Changes In Luminal Diameter Research Articles

Vasoreactivity in an adult rat model of marginal copper deficiency

Short-term severe copper deficiency has been shown to significantly reduce acetylcholine (Ach)-induced vascular smooth muscle relaxation. The current study was designed to examine the long-term relationship of marginal dietary Cu to vasoreactivity. Male adult rats were fed a purified diet with adequate (6.0 μg) or marginal (3.0 or 1.5 μg) Cu/g diet for 6 months. Luminal diameter changes were measured in isolated resistance arterioles. Liver and kidney Cu concentrations were used as indices of Cu status. The results showed a significant decrease in kidney Cu in the 1.5- μg group compared with the adequate controls but no effect on liver Cu. There was a significant correlation between dilation to 10 −6 mol/L Ach and kidney Cu but no relationship between Cu status and 10 −5 mol/L norepinephrine-induced constriction or flow-induced dilation. There was also no dietary effect on baseline vessel tone or dilator capacity. The data are the first to establish a linear relationship between Ach-induced vasodilation and systemic Cu status in a mature long-term model of marginal Cu deficiency.

Alcohol consumption and coronary atherosclerosis progression—the Stockholm Female Coronary Risk Angiographic Study

Objective: To assess the association of alcohol intake with progression of coronary atherosclerosis. Although moderate drinkers have a lower risk of coronary heart disease than abstainers, the relation of alcohol use and coronary atherosclerosis has not been well studied. Methods and results: In the Stockholm Female Coronary Risk Angiographic Study, we evaluated 103 women, aged 65 years or younger, hospitalized with acute myocardial infarction or unstable angina pectoris who underwent serial quantitative coronary angiography 3–6 months following their index event and repeated an average of 3 years and 3 months (range 2–5 years) later. Individual alcoholic beverage consumption was assessed by a standardized questionnaire. We used mixed model analysis to estimate the effect of alcohol consumption on progression of coronary atherosclerosis, as measured by mean luminal diameter change, controlling for age, smoking, body-mass index, education, physical activity, index cardiac event, menopausal status, diabetes, and history of dyslipidemia. Of the 93 women with complete information on alcohol intake, 14 consumed no alcohol (abstainers), 55 consumed up to 5 g of alcohol per day (light drinkers), and 24 consumed more than 5 g of alcohol per day (moderate drinkers). Coronary atherosclerosis progressed by a multivariate-adjusted average of 0.138 mm (95% confidence interval (CI): 0.027–0.249) among abstainers, 0.137 mm (95% CI: 0.057–0.217) among light drinkers, and −0.054 mm (95% CI: −0.154 to 0.047) among moderate drinkers ( P<0.001). The inverse association persisted in analyses stratified by index event. No beverage type appeared to confer particular benefit. Conclusions: Among middle-aged women with coronary heart disease, moderate alcohol consumption (over 5 g/day) was protective of coronary atherosclerosis progression.

THE SUPPLEMENTARY EFFECTS OF HIGH DIETARY FIBER RICE (SUWON 464) ON BLOOD PRESSURE AND LIPID METABOLISM IN SPONTANEOUSLY HYPERTENSIVE RATS

phospho-tyrosine immunoreactivity and hyperphosphorylated beta-catenin. Vascular endothelial growth factor levels were higher in these placentae. A 4-fold increase in endothelial proliferation was seen coupled with a greater total length of capillaries without any change in luminal diameter. Molecular perturbations of vascular endothelial cadherin and beta-catenin occur in fetoplacental vessels from pregnancies complicated by Type 1 diabetes. Phosphorylation and loss of these molecules from adherens junctional domains may be influenced in part by the elevated levels of placental vascular endothelial growth factor. Perturbations of the junctional proteins may explain the observed breach in barrier integrity and may contribute to mechanisms driving proliferation and increases in capillary length.

Effects of ageing and exercise training on endothelium-dependent vasodilatation and structure of rat skeletal muscle arterioles.

