Intrinsic Vessel Research Articles

Optical Coherence Tomography-Guided Stenting for Common Carotid Free-Floating Thrombus.

Digital subtraction angiography (DSA) has traditionally been considered an effective method for visualizing carotid free-floating thrombus (CFFT), but it falls short in providing detailed structures of the lumen and the composition of thrombi, making it challenging to determine the etiology. Intravascular optical coherence tomography (OCT) is a valuable adjunct to DSA that can precisely evaluate the characteristics of the intrinsic vessel wall and accurately distinguish between red and white thrombus, providing clues to the etiology of CFFTs. Moreover, OCT not only precisely determined the scope of a floating thrombus but also provided guidance for decision-making in endovascular treatment.

An optimisation-based approach to reduce fuel consumption and emissions from shipping navigation

This study presents an optimisation-based approach to reduce fuel consumption and emissions from shipping navigation. The main objective is to improve energy efficiency and simultaneously turn a case-study vessel compliant with Carbon Intensity Indicator (CII) proposed by IMO. This optimisation module has been devised as part of a new robust integrated real-time digital solution that will involve a significant number of both technical and operational measures in practice aiming to optimise operational efficiency (duringnavigation and port calls). Namely, the tool will be capable of situational awareness and decision support to reduce fuel consumption and Green House Gas (GHG) emissions from shipping and must be combined with intrinsic vessel systems to improve vessel hydrodynamic performance, resulting also in improved vessel safety and widening of the operational weather window

Lymphatic Clearance and Pump Function.

Lymphatic vessels have an active role in draining excess interstitial fluid from organs and serving as conduits for immune cell trafficking to lymph nodes. In the central circulation, the force needed to propel blood forward is generated by the heart. In contrast, lymphatic vessels rely on intrinsic vessel contractions in combination with extrinsic forces for lymph propulsion. The intrinsic pumping features phasic contractions generated by lymphatic smooth muscle. Periodic, bicuspid valves composed of endothelial cells prevent backflow of lymph. This work provides a brief overview of lymph transport, including initial lymph formation along with cellular and molecular mechanisms controlling lymphatic vessel pumping.

Targeted disruption of tumor vasculature via polyphenol nanoparticles to improve brain cancer treatment

SUMMARYDespite being effective for many other solid tumors, traditional anti-angiogenic therapy has been shown to be insufficient for the treatment of malignant glioma. Here, we report the development of polyphenol nanoparticles (NPs), which not only inhibit the formation of new vessels but also enable targeted disruption of the existing tumor vasculature. The NPs are synthesized through a combinatory iron-coordination and polymer-stabilization approach, which allows for high drug loading and intrinsic tumor vessel targeting. We study a lead NP consisting of quercetin and find that the NP after intravenous administration preferentially binds to VEGFR2, which is overexpressed in tumor vasculature. We demonstrate that the binding is mediated by quercetin, and the interaction of NPs with VEGFR2 leads to disruption of the existing tumor vasculature and inhibition of new vessel development. As a result, systemic treatment with the NPs effectively inhibits tumor growth and increases drug delivery to tumors.

Lymphatic remodelling in response to lymphatic injury in the hind limbs of sheep.

Contractile activity in the lymphatic vasculature is essential for maintaining fluid balance within organs and tissues. However, the mechanisms by which collecting lymphatics adapt to changes in fluid load and how these adaptations influence lymphatic contractile activity are unknown. Here we report a model of lymphatic injury based on the ligation of one of two parallel lymphatic vessels in the hind limb of sheep and the evaluation of structural and functional changes in the intact, remodelling lymphatic vessel over a 42-day period. We show that the remodelled lymphatic vessel displayed increasing intrinsic contractile frequency, force generation and vessel compliance, as well as decreasing flow-mediated contractile inhibition via the enzyme endothelial nitric oxide synthase. A computational model of a chain of lymphatic contractile segments incorporating these adaptations predicted increases in the flow-generation capacity of the remodelled vessel at the expense of normal mitochondrial function and elevated oxidative stress within the lymphatic muscle. Our findings may inform interventions for mitigating lymphatic muscle fatigue in patients with dysfunctional lymphatics.

