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S Kurz

Publications and source records attributed to S Kurz.

At least 19 recordsLinked to original sources
PubMed2001

Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin.

BACKGROUND: Altered endothelial cell nitric oxide (NO(*)) production in atherosclerosis may be due to a reduction of intracellular tetrahydrobiopterin, which is a critical cofactor for NO synthase (NOS). In addition, previous literature suggests that inactivation of NO(*) by increased vascular production superoxide (O(2)(*-)) also reduces NO(*) bioactivity in several disease states. We sought to determine whether these 2 seemingly disparate mechanisms were related. METHODS AND RESULTS: Endothelium-dependent vasodilation was abnormal in aortas of apoE-deficient (apoE(-/-)) mice, whereas vascular superoxide production (assessed by 5 micromol/L lucigenin) was markedly increased. Treatment with either liposome-entrapped superoxide dismutase or sepiapterin, a precursor to tetrahydrobiopterin, improved endothelium-dependent vasodilation in aortas from apoE(-/-) mice. Hydrogen peroxide had no effect on the decay of tetrahydrobiopterin, as monitored spectrophotometrically. In contrast, superoxide modestly and peroxynitrite strikingly increased the decay of tetrahydrobiopterin over 500 seconds. Luminol chemiluminescence, inhibitable by the peroxynitrite scavengers ebselen and uric acid, was markedly increased in apoE(-/-) aortic rings. In vessels from apoE(-/-) mice, uric acid improved endothelium-dependent relaxation while having no effect in vessels from control mice. Treatment of normal aortas with exogenous peroxynitrite dramatically increased vascular O(2)(*-) production, seemingly from eNOS, because this effect was absent in vessels lacking endothelium, was blocked by NOS inhibition, and did not occur in vessels from mice lacking eNOS. CONCLUSIONS: Reactive oxygen species may alter endothelium-dependent vascular relaxation not only by the interaction of O(2)(*-) with NO(*) but also through interactions between peroxynitrite and tetrahydrobiopterin. Peroxynitrite oxidation of tetrahydrobiopterin may represent a pathogenic cause of "uncoupling" of NO synthase.

Acetylcholine↗
PubMed2000

Principles of homeostasis in governing virus activation and latency.

The goal of our work is to understand, from the molecular to the organismal level, the principles that drive and sustain lifelong infection by viruses. These infectious agents live in a dynamic equilibrium (homeostasis) with their hosts in which both immune and nonimmune pathways contribute to viral homeostasis. Disruption of these pathways can have dramatic consequences on pathogenesis. Immune responses to infection provide a vital countermeasure by the host but are nonsterilizing. They effect an essential and primary control mechanism for viral growth. Essential nonimmune pathways for effecting control of a viral life cycle relate to the obligate dependency of the virus on its host. For these reasons, we view infections as a highly dynamic interplay that takes place between the pathogen and host. This, in many cases, leads to the establishment of an incurable lifelong infection that remains benign but can become life threatening once key homeostatic pathways are disrupted. We discuss these issues in the context of our studies using cytomegalovirus as a clinically relevant pathogen.

Animals↗
PubMed1999

Evidence for a causal role of the renin-angiotensin system in nitrate tolerance.

BACKGROUND: We have previously shown that nitroglycerin (NTG) therapy increases vascular expression of endothelin 1 (ET-1) and stimulates vascular superoxide (O2.-) production via activation of NADH/NADPH oxidases. Both phenomena are stimulated by angiotensin II in vitro, and the renin-angiotensin system is activated during early nitrate therapy. We hypothesized that either angiotensin II or ET-1 may increase vascular O2.- production during nitrate therapy. METHODS AND RESULTS: In New Zealand White rabbits, 3 days of treatment with NTG patches increased plasma renin activity for the entire treatment period. After 24 hours of NTG treatment, angiotensin II type 1 (AT1) receptor expression and vascular ACE activity were significantly decreased. At this time, constrictions to angiotensin I and II were depressed, but there was no loss of NTG vasodilator potency. Within 3 days of continuous NTG treatment, relaxations to NTG were markedly blunted. This was associated with an increase in AT1 receptor mRNA expression, a return of ACE activity back to baseline, and a marked increase in constrictions to angiotensin I and II despite continuously increased plasma renin activity. Tolerance was associated with a 2-fold increase in vascular O2.-, as estimated by lucigenin-enhanced chemiluminescence. Concomitant treatment with the AT1 receptor antagonist losartan (5 to 25 mg. kg-1. d-1) dose-dependently normalized vascular O2.- and prevented tolerance to NTG and cross-tolerance to endogenous nitric oxide released by acetylcholine. The nonselective ET-1 receptor blocker bosentan (100 mg. kg-1. d-1) had similar but less pronounced effects. CONCLUSIONS: The positive effects of AT1 and ET-1 receptor blockade on tolerance and O2.- production imply a pathophysiological role for angiotensin II and to some extent for ET-1 in the development of nitrate tolerance.