Ageing reduces endothelium-dependent vasodilatation in humans and animals, and in humans, exercise training reverses the ageing-associated reduction in endothelium-dependent vasodilatation. The purpose of this study was to determine the mechanism(s) by which 10-12 weeks of treadmill exercise enhances endothelium-dependent vasodilatation in muscles of differing fibre composition from young and old rats. Three- and 22-month-old male Fischer 344 rats were assigned to young sedentary, young exercise-trained, old sedentary, or old exercise-trained groups. Arterioles were isolated from the soleus and gastrocnemius muscles; luminal diameter changes were determined in response to the endothelium-dependent vasodilator acetylcholine (ACh, 10(-9)-10(-4) mol l(-1)) alone and in the presence of the nitric oxide synthase (NOS) inhibitor l-NAME (10(-5) mol l(-1)) or the combination of l-NAME and the cyclooxygenase inhibitor indomethacin (10(-5) mol l(-1)). Training ameliorated the ageing-induced reduction in endothelium-dependent vasodilatation in soleus muscle arterioles. Treatment with l-NAME alone and in combination with indomethacin abolished differences in ACh vasodilatation occurring with ageing and training. Expression of endothelial NOS (eNOS) mRNA in soleus arterioles was unaltered by ageing, whereas eNOS protein was increased with age; training elevated both eNOS mRNA and protein. In gastrocnemius muscle arterioles, ageing did not alter maximal vasodilatation, but ageing and training increased maximal arteriolar diameter. These results demonstrate that ageing-induced reductions and training-induced enhancement of endothelial vasodilatation both occur through the nitric oxide signalling mechanism in highly oxidative skeletal muscle, but ageing and training do not appear to act on the same portion of the signalling cascade.

Effects of intravenous dobutamineon coronary vasomotion in humans

ObjectivesWe sought to investigate the vascular mechanisms of dobutamine-induced myocardial ischemia. BackgroundDobutamine stress is often used as a surrogate for exercise. The effects of dobutamine on the epicardial arteries are incompletely understood and possibly different from those of physical exercise. MethodsIntravenous (IV) dobutamine (40 μg/kg per min) was administered in 19 patients with normal, 23 patients with mildly atherosclerotic, and 12 patients with stenotic coronary arteries. In another two groups of patients with stenotic arteries, IV dobutamine was preceded by 1) an intracoronary (IC) bolus of the alpha-adrenergic blocker phentolamine (12 μg/kg, n = 12); and 2) an IC infusion of the nitric oxide substrate l-arginine (150 μmol/l per min for 20 min, n = 11). Intravenous saline instead of dobutamine was infused into eight patients with normal arteries. After dobutamine (or saline), an IC bolus of isosorbide dinitrate (ISDN, 0.2 mg) was given. Coronary vasomotion was evaluated by quantitative coronary angiography on angiograms obtained after each dose of dobutamine, saline, phentolamine, l-arginine, and ISDN. ResultsDobutamine increased the rate–pressure product and heart rate similarly in all patients except those who received saline. Dobutamine induced vasodilation in normal (change in luminal diameter [ΔLD] vs. baseline: 19 ± 2%) and in mildly atherosclerotic arteries (ΔLD: 8 ± 2%, p < 0.05 vs. normal). In stenotic arteries, dobutamine did not induce significant vasomotion (ΔLD: −3 ± 3%); the latter was improved by l-arginine (ΔLD: 10 ± 3%, p < 0.05 vs. stenotic arteries) and fully restored by phentolamine (ΔLD: 19 ± 3%, p < 0.05 vs. stenotic arteries). ConclusionsEndothelial dysfunction and enhanced alpha-adrenergic tone contribute to the loss of dobutamine-induced vasodilation in coronary atherosclerosis. In contrast to physical exercise, dobutamine does not induce “paradoxical vasoconstriction” of atherosclerotic coronary arteries.

A model of physical factors in the structural adaptation of microvascular networks in normotension and hypertension

Adequate function of the microcirculation is vital to any tissue. To maintain an optimal function, microvascular networks must be able to adapt structurally to changes in the physical environment. Here we present a mathematical network model based on vessel wall mechanics. We assume based on experimental observations that longstanding change in transmural pressure elicits a change in the vascular wall-to-lumen ratio for maintaining circumferential wall stress at a certain level. In addition, experimental observations show that chronic change in fluid shear stress at the vascular wall elicits a persistent change in luminal diameter. On this basis we hypothesize that wall influencing substances released from the endothelium in response to shear stress have a certain optimal level in the vascular wall. Deviation from this level will cause vascular remodeling, i.e. a structural change in luminal diameter, until equilibrium is restored. The model explains several of the key features observed experimentally in the microcirculation in normotension and hypertension. Most importantly, it suggests a scenario where overall network structure and network hemodynamics depend on adaptation to local hemodynamic stimuli in the individual vessel. Simulated results show emanating microvascular networks with properties similar to those observed in vivo. The model points to an altered endothelial function as a key factor in the development of vascular changes characteristic of hypertension.