Coronary Artery Anomalies by Multidetector Computed Tomography

The prevalence of coronary artery anomalies (CAAs) is reported to be 0.3% to 2% of the general population. Asymptomatic CAAs are more common and have a better prognosis. Nevertheless, some of these anomalies are linked with symptoms such as syncope, chest pain, and sudden cardiac death. The aim of the study was to determine the prevalence and describe the coronary congenital anomalies and their variations using coronary CT angiography. MD (320) CT angiography was used to prospectively examine 630 patients with either myocardial ischemic symptoms or suspected coronary anomalies by echocardiography or invasive coronary angiography. Contrast injection with ultra-thin cardiac scanning were then carried out. Images were analyzed with multiplanar reformations (MPR), curved multiplanar reformations (cMPR), maximum intensity projections (MIP) & volume rendering techniques (VR). Coronary artery anomalies were found in 217/630 patients (34.44% incidence), 69 (10.95%) anomalies were of vessel origin with good agreement between CTA and ICA results (K= 0.630), 140 (22.22%) were of vessel course and intrinsic vessel anomalies with moderate agreement between CTA and ICA results (K= 0.448), and 8 (1.27%) were of vessel termination with very good agreement between CTA and ICA results (K= 1.000). from this study we conclude that the prevalence of coronary anomalies is substantially higher with coronary CTA than with invasive coronary angiography and ECG gated multidetector coronary CT angiography allows accurate anatomical assessment of coronary artery anomalies.

A Rare Complication of Sarcoidosis

BackgroundCerebral vasculitis is a serious, but uncommon inflammatory condition of the blood vessel walls, with an annual incidence of 1-2 per million. A variety of disorders including encephalopathy, stroke, seizure, acute or subacute focal deficits should be considered as a differential diagnosis. Clinical caseA 56-year old male with a past history of pulmonary sarcoid presented with a unilateral facial numbness and loss of balance arising during sleep. His computed tomography scan of the brain was normal but brain magnetic resonance imaging with gadolinium demonstrated scattered infarcts in mixture of stroke topography not purely in keeping with embolism nor intrinsic small vessel disease. Further investigations including carotid ultrasound, transthoracic echo and 24-hour electrocardiogram were within normal limits. However, computed tomography angiography showed evidence of a widespread intracranial vasculopathy, as well as evidence of dissection of the left common carotid artery. His elevated calcium was consistence with a sarcoidosis relapse and cerebrospinal fluid analysis was in keeping with a central nervous system inflammatory process. Treatment was commenced with high dose steroids with additional pulsed intravenous cyclophosphamide together with antiplatelet therapy and a statin. ConclusionsThis case illustrates the intracranial vasculopathy as a rare complication of sarcoidosis. Although sarcoid is well recognized to affect the central nervous system, it is unusual in the form of cerebral vasculitis.

Importance of ferritin in sera and cerebrospinal fluid as both a predictive and an etiodiagnostic biomarker in ischemic stroke: a single-center prospective study

Background and aim Trace metals such as iron and its storage protein ferritin are known to play an important role in stroke and other neurologic disorders. This prospective study was designed to determine whether cerebrospinal fluid (CSF) ferritin levels aid in evaluation of stroke severity and its prognosis. Patients and methods Thirty-two patients with a diagnosis of acute stroke due to intrinsic or atherosclerotic vessel pathology were included in the study within 24 h from onset of symptoms. Immediately after admission, the clinical condition of the patient was evaluated using the Canadian Stroke Scale and was determined periodically during follow-up. Serum and CSF ferritin levels were assayed and correlated with the known biomarker amyloid β protein 1-42. Results Serum ferritin level revealed significantly greater values in patients with larger-sized lesions (P Conclusion Our results revealed that elevated values of CSF and serum ferritin may indicate a poor prognosis in terms of neurologic deterioration in intracranial atherosclerotic (ICAD)-induced stroke patients.

Small Deep Infarction in Patients with Atrial Fibrillation: Evidence of Lacunar Pathogenesis