Angiotensin I↗
PubMed1999

Protein expression, vascular reactivity and soluble guanylate cyclase activity in mice lacking the endothelial cell nitric oxide synthase: contributions of NOS isoforms to blood pressure and heart rate control.

OBJECTIVE: Both disruption of the endothelial nitric oxide synthase (eNOS) gene and pharmacological inhibition of the NOS produce modest hypertension. It is unclear if and to what extent NOS isoforms other than eNOS contribute to this effect and how loss of one copy of the eNOS gene might impact on vascular reactivity or eNOS protein expression. METHODS: We examined protein expression, vascular reactivity, activity of soluble guanylate cyclase, blood pressure and heart rate in mice completely lacking the eNOS gene (eNOS-/-), wild-type mice (eNOS+/+) and mice heterozygotic for the eNOS gene (eNOS+/-). RESULTS: While eNOS-/- mice had mild hypertension and bradycardia, eNOS+/- mice were normotensive. In control mice, oral administration of L-NAME (approximately 100 mg/kg/day x 21 days) increased blood pressure to levels observed in eNOS-/- mice. In eNOS-/- mice, chronic oral administration of L-NAME had no effect on blood pressure, suggesting that inhibition of other NOS isoforms unlikely contribute to hypertension. L-NAME treatment induced bradycardia in both control and eNOS-/- mice, suggesting that both eNOS and other isoforms of NOS might be involved in heart rate control. Studies of aortic rings from eNOS-/- mice revealed a complete lack of endothelium-dependent vascular relaxation in response to acetylcholine and the calcium ionophore A23187 and an increase in sensitivity to phenylephrine, serotonin and nitroglycerin. Aortic rings from eNOS+/- mice demonstrated only minor alterations of responses to nitroglycerin and a normal relaxation to either acetylcholine or A23187 compared to vessels from eNOS-/+. Western analysis demonstrated that eNOS expression was virtually identical between eNOS+/+ and eNOS+/- mice and was absent in eNOS-/- mice. The activity of lung-isolated soluble guanylate cyclase was identical in the three strains of mice. CONCLUSIONS: We conclude that loss of one copy of the eNOS gene, as observed in heterozygotic animals, has no effect on vascular reactivity, blood pressure or eNOS protein expression. Isoforms of NOS, other than eNOS are unlikely involved in blood pressure regulation but may participate in heart rate control.

Animals↗
PubMed1998

[Chemotherapy of alveolar echinococcosis with benzimidazoles. A prospective long-term study].

BACKGROUND: Mebendazole and albendazole are the drugs of choice for the treatment of alveolar echinococcosis. In this prospective study we present and evaluate the outcome of the long-term treatment with both drugs. PATIENTS AND METHODS: Forty-four patients were treated with either mebendazole or albendazole and they were followed up for an average of 42 months. Success of treatment was defined as non-progression for more than 1 year. RESULTS: The overall success-rate was approximately 80% (35/44). An initial regimen was recurrence-free in 64% of cases under mebendazole and in 73% of cases under albendazole. Half of the cases with recurrent disease could be stabilized after changing the therapeutic regimen. Seven patients received a continuous regimen with albendazole. They were observed over an average of 19 months without signs of progression nor significant side effects. CONCLUSION: This open-labelled prospective study demonstrates the high therapeutic efficacy of both mebendazole and albendazole with similar response rates in the treatment of alveolar echinococcosis. In Germany, serum levels for mebendazole can easily be obtained at numerous institutes, while serum levels for albendazole are rarely available. On the other hand, albendazole reduces costs by over 40%. A simplified mode of intake and a reduced number of side effects argue in favor of the preferred use of albendazole. Albendazole in alveolar echinococcosis is only licensed for intermittent application. Nonetheless, continuous treatment may be considered in inoperable cases or progressive disease.

Adult↗
PubMed1998

Preemptive CD8 T-cell immunotherapy of acute cytomegalovirus infection prevents lethal disease, limits the burden of latent viral genomes, and reduces the risk of virus recurrence.