A pH-mucosa area unit of measure to consider morphology of the oesophagus when evaluating oesophagitis

Gastro-oesophageal pH measurements are routinely carried out to quantify and determine if levels of acid reflux are responsible for symptoms. Although considered the ‘gold standard’, evidence suggests that pH measurements do not correlate well with the degree of oesophagitis seen during endoscopy. In this study the current measure of pH was critically examined taking into account both the effects of changes in luminal diameter and endoscopy observations. The oesophageal lumen diameter was investigated using a barium swallow for 25 patients presenting with oesophageal disorders. For each subject the widest luminal diameter was measured for a series of five controlled swallows. The results showed that the lumen diameter varied widely from 0.9 to 3.8 cm. An alternative approach to the current measurement of pH was explored. In this approach the exposure not only included the luminal pH and time exposed but also the area of mucosa exposed as a result of differing luminal diameters. Although it is currently not possible to assess the diameter or morphology of the oesophageal lumen during a pH study, the analysis highlighted that the current measure of pH exposure time does not include the area of mucosa exposed. These results may explain, to some extent, the poor correlation between pH measurements and degree of oesophagitis seen during endoscopy.

Role of mesangial cells and gap junctions in tubuloglomerular feedback

Tubuloglomerular feedback (TGF) is a process whereby the resistance of the afferent arterioles delivering blood to the glomeruli is regulated by the NaCl concentration of the forming urine in the lumen of the macula densa. Intraglomerular mesangial cells are located between capillaries within the glomerulus, while extraglomerular mesangial cells are located between the macula densa and the afferent arteriole. They are electrically and chemically coupled via gap junctions. The purpose of this study was to investigate the role of mesangial cells and gap junctions in TGF using the isolated, perfused juxtaglomerular apparatus. Juxtaglomerular apparatuses were dissected from male New Zealand white rabbits and perfused in vitro. The NaCl concentration at the macula densa was changed from 17/2 to 65/50 Na/Cl to initiate a TGF response. Afferent arterioles were perfused at 60 mm Hg throughout the experiment. Changes in luminal diameter caused by increasing the NaCl concentration at the macula densa were taken as the TGF response. TGF was measured before and after disrupting the gap junctions or damaging the mesangial cells in paired experiments. During the control period, TGF decreased afferent arteriole diameter by 2.9 +/- 0.2 microm. After mesangial cells were damaged by perfusing Thy 1-1 antibody and complement into the afferent arteriole, the TGF response was completely eliminated. Separate experiments showed no statistically significant change in TGF response with time, or when antibody and complement were perfused into the macula densa lumen. The presence of Thy 1-1 antibody and complement in the afferent arteriole perfusate did not alter the ability of norepinephrine to constrict or acetylcholine to dilate the afferent arteriole. To investigate the role of gap junctions in TGF, we used heptanol to disrupt them. During the control period, TGF decreased afferent arteriole diameter by 2.9 +/- 0.4 microm. After perfusing heptanol into the lumen of the afferent arteriole, the TGF response was completely eliminated. When heptanol was added to the bath, it had no significant effect on TGF response. The data show that after mesangial cells were selectively damaged, the constriction of the afferent arteriole induced by increasing the NaCl concentration at the macula densa was eliminated. However, such treatment had no effect when Thy 1-1 was perfused into the macula densa lumen, and did not alter the response of the afferent arteriole to norepinephrine or acetylcholine. Disruption of the gap junctions also eliminated the TGF response. These data indicate that the mesangial cells play a key role in mediating the TGF response, and that gap junctions among mesangial cells and between mesangial cells and vascular smooth muscle cells communicate the TGF signal to the afferent arteriole.

Shear level influences resistance artery remodeling: wall dimensions, cell density, and eNOS expression.

