Klaus Alexander

Biochemical Evidence for Impaired Nitric Oxide Synthesis in Patients With Peripheral Arterial Occlusive Disease

BACKGROUND We studied urinary nitrate and cGMP excretion rates, indices of systemic NO formation, and plasma concentrations of L-arginine and the endogenous NO synthase inhibitor asymmetrical dimethylarginine (ADMA) and its inactive stereoisomer, symmetrical dimethylarginine, in 77 patients with peripheral arterial occlusive disease (PAOD) in Fontaine stages IIb through IV and in 47 young and 37 elderly healthy control subjects. METHODS AND RESULTS Urinary nitrate excretion was 182.0+/-11.4 micromol/mmol creatinine and cGMP excretion was 186.2+/-13.0 nmol/mmol creatinine in young healthy control subjects. In elderly control subjects, both excretion rates were slightly lower (nitrate, 156.0+/-7.8 micromol/mmol creatinine; cGMP, 150.0+/-8.3 nmol/mmol creatinine; P=NS). In PAOD patients, there was a significant, progressive reduction of urinary nitrate (IIb, 138.4+/-11.9; III, 128.6+/-11.3; and IV, 91.9+/-8.0 micromol/mmol creatinine; P<.05) and cGMP (IIb, 139.9+/-25.2; III, 115.6+/-13.1; and IV, 76.9+/-7.9 nmol/mmol creatinine; P<.05) excretion rates related to the Fontaine stage of PAOD. These changes were independent of changes in renal excretory function. Plasma L-arginine concentrations were not significantly different between the groups, but ADMA concentrations were elevated in PAOD patients (young control subjects, 1.25+/-0.11; elderly control subjects, 1.01+/-0.05 micromol/L; IIb, 2.62+/-0.24; III, 3.06+/-0.48; and IV, 3.49+/-0.26 micromol/L; P<.05 for PAOD versus control subjects). There was a significant linear correlation between urinary nitrate and cGMP excretion rates and a significant negative linear correlation between plasma ADMA concentrations and urinary nitrate excretion. CONCLUSIONS In PAOD patients, there is a progressive reduction in urinary nitrate and cGMP excretion rates, which may be caused in part by accumulation of ADMA, an endogenous inhibitor of NO synthase.

l-Arginine Induces Nitric Oxide–Dependent Vasodilation in Patients With Critical Limb Ischemia A Randomized, Controlled Study

BACKGROUND L-Arginine is the precursor of endogenous nitric oxide (NO), which is a potent vasodilator acting via the intracellular second-messenger cGMP. In healthy humans, L-arginine induces peripheral vasodilation and inhibits platelet aggregation due to an increased NO production. Prostaglandin E1 (PGE1) induces peripheral vasodilation via stimulating prostacyclin receptors. METHODS AND RESULTS We investigated the effects of one intravenous infusion of L-arginine (30 g, 60 minutes) or PGE1 (40 microgram, 60 minutes) versus those of placebo (150 mL 0.9% saline, 60 minutes) on blood pressure, peripheral hemodynamics, and urinary NO3- and cGMP excretion rates in patients with critical limb ischemia (peripheral arterial occlusive disease stages Fontaine III or IV). Blood flow in the femoral artery was significantly increased by L-arginine (+42.3 +/- 7.9%, P<.05) and by PGE1 (+31.0 +/- 10.2%, P<.05) but not by placebo (+4.3 +/- 13.0%, P=NS). Urinary NO3- excretion increased by 131.8 +/- 39.5% after L-arginine (P<.05) but only by 32.3 +/- 17.2% after PGE1 (P=NS). Urinary cGMP excretion increased by 198.7 +/- 84.9% after L-arginine (P<.05) and by 94.2 +/- 58.8% after PGE1 (P=NS). Both urinary index metabolites were unchanged by placebo. CONCLUSIONS We conclude that intravenous L-arginine induces NO-dependent peripheral vasodilation in patients with critical limb ischemia. These effects are paralleled by increased urinary NO3- and cGMP excretion, indicating an enhanced systemic NO production. Increased urinary NO3- excretion may be a sum effect of NO synthase substrate provision (L-arginine) and increased shear stress (PGE1 and L-arginine).

