Duration Of Hyperemia Research Articles

Voltage-dependent K+ channels regulate the duration of reactive hyperemia in the canine coronary circulation

We previously demonstrated a role for voltage-dependent K(+) (K(V)) channels in coronary vasodilation elicited by myocardial metabolism and exogenous H(2)O(2), as responses were attenuated by the K(V) channel blocker 4-aminopyridine (4-AP). Here we tested the hypothesis that K(V) channels participate in coronary reactive hyperemia and examined the role of K(V) channels in responses to nitric oxide (NO) and adenosine, two putative mediators. Reactive hyperemia (30-s occlusion) was measured in open-chest dogs before and during 4-AP treatment [intracoronary (ic), plasma concentration 0.3 mM]. 4-AP reduced baseline flow 34 +/- 5% and inhibited hyperemic volume 32 +/- 5%. Administration of 8-phenyltheophylline (8-PT; 0.3 mM ic or 5 mg/kg iv) or N(G)-nitro-L-arginine methyl ester (L-NAME; 1 mg/min ic) inhibited early and late portions of hyperemic flow, supporting roles for adenosine and NO. 4-AP further inhibited hyperemia in the presence of 8-PT or L-NAME. Adenosine-induced blood flow responses were attenuated by 4-AP (52 +/- 6% block at 9 microg/min). Dilation of arterioles to adenosine was attenuated by 0.3 mM 4-AP and 1 microM correolide, a selective K(V)1 antagonist (76 +/- 7% and 47 +/- 2% block, respectively, at 1 microM). Dilation in response to sodium nitroprusside, an NO donor, was attenuated by 4-AP in vivo (41 +/- 6% block at 10 microg/min) and by correolide in vitro (29 +/- 4% block at 1 microM). K(V) current in smooth muscle cells was inhibited by 4-AP (IC(50) 1.1 +/- 0.1 mM) and virtually eliminated by correolide. Expression of mRNA for K(V)1 family members was detected in coronary arteries. Our data indicate that K(V) channels play an important role in regulating resting coronary blood flow, determining duration of reactive hyperemia, and mediating adenosine- and NO-induced vasodilation.

Fixed Combination of Perindopril and Indapamide at Low Dose Improves Endothelial Function in Essential Hypertensive Patients After Acute Administration

Fixed combination of angiotensin-converting enzyme inhibitors (ACEIs) with thiazide-type diuretics at low dose has been used as first-line therapy for the treatment of essential hypertension but their effect on conduit artery endothelial dysfunction remains unknown. Thirteen hypertensive patients were assessed after acute administration of a placebo, fixed combination of perindopril-indapamide at low dose: D1 (2 mg/0.625 mg) and twice this dose: D2 (4 mg/1.25 mg), during a double-blind, randomized, crossover study, and were compared with 13 matched controls. Mean arterial pressure (MAP), radial artery diameter (echotracking) and flow (Doppler) were measured during flow-mediated dilatation (FMD) induced by post-ischemic hyperemia (PIH). PIH was characterized by peak flow and duration of hyperemia (t(1/2)). Endothelium-independent dilatation was assessed by trinitrine. In hypertensive patients compared with controls, basal radial artery diameter and flow, peak flow, and trinitrine responses were similar while MAP was increased (115 +/- 3 vs. 87 +/- 2 mm Hg), t(1/2) was decreased (11.1 +/- 1.9 vs. 17.2 +/- 2.2 s), and FMD was altered (radial diameter increase: 203 +/- 14 vs. 304 +/- 15 microm). Compared with placebo, only D2 decreased MAP (placebo: 115 +/- 3; D1: 112 +/- 4; D2: 103 +/- 4 mm Hg) and increased t(1/2) (placebo: 11.1 +/- 1.9; D1: 8.7 +/- 1.5; D2:13.0 +/- 1.9 s). Conversely, D1 and D2 increased FMD (placebo: 203 +/- 14; D1: 218 +/- 22; D2: 227 +/- 23 microm) with no change in basal diameter and flow, peak flow, and trinitrine responses. These results demonstrate that a fixed combination of ACEI/diuretic at low dose significantly improves radial artery FMD in hypertensive patients and suggest a direct effect on conduit artery endothelium that may contribute to vascular protection.