Background: It is difficult to clarify whether small deep infarction is caused by cardioembolism or intrinsic small vessel disease in patients with atrial fibrillation (AF). The purpose of this study was to determine whether preexisting small vessel disease would differ according to the presenting infarct pattern and to determine the factors associated with acute single small deep infarction in stroke patients with AF. Methods: Between January 2008 and August 2012, 1,592 consecutive patients with acute ischemic stroke presenting within 7 days of symptom onset were entered in a prospectively maintained stroke registry. For the present study, 231 stroke patients with AF were enrolled irrespective of the stroke subtype. We divided these patients into 2 groups (lacunar infarct pattern, n = 20, vs. nonlacunar infarct pattern, n = 211) according to the acute infarct pattern on diffusion-weighted imaging. Patients with acute single small deep infarction on diffusion-weighted imaging were assigned to the lacunar infarct pattern group. We assessed the severity of preexisting small vessel disease by grading white matter lesions (WMLs) according to the Fazekas scale (periventricular WML score ranging from 0 to 3 and deep WML score ranging from 0 to 3 were added to give a total WML score ranging from 0 to 6), multilacunar state (number of chronic lacunes ≥2) and the presence of microbleeds. Demographic characteristics, vascular risk factors and neuroimaging data were compared between the two groups. Results: Patients with a lacunar infarct pattern showed more severe WMLs than those with a nonlacunar pattern [median total WML score 2.5 (range 2-4) vs. 1.0 (0-2); p < 0.001]. A multilacunar state was more prevalent in the lacunar infarct pattern group compared with the nonlacunar pattern group (65 vs. 28.9%; p = 0.001). However, the presence of microbleeds did not differ between the groups. Multiple logistic regression analyses revealed periventricular WMLs [odds ratio (OR) 4.12, 95% confidence interval (CI) 2.14-7.92], deep WMLs (OR 3.42, 95% CI 1.75-6.66) and multilacunar state (OR 7.85, 95% CI 2.45-25.6) as the predictors of a lacunar infarct pattern. Conclusions: The severity of WMLs and chronic lacunes were independent predictors of the incident infarct pattern, which suggested that acute single small deep infarction might be caused by intrinsic small vessel disease despite the presence of concomitant AF.

Confocal Image-Based Computational Modeling of Nitric Oxide Transport in a Rat Mesenteric Lymphatic Vessel

The lymphatic system plays important roles in protein and solute transport as well as in the immune system. Its functionality is vital to proper homeostasis and fluid balance. Lymph may be propelled by intrinsic (active) vessel pumping or passive compression from external tissue movement. With regard to the former, nitric oxide (NO) is known to play an important role modulating lymphatic vessel contraction and vasodilation. Lymphatic endothelial cells (LECs) are sensitive to shear, and increases in flow have been shown to cause enhanced production of NO by LECs. Additionally, high concentrations of NO have been experimentally observed in the sinus region of mesenteric lymphatic vessels. A computational flow and mass transfer model using physiologic geometries obtained from confocal images of a rat mesenteric lymphatic vessel was developed to determine the characteristics of NO transport in the lymphatic flow regime. Both steady and unsteady analyses were performed. Production of NO was shear-dependent; basal cases using constant production were also generated. Simulations revealed areas of flow stagnation adjacent to the valve leaflets, suggesting the high concentrations observed here experimentally are due to minimal convection in this region. LEC sensitivity to shear was found to alter the concentration of NO in the vessel, and the convective forces were found to profoundly affect the concentration of NO at a Péclet value greater than approximately 61. The quasisteady analysis was able to resolve wall shear stress within 0.15% of the unsteady case. However, the percent difference between unsteady and quasisteady conditions was higher for NO concentration (6.7%). We have shown high NO concentrations adjacent to the valve leaflets are most likely due to flow-mediated processes rather than differential production by shear-sensitive LECs. Additionally, this model supports experimental findings of shear-dependent production, since removing shear dependence resulted in concentrations that are physiologically counterintuitive. Understanding the transport mechanisms and flow regimes in the lymphatic vasculature could help in the development of therapeutics to treat lymphatic disorders.

Intrinsic microvasculature of the sciatic nerve in the rat

Microvasculature associated with the sciatic nerve was examined using high-resolution micro-CT scanning in one group of rats and surgical exploration in another. The results indicate that blood supply to the sciatic nerve is an "open-ended" system in which the vessels run longitudinally within the epineurium and connect with external vasculature primarily at junction points. Although the range of vasculature found extended down to 4-5 μ, only a few isolated vessels of this size were found, with no capillary "mesh" as such, possibly because of the close proximity of the intrinsic vessel to nerve fibers within the epineurium. While the study did not include direct measurements of flow or nerve function, the "open-ended" pattern of vasculature found has important implications regarding the relationship between the two. Specifically, the nerve is less vulnerable to a severe or complete disruption in blood supply than it would be under a close-ended system such as that of the heart or brain, where a severe disruption can occur with the obstruction of only a single vessel. Indeed, the pattern of vasculature found, subject to further study of vasculature at the capillary level, suggests that flow within the intrinsic vessels may be in either direction, depending on circumstances, somewhat like flow within the circle of Willis in the cerebral circulation.