The magnitude of shear stimulus has been shown to determine the level of growth factor expression in cell culture. However, little is known regarding what effect shear level has on specific arterial wall remodeling events in vivo. We have hypothesized that the rate of luminal diameter change and specific remodeling events within the arterial wall layers are dependent on shear level. Selective ligations were made to alter the number of microvascular perfusion units of mesenteric arteries within the same animal to approximately 50%, 200%, and 400% of control. Arterial blood flow and wall shear rate were correlated with the degree of alteration in perfusion units. Luminal diameters were decreased in 50% arteries by day 2 and increased approximately 17% and 33% respectively, in 200% and 400% arteries at day 7. The rate of diameter change was greatest in 50% and 400% arteries. Wall areas (medial +37%; intimal +18% at day 2) and cell densities (intimal +26%; adventitial +44% at day 2) were altered only in the 400% arteries. A positive correlation existed by day 2 between endothelial staining for endothelial nitric oxide synthase and shear level. The results demonstrate that shear level influences the rate of luminal expansion, specific remodeling events within each wall layer, and the degree of endothelial gene expression. A greater understanding of how shear level influences specific remodeling events within each wall layer should aid in the development of targeted therapies to manipulate the remodeling process in health and disease.

Exercise training in coronary artery disease and coronary vasomotion.

Exercise training has assumed a major role in cardiac rehabilitation, mostly because of its positive effects on myocardial perfusion in patients with coronary artery disease. The mechanisms involved in mediating this key effect have long been debated: both regression of coronary artery stenosis and improvement of collateralization have been suggested as potential adaptations. However, the comparatively minute changes in luminal diameter and myocardial contrast staining do not fully explain the significant changes in myocardial perfusion. During the last decade, endothelial dysfunction was identified as a trigger of myocardial ischemia. The impaired production of endothelium-derived nitric oxide (NO) in response to acetylcholine and flow leads to paradoxic vasoconstriction and exercise-induced ischemia. Recently, it was confirmed in humans that training attenuates paradoxic vasoconstriction in coronary artery disease and increases coronary blood flow in response to acetylcholine. Data from cell-culture and animal experiments suggest that shear stress acts as a stimulus for the endothelium to increase the transport capacity for L-arginine (the precursor molecule for NO), to enhance NO synthase activity and expression, and to increase the production of extracellular superoxide dismutase, which prevents premature breakdown of NO. Exercise also affects the microcirculation, where it sensitizes resistance arteries for the vasodilatory effects of adenosine. These novel findings provide a pathophysiological framework to explain the improvement of myocardial perfusion in the absence of changes in baseline coronary artery diameter. Because endothelial dysfunction has been identified as a predictor of coronary events, exercise may contribute to the long-term reduction of cardiovascular morbidity and mortality.

A novel in vitro model of Brunner's gland secretion in the guinea pig duodenum.

A novel in vitro model that combined functional and morphological techniques was employed to directly examine pathways regulating Brunner's gland secretion in isolation from epithelium. In vitro submucosal preparations were dissected from guinea pig duodenum. A videomicroscopy technique was used to measure changes in luminal diameter of glandular acini as an index of activation of secretion. Carbachol elicited concentration-dependent dilations of the lumen (EC(50) = 2 microM) by activating muscarinic receptors on acinar cells. Ultrastructural and histological analyses demonstrated that dilation was accompanied by single and compound exocytosis of mucin-containing granules and the accumulation of mucoid material within the lumen. Inflammatory mediators (histamine, PGE(1), PGE(2)) and intestinal hormones (CCK, gastrin, vasoactive intestinal polypeptide, secretin) also stimulated glandular secretion, whereas activation of submucosal secretomotor neurons by 5-hydroxytryptamine did not. This study directly demonstrates that multiple hormonal, inflammatory, and neurocrine agents activate Brunner's glands, whereas many have dissimilar effects on the epithelium. This suggests that Brunner's glands are regulated by pathways that act both in parallel to and in isolation from those controlling epithelial secretion.

The vasocontractive action of norepinephrine and serotonin in deep arterioles of rat cerebral gray matter.

