Combined first pass and equilibrium radionuclide cardiographic determination of stroke volume for quantitation of valvular regurgitation.

A new noninvasive procedure for quantitation of cardiac valve regurgitation was evaluated using a combination of first pass and gated equilibrium radionuclide cardiography in 38 subjects with and without cardiac valve disease. Left-sided cardiac catheterization was performed to determine the severity of mitral incompetence and aortic regurgitation semiquantitatively. In healthy subjects and in patients without valve disease, stroke volumes were nearly identical with the two methods and the correlation was high (r = 0.98 [p less than 0.001]). The mean regurgitation fraction was 13% in patients with mild mitral incompetence and 2+ aortic regurgitation, 37% in patients with moderate mitral incompetence and 3+ aortic regurgitation and 57% in patients with severe mitral incompetence and 4+ aortic regurgitation. These findings suggest that combined first pass and gated equilibrium radionuclide cardiography, being insensitive to intracardiac shunts and right-sided valve disorders, constitutes a valid noninvasive technique for quantitation of left-sided cardiac valve regurgitation.

Altered peripheral vasodilator profile of nitroglycerin during long-term infusion of N-acetylcysteine.

OBJECTIVES: The aim of this study was to compare the short- and long-term effects of intravenous nitroglycerin plus placebo and nitroglycerin plus N-acetylcysteine on peripheral arteries, veins and microcirculation in humans. BACKGROUND: The thiol donor N-acetylcysteine may potentiate the hemodynamic response to nitrates in nitrate-tolerant and nontolerant patients. The vascular changes responsible for this effect are not clear. METHODS: Eight male volunteers were treated with nitroglycerin (0.1 microgram/kg per min) combined with N-acetylcysteine (2 g intravenously, followed by 5 mg/kg per h) or placebo for 23 h in a double-blind, randomized, crossover study. Venous volume, the diameter of the radial and temporal arteries, calf blood flow and subcutaneous blood flow were measured at baseline and repeated after 1 and 23 h of infusion. RESULTS: Prolonged coadministration of N-acetylcysteine and nitroglycerin potentiated the acute venodilator effect of nitroglycerin as estimated by changes in venous volume (nitroglycerin plus N-acetylcysteine, 4.45 +/- 0.36 ml/100 g; nitroglycerin plus placebo, 3.65 +/- 0.46 ml/100 g, mean +/- SEM, p < 0.05) and prevented development of tolerance as seen after 23 h of treatment with nitroglycerin plus placebo (4.35 +/- 0.25 vs. 3.47 +/- 0.41 ml/100 g, p < 0.05). N-acetylcysteine had no effect on nitroglycerin-induced changes in arterial diameters (p > 0.05) but significantly increased microcirculatory subcutaneous blood flow after 1 h (nitroglycerin plus N-acetylcysteine: 6.3 +/- 1.3 ml/100 g per min vs. nitroglycerin plus placebo: 3.5 +/- 0.3 ml/100 g per min, p < 0.05) and after 23 h (4.4 +/- 0.6 vs. 3.1 +/- 0.5 ml/100 g per min, p < 0.05). CONCLUSIONS: The results suggest that coadministration of nitroglycerin and N-acetylcysteine in humans 1) potentiates and preserves nitroglycerin-induced venodilation and 2) augments the effect of nitroglycerin on small resistance vessels (regulating subcutaneous blood flow) without affecting the response to nitroglycerin in middle-sized arteries. Both the development of nitrate tolerance and the administration of N-acetylcysteine significantly change the normal vasodilator profile of nitroglycerin in humans.

Nitrate tolerance impairs nitric oxide-mediated vasodilation in vivo.

