Retinal vascular caliber and brachial flow-mediated dilation: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND PURPOSE: Retinal vascular caliber changes have been shown to predict stroke, but the underlying mechanism of this association is unknown. We examined the relationship between retinal vascular caliber with brachial flow-mediated dilation (FMD), a measure of systemic endothelial function. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based study of persons 45 to 84 years of age residing in 6 US communities free of clinical cardiovascular disease at baseline. Brachial FMD data were collected at baseline (July 2000 to June 2002), and retinal vascular caliber was measured from digital retinal photographs at the second examination, immediately after the first (August 2002 to January 2004). Data were available for 2851 participants for analysis. RESULTS: The mean brachial FMD was 4.39+/-2.79%. After adjusting for age and gender, brachial FMD was reduced in persons with wider retinal venular caliber (changes in FMD -0.25, 95% CI, -0.36, - 0.13; P<0.001, per SD increase in venular caliber). This relationship persists after adjusting for systolic blood pressure, serum total cholesterol, use of lipid-lowering and antihypertensive medication, body mass index, current smoking status, and hemoglobinA(1C) (-0.18; 95% CI -0.30, - 0.06; P=0.004, per SD increase in venular caliber). Brachial FMD was not associated with retinal arteriolar caliber. CONCLUSIONS: Persons with wider retinal venules have reduced brachial FMD, independent of other vascular risk factors. This suggests that retinal venular caliber, previously shown to predict stroke, may be a marker of underlying systemic endothelial dysfunction.

Are retinal microvascular caliber changes associated with severity of coronary artery disease in symptomatic cardiac patients?

OBJECTIVES: Recent population-based studies have shown that retinal vascular caliber may predict the risk of clinical coronary artery disease (CAD) events. Whether this association is related to macro- or microvascular mechanisms remains unknown. We investigated the relationship of retinal vascular caliber with severity and extent of CAD in symptomatic cardiac patients. MATERIALS AND METHODS: Overall, 98 patients attending diagnostic coronary angiography were recruited. Coronary angiography was used to assess for the severity and extent of CAD. Digital retinal photography was performed immediately prior to cardiac catheterization, and retinal vascular caliber was measured from these photographs by using a computer program and summarized as central retinal arteriolar (CRAE) and venular (CRVE) equivalents. RESULTS: Retinal arteriolar and venular calibers were not associated with increasing severity of CAD, as assessed by Leaman scores (CRAE/CRVE: P for trend=0.17/0.57), presence of clinically significant CAD (CRAE/CRVE: P=0.35/0.32), or number of diseased vessels (CRAE/CRVE: P for trend=0.18/0.69). CONCLUSIONS: Retinal vascular caliber changes are not associated with the severity of obstructive CAD in symptomatic patients. These data suggest that the association of retinal vascular caliber with clinical CAD seen in epidemiological studies may not be applicable to clinical symptomatic patients and may be related to microvascular, rather than macrovascular, mechanisms.

Outcomes after percutaneous coronary intervention of ostial lesions in the era of drug-eluting stents.