Lack of Association of White Matter Lesions with Ipsilateral Carotid Artery Stenosis

Background: White matter lesions (WML) are commonly seen on brain MRI and are generally considered a marker of tissue damage from cerebral small vessel disease. WML are associated with increasing age and vascular risk factors, but their precise cause is unknown. A role for carotid artery atherothromboemboli has been suggested. If this is the case, more WML would be expected ipsilateral to increasing degrees of carotid stenosis. Methods: We recruited patients with ischaemic stroke from two large, separate prospective stroke studies, assessed with brain MRI and carotid Doppler ultrasound. We scored hemispheric WML visually in periventricular and deep locations. We assessed the association between carotid stenosis asymmetry and WML asymmetry, and vice versa. Further, we assessed the association between carotid stenosis and ipsilateral WML, before and after adjusting for vascular risk factors, and tested associations between ipsilateral and contralateral stenoses and WML. Results: We recruited 247 (Study 1) and 253 (Study 2) patients. In Study 1 and Study 2, 36 (15%) and 29 (11%) patients had ≥50% carotid stenosis, and 27 (11%) and 15 (6%) had ≥70% stenosis, respectively. Carotid stenosis was asymmetric in 28 (11%) and 26 (10%) patients and WML were asymmetric in 22 (9%) and 11 (4%) patients in Study 1 and Study 2, respectively. We found no association between carotid stenosis and ipsilateral WML score, before or after adjusting for vascular risk factors or sidedness, but WML were strongly associated with increasing age (p < 0.001). Conclusion: In two large cohorts of ischaemic stroke patients, we found no association between carotid stenosis and ipsi- or contralateral WML. There is now substantial evidence that atherothromboemboli are unlikely to cause most WML or other forms of cerebral small vessel lesions. Future studies should focus on determining what causes the intrinsic small vessel pathological changes that appear to underlie most WML.

Differing Risk Factors and Outcomes In Ischemic Stroke Subtypes: Focus on Lacunar Stroke

Lacunar stroke has been a recognized stroke subtype for many years but its pathophysiology remains unknown, so prevention and treatment are suboptimal. Most lacunar strokes result from an intrinsic cerebral small vessel disease, probably part of a systemic disorder. Hypertension, diabetes and other vascular risk factors (but not atrial fibrillation and ipsilateral carotid stenosis) are equally common in lacunar as in large artery atherothromboembolic stroke, which, together with other factors, suggests that the patient’s response to vascular risk factors, not the vascular risk factors per se, determines whether they develop small vessel or large artery stroke. Inflammation and endothelial failure are probably involved in the pathogenesis of lacunar stroke, but their role needs to be clarified. The cerebral venules as well as arterioles are abnormal in this condition. The disorder may not be primarily ischemic; instead, arteriolar thrombosis may be a late-stage phenomenon secondary to chronic arteriolar wall damage resulting from leakage of plasma components across the BBB. Accurate diagnosis of lacunar stroke, avoiding risk factor-based classifications, is required to underpin future research.

Retinopathy in Ischemic Stroke Subtypes

Lacunar stroke is associated with an intrinsic cerebral small vessel disorder of unknown etiology, although possible causes include increased blood-brain barrier permeability. Retinal arterioles are similar to cerebral small vessels and retinopathy occurs secondary to increased blood-retinal barrier permeability. We hypothesized that there would be higher rates of retinopathy in patients with acute lacunar versus cortical stroke. We prospectively recruited patients presenting with acute lacunar and cortical ischemic stroke. An experienced stroke physician diagnosed and subtyped the stroke based on clinical features and cerebral MRI. We performed 6 dilated digital retinal photographs of each eye in all patients. A carefully trained physician graded retinopathy (one or more of hard or soft exudates, microaneurysms, or hemorrhages) blind to stroke type as definitely present/absent or uncertain. We recruited 220 patients; 6 were excluded with ungradeable photographs leaving 214 patients for analysis (105 lacunar and 109 cortical strokes). Mean age was 68 years (SD, 11 years) and median National Institutes of Health Stroke Scale 2. Similar proportions of each group had diabetes (17% lacunar versus 10% cortical) and hypertension (56% lacunar and 66% cortical). Eighteen percent of lacunar and 19% of cortical patients had any retinopathy. After adjusting for baseline differences in age, hypertension, and diabetes, retinopathy was not associated with ischemic stroke subtype. We have not demonstrated a strong association between retinopathy and ischemic stroke subtype. However, larger samples or assessment of other retinal vascular abnormalities may yield positive associations.