OBJECTIVES: Nitroglycerin (NTG) is metabolized to nitric oxide (NO) in vascular smooth muscle cells. It is currently not clear whether prolonged exposure to NTG and tolerance development directly affects endogenous NO-mediated vasodilation in vivo. This study investigates NO-mediated vasodilation in conscious chronically catheterized rats before and after development of nitrate tolerance. The effect of the thiol compound N-acetylcysteine (NAC), which may affect NTG responsiveness, was also studied. METHODS: Nitrate tolerance was induced by a 72-h intravenous infusion of NTG and confirmed by a 65-68% reduction in the hypotensive response to NTG (P < 0.05). The hypotensive effects of acetylcholine (ACh) and sodium nitroprusside, (SNP) and possible NAC-mediated changes in the responses to these compounds were examined in nontolerant and nitrate-tolerant rats. Furthermore, the hypertensive response to the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) was measured. RESULTS: Nitrate tolerance was associated with a significantly attenuated hypotensive response to ACh (before 24 +/- 1 mmHg; after 17 +/- 2 mmHg, n = 7, P < 0.05). Similarly, the response to SNP was reduced from 32 +/- 1 mmHg to 26 +/- 3 mmHg (n = 7, P < 0.05). NTG-vehicle (placebo) did not affect the response to ACh and SNP (P > 0.05). NAC augmented the effect of NTG, ACh and SNP in both nontolerant and nitrate-tolerant animals (P < 0.05). The hypertensive response to L-NAME (n = 8), was reduced by 67% (from 34 +/- 6 mmHg to 11 +/- 1 mmHg, P < 0.05) after induction of nitrate tolerance. CONCLUSIONS: The results suggest (1) that nitrate tolerance in vivo is associated with cross tolerance to NO-mediated vasodilation produced by both exogenous and endogenous nitrovasodilators and (2) that also responses to nitrovasodilator agents other than NTG are improved by the addition of NAC.

Nitroglycerin-mediated vasorelaxation is modulated by endothelial calcium-activated potassium channels.

OBJECTIVE: Recent in vitro data suggest, large conductance calcium-activated K+ channels (BKCa) modulate the vascular response to nitric oxide (NO). The in vivo implications and the characteristics of this interaction are not clear. This study firstly investigates whether modulation of BKCa affects the vascular response to nitroglycerin (NTG)-derived NO in vivo and in the isolated heart and secondly examines the influence of endothelial BKCa on NTG-mediated vasodilation in vitro. METHODS: The hypotensive effect of NTG was measured in conscious, chronically catheterized rats during i.v. infusions of iberiotoxin (IbTX, a selective inhibitor of BKCa) or placebo. Similarly, NTG-induced flow-changes in the isolated perfused rat heart were examined before and after IbTX treatment (0.1 microM). Concentration-relaxation curves to NTG in the presence of various K+ channel modulating agents were performed in vitro on porcine coronary arteries with and without intact endothelium. RESULTS: I.v. infusion of IbTX reduced the in vivo hypotensive effect of NTG by 55% (before IbTX: 32.0 +/- 3.0 mmHg, vs. after IbTX: 14.5 +/- 3.2 mmHg, P < 0.05) and nearly abolished NTG-induced increase in coronary flow in the isolated perfused heart (P < 0.05). In vitro, this effect depended on an intact endothelium (endothelium intact segments; NTG: pD2 = 5.8 +/- 0.1, Emax = 97.6 +/- 3.2% vs. NTG + IbTX: pD2 = 4.9 +/- 0.2, Emax = 49.7 +/- 6.2%, P < 0.05; endothelium denuded segments; NTG: pD2 = 6.9 +/- 0.1, Emax = 104.0 +/- 1.4% vs. NTG + IbTX: pD2 = 6.7 +/- 0.1, Emax = 100 +/- 1.2%, P > 0.05). CONCLUSION: The results suggest, that modulation of endothelial BKCa significantly affects NTG-induced vasorelaxation in vitro, in the isolated perfused heart and in vivo.

Autoregulation of cerebral blood flow in patients resuscitated from cardiac arrest.

BACKGROUND AND PURPOSE: Under normal circumstances, autoregulation maintains cerebral blood flow (CBF) constant within a wide range of mean arterial pressure (MAP). It remains unknown whether patients resuscitated from cardiac arrest have preserved CBF autoregulation. In this study, CBF autoregulation was investigated within the first 24 hours after resuscitation from cardiac arrest. METHODS: Eighteen patients and 6 healthy volunteers had relative changes in CBF determined by transcranial Doppler mean flow velocity (V(mean)) in the middle cerebral artery during a stepwise rise in MAP by use of norepinephrine infusion. V(mean) was plotted against MAP, and a lower limit of autoregulation was identified by double regression analysis based on the least-squares method. RESULTS: In patients, V(mean) increased from a median of 33 (range 19 to 73) to 37 (22 to 100) cm/s (P:<0.001) during a norepinephrine-induced rise in MAP from 78 (46 to 118) to 106 (60 to 149) mm Hg. Eight of 18 patients had impaired CBF autoregulation, and in 5 of the 10 patients with preserved CBF autoregulation, the lower limit of autoregulation could be identified. The lower limit of CBF autoregulation was 76 mm Hg (41 to 105 mm Hg) in the volunteers and 114 mm Hg (80 to 120 mm Hg) in the 5 patients with preserved autoregulation (P:<0.01). CONCLUSIONS: We conclude that in a majority of patients in the acute phase after cardiac arrest, cerebral autoregulation is either absent or right-shifted. These results indicate that MAP should be kept at a higher level than commonly accepted to secure cerebral perfusion. We recommend, however, that further randomized clinical trials are performed to determine whether sympathomimetic drugs improve neurological outcome.