In the immunocompetent host, primary cytomegalovirus (CMV) infection is resolved by the immune response without causing overt disease. The viral genome, however, is not cleared but is maintained in a latent state that entails a risk of virus recurrence and consequent organ disease. By using murine CMV as a model, we have shown previously that multiple organs harbor latent CMV and that reactivation occurs with an incidence that is determined by the viral DNA load in the respective organ (M. J. Reddehase, M. Balthesen, M. Rapp, S. Jonjic, I. Pavic, and U. H. Koszinowski. J. Exp. Med. 179:185-193, 1994). This predicts that a therapeutic intervention capable of limiting the load of latent viral genome should also reduce the risk of virus recurrence. Here we demonstrate the benefits and the limits of a preemptive CD8 T-cell immunotherapy of CMV infection in the immunocompromised bone marrow transplantation recipient. Antiviral CD8 T cells prevented CMV disease and accelerated the resolution of productive infection. The therapy also resulted in a lower load of latent CMV DNA in organs and consequently reduced the incidence of recurrence. The data thus provide a further supporting argument for clinical trials of preemptive cytoimmunotherapy of human CMV disease with CD8 T cells. However, CD8 T cells failed to clear the viral DNA. The therapy-susceptible portion of the DNA load differed between organs and was highest in the lungs. The existence of an invariant, therapy-resistant load suggests a role for immune system evasion mechanisms in the establishment of CMV latency.

Acute Disease↗
PubMed1998

Cytomegalovirus inhibits the engraftment of donor bone marrow cells by downregulation of hemopoietin gene expression in recipient stroma.

Cytomegalovirus (CMV) disease after bone marrow (BM) transplantation is often associated with BM graft failure. There are two possible reasons for such a correlation. First, a poor hematopoietic reconstitution of unrelated etiology could promote the progression of CMV infection by the lack of immune control. Alternatively, CMV infection could interfere with the engraftment of donor BM cells in recipient BM stroma. Evidence for a causative role of CMV in BM aplasia came from studies in long-term BM cultures and from the murine in vivo model of CMV-induced aplastic anemia. A deficiency in the expression of essential stromal hemopoietins, such as stem cell factor (SCF), has indicated a functional insufficiency of the stromal microenvironment. It remained open to question whether CMV mediates a negative regulation of hemopoietin gene expression (the downregulation model) or whether it causes the default of a positive regulator (the lack-of-induction model). Further, even though implicitly assumed, it has never been formally documented that CMV directly interferes with the engraftment of a BM cell transplant. We addressed these problems in a murine model of CMV infection after experimental male-into-female BM transplantation. The data indicate that the downregulation model applies. Quantitation of the male-sex-determining gene tdy demonstrated an impaired engraftment of donor BM cells in the BM stroma of the female recipients. This graft failure was reflected by a diminished population of SCF-receptor-expressing hematopoietic progenitor cells and correlated with a reduced level of stromal SCF gene expression. Interestingly, high doses of BM cells protected against stromal insufficiency by a mechanism unrelated to control of infection.

Animals↗
PubMed1997

[Intraocular pressure after extracapsular cataract extraction with posterior chamber lens implantation--sulcus versus capsular bag fixation].

BACKGROUND: In this retrospective study the postoperative alteration of intraocular pressure after cataract extraction and posterior chamber lens implantation was analyzed statistically. The influence on intraocular pressure between different positions of the loops (sulcus versus bag) was compared. PATIENTS AND METHOD: The posterior chamber lens implantation was performed on 267 eyes with 129 sulcus implanted and 138 in-the-bag implanted intraocular lenses. The average age of the patients was 74.8 respectively 71.9 years, with an equal ratio of sex. In surgery the viscoelastic experimentation of the nucleus was done via corneoscleral cut. A x-crossed suture sealed the corneoscleral wound followed by subconjunctival injection of corticosteroids. The postoperative medication for 4-6 weeks consisted of a corticosteroid and antibiotic combination. RESULTS: The average intraocular pressure of the sulcus implanted respectively in the bag implanted intraocular lenses increased from 15.4 mm Hg respectively 15.9 mm Hg preoperatively to 16.3 respectively 15.8 mm Hg at the first postoperative day. After two months the intraocular pressure decreased to 14.6 respectively 14.1 mm Hg. That means a pre- to postoperative difference of -0.8 respectively -1.8 mm Hg. CONCLUSIONS: In summary both groups showed a slight decrease in average intraocular pressure after two months. In comparison to the sulcus implanted intraocular lens the decrease of intraocular pressure was more than 1 mm Hg in case of the in the bag implanted lens. This decrease was statistically significant but may be considered of less clinical interest.