Vascular and Metabolic Response to Statin in the Mildly Hypertensive Hypercholesterolemic Elderly

INTRODUCTIONMuch evidence indicates the importance of the endothelium and hypercholesterolemia in atherosclerosis, as well as the decline in endothelial function with aging. However, it is unclear if treating dyslipidemia in elderly patients improves endothelial function and reduces C-reactive protein levels.OBJECTIVESTo evaluate vasomotor function, lipids and C-reactive protein in mildly hypertensive and hypercholesterolemic elderly patients treated with atorvastatin.METHODSForty-seven elderly Brazilian subjects (≥ 65 years old) with LDL cholesterol (LDL-c) ≥ 130 mg/dL were randomly assigned, in a double-blinded manner, to receive either placebo (n = 23) or 20 mg/day of atorvastatin (n = 24) for 4 weeks. Exclusion criteria included diabetes, serious hypertension, obesity, steroid use, hormone replacement, and statin use within the previous six months. All patients underwent clinical examinations, laboratory tests (glucose, lipids, liver enzymes, creatine phosphokinase and high sensitivity C-reactive protein) and assessment of vasomotor function by high-resolution ultrasound examination of the brachial artery (flow-mediated dilation and sublingual nitrate), both before and after treatment.RESULTSThe patients were 65 to 91 years old; there was no significant difference between basal flow-mediated dilation of placebo (7.3 ± 6.1%) and atorvastatin (4.5 ± 5.1%; p = 0.20). The same was observed after treatment (6.6 ± 6.2 vs. 5.0 ± 5.6; p = 0.55). The initial nitrate dilatation (8.1 ± 5.4% vs. 10.8 ± 7.5%; p = 0.24) and that after 4 week treatment (7.1 ± 4.7% vs. 8.6 ± 5.0%; p = 0.37) were similar. Atorvastatin produced a reduction of 20% of the C-reactive protein and 42% in the LDL-c; however, there were no changes in the flow-mediated dilation.CONCLUSIONSAtorvastatin produced a significant change of lipids and C-reactive protein; however, there were no changes in vasomotor function, suggesting the existence of intrinsic age-related vessel alterations.

Myocardial protection in the failing heart: II. Effect of pulsatile cardioplegic perfusion under simulated left ventricular restoration

The open ventricle was studied in pacing-induced experimental heart failure to determine the extent of coronary perfusion and distribution during either continuous or pulsatile cardioplegic perfusion compared with whole blood in the beating heart. In 5 animals that underwent pacing-induced heart failure and in 6 control swine, regional coronary blood flows were measured on bypass in the open left ventricle (simulating exposure for left ventricle restoration) during (1) beating, (2) nonpulsatile cardioplegia, and (3) pulsatile cardioplegia modalities. Mean perfusion pressure was maintained at 80 mm Hg. Flow magnitude and distribution differed in control and failing hearts in the open left ventricle. In control hearts, transmural and endocardial cardioplegic flow of nonpulsatile and pulsatile flow (which were similar to each other) exceeded beating flow by 63% and 70%, respectively, in the open left ventricle condition. Transmural and subendocardial vascular resistance increased in failing hearts during cardioplegic delivery, resulting in lower subendocardial flow under nonpulsatile conditions for the same perfusion pressure. In failing hearts, subendocardial perfusion conditions did not change in the beating state (0.89 vs 0.78 mL/min/g in control and failing open beating states, respectively), but nonpulsatile cardioplegic flow was significantly reduced by 154%, and became lower than beating flow by 32.2% (0.78 vs 0.59 mL/min/g). Conversely, pulsatile cardioplegic delivery improved endocardial flow in the open failing hearts, as cardioplegic perfusion with pulsatility exceeded beating flow by 41%. In heart failure, pulsatility from either the beating heart, which causes extrinsic compression of coronary vessels, or intrinsic vessel distension during pulsatile cardioplegic perfusion preserved endocardial perfusion better than nonpulsatile cardioplegia at the same perfusion pressure. In the failing open ventricle (simulated geometry during ventricular restoration), subendocardial blood flow was maintained in the beating state, but decreased significantly from control values during nonpulsatile cardioplegic perfusion. Conversely, pulsatile cardioplegic delivery improved subendocardial perfusion of the open failing ventricle. These findings of improved subendocardial perfusion during pulsatile delivery (either during beating or cardioplegic perfusion) compared with nonpulsatile cardioplegic delivery may have important implications for myocardial protection in failing hearts.