Cerebral blood flow in patients with chronic heart failure before and after heart transplantation.

BACKGROUND AND PURPOSE: Arterial blood pressure and cardiac output are often reduced in patients with chronic heart failure (CHF). Counterregulatory mechanisms with increased neurohormonal activation and changes in the distribution of cardiac output are assumed to secure vital organ perfusion. However, clinical examination of patients with CHF frequently reveals neurological symptoms with dizziness and memory problems, suggesting altered brain perfusion. In this study we determined whether cerebral blood flow (CBF) is reduced in patients with New York Heart Association (NYHA) functional class III and IV (n=12) compared with healthy control subjects (n=12). Furthermore, we examined whether heart transplantation (n=5) could restore CBF. METHODS: CBF was estimated by single-photon emission computed tomography and (133)Xe as tracer, and middle cerebral artery velocity was measured by transcranial Doppler ultrasound. RESULTS: In the CHF patients, CBF was 36+/-1 mL/min per 100 g, corresponding to a 31% reduction compared with the control group (52+/-5 mL/min per 100 g) (P<0.05). After heart transplantation, CBF increased from 35+/-3 mL/min per 100 g before transplantation to 50+/-3 mL/min per 100 g within the first postoperative month (P<0.05). CONCLUSIONS: We conclude that CBF is substantially, but reversibly, reduced in patients with NYHA class III/IV heart failure. This phenomenon suggests that redistribution of cardiac output inadequately secures brain perfusion in patients with severe CHF.

Effect of ramipril on mitral regurgitation secondary to mitral valve prolapse.

Ramipril 10 mg/day reduced regurgitation in chronic mitral regurgitation secondary to mitral valve prolapse in patients with sinus rhythm.

Serum aminoterminal propeptide of type III procollagen after cardiac transplantation and the effect of rejection.

The present study examines serum concentrations of the aminoterminal propeptide of type III procollagen (S-PIIINP), a marker of type III collagen synthesis, after heart transplantation, and assesses changes induced by rejection. Fourteen transplant patients were included with 12 coronary artery bypass patients serving as controls. Mild to moderate rejection was found in 44 biopsies, and severe rejection in 6. Two severe rejection incidents occurred before postoperative day 10, the remainder at postoperative days 23 to 57. S-PIIINP was elevated in transplant patients at postoperative days 1 to 7 (p < or = 0.01), with return to baseline at postoperative day 60 (p = 0.14, n = 6). S-PIIINP remained unchanged after mild to moderate rejection, but increased 1 to 2 weeks following severe rejection occurring after postoperative day 10. S-PIIINP was elevated in bypass patients from postoperative day 2 throughout the study period of 360 days (p < or = 0.01). Thus, type III collagen turnover after heart transplant and coronary artery bypass grafting resembles wound healing. Collagen synthesis after severe rejection is reflected by S-PIIINP approximately 2 weeks after transplant. The findings may prove to be significant concerning the prognosis of heart transplant patients.

Effect of early revascularisation in cardiogenic shock complicating acute myocardial infarction. A single center experience.

BACKGROUND: Five to 10% of patients with acute myocardial infarction develop cardiogenic shock and the majority of these patients are expected to die within the first few weeks. In this study, we review our recent experience in the management of patients with cardiogenic shock complicating MI and examine the effect of early invasive revascularisation on mortality. METHODS: Thirty-six consecutive patients who developed cardiogenic shock less than 48 h after MI were retrospectively evaluated and divided into two treatment groups. One group received early invasive revascularisation (n=24) and the other group had no early invasive revascularisation, but received similar conventional intensive care medical treatment (n=12). RESULTS: Baseline characteristics and hemodynamic variables were similar in both groups. Apart from invasive revascularisation and the use of intra aortic balloon counterpulsation (IABP), treatment strategies did not differ between the two groups. Thirty-day mortality was 21% in the revascularised group of patients and 58% in the non-revascularised group (P<0.05). CONCLUSIONS: Our data support previous observations suggesting that an aggressive treatment strategy including early invasive revascularisation and IABP is associated with improved short and long-term survival in patients with cardiogenic shock. Since early revascularisation appears safe with a considerable treatment benefit, this approach must be considered in patients with short shock duration early after MI.

