle of view, the distance from the x-ray focus to the object and that from the object to the image intensifier, were carefully kept constant throughout the study. An end-diastolic frame was selected, and the luminal diameter of the segment of the study artery distal to the Doppler guide-wire tip was determined quantitatively by a cinevideodensitometric analysis system (Kontron Instruments, Dortmund, FRG), as previous described (15). In brief, the diameters were measured 3 times, and the averaged value was used for analysis. The Judkins catheter with a known tip diameter was used for calibration to obtain absolute vessel diameters in millimeters. The accuracy and precision of quantitative angiographic measurements were determined from the analysis of cine films of the phantom with the precision-drilled models of coronary arteries with diameter of 1.5, 2.0, and 3.0 mm filled with contrast medium and filmed under 5 cm of water. The accuracy of the contour-detection technique was defined as the average difference of the computed results with the true values, and precision was defined as the pooled standard deviations of the differences. The accuracy was 0.7 ± 0.2%, and the precision was 2.6% (mean ± SD, n = 165) (17). Inter- and intraobserver reproducibility of the measurements with this system were high (r = 0.96 and 0.98, respectively) (11).
Coronary vascular responses to drugs
After completion of the diagnostic catheterization, the following studies were performed:
- Acetylcholine at a dose of 10 μg/min (for 2 min) and substance P at graded doses of 30 and 90 ng/min (for 2 min at each dose) were infused directly into left coronary artery through the Judkins catheter. The order of acetylcholine and substance P infusion was alternated. Drugs were diluted with physiologic saline, and the infusion rate was 1 ml/min. Infusion of the second drug was begun after coronary blood-flow velocity had returned to the baseline level.
- After recovery was noted from the effect of final drug infusion, L-NMMA (200 μmol) was injected intracoronarily for >10 min through the Judkins catheter. We found in our laboratory that this dose (200 μmol) of intracoronary L-NMMA significantly attenuated acetylcholine-induced increase in coronary blood flow in patients with normal coronary arteries by ∼70% (n = 7; p < 0.01) (15). Two minutes later, acetylcholine and substance P infusion was repeated in the same way as that before L-NMMA.
- Intracoronary papaverine (10 mg/ml for 1 min) was given through the Judkins catheter to obtain the maximal coronary-flow reserve.
Measurements of forearm blood flow
The study was done with subjects in a supine position and in a postabsorptive state in an air-conditioned room with room temperature at 25-26°C. Under local anesthesia with 2% procaine, the left brachial artery was cannulated with a 20-gauge intravascular over-the-needle polytetrafluoroethylene cannula (Quick-Cath; Travenol Laboratories, Inc., Baxter Healthcare Corp., Deerfield, IL, U.S.A.) for drug infusion, and the cannula was connected to a pressure transducer (Vigo-Spectramed, Oxnard, CA, U.S.A.) for direct measurement of arterial pressure. The arterial line was kept open by infusing heparinized saline (0.1 ml/min) while no drug was being infused. Heart rate was obtained by counting the pulse rate on arterial pressure recordings.
Forearm blood flow was measured by using a mercury-insilastic strain-gauge plethysmograph with a venous-occlusion technique as previously reported (18,19). In brief, the strain gauge was placed ∼5 cm below the antecubital crease. Forearm blood flow (milliliters per minute per 100 ml of forearm) was calculated from the rate of increase in forearm volume while venous return from the forearm was prevented by inflating the cuff on the upper arm. The pressure in the venous-occlusion or congesting cuff was 40 mm Hg. Circulation to the hand was arrested by a cuff inflated around the wrist. The wrist cuff was inflated before the determination of forearm blood flow and continuously throughout the measurements. An average of four flow measurements made at 15-s intervals was used for later analysis. After the placement of cannula and a strain-gauge plethysmograph, at least 15 min was allowed for subjects to become accustomed to the study conditions before the experiments were begun. Forearm blood flow, arterial pressure, and heart rate were measured at rest and during acetylcholine and substance P administration.