To examine the direct effects of norepinephrine (NE) and serotonin (5-HT) on the contractility of arterioles in the gray matter of the rat cerebrum, we micro-perfused arterioles in vitro and observed the changes in luminal diameter under the stop-flow condition with constant intraluminal pressure. While the average diameter of the lumen of arterioles was 39.9 +/- 9.7 microm (n=7) in Hepes-buffered saline, the average in 10(-7) M NE in the extraluminal solution changed into smaller in saline by 21.1 +/- 5.4% (n=7). The contractile effect of NE shows a dose-dependent curve between the 10(-7) and 10(-5) M. The contractile response to 10(-6) M NE was significantly reduced by yohinbin, an alpha2 blocker. 10(-6) M NE applied to the lumen also caused contraction of arterioles by 12.4 +/- 5.3% in diameter (n=5). 5-HT at 10(-7) M in the extraluminal solution caused contraction of arterioles by 10.9 +/- 4.4% in diameter (n=7). 5-HT in the extraluminal solution caused contraction of arterioles in a dose dependent manner between 10(-10) and 10(-6) M. The contractile effect of 5-HT at 10(-6) M was strongly reduced by 10(-6) M ketanserin, a 5-HT2 receptor antagonist. 5-HT applied to the lumen had no effect at all (n=6), however NE applied to the lumen caused contraction. These results strongly suggest that 5-HT plays a significant role in arteriolar contractility only from the cerebrospinal fluid (CSF) side, while NE is an important regulator of arteriolar contractility from both the CSF and blood circulation sides.

Long-term outcomes after carotid stent placement treatment of carotid artery dissection.

To assess the long-term outcomes after stent placement for the treatment of carotid artery dissections. Between 1992 and 1998, seven patients underwent stenting procedures for treatment of extracranial carotid artery dissections resulting from various causes, including trauma (n = 2), iatrogenesis (n = 2), spontaneous development (n = 2), and fibromuscular dysplasia (n = 1). Stenting procedures were performed for large, nonhealing, dissection-induced pseudoaneurysms (four cases) or severe preocclusive stenosis (three cases). A total of 11 stents were placed (Palmaz stents, n = 8; Wallstents, n = 3). Radiological follow-up examinations were performed after a mean period of 17.7 months (range, 1-67 mo), using conventional or computed tomographic angiography. Clinical follow-up data were obtained after a mean period of 42.9 months (range, 13-72 mo). All stent placements resulted in complete resolution of dissection-induced stenosis. For two of the four patients with aneurysms, the lesions occluded spontaneously at the time of the procedure. The third patient required coil embolization of the pseudoaneurysm. One patient exhibited progressive shrinkage of the aneurysm in serial follow-up examinations, with healing after 18 months. No clinical complications were associated with the procedures. One patient exhibited progression to asymptomatic occlusion 3 months after stenting. The remaining six patients exhibited no significant changes in luminal diameters. All patients remained in clinically stable condition, with no ischemic symptoms, during more than 3.5 years (mean period) of follow-up monitoring. This experience suggests that stents placed for treatment of extracranial carotid artery dissections remain patent and patients remain free of symptoms on a long-term basis. Additional studies will be required to determine the optimal types of stents and intervals for follow-up monitoring using imaging.

Remodeling of in-stent neointima, which became thinner and transparent over 3 years: serial angiographic and angioscopic follow-up.

Recently, it has been reported that the luminal diameter shows phasic changes after stenting: the progression of luminal narrowing followed by its regression. To elucidate the mechanisms involved in the phasic changes in luminal diameter after stenting, we examined the changes in neointimal thickness and the appearance of neointima by a series of angiographic and angioscopic observations for 3 years after stent implantation. In 12 patients who received a Wiktor coronary stent, serial angiographic and angioscopic examinations were performed immediately, 2 to 4 weeks, 3 months, 6 months, and 3 years after the stenting without repetition of angioplasty. Neointimal thickness was determined by angiography as the difference between stent and luminal diameters. The angioscopic appearance of neointima over the stent was classified as transparent or nontransparent according to the visibility of the majority of the stent. Neointimal thickness increased significantly at 3 months (0.75+/-0.32 mm) without further changes at 6 months (0.74+/-0.32 mm). Thereafter, however, it decreased significantly over 3 years (0.51+/-0.26 mm). The angioscopic appearance was classified as transparent in 8 patients (100) immediately after stenting, 6 patients (100%) at 2 to 4 weeks, 2 patients (17%) at 3 months, 2 patients (20%) at 6 months, and 7 patients (58%) at 3 years. The neointima became thick and nontransparent until 6 months and then became thin and transparent by 3 years. We conclude that neointimal remodeling exists after stenting and plays a major role in the alteration of coronary luminal diameter after stenting.