Impaired contribution of voltage‐dependent K+ channels to ischemic coronary vasodilation in Ossabaw swine with metabolic syndrome

This study assessed the contribution of large conductance Ca2+‐activated (BKCa) and voltage‐dependent (KV) K+ channels to coronary ischemic vasodilation in lean and metabolic syndrome (MetS) Ossabaw swine. Experiments were conducted in anesthetized, open‐chest swine fed a normal maintenance diet or an atherogenic diet over 9 weeks that induces MetS. Ischemic vasodilation was assessed by measuring the reactive hyperemic response to a 15‐second occlusion of the left anterior descending coronary artery. Mean body weight was 36 ± 2 kg in lean (n = 8) and 54 ± 3 kg in MetS (n = 7) swine. BKCa inhibition with penitrem A (10 μg/kg iv) had no effect on peak coronary blood flow in either lean (2.9 ± 0.3 ml/min/g) or MetS (2.6 ± 0.3 ml/min/g) swine. The duration of the reactive hyperemic response was also unaffected by penitrem A in lean (94 ± 10 sec) and MetS (88 ± 8 sec) swine. Subsequent inhibition of KV channels with 4‐aminopyridine (0.3 mg/kg, iv) significantly reduced the duration of reactive hyperemia in lean (66 ± 5 sec) but not in MetS swine (77 ± 12 sec). These data indicate that BKCa channels do not contribute to ischemic vasodilation in lean or MetS Ossabaw swine. In addition, our findings reveal that KV channels play a prominent role in coronary ischemic vasodilation in lean, but not MetS, swine suggesting putative mechanisms of ischemic dilation are switched in early obesity and MetS. (Support: HL67804, RR013223, HL062552)

Influence of xantinole nicotinic acid on cutaneous microcirculation in patients with coronary artery disease and hyperlipoproteinemia

Xantinole nicotinic acid (NA) dose dependently lowers plasma levels of atherogenic lipoproteins and increases blood flow through vasodilation. The aim of this study was to evaluate the effect of NA on cutaneous microcirculation in patients with coronary artery disease and hyperlipidemia. In this open pilot study, five men and three women (74.2+/-9.1 yrs; 81.4+/-7.9 kg; 171.6+/-7.0 cm) with angiographically proven coronary artery disease and hyperlipidemia were included. Nailfold capillary microscopy was used for measurements of erythrocyte velocities at rest and after three minutes of ischemia, before and one hour after intake of 1000 mg of NA. The blood pressure (120+/-12/73+/-8 mmHg vs. 113+/-10/72+/-5 mmHg; p=0.19/0.83) and the heart rate (72+/-8/min vs. 70+/-7/min; p=0.38) remained unchanged. The mean capillary red blood cell velocity at rest (v(RBC); 0.27+/-0.23 mm/s vs. 0.32+/-0.18 mm/s; p=0.089) and the time to maximal post ischemia erythrocyte velocity (t(peak); 21.0+/-7.9 s vs. 24.3+/-15.5 s; p=0.49) did not change. The maximal post ischemic erythrocyte velocity (v(maxRBC); 0.93+/-0.33 mm/s vs. 1.19+/-0.19 mm/s; p=0.0096) raised slightly but significantly, the duration of post-ischemia hyperemia (DpH; 101+/-16 s vs. 127+/-15 s; p=0.0005) increased markedly. One patient reported about flush in the whole body. The administration of 1000 mg of NA resulted in a significant improvement of the cutaneous microcirculation in patients with coronary artery disease and hyperlipidemia.

Contribution of anaerobic metabolism to reactive hyperemia in skeletal muscle

Elevated blood flow (reactive hyperemia) is seen in many organs after a period of blood flow stoppage. This hyperemia is often considered to be due in part to a shift to anaerobic metabolism during tissue hypoxia. The aim of our study was to test this hypothesis in skeletal muscle. For this purpose we measured NADH fluorescence at localized tissue areas in cat sartorius muscle during and after arterial occlusions of 5-300 s. In parallel studies, red blood cell (RBC) velocity was measured in venules. Tissue NADH fluorescence rose significantly with occlusions of 45 s or greater, reaching a maximum of 44% above control at 180 s. Peak RBC velocity rose to four times control as occlusion duration was increased from 5 to 45 s, but hyperemia duration was stable at approximately 70 s. With occlusions of 45-240 s, hyperemia duration increased progressively to 210 s while peak flow was unchanged. However, after 300-s occlusions, peak flow rose to six times above control and hyperemia duration fell to 140 s. With occlusions of 45-300 s the time integral both of increased NADH fluorescence and of reduced fluorescence following occlusion release showed a high degree of correlation with the additional hyperemia. We conclude that in this muscle anaerobic vasodilator metabolites are responsible for the increase in reactive hyperemia with arterial occlusions longer than 45 s. Since the durations of reactive hyperemia and reduced fluorescence are substantially different, vasodilator metabolite removal may be due to washout by the bloodstream rather than metabolic uptake.