Aged↗
PubMed1997

Latency versus persistence or intermittent recurrences: evidence for a latent state of murine cytomegalovirus in the lungs.

The state of cytomegalovirus (CMV) after the resolution of acute infection is an unsolved problem in CMV research. While the term "latency" is in general use to indicate the maintenance of the viral genome, a formal exclusion of low-level persistent productive infection depends on the sensitivity of the assay for detecting infectious virus. We have improved the method for detecting infectivity by combining centrifugal infection of permissive indicator cells in culture, expansion to an infectious focus, and sensitive detection of immediate-early RNA in the infected cells by reverse transcriptase PCR. A limiting-dilution approach defined the sensitivity of this assay. Infectivity was thereby found to require as few as 2 to 9 virion DNA molecules of murine CMV, whereas the standard measure of infectivity, the PFU, is the equivalent of ca. 500 viral genomes. Since murine CMV forms multicapsid virions in most infected tissues, the genome-to-infectivity ratio is necessarily >1. This assay thus sets a new standard for investigating CMV latency. In mice in which acute infection was resolved, the viral DNA load in the lungs, a known organ site of CMV latency and recurrence, was found to be 1 genome per 40 lung cells, or a total of ca. 1 million genomes. Despite this high load of CMV DNA, infectious virus was not detected with the improved assay, but recurrence was inducible. These data provide evidence against a low-level persistent productive infection and also imply that intermittent spontaneous recurrence is not a frequent event in latently infected lungs.

Animals↗
PubMed1997

Bone marrow failure by cytomegalovirus is associated with an in vivo deficiency in the expression of essential stromal hemopoietin genes.

Bone marrow (BM) failure associated with cytomegalovirus (CMV) infection is a feared complication after clinical BM transplantation. Experiments in long-term BM cultures have indicated that BM stromal cells (BMSC) are targets of productive CMV infection, but an in situ infection of BM stroma remained to be documented, and the pathomechanism is open to question. Here we describe a murine in vivo model of lethal CMV aplastic anemia (CMV-AA). The reconstitution of hematopoietic progenitor cells expressing stem cell factor (SCF) receptor was found to be defective in CMV-AA. While murine CMV replication in permissive parenchymal tissues is cytolytic, the hematopoietic cord was found to be a site of very limited virus production with foci of reticular BMSC expressing the intranuclear viral IE1 protein, but with only a few BMSC positive for viral genome in the in situ hybridization. XX-XY BM chimeras were established in order to quantitate Y-chromosome-tagged BMSC by a PCR specific for the male-sex-determining gene Tdy. This approach revealed that murine CMV infection is not associated with a significant loss of BMSC. Despite the physical integrity of the stromal network, the functional integrity of the stroma was impaired. While housekeeping genes were expressed normally in BMSC of infected mice, the expression of genes encoding the essential hemopoietins SCF, granulocyte colony-stimulating factor, and interleukin-6 was markedly reduced. In conclusion, the mechanism of BM failure is not a stromal lesion but an insufficient stromal function. These findings explain CMV-AA as a manifestation of multiple hemopoietin deficiency.

Anemia, Aplastic↗
PubMed1997

Role for endothelin-1 in angiotensin II-mediated hypertension.

Experiments in cultured vascular smooth muscle cells have shown that angiotensin II (Ang II) stimulates expression of endothelin-1. We sought to examine role of endothelin-1 in the effects of Ang II in vivo. Ang II infusion in rats (0.7 mg/kg per day for 5 days) was associated with marked increases in vascular smooth muscle endothelin-1 levels, as assessed by immunostaining. Administration of the selective endothelin type A (ET(A)) receptor antagonist PD 155080 (50 mg/kg per day) abrogated the hypertensive response to a 5-day infusion of Ang II (0.7 mg/kg per day), as did losartan (25 mg/kg per day). ET(A) receptor blockade during Ang II-mediated hypertension was associated with marked elevations of plasma endothelin-1 levels. Ang II-mediated hypertension was associated with heightened vascular responsiveness to a variety of vasoconstrictor agents except endothelin-1. Blockade of ET(A) receptor invariably corrected this vasoconstrictor hyperresponsiveness. We conclude that some of the vascular effects of Ang II thought to be unique to this hormone are likely mediated by endothelin-1.

