Nitroglycerin-induced Vasodilation Research Articles

Halothane Attenuates Nitroglycerin-Induced Vasodilation and a Decrease in Intracellular Ca2+ in the Rat Thoracic Aorta

Although halothane inhibits endothelium-mediated vasorelaxation, the sites of inhibition remain controversial. Because the cytosolic concentration of Ca2+ ([Ca2+]i) has crucial roles for tension development, we examined the effects of halothane on nitroglycerin-induced vasorelaxation from the standpoint of [Ca2+]i. Isolated spiral strips of rat thoracic aorta without endothelium were suspended for isometric tension recordings in a physiologic salt solution. Muscle contraction was evoked with 10(-8) M norepinephrine, followed by endothelium-independent vasorelaxation with nitroglycerin 10(-7) and 10(-6) M. The effects of halothane 1.5% and 3% on nitroglycerin-induced vasorelaxation were evaluated along with the concomitant measurement of [Ca2+]i using fura-2-Ca2+ fluorescence. In other muscle strips, incremental doses of norepinephrine were administered during halothane exposure to induce contractions comparable to those without halothane. Nitroglycerin dose-dependently reduced norepinephrine-induced muscle contractions, but the decrease in [Ca2+]i reached a plateau at 10(-7) M, which indicates that nitroglycerin induced [Ca2+]i-dependent and [Ca2+]i-independent vasorelaxation. Both concentrations of halothane inhibited nitroglycerin-induced decreases in muscle tension and [Ca2+]i, not only when the same dose of norepinephrine was used for contraction during halothane exposure, but also at incremental doses of norepinephrine. In conclusion, halothane inhibits nitroglycerin-induced vasorelaxation partly by suppressing Ca2+ changes in the smooth muscle. We examined nitroglycerin-induced vasorelaxation in the rat thoracic aorta, along with the concomitant measurement of the cytosolic concentrations of Ca2+, and found that halothane attenuated endothelium-independent vasorelaxation by suppressing Ca2+ dynamics in the smooth muscle.

Impaired brachial artery endothelial function is not predicted by elevated triglycerides

OBJECTIVESThe purpose of this study was to determine if patients with modest hyperlipidemia, and no other risk factors for coronary artery disease (CAD), have impaired endothelium-dependent (ED) vasoactivity.BACKGROUNDHypercholesterolemia impairs ED vasodilation, but the impact of elevated triglycerides on endothelial function is not as well established.METHODSHigh-resolution ultrasound was used to determine flow-mediated dilation (FMD) in the brachial artery (BA) after a 5-min arterial occlusion (endothelium-dependent stimulus) and nitroglycerin-induced dilation (endothelium-independent stimulus). We studied 40 healthy controls (Group 1), 38 patients with elevated low-density lipoprotein (LDL) cholesterol (Group 2) and 35 patients with elevated triglycerides (Group 3). Patients were excluded if they had known CAD or other risk factors for CAD, or if they were receiving lipid-lowering or vasoactive medications.RESULTSControl patients (Group 1) had normal LDL cholesterol (2.6 ± 0.8 mmol/liter) and triglyceride levels (1.0 ± 0.5 mmol/liter) compared with Group 2 (5.2 ± 1.2 mmol/liter, 1.8 ± 0.6 mmol/liter) and Group 3 (3.5 ± 0.9 mmol/liter, 4.2 ± 2.5 mmol/liter) subjects (p < 0.001). Baseline BA diameters were the same across the three groups. There was no significant attenuation of flow-mediated vasodilation (FMD) in either of the hyperlipidemic groups (Group 1: 10.9 ± 5.0% vs. Group 2: 8.6 ± 6.1% vs. Group 3: 9.4 ± 3.9%; p = 0.14). However, nitroglycerin-induced vasodilation was mildly reduced (Group 1: 21.0 ± 5.0% vs. 16.9 ± 7.6% vs. 17.3 ± 7.7%; p = 0.01). By multivariate analysis, after controlling for baseline diameters, only the ratio of LDL/high-density lipoprotein predicted a minor impairment in FMD.CONCLUSIONSIn patients free from other cardiac risk factors, modest elevations of triglycerides or LDL cholesterol do not significantly attenuate BA endothelial-dependent vasodilation. Synergism with other cardiac risk factors may be required to significantly impair endothelial function in these patients.