N-terminal proBNP and mortality in hospitalised patients with heart failure and preserved vs. reduced systolic function: data from the prospective Copenhagen Hospital Heart Failure Study (CHHF).

UNLABELLED: Preserved systolic function among heart failure patients is a common finding, a fact that has only recently been fully appreciated. The aim of the present study was to examine the value of NT-proBNP to predict mortality in relation to established risk factors among consecutively hospitalised heart failure patients and secondly to characterise patients in relation to preserved and reduced systolic function. MATERIAL: At the time of admission 2230 consecutively hospitalised patients had their cardiac status evaluated through determinations of NT-proBNP, echocardiography, clinical examination and medical history. Follow-up was performed 1 year later in all patients. RESULTS: 161 patients fulfilled strict diagnostic criteria for heart failure (HF). In this subgroup of patients 1-year mortality was approximately 30% and significantly higher as compared to the remaining non-heart failure population (approx. 16%). Using univariate analysis left ventricular ejection fraction (LVEF), New York Heart Association classification (NYHA) and plasma levels of NT-proBNP all predicted mortality independently. However, regardless of systolic function, age and NYHA class, risk-stratification was provided by measurements of NT-proBNP. Having measured plasma levels of NT-proBNP, LVEF did not provide any additional prognostic information on mortality among heart failure patients (multivariate analysis). CONCLUSION: The results show that independent of LVEF, measurements of NT-proBNP add additional prognostic information. It is concluded that NT-proBNP is a strong predictor of 1-year mortality in consecutively hospitalised patients with heart failure with preserved as well as reduced systolic function.

Myocardial perfusion scintigraphy as a screening method for significant coronary artery stenosis in cardiac transplant recipients.

BACKGROUND: Several studies have explored the feasibility of using myocardial perfusion imaging to detect allograft vasculopathy after heart transplantation. We undertook the present prospective consecutive study to comparatively evaluate the role of serial myocardial perfusion single-photon emission computed tomography (SPECT) scanning and coronary arteriography (CAG) in detecting coronary artery stenosis suitable for coronary angioplasty in heart transplant recipients. METHODS: Within a 2-week interval during a follow-up period of 5.6 (95% confidence limits 2.1 to 12) years, 255 serial CAGs and myocardial perfusion scintigraphies were performed in 67 patients. Arteriography and scintigraphy were performed once yearly after heart transplantation. We retrospectively analyzed the data. RESULTS: Myocardial scintigraphy showed pathologic reversible defects in 9 out of 67 patients. Four of these patients had significant (>50% and also >70%) focal segmental stenosis in the middle and proximal parts of the coronary arteries (Type A lesions), 1 had diffuse and circumferential narrowing in the distal parts (Type B lesions), whereas CAG showed no lesions in the remaining 4 patients. The patients with significant Type A lesions were revascularized with percutaneous coronary angioplasty. Coronary arteriography showed that 1 patient had extensive Type A and Type B lesions, whereas myocardial perfusion scans detected no. The predictive value of a negative (normal) SPECT was 98% (95% confidence limits 94% to 100%) for the detection of lesions suited for revascularization. CONCLUSIONS: Annual myocardial SPECT seems well suited to screen for significant coronary artery stenosis. A SPECT study without reversible defects virtually excludes lesions suitable for coronary artery revascularization.

Ability of antimyosin scintigraphy monitoring to exclude acute rejection during the first year after heart transplantation.

BACKGROUND: Antimyosin Fab fragment has been shown to bind to myosin leaked from necrotic cardiac cells but not to myosin in undamaged cells. The purpose of this investigation was to evaluate indium 111-antimyosin Fab fragment scintigraphy as a noninvasive technique in the diagnosis of acute rejection after heart transplantation. Simultaneous endomyocardial biopsy served as the gold standard. METHODS: Twenty-two patients had scintigraphic studies at weeks 3 to 4, 6, 10, 26, and 52, but the next 16 patients underwent scintigraphy more often, that is, at all scheduled biopsies performed from week 3 to week 26 after transplantation. From analysis of the first 70 studies, an interstudy decrease in the patient's heart-to-lung ratio was classified as normal, that is, no rejection, whereas an unchanged or increased heart-to-lung ratio was considered pathologic. RESULTS: By use of this definition of negative and positive scintigraphic results, prospective analysis of 88 conclusive, consecutive studies showed 6 true- and 31 false-positive studies (prevalence of rejection 8%), giving a low predictive value of a pathologic change in heart-to-lung ratio. Of the 51 studies with decreasing heart-to-lung ratio only 1 was a false negative, giving a predictive value of a negative study of 98% (95% confidence limits 90% to 100%). CONCLUSIONS: In conclusion, antimyosin scintigraphy is a promising noninvasive technique in the routine surveillance of acute heart rejection. Because of many false-positive results in the studies, biopsy should be used as a control for a pathologic heart-to-lung ratio.