Forearm vascular responses to drugs
We examined forearm vasodilator responses to intraarterial infusion of acetylcholine and substance P at graded doses. Acetylcholine (4, 8, and 16 μg/min) and substance P (0.8, 1.6, and 3.2 ng/min) were infused intraarterially for 2 min at each dose. The maximal infusion volume for the maximal dose of acetylcholine and substance P was 0.6 ml/min. We previously showed that infusion of saline at 0.6 ml/min did not affect forearm blood flow (20). The order of acetylcholine and substance P infusion was alternated. Infusion of the second drug was begun after forearm blood flow had returned to the baseline level. Because forearm blood flow reached the steady state by 1 min after starting infusion of each drug, we used the last 1-min measurements during drug infusion of each dose for later analysis.
After forearm blood flow had returned to the baseline level, L-NMMA was infused into the brachial artery at 8 μmol/min for 5 min, and thereafter acetylcholine or substance P was infused in the same way as before L-NMMA.
L-NMMA was obtained from Clinalfa AG, Laüfelfingen, Switzerland. Because acetylcholine is unstable in solution, 100 mg of acetylcholine (Daiichi Pharmaceutical, Tokyo, Japan) was lyophilized and stored in a vial (0.4 mg acetylcholine per vial). It was dissolved in physiologic saline immediately before use. Substance P was obtained from Sigma Chemical Co. (St. Louis, MO, U.S.A.) and prepared for human use at the pharmaceutical division of our hospital.
Data are expressed as mean ± SD except in figures. The effects of L-NMMA on the resting values were analyzed by paired t test. Hemodynamic values during infusions of acetylcholine and substance P were compared by one-way analysis of variance (ANOVA). Hemodynamic responses to acetylcholine or substance P before and after L-NMMA were compared by two-way ANOVA for repeated measures. When the difference was significant, values at each dose were compared by post hoc t test. The inhibitory effects of L-NMMA on the blood-flow responses to drugs between the coronary and forearm vessels were compared by paired t test. The reduction of blood-flow responses to drugs after L-NMMA (%) was calculated according to the following formula: reduction of blood-flow responses to drugs after L-NMMA (%) = [(drug-induced increase in blood flow after L-NMMA-drug − induced increase in blood flow before L-NMMA) ÷ drug-induced increase in blood flow before L-NMMA] × 100. A value of p < 0.05 was considered to be statistically significant.
Effects of L-NMMA on coronary artery diameter and coronary blood flow
Intracoronary infusions of acetylcholine or substance P did not alter significantly mean blood pressure or heart rate (Tables 1 and 2). Acetylcholine at a dose of 10 μg/min significantly (p < 0.01) increased coronary blood flow (Fig. 1) but did not alter coronary artery diameter (Fig. 2). Substance P significantly increased coronary blood flow in a dose-dependent manner (p < 0.01; Fig. 1) and dilated coronary artery diameter (p < 0.01; Fig. 2). The percentage increases in the coronary diameter induced by 30 and 90 ng/min of substance P were 12.2 ± 7.2% (from 3.31 ± 0.88 to 3.69 ± 0.88 mm) and 17.2 ± 8.5% (from 3.31 ± 0.88 to 3.87 ± 1.02 mm), respectively.
L-NMMA infusion decreased baseline coronary blood flow (p < 0.05; Fig. 1) but did not significantly alter coronary artery diameter (Fig. 2). L-NMMA pretreatment significantly attenuated the coronary blood-flow response to acetylcholine (p < 0.01; Fig. 1). L-NMMA pretreatment also decreased the coronary blood-flow responses to substance P (p < 0.01; Fig. 1) and substance P-induced large epicardial coronary artery dilation (p < 0.01; Fig. 2). L-NMMA reduced the percentage increases in the coronary diameter induced by 30 and 90 ng/min of substance P from 12.2 ± 7.2% to 6.7 ± 6.0% and from 17.2 ± 8.5% to 9.7 ± 8.2%, respectively. Coronary flow reserve as assessed by intracoronary papaverine was preserved in all patients (data not shown).