Comparison of effects of ascorbic acid on endothelium-dependent vasodilation in patients with chronic congestive heart failure secondary to idiopathic dilated cardiomyopathy versus patients with effort angina pectoris secondary to coronary artery disease

Impaired endothelium-dependent vasodilation has been reported to play an important role in the pathogenesis of cardiovascular diseases such as coronary artery disease (CAD) and congestive heart failure (CHF). However, the precise mechanism of endothelial dysfunction has not been elucidated in these conditions. To evaluate the role of oxidative stress in endothelial dysfunction, the effect of antioxidant ascorbic acid on brachial flow-mediated, endothelium-dependent vasodilation during reactive hyperemia and nitroglycerin-induced endothelium-independent vasodilation was examined with high resolution ultrasound in 12 patients with CHF caused by idiopathic dilated cardiomyopathy without established coronary atherosclerosis and in 10 patients with CAD. Flow-mediated vasodilation in CHF (4.4 ± 0.5%) and CAD (4.0 ± 0.8%) was significantly (p <0.05) attenuated compared with that in 10 control subjects (9.6 ± 0.9%). However, nitroglycerin-induced vasodilation was similar in 3 groups (13.7 ± 1.3% in control, 13.9 ± 1.1% in CHF, 12.7 ± 1.4% in CAD). Ascorbic acid could significantly improve flow-mediated vasodilation only in patients with CAD (9.1 ± 0.9%) but not with CHF (5.6 ± 0.6%), and had no influence on nitroglycerin-induced vasodilation (13.6 ± 1.1% in CHF, 14.0 ± 1.3% in CAD). These results suggest that, in brachial circulation, augmented oxidative stress mainly leads to endothelial dysfunction in CAD but not in CHF caused by idiopathic dilated cardiomyopathy.

Preferential Effect of Nitroglycerin on Large Microvessels

In Response: We appreciate the valuable comments of Drs. Wang and Shernan. Because the purpose of our study [1] was to investigate the effect of mild hypothermia on nitroglycerin-induced vasodilation, their comment does not affect our results. However, we believe that this letter raises an important point. In our study, using an in vivo technique, topically applied nitroglycerin produced a dose-dependent dilation of both large and small pial (cerebral) arterioles in normothermic conditions. Similar results of in vivo techniques have been reported by several authors [2]. Unfortunately, there have been no reports investigating the influence of vessel size on the sensitivity of cerebral microvessels to nitroglycerin using an in vitro technique. In contrast, in vitro studies by Wang et al. [3] demonstrated that nitroglycerin caused preferential dilation of large porcine coronary arterioles and produced only minimal relaxation of small arterioles. These findings were confirmed by in vivo studies, which showed that nitroglycerin caused dilation of large coronary vessels without significantly affecting coronary blood flow [4]. Because most factors including in vivo or in vitro study, species, and different vascular beds are different, it is difficult to compare them simply. Further study is required regarding the influence of vessel size on the sensitivity of cerebral microvessels to nitroglycerin. Masahiko Kawaguchi, MD Hitoshi Furuya, MD Department of Anesthesiology; Nara Medical University; Nara 634-8522, Japan