Analysis of Variance↗
PubMed1997

Do mammography, sonography, and MR mammography have a diagnostic benefit compared with mammography and sonography?

OBJECTIVE: The purpose of our study was to assess the added value of MR mammography, mammography, and sonography compared with mammography and sonography in diagnostic evaluation of the breast. MATERIALS AND METHODS: We evaluated reports of MR mammography, conventional mammography, and sonography of the breast in 89 patients who had been referred for surgical biopsy. The dynamic MR mammography examinations were obtained on a 1.0-T MR imager using a double-breast coil and a three-dimensional axial fast low-angle shot sequence. Each type of study was interpreted by a different observer. All mammograms and sonograms were available to all observers. Without knowledge of biopsy results, observers classified mammograms and sonograms (which we call the standard method) as well as mammograms, sonograms, and MR mammograms (which we call the combined method). Classifications were on a per-breast basis: no disease; probably a benign or malignant lesion; and most likely a benign or malignant lesion. A classification of no disease or most likely a benign or malignant lesion was considered to represent a high confidence of the observer in the diagnosis. RESULTS: Of 98 breasts evaluated with the standard method, observer confidence was high for 44% of all malignant lesions versus 86% with the combined method. The highest specificity (92%) was achieved by interpretation of the standard method (combined method, 64%). The highest sensitivity (95%) was achieved by interpretation of the combined method (standard method, 83%). Overall accuracy was 87% for the standard method and 83% for the combined method. In separate analyses of nonpalpable and palpable lesions, the combined method achieved an accuracy of 74% for nonpalpable lesions and 88% for palpable lesions. The standard method achieved an accuracy of 85% for nonpalpable lesions and 88% for palpable lesions. CONCLUSION: MR mammography as an adjunct to mammography and sonography reveals breast cancer with a higher confidence and sensitivity than do mammography and sonography only. The combined method can be recommended if the greatest possible sensitivity or negative predictive value is wanted. However, the combined method is not useful for screening or workup of suspicious lesions because of its lower specificity and accuracy.

Breast↗
PubMed1996

Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug.

Hydralazine has been shown to reduce mortality in patients with congestive heart failure when given concomitantly with isosorbide dinitrate. Recently, we demonstrated that nitrate tolerance is in part due to enhanced vascular superoxide .O2- production. We sought to determine mechanisms whereby hydralazine may prevent tolerance. Rabbits either received no treatment, nitroglycerin patches (1.5 micrograms/kg/min x 3 d), hydralazine alone (10 mg/kg/d in drinking water), or hydralazine and nitroglycerin. Aortic segments were studied in organ chambers and relative rates of vascular .O2- production were determined using lucigenin-enhanced chemiluminescence. Nitroglycerin treatment markedly inhibited relaxations to nitroglycerin (maximum relaxations in untreated: 92 +/- 1 vs. 64 +/- 3% in nitroglycerin-treated patients and increased vascular .O2- production by over two-fold (P < 0.05). Treatment with hydralazine in rabbits not receiving nitroglycerin significantly decreased .O2- production in intact rabbit aorta and increased sensitivity to nitroglycerin. When given concomitantly with nitroglycerin, hydralazine completely prevented the development of nitrate tolerance and normalized endogenous rates of vascular .O2- production. Studies of vessel homogenates demonstrated that the major source of .O2- was an NADH-dependent membrane-associated oxidase displaying activities of 67 +/- 12 vs. 28 +/- 2 nmol .O2-.min-1.mg protein-1 in nitroglycerin-treated vs. untreated aortic homogenates. In additional studies, we found that acute addition of hydralazine (10 microM) to nitroglycerin-tolerant vessels immediately inhibited .O2- production and NADH oxidase activity in vascular homogenates. The chemiluminescence signal was inhibited by a recombinant heparin-binding superoxide dismutase (HBSOD) demonstrating the specificity of this assay for .O2-. These observations suggest that a specific membrane-associated oxidase is activated by chronic nitroglycerin treatment, and the activity of this oxidase is inhibited by hydralazine, providing a mechanism whereby hydralazine may prevent tolerance. The ability of hydralazine to inhibit vascular .O2- anion production represents a novel mechanism of action for this drug.

Animals↗
PubMed1996

New insights into mechanisms underlying nitrate tolerance.