Effects of L-NMMA on forearm blood flow
Intraarterial infusions of acetylcholine or substance P did not alter mean blood pressure or heart rate (Tables 3 and 4). The graded doses of acetylcholine and substance P caused progressive increases in forearm blood flow (Fig. 3).
L-NMMA did not alter heart rate or arterial pressure but decreased baseline forearm blood flow (p < 0.01; Fig. 3). L-NMMA significantly decreased the forearm blood-flow responses to acetylcholine (p < 0.01; Fig. 3), and the inhibitory effects of L-NMMA on the forearm blood-flow responses to acetylcholine were equal to that on the coronary blood-flow responses to acetylcholine (Fig. 4). L-NMMA significantly decreased the forearm blood-flow responses to substance P (p < 0.05; Fig. 3), but the inhibitory effects of L-NMMA on the blood-flow responses to substance P were significantly smaller in the forearm than in coronary vessels (Fig. 4).
The major findings in our study are that L-NMMA attenuated vasodilator effects of both acetylcholine and substance P in human coronary and forearm vessels and that the inhibitory effects of L-NMMA on substance P-induced vasodilation were significantly smaller in the forearm than in coronary vessels. These results suggest that the role of nitric oxide in substance P-induced vasodilation differs between the coronary and forearm circulation in humans. Substance P-induced coronary vasodilation is likely to be mediated considerably by endothelium-derived nitric oxide, but the contribution of nitric oxide to substance P-induced forearm vasodilation may be minor. Thus vasodilator mechanisms of substance P differ considerably among vascular beds in humans.
Effects of L-NMMA on acetylcholine-induced coronary and forearm vasomotion
Acetylcholine dilates blood vessels by several different mechanisms: a release of nitric oxide from the endothelium (21-23) and endothelium-derived hyperpolarizing factors (EDHF) (24-27), prejunctional inhibition of adrenergic neurotransmission (28,29), and a release of prostacyclin from blood vessels (22,23). In humans, it has been demonstrated that L-NMMA inhibits (13-15) and L-arginine augments acetylcholine-induced vasodilation (6,30-32). To determine the contribution of nitric oxide to vasodilation in humans, we used L-NMMA, an inhibitor of nitric oxide synthesis. We and other investigators previously demonstrated that L-NMMA attenuated acetylcholine-induced vasodilation (13-15). The results of this study demonstrated that L-NMMA reduced acetylcholine-induced increase in blood flow by 75-100% in both the coronary and forearm arteries, which confirmed that acetylcholine-induced vasodilation may be mediated mainly by nitric oxide.
We used only one dose of acetylcholine (10 μg/min) to examine the coronary vascular responses to acetylcholine in this study. However, we have observed that 200 μmol of L-NMMA attenuated coronary vasodilation induced by higher doses of acetylcholine (15). Other endothelium-derived relaxing factors such as EDHF may contribute to the acetylcholine-induced vasodilation that remains after the inhibition of nitric oxide synthesis with L-NMMA. This possibility was not tested in this study and remains to be determined.
Effects of L-NMMA on substance P-induced coronary and forearm vasomotion
Substance P is an endothelium-dependent vasodilator (33,34) without direct effect on vascular smooth muscle (35). Intracoronary substance P dilated large epicardial coronary artery dose-dependently in our study. Our results are compatible with those of previous studies (3-5). Crossman et al. (36) reported that intracoronary substance P increased coronary sinus oxygen saturation, which suggests the increase in coronary blood flow. In our study, we measured coronary blood flow directly with use of the intracoronary Doppler guide wire and quantitative coronary arteriography techniques and demonstrated that intracoronary substance P increased coronary blood flow in a dose-dependent manner. To examine the effects of substance P in the coronary circulation, we used the doses of 30-90 ng/min. These doses were 10- to 30-fold higher than the doses we used in the forearm study. We adopted these doses of substance P because of the known differences in the magnitude of baseline blood flow in the coronary and forearm circulations. To explore the mechanism(s) of substance P-induced coronary vasodilation in humans, the effect of L-NMMA was tested.