BACKGROUND: Ostial lesions are a difficult subset associated with suboptimal outcomes after percutaneous coronary intervention (PCI). The aim of this study was to analyze outcomes of ostial lesions in contemporary Australian interventional practice. METHODS: The study population comprised 1,713 consecutive patients who underwent PCI for proximal lesions of the left anterior descending, left circumflex, and right coronary arteries, who were prospectively enrolled in the Melbourne Interventional Group Registry (February 2004-December 2006). We compared the in-hospital, 30-day, and 1-year outcomes of the 109 patients undergoing PCI for ostial, with the 1,604 patients with proximal nonostial lesions. Left main and bifurcation lesions were excluded. RESULTS: Patients in the ostial group were older (mean age 68.8 +/- 11 vs. 64.9 +/- 12 years; P = 0.001), and there was a greater proportion of women (38.5% vs. 28.0%; P = 0.021). Other clinical characteristics were similar. The nonostial group were more likely receive a stent (94.6% vs. 87.2%; P = 0.005) but drug-eluting stents (DES) were deployed more often in the ostial group (47.9% vs. 66.1%; P < 0.0001). There was lower procedural success, with no significant difference in in-hospital death, bleeding or emergency PCI, but unplanned in-hospital coronary artery bypass grafting was more frequent in the ostial group (4.8% vs. 1.0%; P = 0.007). There was no difference in 30-day major adverse cardiac events. However, 12-month death (8.8% vs. 4%, log rank P = 0.032) and MACE (24.2% vs. 13.8%, log rank P = 0.005) were higher in the ostial group than the nonostial group with trends to increased incidence of myocardial infarction (6.6% vs. 4.7%, P = NS), and target vessel revascularization (13.2% vs. 7.9%, P = NS). CONCLUSION: In contemporary, Australian interventional practice, PCI for ostial lesions is associated with a high incidence of adverse outcome at one year despite the introduction of DES.

Acute retinal arteriolar emboli after cardiac catheterization.

BACKGROUND AND PURPOSE: There are concerns that cardiac catheterization may cause retinal embolization, a risk marker for cerebrovascular emboli and stroke. We describe the incidence of acute retinal embolism after cardiac catheterization. METHODS: One hundred unselected patients attending a tertiary referral center for diagnostic cardiac catheterization were recruited. Digital retinal photography (optic disc and macular fields) was performed precatheterization and within 3 hours postcatheterization. New retinal emboli were identified by a senior researcher and confirmed by a retinal specialist. RESULTS: There was one case of retinal embolus precatheterization. Two patients (incidence 2.02%; 95% CI, 0.25 to 7.11) developed new retinal arteriolar emboli after catheterization. No patient developed clinically apparent visual or neurological changes. CONCLUSIONS: The risk of acute retinal embolism immediately after cardiac catheterization is 2%. This finding indicates that the retinal, and possibly the cerebral circulation, may be compromised more frequently than is clinically apparent as a complication of cardiac catheterization.

Tako-tsubo-like cardiomyopathy after EpiPen administration.

Tako-tsubo-like cardiomyopathy is characterized by acute chest pain, electrocardiographic changes and increased cardiac enzymes in the absence of obstructive coronary vessel disease. We describe the development of tako-tsubo-like cardiomyopathy in an elderly woman after the use of an EpiPen for generalized urticaria and angioedema. As adrenaline may participate in the pathogenesis of this condition, the need for careful patient selection and education in the use of adrenaline self-injectors remains imperative.

Effect of adenosine triphosphate-sensitive potassium channel inhibitors on coronary metabolic vasodilation.

The ATP-sensitive potassium (K(ATP)) channel is a distinct type of potassium ion channel that is found in the vascular smooth muscle cells of a variety of mammalian species, including humans. The activity of K(ATP) channels is determined by many factors including cellular ATP and ADP levels, thus providing a link between cellular metabolism and vascular tone through its effects on membrane potential. Experimental studies using inhibitors of K(ATP) channels, such as the sulfonuylurea class of drugs, indicate that these channels modulate coronary vascular tone including the hyperaemia induced by increased myocardial metabolism. This review examines the evidence linking K(ATP) channels to the regulation of coronary vascular tone and the potential clinical implications of pharmacologic therapies that act on K(ATP) channels.

Risk factors for the development of retroperitoneal hematoma after percutaneous coronary intervention in the era of glycoprotein IIb/IIIa inhibitors and vascular closure devices.