Coronary stenosis dilatation induced by L-arginine

L-arginine, a substrate in the production of endotheliumderived nitric oxide (NO), may stimulate the release of NO. L-arginine improves the coronary blood flow response to acetylcholine in patients with normal coronary arteries and hypercholesterolaemia. However, it is unknown whether local administration of L-arginine dilates coronary stenoses in patients with stable angina. This study assessed the effects of L-arginine and D-arginine at the stenotic site in patients with coronary artery disease and stable angina. 15 patients with chronic stable angina, coronary artery disease, and a positive treadmill exercise test ( 0·1 mV ST segment depression) at between 5 and 7 METS with the modified Bruce protocol, were studied in the cardiac catheterisation laboratory of the Hippokration Hospital, Athens University. The protocol was approved by the research ethics committee of the Hippokration Hospital and each patient gave written informed consent. Antianginal medication was stopped 24 h before the study. The patients were allowed to use sublingual glyceryl trinitrate as necessary, but no study was done within 3 h of its administration. None of the study patients had taken glyceryl trinitrate on the day of the study. Following the diagnostic coronary angiogram, an optimum radiographic projection was selected and kept constant for subsequent angiograms. In ten patients (seven male, three female, mean age 58 [SD 8] years) intracoronary infusion of 0·9% saline (2 mL/min) for 2 min was followed by intracoronary infusion of 150 μmol/min of L-arginine for 8 min. In five patients (four male, one female, mean age 61 [10] years) the same protocol was used, substituting 150 μmol/min of D-arginine for L-arginine. The chosen dose and the infusion time of L-arginine administration was consistent with a study showing a response after L-arginine administration in the brachial artery. The arterial segments in each frame were analysed at the Hammersmith Hospital in random order with quantitative computerised analysis, with an automated edge contour detection analysis system. The percentage change in luminal diameter from baseline was calculated at the end of the 8 min infusions and the values for L-arginine and D-arginine and normal saline were compared with Student’s t-test. The infusions of L-arginine and D-arginine did not affect systolic blood pressure (mean [SE]) (L-arginine: mean 152 [7·1] vs 150 [7·2] mm Hg, p=0·82 D-arginine: 154 [11·2] vs 157 [11·6] mm Hg, before and after infusions, respectively, p=0·27). L-arginine administration was associated with significant dilatation of stenoses (11·7 [2·3]%: p=0·004 vs D-arginine, p=0·001 vs normal saline) (figure), but there was no significant change with D-arginine (2·0 [0·04]%) (figure). No patients were receiving longacting nitrates, and the previous antianginal treatment did not affect the response to L-arginine ( -blockers: 11·1 [6·0]%; calcium antagonists 10·5 [4·7]%; -blockers and calcium antagonists 12·5 [3·4]%). Arginine, a semiessential aminoacid serves as the substrate for the enzyme NO synthase, which converts arginine to citrulline and NO, reducing vascular tone. A recent study in experimental models suggested possible beneficial effects of L-arginine administration. Long-term oral therapy with L-arginine reduced endothelial dysfunction and inhibited the development of atherosclerosis, but the mechanisms by which it exerts its vasodilator effect are not completely understood. Possible explanations include an effect on endothelial synthesis and release of NO, and direct or indirect physiological actions on the vascular smooth muscle to augment its responsiveness to NO. In our study a significant dilation was found in coronary stenotic segments after L-arginine administration in patients with coronary artery disease and stable angina. These data suggest that the 25

Acetylcholine induces conducted vasodilation by nitric oxide-dependent and -independent mechanisms.