L-NMMA reduced the magnitude of substance P-induced increase in coronary blood flow by ∼60%. Chester et al. (37) reported that L-NMMA reduced substance P-induced vasodilation in human epicardial coronary arteries removed from patients undergoing heart transplantation for reasons other than ischemic heart disease. Our results offer the evidence that substance P dilates coronary vessels at least in part by endothelium-derived nitric oxide in vivo.
In our study, L-NMMA slightly but significantly decreased substance P-induced vasodilation in human forearm arteries. The difference between forearm blood-flow responses at graded doses of substance P before and after L-NMMA is not accounted for solely by the difference in baseline forearm blood flow, because the difference was greater during than before infusion of substance P. We also compared dose-response curves of substance P-induced increases in forearm blood flow (forearm blood flow during substance P infusion - forearm blood flow before substance P infusion) before and after L-NMMA. There was a significant difference (p < 0.05) between substance P-induced increases in forearm blood flow before and after L-NMMA, and L-NMMA reduced substance P-induced increases in forearm blood flow by ∼20%. These results in our study suggest that substance P-induced increases in forearm blood flow were indeed blunted by L-NMMA pretreatment and that the magnitude of the inhibitory effect of L-NMMA on forearm blood-flow responses to substance P was small. On the other hand, the same dose of L-NMMA (40 μmol) reduced low and high doses of acetylcholine-induced forearm vasodilation by ∼100% and 75%, respectively. These results indicate that 40 μmol of L-NMMA in forearm circulation is comparable to 200 μmol of L-NMMA in coronary circulation with regard to the capability of inhibiting stimulated nitric oxide formation. Therefore the results of our study suggest that the contribution of nitric oxide to substance P-induced vasodilation differs significantly between coronary and forearm circulation in humans.
Our result (that substance P-induced vasodilation is partially mediated by nitric oxide in human forearm vessels) is compatible with the results of recent studies (38,39). However, inhibitory effect of L-NMMA on the substance P-induced forearm vasodilation was less in our study. We did not coinfuse L-NMMA in our study, which might cause the difference between their studies and our study.
L-NMMA attenuated substance P-induced large epicardial coronary artery dilation. This result is compatible with that of a recent study (37) and suggests that substance P-induced vasodilation in the large epicardial coronary artery is mediated by nitric oxide synthesis. However, it is known that the increase in blood flow itself causes vasodilation in the large epicardial coronary artery (40). Thus the reduction of substance P-induced vasodilation by L-NMMA in the large epicardial coronary artery may be due at least in part to the decreased coronary blood flow and vascular shear stress.
Because the plethysmographic measurements allowed us to measure the vasodilator responses of forearm resistance vessels but not those of conduit vessels, we were not able to determine whether vasodilation in response to substance P in the conduit vessels was mediated by nitric oxide.
It has been demonstrated that substance P causes vasodilation by releasing EDHF (41-43). In humans, substance P-induced coronary and forearm vasodilation may be mediated by EDHF. This possibility was not tested in our study and remains to be determined.
In eight patients studied, three had hypercholesterolemia or hypertension or both, and five had no risk factor. The results were similar between those with and without risk factors. However, it would be difficult from our study with this relatively small number of patients to draw definitive conclusion on the effects of risk factors on substance P-induced vasodilation.
Our study suggests that nitric oxide contributes to substance P-induced vasodilation to different degrees in the coronary and forearm vasculatures in humans. The contribution of nitric oxide to substance P-induced vasodilation is greater in the coronary than in the peripheral circulation.
Acknowledgment: We thank Fumiko Amano for technical assistance. We thank Drs. Daisuke Teshima and Osamu Fujishima at the Pharmacological Section of Kyushu University Hospital for preparing drugs. Dr. T. Tagawa is a Research Fellow of the Japan Society for the Promotion of Science.
This study was supported by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Science and Culture.
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