OBJECTIVES: We sought to determine the incidence, clinical features, and risk factors for retroperitoneal hematoma (RPH) after percutaneous coronary intervention (PCI). BACKGROUND: Little is known about the clinical features, outcomes, and determinants of this serious complication in the contemporary era of PCI. METHODS: A retrospective analysis yielded 26 cases of RPH out of 3,508 consecutive patients undergoing PCI between January 2000 and January 2004. Cases were compared with a randomly selected sample of 50 control subjects without RPH. RESULTS: The incidence of RPH was 0.74%. Features of RPH included abdominal pain (42%), groin pain (46%), back pain (23%), diaphoresis (58%), bradycardia (31%), and hypotension (92%). The mean systolic blood pressure nadir was 75 mm Hg. The hematocrit dropped by 11.5 +/- 5.1 points from baseline in RPH patients, as compared with 2.3 +/- 3.3 points in controls (p < 0.0001). The mean hospital stay was longer in RPH patients (2.9 +/- 3.8 days vs. 1.7 +/- 1.5 days, p = 0.06). The following variables were found to be independent predictors of RPH: female gender (odds ratio [OR] 5.4, p = 0.005), low body surface area (BSA <1.73 m(2); OR 7.1, p = 0.008), and higher femoral artery puncture (OR 5.3, p = 0.013). There was no association between RPH and arterial sheath size, use of glycoprotein IIb/IIIa inhibitors, or deployment of a vascular closure device. CONCLUSIONS: Female gender, low BSA, and higher femoral artery puncture are significant risk factors for RPH. Awareness of the determinants and clinical features of RPH may aid in prevention, early recognition, and prompt treatment.

Effect of ATP-sensitive potassium channel inhibition on resting coronary vascular responses in humans.

Experimental data suggest that vascular ATP-sensitive potassium (K(ATP)) channels regulate coronary blood flow (CBF), but their role in regulating human CBF is unclear. We sought to determine the contribution of K(ATP) channels to resting conduit vessel and microvascular function in the human coronary circulation. Twenty-five patients (19 male/6 female, aged 56 +/- 12 years) were recruited. Systemic and coronary hemodynamics were assessed in 20 patients before and after K(ATP) channel inhibition with graded intracoronary glibenclamide infusions (4, 16, and 40 microg/min), in an angiographically smooth or mildly stenosed coronary artery following successful elective percutaneous coronary intervention to another vessel. Coronary blood velocity was measured with a Doppler guidewire and CBF calculated. Adenosine-induced hyperemia was determined following bolus intracoronary adenosine injection (24 microg). Time control studies were undertaken in 5 patients. Compared with vehicle infusion (0.9% saline), glibenclamide reduced resting conduit vessel diameter from 2.5 +/- 0.1 to 2.3 +/- 0.1 mm (P<0.01), resting CBF by 17% (P=0.05), and resting CBF corrected for rate pressure-product by 18% (P=0.01) in a dose-dependent manner. A corresponding 24% increase in coronary vascular resistance was noted at the highest dose (P<0.01). No alteration to resting CBF was noted in the time control studies. Glibenclamide reduced peak adenosine-induced hyperemia (P=0.01) but did not alter coronary flow reserve. Plasma insulin increased from 5.6 +/- 1.2 to 7.6 +/- 1.3 mU/L (P=0.02); however, plasma glucose was unchanged. Vascular K(ATP) channels are involved in the maintenance of basal coronary tone but may not be essential to adenosine-induced coronary hyperemia in humans.

Novel index for invasively assessing the coronary microcirculation.