Preferential Effect of Nitroglycerin on Large Microvessels

In Response: We appreciate the valuable comments of Drs. Wang and Shernan. Because the purpose of our study [1] was to investigate the effect of mild hypothermia on nitroglycerin-induced vasodilation, their comment does not affect our results. However, we believe that this letter raises an important point. In our study, using an in vivo technique, topically applied nitroglycerin produced a dose-dependent dilation of both large and small pial (cerebral) arterioles in normothermic conditions. Similar results of in vivo techniques have been reported by several authors [2]. Unfortunately, there have been no reports investigating the influence of vessel size on the sensitivity of cerebral microvessels to nitroglycerin using an in vitro technique. In contrast, in vitro studies by Wang et al. [3] demonstrated that nitroglycerin caused preferential dilation of large porcine coronary arterioles and produced only minimal relaxation of small arterioles. These findings were confirmed by in vivo studies, which showed that nitroglycerin caused dilation of large coronary vessels without significantly affecting coronary blood flow [4]. Because most factors including in vivo or in vitro study, species, and different vascular beds are different, it is difficult to compare them simply. Further study is required regarding the influence of vessel size on the sensitivity of cerebral microvessels to nitroglycerin. Masahiko Kawaguchi, MD Hitoshi Furuya, MD Department of Anesthesiology; Nara Medical University; Nara 634-8522, Japan

B024 Losartan maintains parasympathetic output during nitroglycerin-induced vasodilation

B024 Losartan maintains parasympathetic output during nitroglycerin-induced vasodilation

Mild hypothermia can attenuate nitroglycerin-induced vasodilation of pial arterioles in the cat.

The purpose of the present study was to investigate the effect of mild hypothermia on nitroglycerin-induced vasodilation of cerebral vessels. The cranial window technique, combined with microscopic video recording, was used in an experiment involving 26 cats anesthetized with isoflurane. Animals were randomly assigned to either a normothermic or a mildly hypothermic group (33 degrees C). We administered three different concentrations of nitroglycerin (10[-6], 10[-5], 10[-4] M) under the window and measured the diameter of small (< 100 microm) and large (100-200 microm) pial arterioles. In the normothermic group (n = 13), nitroglycerin produced a significant dilation of both small and large arterioles in a dose-dependent manner. In the hypothermic group (n = 13), a significant dilation of arterioles was observed only after topical application of nitroglycerin at a concentration of 10(-4) M. The percent increase in diameter of small and large arterioles was less in the hypothermic group than the normothermic group. Our in vivo study demonstrates that topically applied nitroglycerin produces a dose-dependent dilation of pial arterioles in normothermic cats anesthetized with isoflurane, but the reduction of temperature to 33 degrees C significantly attenuates nitroglycerin-induced vasodilation of pial arterioles. Although nitroglycerin may be used in hypothermic patients, the effect of mild hypothermia on nitroglycerin-induced vasodilation of cerebral vessels is unknown. In this study, we investigated the effects of nitroglycerin on pial arteriolar diameter in normothermic and hyperthermic cats. Hypothermia was found to attenuate nitroglycerin-induced vasodilation.

Mild Hypothermia Can Attenuate Nitroglycerin-Induced Vasodilation of Pial Arterioles in the Cat

The purpose of the present study was to investigate the effect of mild hypothermia on nitroglycerin-induced vasodilation of cerebral vessels. The cranial window technique, combined with microscopic video recording, was used in an experiment involving 26 cats anesthetized with isoflurane. Animals were randomly assigned to either a normothermic or a mildly hypothermic group (33[degree sign]C). We administered three different concentrations of nitroglycerin (10-6, 10-5, 10-4 M) under the window and measured the diameter of small (<100 [micro sign]m) and large (100-200 [micro sign]m) pial arterioles. In the normothermic group (n = 13), nitroglycerin produced a significant dilation of both small and large arterioles in a dose-dependent manner. In the hypothermic group (n = 13), a significant dilation of arterioles was observed only after topical application of nitroglycerin at a concentration of 10-4 M. The percent increase in diameter of small and large arterioles was less in the hypothermic group than the normothermic group. Our in vivo study demonstrates that topically applied nitroglycerin produces a dose-dependent dilation of pial arterioles in normothermic cats anesthetized with isoflurane, but the reduction of temperature to 33[degree sign]C significantly attenuates nitroglycerin-induced vasodilation of pial arterioles. Implications: Although nitroglycerin may be used in hypothermic patients, the effect of mild hypothermia on nitroglycerin-induced vasodilation of cerebral vessels is unknown. In this study, we investigated the effects of nitroglycerin on pial arteriolar diameter in normothermic and hyperthermic cats. Hypothermia was found to attenuate nitroglycerin-induced vasodilation. (Anesth Analg 1998;86:546-51)