Hepatitis A, B, and non-A, non-B in Danish hospital nursing staff.

A stratified age matched sample of 564 general hospital nurses, assistant nurses, and porters was studied for antibody to hepatitis A virus (anti-HAV), hepatitis B surface antigen (HBsAg), and antibody to hepatitis B surface antigen (anti-HBs), and these data were compared with serum aspartate aminotransferase (AST) and identified episodes of hepatitis. The overall prevalence of anti-HBs was increased twofold compared with blood donors, while no evidence of increased exposure to hepatitis A virus was found. The serological survey showed porters to have a significantly higher prevalence of hepatitis A virus (52%) as well as hepatitis B virus (10.2%) markers compared with the nurses and assistant nurses (39% and 5.3% respectively). In contrast, the clinical data showed the incidence of hepatitis to be four times higher in nurses than in the two other groups during hospital employment. The serological survey may reflect differences in social background of the groups, while the clinical data identified nurses as having the highest occupational hepatitis risk. A number of episodes of hepatitis in nurses appeared to be due to non-A, non-B agents. AST values, however, did not show any case of liver inflammation not attributable to alcohol. Thus chronic non-A, non-B infections could not be shown in this population group.

Localisation of immunoglobulin on the liver cell surface in primary biliary cirrhosis.

Direct immunofluorescence studies were performed on isolated liver cells in order to detect surface localisation of IgG in acute and chronic hepatitis and primary biliary cirrhosis. Membrane-bound IgG was demonstrated in nine patients. Six of eight patients with primary biliary cirrhosis showed granular fluorescence on their liver cell surfaces suggesting that an antibody or immune complex-mediated cytotoxicity might be involved in the pathogenesis of this disease.

Hepatitis B and A virus antibodies in alcoholic steatosis and cirrhosis.

Sera from 74 alcoholics with cirrhosis and 63 alcoholics with steatosis were tested for antibody to hepatitis B surface antigen, to hepatitis B core antigen, and to hepatitis A virus by radioimmunoassay or enzyme-linked immunosorbent assay. No significant difference between the two groups of alcoholics could be found concerning the prevalence of these antibodies. The total group of patients had antibody to hepatitis B surface antigen or hepatitis B core antigen, or both, significantly (p less than 0.001) more often (26%) than sex- and age-matched controls (4%). No significant difference was found between patients and controls concerning the prevalence of antibody to hepatitis A virus (46% v 40%). In patients with cirrhosis, no correlation between wedged hepatic vein pressure or wedged-to-free hepatic vein pressure and any of the viral antibodies could be established. The present results suggest that hepatitis B virus does not play a major role in the progression of alcoholic liver disease, but longitudinal studies are needed to solve this problem. The reason for the increased prevalence of antibodies to hepatitis B virus in these patients is unknown.

Isolation of Mallory bodies and an attempt to demonstrate cell mediated immunity to Mallory body isolate in patients with alcoholic liver disease.

Mallory bodies were isolated from necropsy livers from patients with alcoholic hepatitis with and without cirrhosis with a Ficoll viscosity barrier. The purity of Mallory bodies in the isolate varied between 70 and 90%, estimated by counting Mallory bodies and non-Mallory body structures in haematoxylin-eosin stained smears. Electron microscopy confirmed the presence of Mallory bodies in the isolates. The Mallory body isolate was used as antigen in the agarose leucocyte migration inhibition test in order to test the cell-mediated immunity. No significant difference in leucocyte migration was found between controls and patients with alcoholic hepatitis, alcoholic steatosis, alcoholic cirrhosis and miscellaneous liver diseases.

Prevalence of hepatitis B virus infection among alcoholic patients with liver disease.