BACKGROUND: A relatively simple, invasive method for quantitatively assessing the status of the coronary microcirculation independent of the epicardial artery is lacking. METHODS AND RESULTS: By using a coronary pressure wire and modified software, it is possible to calculate the mean transit time of room-temperature saline injected down a coronary artery. The inverse of the hyperemic mean transit time has been shown to correlate with absolute flow. We hypothesize that distal coronary pressure divided by the inverse of the hyperemic mean transit time provides an index of microcirculatory resistance (IMR) that will correlate with true microcirculatory resistance (TMR), defined as the distal left anterior descending (LAD) pressure divided by hyperemic flow, measured with an external ultrasonic flow probe. A total of 61 measurements were made in 9 Yorkshire swine at baseline and after disruption of the coronary microcirculation, both with and without an epicardial LAD stenosis. The mean IMR (16.9+/-6.5 U to 25.9+/-14.4 U, P=0.002) and TMR (0.51+/-0.14 to 0.79+/-0.32 mm Hg x mL(-1) x min(-1), P=0.0001), as well as the % change in IMR (147+/-66%) and TMR (159+/-105%, P=NS versus IMR % change), increased significantly and to a similar degree after disruption of the microcirculation. These changes were independent of the status of the epicardial artery. There was a significant correlation between mean IMR and TMR values, as well as between the % change in IMR and % change in TMR. CONCLUSIONS: Measuring IMR may provide a simple, quantitative, invasive assessment of the coronary microcirculation.

Comparison of coronary thermodilution and Doppler velocity for assessing coronary flow reserve.

BACKGROUND: Thermodilution coronary flow reserve (CFRthermo) is a new technique for invasively measuring coronary flow reserve (CFR) with a coronary pressure wire and is based on the ability of the pressure transducer to also measure temperature changes. Whether CFRthermo correlates well enough with absolute flow-derived CFR (CFRflow) to replace Doppler wire-derived CFR (CFRDoppler) remains unclear. METHODS AND RESULTS: In an open-chest pig model, CFRthermo was measured in the left anterior descending (LAD) artery and compared with CFRDoppler and CFRflow, measured with an external flow probe placed around the LAD. In 9 pigs, CFR was measured simultaneously by all 3 means in the normal LAD and after creation of an epicardial LAD stenosis. To determine the added effect of microvascular disease, measurements of flow reserve were also performed after disruption of the coronary microcirculation with embolized microspheres. Intracoronary papaverine (20 mg) was used to induce hyperemia. In a total of 61 paired measurements, CFRthermo correlated strongly with the reference standard CFRflow (r=0.85, P<0.001). CFRDoppler correlated less well with CFRflow (r=0.72, P<0.001). Bland-Altman analysis showed a closer agreement between CFRthermo and CFRflow. CONCLUSIONS: CFRthermo correlates better with CFRflow than does CFRDoppler.

Effect of ATP-sensitive potassium channel inhibition on coronary metabolic vasodilation in humans.

OBJECTIVE: Experimental evidence indicates that ATP-sensitive potassium (K(ATP)) channels regulate coronary blood flow (CBF). However, their contribution to human coronary metabolic vasodilation is unknown. METHODS AND RESULTS: Seventeen patients (12 male, age 58+/-10 years) were studied. Coronary hemodynamics were assessed before and after K(ATP) channel inhibition with subselective intracoronary glibenclamide infused at 40 microg/min in an angiographically smooth coronary artery after successful percutaneous coronary intervention to another vessel. Metabolic vasodilation was induced by 2 minutes of rapid right ventricular pacing. Coronary blood velocity was measured with a Doppler guidewire and CBF calculated. The time course of hyperemia was recorded for 2 minutes after pacing, and hyperemic volume was estimated from the area under the flow-versus-time curve (AUC). Compared with vehicle infusion (0.9% saline), glibenclamide reduced resting CBF by 9% (P=0.04) and increased resting coronary vascular resistance (CVR) by 15% (P=0.03). Glibenclamide reduced pacing-induced peak CBF (50.8+/-6.8 versus 42.0+/-5.4 mL/min, P=0.001), peak CBF corrected for baseline flow (25.1+/-4.6 versus 17.6+/-3.1 mL/min, P=0.01), and increased minimum CVR (2.6+/-0.3 versus 3.1+/-0.3 mm Hg/mL per minute, P=0.002). Compared with vehicle, glibenclamide reduced total AUC at 2 minutes (3535+/-397 versus 3027+/-326 mL, P=0.001). CONCLUSIONS: Vascular K(ATP) channels appear to be involved in functional coronary hyperemia after metabolic stimulation.