Coronary angioplasty ameliorates hypoperfusion-induced endothelial dysfunction in patients with stable angina pectoris

This study sought to investigate the effect of coronary angioplasty on chronic hypoperfusion-induced endothelial dysfunction in patients with coronary heart disease. The endothelium is an important component for organ flow regulation. Ischemia with or without reperfusion is known to cause endothelial dysfunction. We tested the hypothesis that chronic hypoperfusion impairs endothelial function in the angiographically normal coronary artery segment distal to stenosis and that the impairment by chronic hypoperfusion is reduced by coronary angioplasty. In 13 patients with stable angina pectoris, substance P (10, 30 and 100 pmol) and nitroglycerin (200 micrograms) were sequentially infused into the coronary artery in a cumulative manner on the day after coronary angioplasty. In 10 of these patients, vascular responses to these agents were again investigated 3 months after angioplasty. Changes in vascular diameter were evaluated in vessels located proximal and distal to the target lesion, both of which were angiographically normal, by performing computer-assisted quantitative coronary angiography. In five patients, the transstenotic pressure gradient was also measured with a pressure sensor-mounted guide wire before angioplasty. On the day after angioplasty, the magnitude of dilation by substance P in distal segments was significantly less than that in proximal segments and inversely correlated with the transstenotic pressure gradient (p < 0.05) and lesion stenosis (p < 0.05). There was no difference in nitroglycerin-induced vasodilation between the two vessel segment groups. Three months later, the impaired response to substance P in the distal segment was restored to normal. We conclude that chronic hypoperfusion impairs endothelium-dependent dilation of coronary artery distal to critical stenosis in patients with ischemic heart disease and that coronary angioplasty ameliorates the endothelial dysfunction within 3 months.

Short-term exposure to lipopolysaccharide is associated with microvascular contractile dysfunction in vivo

The purpose of this study was to determine whether short-term exposure of resistance arterioles to lipopolysaccharide in situ is associated with changes in vasomotor tone. Using intravital microscopy, we found that suffusion of Escherichia coli lipopolysaccharide (3 μg/ml) over hamster cheek pouch arterioles for l h was associated with a significant immediate biphasic response: vasoconstriction followed by vasodilation ( p < 0.05). The former was attenuated by indomethacin, and the latter by SK&F 108566, a selective, non-peptide angiotensin II receptor antagonist ( p < 0.05). The nitric oxide synthase inhibitor, N G -L-nitro arginine, had no significant effects on lipopolysaccharide-induced responses. Allopurinol, a scavenger of reactive oxygen species, significantly attenuated lipopolysaccharide-induced vasodilation. Acetylcholine- and nitroglycerin-induced vasodilation were significantly potentiated after lipopolysaccharide. These responses were recorded in the absence of any significant changes in systemic arterial blood pressure. Collectively, these data suggest that short-term exposure of the peripheral microcirculation to lipopolysaccharide in situ is associated with an ischemia-reperfusion-like injury. These changes may contribute to end organ failure observed several hours after exposure to lipopolysaccharide.

Neutral endopeptidase modulates substance P-induced vasodilation in vivo.