Conducted vasodilation has been proposed as an important component of local vascular control. Because conducted vasomotor responses have previously been studied only in response to short pulses (<500 ms) of agonist, this study examined conducted vasodilation in response to sustained stimuli. In addition, we examined the contribution of nitric oxide (NO) to initiation and maintenance of conducted responses induced by acetylcholine (ACh). Responses to 2-min applications of ACh, sodium nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate were obtained in cannulated, perfused hamster cheek pouch arterioles (approximately 60 microm in diameter). Changes of luminal diameter in response to pressure ejection of agonists from a micropipette placed close to the downstream end of the vessel were observed at the site of stimulation ("local") as well as 570 and 1,140 microm upstream. At the local site, ACh stimuli produced large changes in diameter (approximately 70% of the maximum response) that peaked within 45 s before declining slowly to levels of approximately 50% of the maximum response. A similar response pattern was observed at both upstream sites, with the conducted responses being maintained for the duration of the stimulus. Local responses of similar magnitude were found with sodium nitroprusside and 8-bromoguanosine 3',5'-cyclic monophosphate, but only minimal responses were observed at the conducted sites. In a separate set of arterioles, ACh responses were obtained before and during perfusion with 10 microM N(omega)-nitro-L-arginine. Inhibition of NO synthesis diminished the local response to ACh, but the initial phase of the conducted response was unaffected. Furthermore, the conducted responses faded more rapidly in the presence of N(omega)-nitro-L-arginine. We conclude from these results that local NO synthesis alone is insufficient to initiate conducted responses but that NO synthesis contributes to maintenance of sustained conducted responses.

Retardation of coronary atherosclerosis: the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) and other angiographic trials.

A large number of both primary and secondary preventive trials suggest that treatment of elevated plasma lipids may reduce the frequency of coronary heart disease (CHD) events. Meta-analyses indicate that for every 10% reduction of cholesterol, CHD mortality is lowered by 13% and all-cause mortality by 10%. Experience from several angiographic trials also suggests that coronary atherosclerosis can be retarded, and in some instances limited regression induced, by low-density lipoprotein (LDL)-cholesterol reduction and/or high-density lipoprotein (HDL)-cholesterol elevation. Coronary angiographic studies have shown that although the effects on retardation/regression of altherogenic lesions have been small, with luminal diameter changes of around 0.10 mm, the effects on clinical events were more substantial, with reductions of the order of 50%. There is also evidence that it is the mild and moderate lesions that are of particular concern with respect to the occurrence of clinical coronary events. The progression of atherosclerosis and the occurrence of coronary events are probably not exclusively dependent on a lowering of LDL-cholesterol concentrations. Analyses from the Monitored Atherosclerosis Regression Study (MARS), the Cholesterol Lowering Atherosclerotic Study (CLAS), and the Programs on the Surgical Control of the Hyperlipidaemias (POSCH) indicate that triglyceride-rich lipoproteins may also be of importance for the progression of mild/moderate lesions in subjects treated with cholesterol-lowering regimens. Recently, the results of the 5-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) demonstrated that bezafibrate significantly retarded the progression of coronary atheroma and coronary events in young male survivors of myocardial infarction, as assessed by changes in minimum lumen diameter. This positive outcome is most likely due to the beneficial treatment effects on the levels of serum triglycerides (-31%), plasma fibrinogen (-12%), and HDL cholesterol (+9%). The results of the BECAIT on progression of coronary atherosclerosis are comparable with those of two recent angiographic trials with HMG-CoA reductase inhibitors, the Multicenter Anti-Atheroma Study (MAAS), and the Regression Growth Evaluation Statin Study (REGRESS), despite different lipid and metabolic effects. BECAIT is the first controlled angiographic study to show that a fibrate can significantly retard the progression of coronary atherosclerosis. The exact mechanisms by which this occurs remain to be elucidated. However, the results of BECAIT illustrate the importance of factors other than LDL cholesterol in the progression of coronary atherosclerosis.

Coronary vascular and endothelial reactivity changes in transgenic mice overexpressing atrial natriuretic factor.