Abnormal endothelial function in female patients with hypothyroidism and borderline thyroid function

Background It has been suggested that hypothyroidism is associated with an increased risk for cardiovascular disease. The aim of this study was to assess non-invasively NO-dependent endothelial function of resistance arteries in subjects with hypothyroidism of varying severity. Methods Ninety-six female subjects (aged: 42 ± 13 years) comprised the study population. Subjects were divided into five groups based on TSH levels at presentation: Group 0 ( n = 23) with TSH: 0.3–2.0 μU/ml, Group 1 ( n = 22) with TSH: 2.1–4.0 μU/ml (upper normal), Group 2 ( n = 18) with TSH: 4.1–10 μU/ml (subclinical hypothyroidism), Group 3 ( n = 22) with TSH > 10 μU/ml (overt hypothyroidism). One additional group with well-controlled hypothyroidism on l-thyroxine therapy (Group 4, n = 11, TSH: 0.3–2.0 μU/ml) was also studied. Endothelial function of resistance arteries was assessed by measuring forearm blood flow response during reactive hyperemia utilizing venous occlusion strain-gauge plethysmography. Results Duration of reactive hyperemia was significantly different among groups of subjects with varying hypothyroidism (83.7 ± 58.3 s, 53.2 ± 35.7 s, 52.8 ± 47.5 s, 12.9 ± 13.3 s and 69.5 ± 26.2 s in Groups 0, 1, 2, 3 and 4, respectively, p < 0.001, ANOVA). Duration of reactive hyperemia was significantly shorter in subjects with upper normal TSH values (Group 1) compared to controls (53.2 ± 35.7 s vs. 83.7 ± 58.3 s, p = 0.013), while it was comparable to that of subjects with subclinical hypothyroidism (Group 2) (52.8 ± 47.5 s). However, duration of reactive hyperemia in Group 1 was significantly longer compared to Group 3 (overt hypothyroidism) (53.2 ± 35.7 s vs. 12.9 ± 13.3 s, p = 0.002). Similarly, duration of reactive hyperemia in subjects with subclinical hypothyroidism was significantly longer compared to subjects with overt hypothyroidism (52.8 ± 47.5 s vs. 12.9 ± 13.3 s, p = 0.003). Duration of reactive hyperemia in Group 4 (well-controlled hypothyroidism on l-thyroxine therapy) did not differ significantly compared to controls. There was a highly significant linear correlation between duration of reactive hyperemia and TSH ( r = − 0.383, p < 0.001). Conclusion Endothelial dysfunction was detected in the microvasculature of patients with hypothyroidism. Duration of reactive hyperemia decreased with increasing TSH levels. Since endothelial dysfunction is a factor leading to atherosclerosis, this abnormality may partly explain predisposition of patients with thyroid failure to cardiovascular disease.

Association of dehydroepiandrosterone-sulfate with endothelial function in young women with polycystic ovary syndrome

The aim of this study was to assess non-invasively endothelial function of young women with polycystic ovary syndrome (PCOS) in comparison with healthy age-matched women and a group of young women with idiopathic hirsutism (IH). The possible role of metabolic and hormonal parameters on endothelial function was also examined. Descriptive clinical trial. Fifty-six women, 27 with PCOS, 16 with IH and 13 healthy age-matched women were studied. Endothelial function of resistance arteries was assessed by venous occlusion plethysmography. Metabolic and hormonal parameters were estimated in this study population. The duration of reactive hyperemia (durRH) was shorter in PCOS group when compared with normal controls (63.75 +/- 13.33 s vs 113.18 +/- 20.92 s, P = 0.036). A similar finding was observed when PCOS were compared with IH group (63.75 +/- 13.33 s vs 105 +/- 17.20 s, P = 0.05). The durRH did not differ between IH and control group (105 +/- 17.20 s vs 113.18 +/- 20.92 s, ns). A significant positive linear correlation was found between the durRH and dehydroepiandrosterone-sulfate (DHEA-S) levels (r = +0.48, P = 0.04) in the PCOS group. The basal insulin resistance index (HOMA) differed significantly between PCOS, IH and control groups. There was no significant correlation between durRH and HOMA index or testosterone levels in the PCOS group. Endothelial dysfunction may be an early sign of cardiovascular system abnormalities in young PCOS women. It is possible that increased DHEA-S levels may offer a cardioprotective advantage that attenuates the effects of cardiovascular risk factors that accompany PCOS.