The purpose of this study was to investigate whether neutral endopeptidase (NEP; EC 3.4.24.11) modulates substance P-induced vasodilation in the oral mucosa in vivo. Using intravital microscopy, we measured the diameter of second-order arterioles (44-70 microns) in the hamster cheek pouch during suffusion of capsaicin and substance P. We found that capsaicin (0.1 and 10.0 nM) induced significant concentration-dependent vasodilations (13 +/- 4 and 39 +/- 7% increase from baseline, respectively; P < 0.05) that were significantly potentiated by phosphoramidon (10.0 nM), a selective NEP inhibitor (35 +/- 15 and 61 +/- 12% increase from baseline, respectively; P < 0.05). Substance P (0.1 and 10.0 nM) also induced significant concentration-dependent vasodilations (7 +/- 3 and 25 +/- 8% increase from baseline, respectively; P < 0.05) that were mediated by the COOH-terminal of the molecule. Substance P-induced responses were significantly potentiated by phosphoramidon (34 +/- 9 and 53 +/- 10% increase from baseline, respectively; P < 0.05) and thiorphan (10.0 microM), a selective NEP inhibitor (44 +/- 11 and 53 +/- 10% increase from baseline, respectively; P < 0.05). Substance P-(1-9) had no significant effects on arteriolar diameter. Suffusion of captopril, leupeptin, Bestatin, and DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid together had no significant effects on substance P-induced vasodilation. Phosphoramidon did not potentiate nitroglycerin-induced vasodilation. These data indicate that NEP modulates substance P-induced vasodilation in the hamster cheek pouch in vivo. We suggest that any decrease in tissue NEP activity may amplify neurogenic vasodilation in the oral mucosa.

Coronary reactivity to nitroglycerin: Intravascular ultrasound evidence for the importance of plaque distribution

Objectives. This study was designed to assess the extent and timing of vasodilation after intracoronary administration of nitroglycerin using intravascular ultrasound. We also sought to relate the magnitude of nitroglycerin-induced dilation to the distribution of atherosclerotic plaque.Background. Although previous angiographic studies have shown that nitroglycerin can dilate both normal and stenotic coronary arteries, it remains uncertain whether atherosclerotic vessels can respond to nitroglycerin to the same extent as normal arteries in the clinical setting.Methods. We analyzed a total of 48 segments from 48 patients by means of a multielement 3.5F to 5.5F 20-MHz intravascular ultrasound system before and after intracoronary administration of nitroglycerin (250 μg). Videotaped images were digitized, and the lumen cross-sectional area was measured with an electronic cursor. In noncircumferential lesions, the perimeters of the normal and diseased portions were measured separately to compare the reactivity to nitroglycerin in each portion.Results. Of 48 sites examined 14 were normal by ultrasound, and 34 revealed atherosclerotic lesions. In the 14 normal segments nitroglycerin produced a large increase in cross-sectional area (31 ± 16% [mean ± SD]) within 60 s after injection. In the 34 atherosclerotic segments, nitroglycerin-induced dilation was impaired, and the cross-sectional area increased only 12 ± 8% (p < 0.01). In 15 of 34 atherosclerotic segments, a noncircumferential lesion was identified, and the cross-sectional area after nitroglycerin increased an average of 17 ± 6%. In the remaining 19 sites, circumferential disease was present, and the cross-sectional area increased by only 8 ± 7% (p < 0.05 vs. normal or noncircumferential atherosclerotic segments). In noncircumferential lesions, the increase in the perimeter of the normal portion of the wall was significantly greater (14 ± 6%) than the increase in the diseased portion (5 ± 3%, p < 0.05).Conclusions. These data indicate that vasoreactivity after nitroglycerin administration is reduced in segments with atherosclerosis by ultrasound. We suggest that nitroglycerin-induced vasodilation at the stenotic segments can be produced primarily by expansion of the nondiseased portion of the vessel wall.

Coronary vasoconstriction in response to acetylcholine after balloon angioplasty: possible role of endothelial dysfunction.