Time course of plasma adhesion molecules in acute coronary syndromes.

BACKGROUND: Atherosclerosis is an inflammatory process in which adhesion molecules play an intimate role in both the initiation and progression of lesions. It is postulated that they also play a role in the presentation of acute coronary syndromes and that plasma levels thereafter may be of potential prognostic significance. The stability of sample levels under different laboratory conditions is unknown. METHODS: Stability of plasma levels was assessed in six healthy subjects under four different laboratory conditions. The time course of levels was studied in 57 patients with acute chest pain, 21 of non-cardiac aetiology, 23 unstable angina and 13 acute myocardial infarction, at mean times of 2.3, 8.2 and 17.3 h after the onset of pain. Samples were assayed for intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin, E-selectin and C-reactive protein (CRP). RESULTS: ICAM-1, VCAM-1, P-selectin and E-selectin levels did not differ under different laboratory conditions. Levels were similar at presentation in patients with acute chest pain of non-cardiac aetiology, unstable angina or acute myocardial infarction (median levels ICAM-1 269 microg/l, VCAM-1 379 microg/l, P-selectin 167 microg/l and E-selectin 53 microg/l). Levels did not change in the 24 h following the onset of pain. CRP levels did not differ at presentation between groups (median level 2.1 mg/l), but rose more than 12 h after the onset of pain in the group with acute myocardial infarction (P < 0.05). CONCLUSION: Adhesion molecule levels are stable under normal laboratory sample handling conditions. Levels do not change in the 24 h following the onset of chest pain of non-cardiac or acute ischaemic aetiology.

"Tako-tsubo-like left ventricular dysfunction": a clinical entity mimicking acute myocardial infarction with a favorable prognosis.

An emotionally-distressed, elderly Caucasian woman presented with chest pain and hypertension. Electrocardiogram showed inferior ST-segment elevation, and an urgent cardiac catheterization was performed. Coronary angiography revealed normal appearing coronary arteries; however, left ventriculography showed extensive left ventricular apical akinesis. The patient had a mild rise in cardiac enzyme levels indicative of myocardial injury. She was discharged after an uncomplicated in-hospital course. One month later, the left ventricular wall motion abnormality had improved. In this report, the authors discuss this compilation of findings known as tako-tsubo-like left ventricular dysfunction.

Reliability of different image analysis methods for scanning laser Doppler flowmetry.

PURPOSE: To assess reliability and reproducibility of different analysis methods for retinal capillary flow, volume, and velocity from scanning laser Doppler flowmetry (SLDF) topography. MATERIAL AND METHODS: SLDF topography analysis using the default retinal flowmeter (HRF) were compared to that using automatic full-field perfusion image analyzer (AFFPIA) and quantified as intraclass correlation coefficients (ICC). RESULTS: The AFFPIA full-field method had the highest reliability, with ICC 0.99 for capillary flow. The reproducibility using the AFFPIA full-field method was high ICC 0.74 for capillary flow. CONCLUSIONS: The AFFPIA full-field method is highly reliable and superior to the default HRF software.

CT coronary angiography predicts the outcome of percutaneous coronary intervention of chronic total occlusion.