The Magnitude of FMD is Determined by the Area Under the Curve of the Reactive Hyperemia

The reactive hyperemia (RH) test commonly used to assess flow mediated dilation (FMD) in human conduit arteries creates a large, transient shear stimulus. PURPOSE: To identify the relative importance of the peak vs. the duration of shear rate in determining the peak FMD response. METHODS: Brachial artery (BA) blood flow velocity was measured with Doppler ultrasound and echo ultrasound BA images were analyzed with automated edge detection software (shear rate = velocity/diameter). 1) Duration manipulation experiment (DME) - 10 healthy males underwent six RH trials with different hyperemic durations (10s–2 min). The duration of hyperemia was manipulated by re-inflating the occlusion cuff after 10s, 20s, 30s, 40s, or 50s. 2) Peak manipulation experiment (PME) - 8 healthy males underwent three RH trials. Three peak shear rate magnitudes (large (L), medium (M) and small (S)) were created by applying BA compression upon cuff release. The post-peak area under the curve (AUC) of shear rate was also controlled with arterial compression. RESULTS: DME - Peak shear rate (AUC in 1st 9s post cuff release) was not different between trials (P = 0.309). Re-inflation of the occlusion cuff at times indicated resulted in the remaining AUC being significantly different between trials (10 s −2025.37 ±504.21; 20 s −3393.54±857.03; 30s-4329.30±1198.47; 40s–4784.20±1345.00; 50s–5215.83±1466.63 2min −7124.39±2160.67 p<0.001). The respective peak % changes in diameter were: 10s-2.67±1.34; 20s-6.21±1.95; 30s-7.89±2.95; 40s-8.3±3.21; 50s-7.91±3.20; 2min-9.34±4.10, with 10 and 20 s being significantly less than 2min (p<0.001). PME - Peak shear rate (AUC in 1st 9s post cuff release) was significantly different between trials (L- 998.04±305.16, M-700.66±225.89, S-487.48±1 67.55 p<0.001). The AUC of the post-peak shear rate was not significantly different between trials (P = 0.695). The peak % change in diameter was not significantly different between trials (L-6.99±2.72%, M-7.56±2.6%, S-6.87±1.99%, P = 0.437). CONCLUSIONS: Manipulation of the duration of the shear rate had an impact on the peak FMD response while independent manipulation of peak shear rate did not. We conclude that the shear rate AUC following the peak is a critical determinant of the peak FMD response and needs to be accounted for in quantifying the stimulus for FMD. Supported by ACSM Doctoral Research Grant, NSERC, CFI New Opportunities Fund

EFFECTS OF ORAL BERAPROST SODIUM, A PROSTAGLANDIN I2 ANALOGUE, ON ENDOTHELIUM DEPENDENT VASODILATATION IN THE FOREARM OF PATIENTS WITH CORONARY ARTERY DISEASE

1. Previous clinical studies with prostaglandin I(2) (PGI(2)) analogue beraprost sodium suggested the potential effects on protection of cardiovascular events in patients with peripheral artery disease. Although the mechanism is not well known, experimental studies have shown protective effects of endothelial cells. This study was designed to examine the effects of beraprost sodium on vascular endothelial function in the forearm of patients with coronary artery disease. 2. Beraprost sodium (120 microg/day) was orally administered to 14 coronary artery disease patients for 4 weeks and then stopped for 4 weeks. Eleven control patients did not receive beraprost sodium treatment. Reactive hyperemia was induced in the forearm, endothelium-dependent vasodilatation was assessed by plethysmography, and urinary 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) was measured at baseline, 4 weeks and 8 weeks. 3. Both groups had similar reactive hyperemic responses at baseline. In the control group, reactive hyperemic response and urinary 8-iso-PGF(2alpha) remained unchanged for 8 weeks. In the beraprost group, maximum forearm blood flow increased significantly (P = 0.01) after 4 weeks of treatment and returned to baseline at 8 weeks. Duration of hyperemia increased significantly (P = 0.003) after 4 weeks, and remained greater than baseline at 8 weeks (P = 0.02). Urinary 8-iso-PGF(2alpha) decreased significantly (P = 0.03) after 4 weeks, and tended to be lower at 8 weeks (P = 0.07). Changes in reactive hyperemia correlated weakly but significantly with changes in 8-iso-PGF(2alpha) (P < 0.001). 4. Beraprost sodium decreased oxidative stress and improved forearm endothelium-dependent vasodilatation in coronary artery disease patients. The favorable effects on vascular endothelium could potentially lead to a decrease in vascular events.

Short Duration of Reactive Hyperemia in the Forearm of Subjects With Multiple Cardiovascular Risk Factors