Controlled trial of high-versus low-dose aspirin treatment after percutaneous transluminal angioplasty in patients with peripheral vascular disease

Percutaneous transluminal angioplasty of aortoiliac and femoropopliteal atherosclerotic lesions can provide long-lasting hemodynamic improvement. High-dose aspirin is commonly prescribed as reocclusion prophylaxis, but low doses would be preferable because of fewer adverse effects. We performed a double-blind, randomized, controlled clinical trial in patients with peripheral vascular disease with lesions appropriate for angioplasty. We compared the efficacy and side effects of two doses of aspirin (50 mg vs. 900 mg daily) during a period of 12 months after angioplasty. A total of 359 patients were evaluated: 175 were randomly assigned to treatment with 900 mg aspirin daily and 184 to 50 mg aspirin a day. Thirty-nine patients developed restenosis at the angioplasty site; the cumulative percentage of event-free survival after 1 year (patency rate) was 85% in the 900-mg group and 84% in the 50-mg group. An equivalence test showed the two groups equivalent with respect to restenosis rates (P = 0.003 for an equivalence region of < 10% difference). Nine patients (5%) in the 900-mg group had serious gastrointestinal side effects (peptic ulcer, eight; erosive gastritis requiring transfusion, one) compared to two (peptic ulcer) in the 50-mg group (P = 0.03). The results of our study show that a dose of 50 mg aspirin a day is as effective as one of 900 mg for the prevention of restenoses after lower limb angioplasty, and that severe gastrointestinal side effects are less frequent.

Quantitative Reflection Spectrophotometry: Spatial and Temporal Variation of Hb Oxygenation in Human Skin

Applying a fast scanning reflection spectrophotometer and multicomponent spectra analysis, oxygen saturation (SHb) and relative concentration (CHb) of hemoglobin in the skin were determined at eight skin sites in 11 healthy persons. SHb was significantly higher at the tip of the index finger and big toe (90 +/- 3.9 and 92 +/- 4.2%, respectively) compared with the forehead, volar forearm, back of hand, abdomen, calf and forefoot where mean values varied between 52 and 67% (p < 0.001). CHb also was higher at acral sites (big toe: 2.04 +/- 0.14 arbitrary units (AU); index finger: 2.13 +/- 0.19 AU) than at the other locations (p < 0.0001) where it was between 0.56 +/- 0.12 AU (abdomen) and 0.95 +/- 0.28 AU (forefoot). In the course of time, rhythmical oscillations of both parameters at a frequency of 3-5/min were seen in 68% of the measurements, predominantly at the six proximal sites. Heating the measuring site to 44 degrees C caused a biphasic increase of CHb and SHb which was significant at the proximal sites (p < 0.0001). SHb values came into the range of arterial blood. Temporal and spatial variation of both parameters decreased. Reflection spectrophotometry gives the possibility to directly assess dermal hemoglobin saturation, its physiological variability and reactions to provocation stimuli. Concentration and saturation of hemoglobin in dermal vessels appear definitely different at acral compared with proximal sites.

Skin Surface Oxygen Pressure Fields During Administration of Prostaglandin E1 in Patients with Arterial Occlusive Disease

SummaryProstaglandin E1 is offered as a new therapeutic agent in the treatment of severe peripheral arterial occlusive disease. Especially when treating patients with ulcers or gangrene, the oxygen tension of the skin should improve during PGE1 administration. The new technique of assessing skin surface oxygen pressure histograms allows study of the skin microcirculation in vivo. Oxygen histograms were determined on the forefeet of 19 patients with different degrees of disease and different occlusion levels before and during a single intraarterial infusion of PGE1 at a dosage of 1.5 ng/kg body weight/min. Only 9 patients showed improvement during the infusion period. Skin oxygen pressure was increased to a large extent only in patients assumed to suffer from diabetic microangiopathy. The effect of a long-term therapy with PGE1 on skin microcirculation remains to be settled.

Comparison of Laser-Doppler-Flux and tcPO2 in Healthy Probands and Patients with Arterial Ischemia

Transcutaneous PO2 (tcPO2) and Laser-Doppler-Flux (LDF) were compared on the dorsum of the foot in 20 healthy probands and 35 patients with peripheral arterial occlusive disease at clinical stage II b or IV. The probes were kept at a temperature of 37 degrees C. Using different procedures, we brought about dynamic changes and compared the reaction of the two signals. Venous occlusion resulted in a decrease of both signals to a similar extent in both groups. During leg dependency both signals decreased in the probands suggesting a normal vasoconstrictor response. In most of the patients an increase was observed, but some showed a decrease even at clinical stage IV. LDF had a stronger tendency towards a decrease. On leg elevation, LDF slightly increased in probands and decreased in patients. Here, the tendency towards a decrease was higher for tcPO2. After arterial occlusion reactive hyperemia was more pronounced in probands. Differences between tcPO2 and LDF seem to be mainly due to the different capillary systems contributing to the signal.

Hypothenar hammer syndrome successfully managed with intravenous prostaglandin E1 and heparin and with correction of the thrombogenic risk profile : A case report

A fifty-one-year-old man presented with a history, symptoms, and clinical findings typical of a hypothenar hammer syndrome in his dominant hand. A thrombotic obstruction in the distal section of the ulnar artery with multiple downstream occlusions of proper digital arteries were documented angiographically. Coexistence of additional cardiovascular risk factors (smoking-induced polycythemia, obesity, hypercholesterolemia, and hyperten sion) was identified. Conservative management with intravenous heparin and prostaglandin E1 together with measures directed at controlling the additional risk factors (repeated venesection, immediate smoking cessation, and low-lipid diet) resulted in a striking clinical and angiographic improvement of the digital perfusion, without resort to interventional measures or thrombolysis.