Abnormal endothelium-dependent vasomotion has frequently been observed early after coronary angioplasty. The aim of this study was to investigate endothelium-mediated coronary vasomotion caused by increasing intracoronary infusions of acetylcholine into epicardial coronary arteries 3-6 months after coronary angioplasty in patients without restenosis (50% luminal diameter reduction). Intracoronary acetylcholine was infused during follow-up coronary angiography followed by an intracoronary bolus of 250 g nitroglycerin in 18 patients who had undergone successful angioplasty of 21 isolated coronary artery lesions. Using an automated edge-detection program, coronary artery measurements were performed in the proximal reference segment, in the proximal part of the angioplasty site, at the site of previous maximal stenosis, in the distal part of the angioplasty site, and in the distal reference segment. In the segments of the coronary artery not manipulated by balloon catheter, acetylcholine did not produce significant luminal diameter changes (+2 +/- 23% in the proximal segment and -3 +/- 27% in the distal segment at 10(-4) mol/l). All the angioplasty vessel segments, excluding the proximal reference segments, showed an abnormal dose-related reactivity to the acetylcholine. Maximal vasoconstriction was observed at 10(-4) mol/l and was 4.9 +/- 11.1% in the proximal reference segment, 9.3 +/- 19.1% in the proximal angioplasty site (P = 0.0314), 20.3 +/- 24.1% at the site of previous maximal stenosis (P = 0.0005), 10.7 +/- 16.8% at the distal angioplasty site (P = 0.0098), and 9.3 +/- 14.1% in the distal reference segment (P = 0.0032). The maximal response of the angioplasty site to acetylcholine and to nitroglycerin did not correlate either with the time to follow-up or with the follow-up stenosis. Nitroglycerin-induced vasodilation was significant in all segments, but was lower in the lesion-related segments. Acetylcholine evoked the same effect on both the vessels that were manipulated and those that were not. Three to 6 months after coronary angioplasty, endothelium-dependent vasodilation was impaired not only at the site of previous maximal stenosis, but also in segments directly injured by balloon inflation. In contrast, endothelium-independent vasodilation by nitroglycerin is maintained in all segments. These observations suggest that the endothelium is still functionally impaired in the area of balloon dilation.

Role of potassium concentration in cardioplegic solutions in mediating endothelial damage

We studied the effect of potassium concentration in cardioplegic solutions on endothelial function by examining its influence on 5-hydroxytryptamine- (5-HT) and nitroglycerin-induced vasodilation in the isolated rat heart. Forty-eight rat hearts were perfused on a modified Langendorff preparation. After a baseline record of increase in coronary flow induced by 10 −7 M 5-HT and 10 μg/mL nitroglycerin, the hearts were perfused for 30 or 60 minutes with either St. Thomas' solution or Bretschneider solution containing 20 mmol/L of potassium or for 30 minutes with either solution containing 30 mmol/L of potassium (n = 8 in each). Initially, 5-HT and nitroglycerin caused a 39.0% ± 3.3% and 39.7% ± 2.8% increase in coronary flow, respectively. After 30 or 60 minutes' perfusion with St. Thomas' solution containing 20 mmol/L of potassium, there was little change in the response to 5-HT or nitroglycerin (5-HT, 43.1% ± 4.1%; nitroglycerin, 38% ± 3.2%). Similarly, perfusion with Bretschneider solution (20 mmol/L K +) for 30 or 60 minutes did not alter the degree of vasodilation (5-HT, 39.2% ± 2.9%; nitroglycerin, 38.0% ± 3.3%). However, perfusion with St. Thomas' solution containing 30 mmol/L of potassium for 30 minutes abolished the endothelial-dependent 5-HT-induced vasodilation (5-HT, −1.6% ± 1.4%; nitroglycerin, 36.9% ± 2.2%). Perfusion with Bretschneider solution (30 mmol/L K +) gave similar results (5-HT, −2.1% ± 1.2%; nitroglycerin, 36.4% ± 1.7%). We conclude that the concentration of potassium in cardioplegic solutions plays a critical role in causing functional endothelial damage.