Peripheral vascular endothelial dysfunction is an independent predictor of cardiovascular events, and can be assessed noninvasively by measuring reactive hyperemia, either by vascular ultrasound measurement of flow-mediated vasodilatation or, less commonly, by measurement of blood flow using plethysmography. In the present study reactive hyperemia was measured using plethysmography in healthy subjects with multiple cardiovascular risk factors. Reactive hyperemia was measured following 5-min occlusion of the upper arm in 449 healthy subjects (302 men, 147 women, age range 20-70 years) with (n=352) and without (n=97) risk factors such as smoking, hypertension, diabetes mellitus, hypercholesterolemia, obesity, family history of cardiovascular disease, and menopause. Maximum blood flow and minimum vascular resistance in reactive hyperemia did not differ between subjects with and without risk factors regardless of gender. Duration of reactive hyperemia, however, was significantly shorter in subjects with risk factors. Age-adjusted mean value of duration of reactive hyperemia was significantly smaller in men with a smoking habit, diabetes mellitus, hypercholesterolemia or obesity, and in women with smoking habit, hypertension, diabetes mellitus or obesity. The number of risk factors significantly correlated with the duration of reactive hyperemia in both men (r=-0.56, p<0.001) and women (r=-0.62, p<0.001), suggesting that endothelial dysfunction increases with the number of risk conditions clustering in a single individual. Duration of reactive hyperemia reflects cardiovascular risk factors and decreases with the number of risk conditions. These findings suggest that the duration of reactive hyperemia measured with plethysmography is potentially useful for assessing endothelial dysfunction.

Ocular 'nonscarring' mucous membrane pemphigoid associated with antilaminin-5 antibodies

Mucous membrane pemphigoid is a rare, chronic autoimmune disease characterized by subepidermal blistering and scarring, predominantly affecting mucous membranes. Ocular involvement frequently occurs and often represents the only manifestation of the disease. We describe a 62-year-old woman with a bilateral 18-month duration of conjunctival hyperaemia, associated with erythema and oedema of the eyelids, lacking any typical ocular signs of mucous membrane pemphigoid such as sub-conjuctival fibrosis and scarring. Histology was not significant. Direct immunofluorescence of the conjunctiva showed IgG, IgA and complement deposition along the basement membrane zone. Immunoprecipitation analysis of affinity purified laminin-5 revealed a band consistent with the beta3 chain of laminin-5. This represents the first case of pure ocular mucous membrane pemphigoid associated with anti-laminin-5 antibodies.

The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia

ObjectivesWe studied the effects of sildenafil, a phosphodiesterase 5 inhibitor, on coronary and peripheral vascular function, platelet activation, and myocardial ischemia. BackgroundNitric oxide vasodilates and inhibits platelet activation by generating cyclic guanosine 5′-monophosphate, which is metabolized by phosphodiesterase type 5. MethodsThe effect of oral sildenafil on resting coronary vascular tone, endothelium-dependent and -independent function and platelet activation was measured in 24 patients. An additional 24 patients with coronary artery disease (CAD) and ischemia during exercise, and 12 control subjects received either 100 mg of sildenafil, 10 mg of isosorbide dinitrate (ISDN) or placebo during exercise on three separate days in a randomized, double-blind manner. Flow-mediated dilation of the brachial artery was measured, and CAD patients underwent treadmill exercise testing. ResultsSildenafil (100 mg) vasodilated epicardial coronary arteries (+6.9 ± 1.3%, p < 0.0001). Coronary epicardial and microvascular responses with acetylcholine and cold-pressor testing improved, with a greater enhancement in patients with CAD and endothelial dysfunction. Verapamil responses were unchanged. Both resting and adenosine diphosphate-stimulated platelet IIb/IIIa receptor activation was inhibited by sildenafil (p < 0.05). Brachial arteries dilated in response to sildenafil in controls. Peak flow-mediated dilation was similar, but the duration of hyperemia was prolonged after sildenafil administration (p < 0.001). Compared with placebo, ISDN improved myocardial ischemia during exercise (p < 0.05), whereas the effect of sildenafil was intermediate between the two. ConclusionsSildenafil dilates epicardial coronary arteries, improves endothelial dysfunction and inhibits platelet activation in patients with CAD. It has an intermediate effect on myocardial ischemia compared with ISDN and placebo.

Primary Cutaneous Microangiopathy in Heart Recipients

In this study we investigated whether a disturbance in microcirculation is detectable in heart recipients with cardiac allograft vasculopathy (CAV) and severe hypercholesterolemia (n = 11) and in 7 heart recipients without CAV in comparison to patients with severe coronary artery disease (n = 49) and age-matched apparently healthy subjects (n = 100). For this purpose, the flow velocity of erythrocytes through cutaneous capillaries at the nail fold of the finger was measured under resting conditions. In addition, reactive hyperemia in the same capillaries after a 3-min ischemia was determined. Patients with CAV and severe lipid disorder showed a pathological reduction in mean capillary erythrocyte velocity under resting conditions with vRBC = 0.10 ± 0.07 mm/s. The latter was significantly and relevantly lower than in patients with coronary three-vessel disease (vRBC = 0.46 ± 0.35 mm/s). It was notable that under resting conditions temporary cessation of flow occurred in 8 of the 11 patients which did not occur in healthy subjects and rarely in patients with three-vessel disease (1 of 49 patients). In comparison to age-matched healthy subjects (vmax = 1.46 ± 0.52 mm/s), the patients with three-vessel disease showed a significant reduction in postischemic maximum erythrocyte velocity (vmax = 0.85 ± 0.55 mm/s), with a considerable shortening of the duration of reactive hyperemia. Patients with CAV demonstrated a total loss of postischemic reactive hyperemia (only 1 of the 11 patients presented a weak reactive hyperemia). Since no macroangiopathy was detectable in the upstream arm arteries, primary cutaneous microangiopathy can be assumed in patients with cardiac allograft vasculopathy and severe hypercholesterolemia.