Intravenous infusion of iloprost in arterial occlusive disease : dose-dependent effects on skin microcirculation

SummaryTranscutaneous oxygen pressure (tcPo2), laser Doppler flux and capillary microscopy have been used to examine the forefoot skin in 5 healthy men and 8 patients with severe peripheral arterial occlusive disease in order to evaluate the dose dependent effects of iloprost on skin microcirculation. Iloprost was infused IV starting at 0.0625 ng·kg−1·min−1 and doubling the dose every 15 min up to 2 ng·kg−1·min−1.While tcPo2 at an electrode core temperature of 44°C decreased in both patients and controls, there was a significant dose dependent increase in tcPo2 (37°C) in the controls from 0.25 ng·kg−1·min−1. In the patients the reaction was variable: it was decreased in two and increased in 6, with a maximum either at 0.25–0.5 ng·kg−1·min−1 (n=3) or at the highest dose (1.0 or 2.0 ng·kg−1·min−1; n=3). Mean laser Doppler flux in both groups was increased, although the reaction was not consistent in the patients. Density of forefoot skin capillaries was reduced in 3 patients, and in the others the flow velocity was very low. During infusion of iloprost, both an increase in capillary density and blood cell velocity were observed. The effects were of variable intensity and occurred at varying doses, some appeared early and diminished as the dose was increased, and others were found only at 2 ng·kg−1·min−1.Adverse effects were numerous, extending from harmless skin flushing to mental changes and a quickly reversible attack of angina pectoris. It may be possible to divide patients into those with early effects on the microcirculation, at doses of 0.25–0.5 ng·kg−1·min−1, and those in whom the microcirculatory response is preceded and counteracted by the adverse effects.

Orthostatic Vasoconstrictor Response in Patients with Occlusive Arterial Disease Assessed by Laser Doppler Flux and Transcutaneous Oximetry

Posturally induced microvascular constriction normally causes a decrease of transcutaneous oxygen pressure (tCPO2) and laser Doppler flux (LDF) measured on the forefoot at 37°C. The authors used both methods to assess the vasoconstrictor response (VCR) in 31 patients with various degrees of peripheral arterial occlusive disease (PAOD) and analyzed factors that could have influenced the response. Disturbed VCR was indicated by a signal increase following leg dependency, which occurred significantly more often in tCPO2 than in LDF measurements (69% vs 32%, P < 0.001). Correspondingly the median sitting/supine ratio was 2.4 for tcPO 2 and 0.7 for LDF (P < 0.0001). Age and clinical stage had no influence on the VCR. With ankle artery pressures below 50 mmHg an increase of LDF was more probable. TcPO2 predominantly increased with ankle artery pressures up to 100 mmHg, though the sitting/supine ratio of tcPO2 was correlated with ankle artery pressure. In nondiabetics the response of tcPO2 but not of LDF was influenced by the values at rest. Differences between the two methods may be explained in part by their different sample volumes. The authors assume that tcPO2 is predominantly monitoring a local myogenic response while LDF is reflecting venoarteriolar response.

Vital Capillary Microscopy of Skin Areas at the Forefoot of Diabetic Patients using Intraarterial Injection of Na-Fluorescein

A modified technique of vital capillary microscopy with intraarterial application of Na-fluorescein has been introduced in the study of nutritional skin microcirculation to assess skin microcirculation of different diabetic patients, comprising one group without neurocutaneous complications (group 2; n = 9), one suffering only from neuropathy (group 3; n = 9) and one with trophic skin lesions in the contralateral foot (group 4; n = 8), all without macroangiopathy, compared to healthy controls (group 1; n = 9). Femoroarterial injection of small boli (10 mg) of Na-fluorescein allowed repeated investigation of the dye appearance times (AT) and capillary-filling times of forefoot skin capillaries within small periods of time before, during and after reactive hyperemia. At rest, AT was significantly shorter in patients of group 4 (16.8 +/- 4.4 s; p < 0.05) compared with groups 1-3 (34.3 +/- 12.8; 31.7 +/- 11.7 and 35.9 +/- 15.3 s). Fifteen seconds after the end of arterial occlusion, dye propagation to the skin was markedly accelerated in groups 1-3 (19.8 +/- 14.0; 14.4 +/- 7.6 and 18.7 +/- 10.6 s, respectively; p < 0.001), but prolonged in group 4 (18.4 +/- 7.4 s). After 10 min, the values at rest were reestablished. No differences between the four groups were found concerning capillary density and morphology. It is concluded that the development of skin lesions in diabetic patients without significant macroangiopathy may be favored by hyperperfusion and impaired vasoregulation. Intraarterial dye injection presents a valuable tool to assess dynamic alterations of the microcirculation at the level of skin capillaries.