The 1986 Upjohn award lecture. Interaction of chemicals with hemoproteins: implications for the mechanism of action of porphyrinogenic drugs and nitroglycerin.

The ferrochelatase inhibitory activity of a variety of analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) was studied in chick embryo liver cells. The ferrochelatase inhibitory activity of the 4-butyl, 4-pentyl, and 4-hexyl analogues was considered to be due to catalytic activation by cytochrome P-450 leading to heme alkylation and formation of the corresponding N-alkylporphyrins. The relative ferrochelatase inhibitory activity of the DDC analogues has implications for a postulated model of the binding of porphyrins in the ferrochelatase active site. 3-[2-(2,4,6-Trimethylphenyl)thioethyl]-4-methylsydnone (TTMS) was shown to be a potent porphyrinogenic agent and to inhibit ferrochelatase in chick embryo liver cells. A related sydnone, 3-benzyl-4-phenylsydnone did not inhibit ferrochelatase activity. These results supported the idea that the porphyrinogenicity of TTMS was due to catalytic activation by cytochrome P-450 leading to heme alkylation and formation of N-vinylprotoporphyrin which inhibits ferrochelatase. Polychlorinated biphenyls, phenobarbital, nifedipine, and a large number of structurally different chemicals which are porphyrinogenic in chick embryo liver cells inhibit uroporphyrinogen decarboxylase by an unknown mechanism. Thus drug-induced porphyrin biosynthesis in chick embryo liver cell culture appears to be caused by inhibition of either ferrochelatase or uroporphyrinogen decarboxylase. The biotransformation of nitroglycerin by human red blood cells is due to a combination of a sulfhydryl-dependent enzymatic process and an interaction with reduced hemoglobin.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulse-wave model of brachial arterial pressure modulation in aging and hypertension.

We apply a pulse-wave theory to a model of the human arm arterial system that predicts the changes in the arterial pressure waveform as it traverses the vasculature (increased pulse pressure, sharper main wave, disappearance of the aortic incisura, and appearance of a diastolic dicrotic wave) and also predicts the observed modulation of the waveform during phenylephrine-induced vasoconstriction and nitroglycerin-induced vasodilation. The model considers the arm arterial system as a tapered, distensible tube that bifurcates and then ends in a loop, with sidebranch networks represented by distributed Windkessels. The model uses verifiable values for realistic parameters. We found that the vertical modulation of the dicrotic wave, in humans, decreased with advancing age and with high blood pressure. The model explained these findings in terms of increasing vascular rigidity and decreasing small vessel vasodilator responsiveness. We noted a significant negative correlation between the arterial level of plasma norepinephrine and the amount of modulation of the dicrotic wave after nitroglycerin among subjects 40 yr old or younger, suggesting a sympathetic neurogenic contribution to the vascular abnormalities observed in relatively young patients with essential hypertension.

Inhibitory effect of Cu 2+ on nitroglycerin-induced vasodilation

The mechanism of nitroglycerin-induced vasodilation was examined in isolated arteries. Nitroglycerin relaxed the large coronary artery preferentially whereas nitroprusside and the so-called non-specific vasodilators showed the same activities on both the large and small coronary arteries. Nitroglycerin-induced vasodilation but not the vasodilation induced by the other agents was antagonized markedly by pretreatment with CuSO 4. Other metal ions except Fe 2+ had no antagonizing effect. The Cu 2+-induced antagonism was restored by treatment with sulfhydryl reagents. Nitroglycerin formed inorganic nitrite by non-enzymatic reaction with the tissue sulfhydryl groups; the reaction was also inhibited by Cu 2+. Cu 2+ suppressed the membrane stabilizing effect of Ca 2+. It seems that nitroglycerin reacts with the sulfhydryl groups on the inner surface of the cell membrane, which may take part in the selectivity of this drug, and subsequently the intermediate(s) formed may activate guanylate cyclase.