The hemodynamic and anti-ischemic efficacy of organic nitrates is rapidly blunted due to the development of nitrate tolerance. The mechanisms underlying this phenomenon remain poorly understood and likely involve several independent factors. More recent experimental observations suggest that tolerance may be the consequence of intrinsic abnormalities of the vasculature, including enhanced vascular superoxide and endothelin production. Superoxide anions degrade nitric oxide derived from nitroglycerin, whereas autocrine-produced endothelin within vascular smooth muscle sensitizes the vasculature to circulating neurohormones, such as catecholamines and angiotensin II, all of which may compromise the vasodilator potency of nitroglycerin. Interestingly, these vascular consequences of in vivo nitroglycerin treatment can be mimicked by incubating cultured endothelial and smooth muscle cells with angiotensin II. Further, nitrate tolerance and rebound following sudden cessation of prolonged nitroglycerin therapy can be prevented by concomitant treatment with high-dose angiotensin-converting enzyme inhibition or angiotensin-I receptor blockade. These data strongly suggest that increased circulating levels of angiotensin II, which are encountered during in vivo nitroglycerin treatment, initiate cellular events that ultimately attenuate the nitroglycerin vasodilator effects during prolonged treatment periods.

Animals↗
PubMed1996

Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone.

We tested the hypothesis that angiotensin II-induced hypertension is associated with an increase in vascular .O2- production, and characterized the oxidase involved in this process. Infusion of angiotensin II (0.7 mg/kg per d) increased systolic blood pressure and doubled vascular .O2- production (assessed by lucigenin chemiluminescence), predominantly from the vascular media. NE infusion (2.75 mg/kg per d) produced a similar degree of hypertension, but did not increase vascular .O2- production. Studies using various enzyme inhibitors and vascular homogenates suggested that the predominant source of .O2- activated by angiotensin II infusion is an NADH/NADPH-dependent, membrane-bound oxidase. Angiotensin II-, but not NE-, induced hypertension was associated with impaired relaxations to acetylcholine, the calcium ionophore A23187, and nitroglycerin. These relaxations were variably corrected by treatment of vessels with liposome-encapsulated superoxide dismutase. When Losartan was administered concomitantly with angiotensin II, vascular .O2- production and relaxations were normalized, demonstrating a role for the angiotensin type-1 receptor in these processes. We conclude that forms of hypertension associated with elevated circulating levels of angiotensin II may have unique vascular effects not shared by other forms of hypertension because they increase vascular smooth muscle .O2- production via NADH/NADPH oxidase activation.

Acetylcholine↗
PubMed1996

Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia. Role of oxidized LDL.

BACKGROUND: Risk factors for atherosclerosis such as hypercholesterolemia and hypertension are associated with endothelial dysfunction of conduit and resistance vessels; however, the interaction of these risk factors and underlying mechanisms affecting endothelial function remain to be determined. The present study investigated the role of long-term smoking and hypercholesterolemia and their impact on endothelial function of peripheral resistance vessels in relation to plasma levels of autoantibodies against oxidized LDL, which has been implicated in the development of endothelial dysfunction and atherosclerosis. METHODS AND RESULTS: The vascular responses to the endothelium-dependent agent acetylcholine (7.5, 15, 30, and 60 micrograms/min) and the endothelium-independent agent sodium nitroprusside (1,3, and 10 micrograms/min) were studied in normal control subjects (n = 10), patients with hypercholesterolemia (n = 15), long-term smokers (n = 15), and hypercholesterolemic patients who smoked (n = 15). Drugs were infused into the brachial artery, and forearm blood flow (FBF) was measured by venous occlusion plethysmography. The FBF responses to acetylcholine were significantly blunted in all three patient groups compared with normal control subjects (P < .05). The acetylcholine-induced increase in FBF was significantly attenuated in patients with hypercholesterolemia who smoked compared with hypercholesterolemic nonsmokers and normocholesterolemic smokers (P < .05 for both). The response to sodium nitroprusside was not statistically different in all four groups. Plasma levels of autoantibody titer against oxidized LDL were inversely related to acetylcholine-induced changes in FBF (r = -.53, P < .002) and were substantially increased in the group with both risk factors. CONCLUSIONS: These results demonstrate that cigarette smoking and hypercholesterolemia synergistically impair endothelial function and that their combined presence is associated with increased plasma levels of autoantibodies against oxidized LDL. These observations raise the possibility that long-term smoking potentiates endothelial dysfunction in hypercholesterolemic patients by enhancing the oxidation of LDL.

Acetylcholine↗