Effect of sildenafil on coronary active and reactive hyperemia

Sildenafil, a selective inhibitor of phosphodiesterase type 5, produces relaxation of isolated epicardial coronary artery segments by causing accumulation of cGMP. Because shear-induced nitric oxide-dependent vasodilation is mediated by cGMP, this study was performed to determine whether sildenafil would augment the coronary resistance vessel dilation that occurs during the high-flow states of exercise or reactive hyperemia. In chronically instrumented dogs, sildenafil (2 mg/kg per os) augmented the vasodilator response to acetylcholine, with a leftward shift of the dose-response curve relating coronary flow to acetylcholine dose. Sildenafil caused a 6. 7 +/- 2.1 mmHg decrease of mean aortic pressure, which was similar at rest and during treadmill exercise (P < 0.05), with no change of heart rate, left ventricular (LV) systolic pressure, or LV maximal first time derivative of LV pressure. Sildenafil tended to increase myocardial blood flow at rest and during exercise (mean increase = 14 +/- 3%; P < 0.05 by ANOVA), but this was associated with a significant decrease in hemoglobin, so that the relationship between myocardial oxygen consumption and oxygen delivery to the myocardium (myocardial blood flow x arterial O(2) content) was unchanged. Furthermore, sildenafil did not alter coronary venous PO(2), indicating that the coupling between myocardial blood flow and myocardial oxygen demands was not altered. In addition, sildenafil did not alter the peak coronary flow rate, debt repayment, or duration of reactive hyperemia that followed a 10-s coronary occlusion. The findings suggest that cGMP-mediated resistance vessel dilation contributes little to the increase in myocardial flow that occurs during exercise or reactive hyperemia.

Postischemic vasodilation, endothelial activation, and cardiovascular remodeling in end-stage renal disease

Cardiovascular complications are the major cause of death in end-stage renal disease (ESRD) patients. These complications are associated with concomitant cardiac and vascular remodeling, including left ventricular (LV) hypertrophy and hypertrophy of arterial walls. The endothelium influences the process of arterial remodeling. ESRD patients are characterized by the development of both cardiovascular remodeling and endothelial dysfunction. Common carotid artery (CCA) intima-media thickness (IMT), CCA diameter, CCA distensibility, LV mass, and function were determined in 60 stable ESRD patients on hemodialysis and 34 age-, sex-, and blood pressure (BP)-matched controls, and their relationships with endothelial alterations were estimated by forearm postischemic vasodilation [flow debt repayment (FDR)] measured by venous plethysmography. We also evaluated the relationships between FDR and several cardiovascular risk factors or markers of inflammatory response or endothelial activation, for example, duration of dialysis, BP, smoking habits, cholesterol, parathormone (PTH), serum albumin, plasma fibrinogen, C-reactive protein (CRP), plasma homocysteine, plasminogen activator inhibitor (PAI-1), and von Willebrand factor (vWF). ESRD patients had increased LV mass, CCA diameter and CCA IMT, and had decreased CCA distensibility (P < 0.05). While the postischemic peak flow was comparable in controls and ESRD patients (29.2 +/- 9.1 vs. 27.9 +/- 0.2 mL/100 mL/min), FDR was lower in ESRD patients (116 +/- 31 vs. 88 +/- 32%, P < 0.001) because of the shorter duration of vasodilation (127 +/- 36 vs. 96 +/- 32 s, P < 0.001). The time to complete FDR was longer in ESRD patients (110 +/- 54 vs. 162 +/- 72 s, P < 0.001). ESRD patients had lower high-density lipoprotein cholesterol and serum albumin (P < 0.01) and higher triglycerides, fibrinogen, plasma homocysteine, vWF (P < 0.01), and PAI-1 (P < 0.05). For ESRD patients, significant negative age- and pressure-independent correlations were established between FDR and CCA diameter, duration of dialysis, and PAI-1. FDR was positively correlated with serum albumin. FDR and time to FDR were negatively correlated with CCA IMT and LV mass. CCA distensibility was positively associated with FDR (P < 0.001) and negatively with time to FDR (P < 0.001). The PAI-1 concentration was positively correlated with CCA IMT (P < 0.01) and negatively with CCA distensibility (P < 0.001). Our data provide the first evidence that cardiac and arterial remodeling in ESRD patients are inversely related to forearm reactive hyperemia. The diminished hyperemic response is due to the shorter duration of hyperemia and is associated with higher concentrations of serum markers of endothelial activation, suggesting that, in ESRD patients, endothelial dysfunction may be a factor influencing cardiovascular changes.