BACKGROUND: The success rate of percutaneous coronary intervention (PCI) of chronic total occlusions (CTO) is relatively low. Further evaluation of CTO lesion with CT coronary angiography (CT-CA) may help to better select patients that would benefit from percutaneous revascularization. We aimed to test the possible association between failed PCI and transluminal calcification of CTO as assessed by CT-CA. METHODS: Patients with CTO awaiting PCI were scanned with a 16-slice CT. A cardiologist and a radiologist assessed transluminal calcification of CTO lesions on CT images while an interventional cardiologist at a core laboratory assessed conventional variables of invasive fluoroscopic coronary angiography (FCA) associated with failed PCI of CTO. The significance of CT and FCA variables in association with failed PCI were analyzed. RESULTS: In a cohort of 39 patients with 43 CTO lesions, 24 lesions were successfully revascularized. Transluminal calcification > or =50% as assessed on CT-CA was strongly associated with failed PCI (odds ratio [OR] of PCI success = 0.10, 95% confidence interval [CI]: 0.02-0.47, P = 0.003). Blunt stump as seen on FCA was also associated with failed PCI (OR of PCI success = 0.24, 95% CI: 0.07-0.86, P = 0.029). There was no significant evidence to support that the duration of CTO, presence of side branch and bridging collaterals, and the absence of microchannels as assessed with FCA were associated with failed PCI. On multivariate analysis, transluminal calcification > or =50% on CT-CA was the only significant predictor of failed PCI. CONCLUSIONS: Heavy transluminal calcification as assessed with CT-CA is an independent predictor of failed PCI of CTO. CT-CA may have a role in the work-up of CTO patients prior to PCI.

Arterial remodeling correlates positively with serological evidence of inflammation in patients with chronic stable angina pectoris.

Positive coronary artery remodeling is associated with unstable coronary syndromes. Serum inflammatory markers, including high-sensitivity CRP (hsCRP), can predict future risk of acute coronary events in patients with stable coronary artery disease. We sought to elucidate the relationship of specific serum inflammatory markers with intravascular ultrasound (IVUS) estimation of coronary artery remodeling in patients with stable coronary artery disease. Thirty-one sequential patients at our institution undergoing IVUS-assisted percutaneous coronary intervention (PCI) with stable coronary artery disease were enrolled. Automated IVUS pullback and offline analysis were performed in all patients. Images were analyzed for vessel wall area (VWA) and lumen area (LA), at the culprit lesion and at a proximal reference site, and the remodeling index (RI) was calculated. Positive and negative remodeling were defined as a RI of > 1.05 and < 0.95, respectively. ELISA essays were performed for soluble VCAM-1, ICAM-1 and E-selectin. The distribution of data followed a lognormal distribution. By defining arterial remodeling as simply positive or negative, significant differences were identified for log E-selectin only (1.80 +/- 0.04 versus 1.62 +/- 0.05, respectively; p = 0.02). The RI correlation coefficient was 0.38 (p = 0.04) for log sVCAM-1 and 0.42 (p = 0.02) for log sICAM-1. The log E-selection and RI correlation coefficient, although weaker at 0.32, showed a trend toward significance (p = 0.08). There was no significant correlation between log hsCRP and RI (p = 0.42). Using step-wise multivariate analysis, log sVCAM-1 only remained an independent predictor of the RI (p = 0.03). Positive coronary artery remodeling correlates with serological markers of inflammation in patients with stable coronary artery disease.

Transient left ventricular dysfunction under severe stress: brain-heart relationship revisited.

PURPOSE: Transient left ventricular dysfunction in patients under emotional or physical stress, also known as tako-tsubo-like left ventricular dysfunction, has been recently been recognized as a distinct clinical entity. The aims of this review are to define this phenomenon and to explore its similarities to the left ventricular dysfunction seen in patients with acute brain injury. METHODS: MEDLINE database, bibliographies of each citation for relevant articles, and consultation with clinical experts were used to examine the clinical picture of tako-tsubo-like left ventricular dysfunction. RESULTS: We identified case series and a systematic review that report on patients with this syndrome. This phenomenon occurs predominantly in female patients, presenting with a variety of ST-T segment changes and mildly elevated cardiac enzymes that mimic an acute coronary syndrome. The left ventricular dysfunction, typically showing a hyperkinetic basal region and an akinetic apical half of the ventricle, occurs in the absence of obstructed epicardial coronary arteries. The ventricular dysfunction usually resolves within weeks with a generally favorable prognosis. This phenomenon has similarities to that seen in patients with acute brain injury with regard to clinical presentation, pathology, and its reversible nature. CONCLUSIONS: Transient left ventricular dysfunction occurs in the absence of obstructive epicardial coronary artery disease. In its broadest sense, this phenomenon may encompass a range of disorders including left ventricular dysfunction after central nervous system injury.