Pulmonary Hypertension and Cor Pulmonale in COPD

Pulmonary artery hypertension (PAH) is the primary cardiovascular complication encountered in chronic obstructive pulmonary disease (COPD). Cor pulmonale can range clinically from mild changes in right ventricular function to frank right heart failure. The prevalence of PAH increases as COPD worsens, and the development of PAH and cor pulmonale appears to affect survival of patients with COPD. Potential causes proposed to explain the development of PAH in COPD include gas exchange abnormalities, destruction of the pulmonary vascular bed, alterations in respiratory mechanics, changes in intrinsic pulmonary vessel tone, and increased blood viscosity. Standard clinical evaluation, including history, physical examination, spirometry, electrocardiography, and chest radiography, is generally inadequate in identifying right ventricular dysfunction. Noninvasive techniques, such as echocardiography, radionuclide ventriculography, and magnetic resonance imaging, have largely replaced invasive pulmonary artery catheterization in the initial assessment of cor pulmonale. The goals of therapy consist of attenuation of PAH, enhancement of right ventricular function, alleviation of clinical symptoms, and improvement in survival. The agents that have been most extensively evaluated for these purposes include oxygen, vasodilators, theophylline, and inotropic medications.

Small Centrum ovale Infarcts – A Pathological Study

There are limited data, mainly clinical and radiological, on small centrum ovale infarcts (SCOIs). From a consecutive series of 159 autopsy brains we identified 12 cases which on gross pathological examination harboured a total of 21 SCOIs. In the majority of lesions histology revealed a significant component of incompletely infarcted brain. Clinicopathological data suggested that the underlying mechanism was likely to have been cardioembolic in 3 cases, and possibly embolic from heart or aortic arch in a further 5. Two cases were due to ipsilateral carotid artery atheroma (i.e. 10 of 12 cases had possible embolic sources). The majority of lesions appeared to lie in arterial borderzones. The combined data suggest that SCOIs are pathologically and pathogenetically heterogeneous, and therefore that the term ‘lacune’ is inappropriate because this implies intrinsic small vessel disease as the underlying cause. Clinically, potentially treatable cardiac and large vessel pathology should be excluded.

Incomplete lacunar infarction (Type Ib lacunes)

The aetiopathogenesis of small, deep (lacunar) infarcts remains controversial. The view that they are caused by occlusive intrinsic small vessel disease is widely held, but is based on only a small number of detailed pathology studies. We describe and illustrate a variant of small, microvessel-associated basal ganglia lesion, the histopathological features of which are distinct from those of classical Types I, II and III lacunes. Their appearances suggest a state of incomplete infarction. The pathogenetic significance of such lesions is discussed, in particular the role of mechanisms causing temporary or only moderately severe ischaemia.

Effects of exercise training on regulation of tone in coronary arteries and arterioles

A large number of studies now support the concept that exercise training alters functional control of the coronary circulation. Recent work has approached this area using ex vivo coronary arterial preparations (proximal coronary arteries, near-resistance arteries, resistance arterioles) isolated from exercise-trained animals and contracting independently of confounding in vivo influences. The combined results of these studies indicate that training-induced alterations in vascular control mechanisms do not occur uniformly throughout the coronary vascular tree. Proximal epicardial coronary arteries (approximately 2.0 mm diameter) isolated from exercise-trained pigs exhibited significantly reduced contractile responsiveness to the alpha-adrenergic receptor agonist, norepinephrine, but unaltered contractile responsiveness to K+, acetylcholine, and endothelin. Also, proximal arteries from exercise-trained animals demonstrated enhanced sensitivity to the vasodilator effects of adenosine. At the other end of the vascular spectrum, in resistance arterioles (< 150 microns diameter) the relaxation responses to adenosine were unaffected by exercise training, but bradykinin-induced vasodilation (endothelium-dependent) was significantly enhanced. In near-resistance arteries (150-240 microns diameter) responses to both bradykinin and adenosine were enhanced by exercise training. Thus, exercise training is associated with intrinsic vessel size-dependent alterations in coronary smooth muscle and endothelium-mediated regulatory mechanisms.