Capillary Microscopic and Rheological Dimensions for the Diagnosis of von Willebrand Disease in Comparison to other Haemorrhagic Diatheses

SummaryIt is known that angiodysplasia influence macrocirculation as well as microcirculation in patients with vWD. In the present study it was examined if intravital capillary microscopic dimensions (morphologic and dynamic) in skin (nailfold) in combination with rheologic parameters could give indications for the presence of vWD in patients with haemorrhagic diathesis.Patients with vWD (n = 100; 92 type 1: definite type 1:78 and possible type 1:14; 8 type 2A) have in comparison to patients with other haemorrhagic diathesis [thrombocytopathy (n = 122), thrombocytopenia (n = 101), severe haemophilia A (n = 50) and severe haemophilia B (n = 20), congenital dysfibrinogenaemia (n = 22), oral anticoagulation with phenprocoumone (n = 112)] and to apparently healthy subjects (n = 100) a significantly increased capillary torquation (median index: 3.5), a venolar and an arteriolar capillary dilatation (median: 16.5 µm; median: 15.1 µm) and the highest part of microscopic bleedings (extravasates) with 40% in the video capillary microscopy as morphological changes. Only the congenital dysfibrinogenaemia appears with a larger dilatation in venolar capillaries (median: 14.5 µm). Microscopic bleedings are much less common in other haemorrhagic diatheses with a frequency between 4% and 13%.In the vWD a significantly reduced duration of reactive hyperaemia (median: 150 sec). This is the only dynamic change that can be taken as a possible hint for a loss of flexibility within the precapillary vessels. A significantly reduced plasma viscosity (&lt; 1.25 mPas) is typical for the vWD due to the increase of the shear stress in blood plasma because of the reduction of vWF-activities. Changes of the capillary morphology (dilatation, extravasates, capillary torquation) and the hypoplasmaviscosity are most sensitive for the vWD (75%, 65%, 40%, 80%) with a fairly high specifity (up to 93%) and a positive predictive value of 99%.As a conclusion it seems reasonable to discuss the introduction of video capillary microscopy as a screening test for haemostasiological and angiological centers.

Ischemic and pressure-induced hyperemia: A comparison

Objective: There is reason to question whether hyperemia after pressure occlusion is caused solely by local ischemia. This study quantitatively compared the response to the two forms of occlusion on the finger. Design: Blood flow was measured by laser Doppler continuously before, during, and for 40 minutes after a 2-minute occlusion of flow at the finger dorsum and at the plantar surface of the finger tip (finger pulp), which has a much higher arteriolar density than the dorsum. Occlusion to the same low level was carried out either with a cuff at the base of the finger or by direct pressure of the laser Doppler probe head. Comparison experiments were performed with the probe head heated to 44°C to elicit maximal local vasodilation. Setting: Outpatient clinic. Participants: Eleven healthy volunteers. Main Outcome Measures: Magnitude and duration of skin blood flow after occlusion. Results: Cuff occlusion at the base of the finger produced a typical, short-lived hyperemic response at both finger dorsum and finger pulp. The peak level at finger dorsum was 17.6 ± 1.4mL/min/100g, approximately a twofold increase over the baseline flow level. The duration of the hyperemic response was 3.6 ± 0.8 minutes. The baseline flow at the finger pulp was three times greater than at the finger dorsum, and peak flow after occlusion was also three times higher (44.3 ± 2.6 mL/min/ 100g). The duration of hyperemia at finger pulp was 4.2 ± 0.9 minutes. After pressure occlusion at the finger dorsum the hyperemic peak was higher (26.7 ± 4.2 mL/min/100g; p < .05) and the duration of hyperemia was four times longer (16.9 ± 2.3 minutes; p < .01) than after cuff occlusion. At the finger pulp, the pressure-induced hyperemic peak was also greater than the peak after cuff occlusion (56.3 ± 1.7mL/min/100g; p < .05), with a longer duration than after cuff occlusion (11.1 ± 1.1 min; p < .01). Thermal stimulation significantly reduced the differences between cuff- and pressure-induced occlusion. There was a slow increase in flow over the 40-minute monitoring period. The maximal flow reached was approximately 100mL/min/100g at both finger dorsum and finger pulp. At both sites, however, the maximal flow level was attained more rapidly than the control condition without prior occlusion. Conclusions: These results confirmed that the pressure-induced hyperemic response is greater and of longer duration than that produced by flow ischemia alone. Thermal stimulation essentially abolishes the differences, suggesting that there is a common mechanism of vasodilatation. The mechanistic differences between pressure-induced and ischemic hyperemia remain to be determined.