Acute and chronic effects of flavanol-rich cocoa on vascular function in subjects with coronary artery disease: a randomized double-blind placebo-controlled study.

Evidence suggests that flavonoid-containing diets reduce cardiovascular risk, but the mechanisms responsible are unclear. In the present study, we sought to determine the effect of flavanol-rich cocoa on vascular function in individuals with CAD (coronary artery disease). Forty subjects (61+/-8 years; 30 male) with CAD were recruited to a 6-week randomized double-blind placebo-controlled study. Subjects consumed either a flavanol-rich chocolate bar and cocoa beverage daily (total flavanols, 444 mg/day) or matching isocaloric placebos daily (total flavanols, 19.6 mg/day) for 6 weeks. Brachial artery FMD (flow-mediated dilation) and SAC (systemic arterial compliance) were assessed at baseline, 90 min following the first beverage and after 3 and 6 weeks of daily consumption. Soluble cellular adhesion molecules and FBF (forearm blood flow) responses to ACh (acetylcholine chloride; 3-30 microg/min) and SNP (sodium nitroprusside; 0.3-3 microg/min) infusions, forearm ischaemia and isotonic forearm exercise were assessed at baseline and after 6 weeks. FMD, SAC and FBF responses did not differ between groups at baseline. No acute or chronic changes in FMD or SAC were seen in either group. No difference in soluble cellular adhesion molecules, FBF responses to ischaemia, exercise, SNP or ACh was seen in the group receiving flavanol-rich cocoa between baseline and 6 weeks. These data suggest that over a 6-week period, flavanol-rich cocoa does not modify vascular function in patients with established CAD.

Effects of inhibition of ATP-sensitive potassium channels on metabolic vasodilation in the human forearm.

Experimental data suggest that vascular ATP-sensitive potassium (K(ATP)) channels may be an important determinant of functional hyperaemia, but the contribution of K(ATP) channels to exercise-induced hyperaemia in humans is unknown. Forearm blood flow was assessed in 39 healthy subjects (23 males/16 females; age 22+/-4 years) using the technique of venous occlusion plethysmography. Resting forearm blood flow and functional hyperaemic blood flow (FHBF) were measured before and after brachial artery infusion of the K(ATP) channel inhibitors glibenclamide (at two different doses: 15 and 100 microg/min) and gliclazide (at 300 microg/min). FHBF was induced by 2 min of non-ischaemic wrist flexion-extension exercise at 45 cycles/min. Compared with vehicle (isotonic saline), glibenclamide at either 15 microg/min or 100 microg/min did not significantly alter resting forearm blood flow or peak FHBF. The blood volume repaid at 1 and 5 min after exercise was not diminished by glibenclamide. Serum glucose was unchanged after glibenclamide, but plasma insulin rose by 36% (from 7.2+/-0.8 to 9.8+/-1.3 m-units/l; P =0.02) and 150% (from 9.1+/-1.3 to 22.9+/-3.5 m-units/l; P =0.002) after the 15 and 100 microg/min infusions respectively. Gliclazide also did not affect resting forearm blood flow, peak FHBF, or the blood volume repaid at 1 and 5 min after exercise, compared with vehicle (isotonic glucose). Gliclazide induced a 12% fall in serum glucose (P =0.009) and a 38% increase in plasma insulin (P =0.001). Thus inhibition of vascular K(ATP) channels with glibenclamide or gliclazide does not appear to affect resting forearm blood flow or FHBF in healthy humans. These findings suggest that vascular K(ATP) channels may not play an important role in regulating basal vascular tone or skeletal muscle metabolic vasodilation in the forearm of healthy human subjects.