The aim of this investigation was to elucidate a possible role of hepatitis B virus (HBV) in the pathogenesis of liver diseases in alcoholics. Two hundred and fifty-three alcoholics with liver disease were admitted to two medical departments in Copenhagen during a 15 months period. Seventy-nine patients (31%) showed serological signs (HBsAg, anti-HBs) of previous or active HBV infection. This is a significantly higher prevalence than found in an age-matched control population. Among the 79 patients with HBV markers, a total of 11 was found to be HBsAg-positive. From these 11 patients liver specimens were available for re-evaluation in nine cases. In only three of these liver biopsies, morphological changes indicating alcohol as the aetiological cause were found. In conclusion, different or concomitant aetiology must be considered in alcoholics with liver disease.

Independent effects of liver disease and chronic alcoholism on thyroid function and size: the possibility of a toxic effect of alcohol on the thyroid gland.

In an autopsy study we found thyroid volume significantly decreased in alcoholics with liver cirrhosis as compared to matched controls: 15 mL (range, 7 to 37 mL) v 25 mL (range, 13 to 90 mL) (P less than .01). At the same time the amount of fibrosis of the thyroid glands was higher in the alcoholics as compared to the matched controls: 20% (range, 6% to 40%) v 12% (range, 6% to 23%) (P less than .01). In order to evaluate the relative importance of alcohol consumption and liver disease on thyroid function and ultrasonically determined size, three groups of patients and matched controls (sex, age, weight, and smoking habits) were investigated: group 1, 18 patients with nonalcoholic liver cirrhosis; group 2, 21 consecutive chronic alcoholics (greater than 100 g of alcohol daily for greater than 5 years) without liver cirrhosis (all had biopsy proven fatty change or normal liver); group 3, 31 nonalcoholic patients with chronic nonhepatic, nonrenal disease. In group 1 median thyroid volume and serum FT4I, FT3I, and TSH levels were unchanged compared with the controls. In group 2 median thyroid volume was 13 mL (range, 9 to 32 mL) compared with 27 mL (range, 12 to 44 mL) in the controls (P less than .005). Serum T3 and FT3I levels were reduced, while T4, FT4I, and TSH levels were unaltered. In group 3 serum T3 and FT3I levels were reduced while serum FT4I and TSH levels and thyroid volume were unaltered compared with the controls. It is suggested that alcohol may have a toxic effect on the thyroid gland independent of the degree of liver damage.

HBeAg, anti-HBe and anti-HBc IgM in patients with hepatitis B.

Using radioimmunoassay, 70 consecutive patients with acute type B hepatitis were investigated for the presence of HBeAg and anti-HBe. The results indicate that HBeAg is found constantly in the early phase of acute hepatitis B. The presence of HBeAg for more than 10 weeks after the onset of symptoms seems to be of prognostic value and signifies the development of a chronic HBsAg carrier state. Anti-HBc titres were determined in 40 patients with acute hepatitis B with differing outcomes of their disease. The anti-HBc titres were generally above 1:100 at the time of admission to the hospital and in those patients who remained HBsAg-positive the anti-HBc titres remained about 1:1000 during the 12 month follow-up period. Anti-HBc IgM was constantly present in 42 patients with acute hepatitis B and was found to persist from 7 months to several years in those patients who became chronic HBsAg carriers. Anti-HBc IgM was found to persist for more than 2 years in five of the 12 patients investigated who developed chronic liver disease in spite of an early clearance of HBsAg.

Tetrahydrobiopterin improves endothelium-dependent vasodilation in nitroglycerin-tolerant rats.

Tolerance to nitroglycerin is caused by a nitroglycerin-mediated increase in vascular superoxide anion production. Administration of tetrahydrobiopterin (co-factor for endogenous nitric oxide (NO) formation) may potentially influence nitroglycerin tolerance in at least two different ways. Firstly, tetrahydrobiopterin may act as a scavenger of the nitroglycerin-mediated production of superoxide anions. Secondly, tetrahydrobiopterin may protect endothelial NO synthesis from the deleterious effects of increased oxidative stress. This study investigates whether in vivo nitroglycerin tolerance is affected by tetrahydrobiopterin supplementation and assesses the in vivo role of tetrahydrobiopterin in endogenous NO-mediated vasodilation in normal and nitroglycerin-tolerant rats. The results show that tetrahydrobiopterin does not affect nitroglycerin-derived, NO-mediated vasodilation, but reduces baseline mean arterial blood pressure (by 8 mm Hg, P<0.05) and normalizes endothelium-dependent responses to N(G)-monomethyl-L-arginine (L-NMMA) (from 7+/-1 to 22+/-4 mm Hg, P<0.05) in nitroglycerin-tolerant rats. It is concluded that altered bioavailability of tetrahydrobiopterin is involved in the pathophysiology of endothelial dysfunction seen in nitroglycerin tolerance.