Hepatic haemodynamics during and after brief occlusion of the hepatic artery

Experiments in an instrumented, anaesthetised canine model have: (a) measured the effect of a 5–10 min period of hepatic artery occlusion on hepatic haemodynamics and oxygen consumption ( n = 5); and (b) quantified the post-occlusion reactive hyperaemic responses of the hepatic artery to periods of occlusion ranging from 1 s to 5 min in dogs with interrupted portal blood flow ( n = 5) compared with animals possessing a normal hepatic circulation ( n = 5). (a) Hepatic artery occlusion for 5–10 min produced no significant change in portal venous blood flow or portal vascular resistance. A decrease in total hepatic oxygen consumption (mean, 41%) occurred, which was proportionately greater than the loss of total hepatic blood flow (mean, 33%). (b) Portal flow interruption caused a mean increase in hepatic arterial blood flow of 17.4 ml 100 g −1 per min. The maximum peak hyperaemic response of the hepatic artery after arterial flow occlusion was the same for both groups of dogs studied (34–35 ml 100 g −1 per min), a value achieved following 1 min arterial occlusion in the dogs with intact portal blood supply, and following 4 min arterial occlusion in portally-deprived animals. After a 5 min period of arterial occlusion, there was a 5-fold greater duration of reactive hyperaemia ( P = 0.002) and a 12-fold greater hyperaemic flow volume ( P = 0.049) in the portally-deprived dogs compared with normal dogs. These findings probably reflect a more marked hepatic oxygen debt and accumulation of vasoactive metabolites such as adenosine during hepatic arterial occlusion in the dogs lacking portal blood flow.

Evaluation of the Determinants of Flow — Mediated Radial Artery Vasodilatation in Humans

The relative importance of the early peak response during hyperaemia and of the duration of the hyperaemic phase (tl/2: blood flow velocity half time and AUCt1/2: area under the curve of flow velocity at tl/2) in the magnitude of the flow-dependent vasodilatation of the radial artery was determined in humans. Radial artery diameter was measured continuously in 18 healthy volunteers using an echotracking system coupled to a Doppler device for the measurement of the radial blood flow. In 9 subjects, arterial parameters were measured at baseline and during 3 hyperaemic tests performed after 2, 5 or 10 minutes of ischaemia. Reproducibility of the measured parameters was studied in 9 other subjects. Radial artery diameter, AUCt1/2 and t1/2 increased proportionally with the duration of ischaemia. In contrast, the peak flow response was already maximal after 5 minutes of ischaemia. The regression analysis showed that the best fit model after stepwise analysis only included t1/2 (r=0.85, p<0.001). There was no correlation between the peak flow values andthe duration of hyperaemia (14.29, pd.14). These results demonstrate that conduit arteries postischaemic flow-dependent vasodilatation in humans is both determined by the peak value and by the duration of the hyperaemic phase and suggest that these two components must be consirered when comparing this index of NO release between different groups of subjects.

Comparison of pharmacologic stress agents

In choosing a pharmacologic agent for stress testing, the clinician must keep a number of things in mind, such as the diagnostic utility of the agent or in what situations a vasodilator or catecholamine will be the better choice. Although all stress agents produce similar diagnostic accuracy for CAD, vasodilators have a higher cardiac uptake than catecholamines, and the addition of exercise improves the heart/background contrast ratios. With regard to physiologic comparisons, exercise or dobutamine will double coronary perfusion compared with baseline flow, but vasodilators produce a threefold or fourfold increase. The clinician should also keep in mind that adenosine will produce the shortest duration of hyperemia, whereas dobutamine and arbutamine produce a longer effect, and dipyridamole has the longest duration. If electrophysiologic considerations are important, exercise and catecholamines accelerate sinoatrial and atrioventricular conduction and are not typically associated with heart block. In contrast, adenosine can cause transient atrioventricular block, but this rarely occurs with dipyridamole. Clinical factors also must be considered. Although clinical utility of pharmacologic stress agents in the first 24 hours after infarction has not been demonstrated, the prognostic utility of vasodilators in the subsequent 2- to 4-day period has been shown. With patients with pulmonary disease (asthma) who do not have wheezing, dipyridamole can be used, but dobutamine or arbutamine should be used in patients with recent respiratory failure or bronchospasm before testing. In patients with left bundle branch block, vasodilators are the preferred stress agents rather than synthetic catecholamines or dynamic exercise. In the first crossover thallium imaging, there was good overall agreement in segmental perfusion comparing adenosine and dipyridamole, but there was a tendency for adenosine to detect more ischemia. The clinical significance (if any) for these findings has yet to be determined.