Recent advances in genetic methods permit the introduction of random and defined mutations into the mouse germ line, producing novel mouse strains, some of which affect the heart and vasculature. A TTR-ANF transgenic strain of mice, which constitutively expresses a fusion gene consisting of the transthyretin promoter and the ANF structural gene, has been shown to result in a lifelong elevation of plasma atrial natriuretic factor (ANF) and a chronically lowered arterial blood pressure. However, no established method for efficient functional analysis of possible alterations in coronary vascular function in mice has been reported. In the present study, we describe an isolated mouse coronary artery preparation that permits an effective and reproducible evaluation of coronary endothelial and vascular function. Both left main and right coronary arteries (resting luminal diam 70-90 microns) were isolated and pressurized, and changes in luminal diameter were determined by videomicroscopy. The coronary pressure-luminal diameter relationship was not significantly different between TTR-ANF transgenic and nontransgenic littermates. Relaxation of coronaries to 0.1-100 nM ANF was significantly reduced in transgenic [maximum effect (Emax) = 43 +/- 10% (mean +/- SE) of 11 vessels] compared with nontransgenic (Emax = 73 +/- 7%, n = 15) mice. Similarly, the relaxant response to an endothelium-dependent dilator, acetylcholine, but not to endothelium-independent dilators sodium nitroprusside and isoproterenol, was significantly decreased in transgenic (Emax = 46 +/- 10%, n = 12) compared with nontransgenic (Emax = 85 +/- 5%, n = 14) mice. In contrast, the dose-dependent vasoconstriction to endothelin-1, KCl and the thromboxane mimetic U-46619 was not significantly different between the two groups. These results indicate that lifelong ANF elevation in mice is associated with a decreased responsiveness of coronary vasorelaxation to ANF, possibly resulting from receptor downregulation and/or desensitization. Endothelium-dependent relaxation was also significantly depressed in transgenic mouse coronary arteries, but smooth muscle-specific dilation and constriction were not affected. The present findings are consistent with previous studies of TTR-ANF transgenic mice showing that ANF regulates arterial blood pressure and vascular function.

Luminal diameter and vasa vasorum response to stent dilation in the rabbit aorta

We examined the changes in luminal diameter and vasa vasorum after stent dilation of the aorta of nonatherosclerotic rabbits. Balloon-expandable stents were placed in the aortas of rabbits at the L3 level and were expanded. After 8 weeks, the rabbits were euthanized, perfused with barium sulfate particles, frozen, sectioned, and X-rayed. The luminal intrastent diameter (2.3 +/- 0.23 mm) was significantly different (p < .05) from the expanded stent diameter but was not different from the luminal diameter above (2.3 +/- 0.53 mm) and below (1.9 +/- 0.18 mm) the stent. The number of vasa vasorum at the stent (46 +/- 7.2) was significantly increased compared with above (21 +/- 4.8, p < .001) and below (14.4 +/- 4.6, p < .001) the stent. After 8 weeks, luminal diameter was uniform. The increased vasa vasorum in the stented section suggested an increase in blood flow to the aortic wall, which may be important to the remodeling process.

Red blood cell flow cessation and diameter reductions in skeletal muscle capillaries in vivo - the role of oxygen.

When perfusion pressure is reduced, red blood cell flow in the capillaries of skeletal muscle ceases at a positive pressure difference across the vascular bed, while arterioles dilate and venules are not constricted. This flow cessation (i.e., cessation of red blood cell flow) and luminal diameter changes in capillaries following femoral arterial pressure reduction were investigated in the rabbit tenuissimus muscle in situ (n = 42) using intravital video microscopy. Arterial pressure was reduced by occlusion of the aorta distal to the renal arteries. During the experiments, leg and muscle were placed in a sealed box. The muscle was exposed to low PO2 by leading a gas mixture deprived of O2 through the box. Locally at the muscle surface, i.e., under the microscope objective, PO2 was varied by varying the PO2 in the superfusion solution. In all experiments, the remainder of the muscle was kept at low (< 20 mm Hg) PO2. The incidence of flow cessation was virtually zero at low local (< 20 mm Hg) PO2 and became almost 100% at local values above 70 mm Hg. Initial equivalent capillary diameters were 3.1-5.8 microm (median 4.0 microm) and did not correlate with local O2 tension. During aorta occlusion, capillary diameters significantly (P < 0.0001) decreased by a median value of 8% at all local PO2 values; in 14 out of 54 capillaries local diameter became less than 2.8 microm. The extent of diameter reduction did not correlate with PO2. In the 14 capillaries in which the diameter became less than 2.8 microm flow cessation occurred in only four cases. The minimal diameter reached was always at the site of an endothelial nucleus. The capillary diameter reductions are probably due to passive recoil. In the 48 capillaries in which flow ceased, only in four cases did a red blood cell stop at the site of the nucleus. We conclude that capillary diameter reductions (local and generalized) lead to a considerable increase in capillary resistance which contributes to the occurrence of flow cessation but cannot solely explain it.