Artery Cross-sectional Area Research Articles

Differential Effects of Angiotensin Converting Enzyme Inhibition and Diuretic Therapy on Reductions in Ambulatory Blood Pressure, Left Ventricular Mass, and Vascular Hypertrophy

Diuretic-based therapy is less effective in reducing the cardiac complications of hypertension than the risk of stroke and may be less effective in reducing left ventricular (LV) mass than is therapy with angiotensin converting enzyme (ACE) inhibition. In view of the strong association of LV hypertrophy with cardiovascular risk, this study was designed to compare the impact of therapy with a diuretic and ACE inhibition on cardiac and vascular structure. Fifty essential hypertensives (74% male, 88% nonwhite) participated in a double-blind study for 6 months and were randomized to either ramipril or hydrochlorothiazide (HCTZ). Echocardiography, carotid ultrasonography, and ambulatory blood pressure (BP) monitoring were performed at baseline and 3 and 6 months after initiation of therapy. The 22 ramipril patients were comparable to the 28 HCTZ patients at baseline in age, race, and 24-h BP. Although HCTZ resulted in a greater reduction in 24-h BP, only treatment with ramipril resulted in a decrease in LV mass (193 to 179 g, P < .005, v 184 to 182 g, P = NS), attributable to a reduction in wall thicknesses but not in chamber diameter. In multivariate analysis, both change in BP and treatment group were independent predictors of change in LV mass. Importantly, although neither drug reduced carotid artery cross-sectional area, relative wall thickness increased due to a tendency for vessel diameter to decrease and wall thickness to increase, particularly in the diuretic group. Ramipril caused a sustained fall in plasma angiotensin II, whereas HCTZ increased angiotensin II levels. Although diuretic therapy was more effective in lowering ambulatory BP in this predominantly nonwhite population, only therapy with ACE inhibition was associated with regression of LV mass. Vascular geometry was altered consistent with the reduction in distending pressure resulting in vascular remodelling.

Effect of nitrates on arterial blood vessels exemplified by the radial artery

Nitrates act, in part, by causing systemic venodilation. In addition, nitrates lead to dilation of arterial conductance vessels. The maximal dilation capacity and threshold of arterial conductance vessels have so far not been examined thoroughly. Therefore, we tested the radial artery diameter before and after i.v. nitroglycerin infusions at increasing dosages (0.015, 0.05, 0.15, 0.5, and 1.5 micrograms/kg/min), 7 min each dose in 28 patients with suspected coronary artery disease (mean age +/- SEM 58 +/- 2 years) using a high resolution ultrasound devise. The low doses of 0.05 and 0.15 microgram/kg/min, equal to dose of 2.5 mg/12 hours and 7.5 mg/12 hours in a patient with 70 kg, led to substantial increases in the cross sectional luminal area of the radial artery of 14.8 +/- 1.5% and 29.3 +/- 2.2%*, (*p < 0.05 vs baseline). The maximal increase (dilatory capacity) was 53.8 +/- 3.8% (mean diameter at baseline: 2.7 +/- 0.1 mm, maximal 3.4 +/- 0.1 mm, p < 0.001). The nitrate sensitivity of the radial artery was estimated by calculation of the ED50, the dose that caused half-maximal dilation of the radial artery. The ED50 of the radial artery was 0.13 +/- 0.003 microgram/kg/min. In conclusion, nitroglycerin leads to a dose dependent dilatation of peripheral conductance vessels. Low doses of 0.05 and 0.15 microgram/kg/min lead to significant arterial dilation. The maximal dilatory capacity of the radial artery is 53.8 +/- 3.5%.

Diameter and Cross-sectional Area Relationship of the Human Main Pulmonary Artery: Evaluated by Epicardial Echocardiography

Correct assessment of vessel cross-sectional area (CSA) is essential for reliable cardiac output (CO) measurements by means of pulsed Doppler echocardiography. In 23 patients who underwent coronary artery bypass grafting (CABG) the main pulmonary artery CSA and diameter changes were assessed by epicardial two-dimensional echocardiography using a 7.5 MHz cm2 transducer. Our data indicate that the shape of the pulmonary artery changes over time. Time averaged CSA ranged from 3.51 to 8.29 cm2 (mean 5.04 cm2; SD 1.3 cm2

Successful Directional Atherectomy of De Novo Coronary Lesions Assessed With Three-Dimensional Intravascular Ultrasound and Angiographic Follow-Up

Recent histopathologic and intravascular ultrasound (IVUS) data indicate that inadequate compensatory enlargement of atherosclerotic lesions contributes to the development of significant arterial stenoses. Such lesions may contain less plaque, which may have implications for atheroablative interventions. In this study, we compared lesions with (group A, n = 16) and without inadequate compensatory enlargement (group B, n = 30) as determined by IVUS. The acute results and the follow-up lumen dimensions of angiographically successful directional coronary atherectomy procedures were compared. Inadequate compensatory enlargement was considered present when the preintervention arterial cross-sectional area at the target lesion site was smaller than that at the (distal) reference site. Three-dimensional IVUS analysis and quantitative angiography were performed in 46 patients before and after intervention. IVUS measurements included the arterial, lumen, and plaque (arterial minus lumen) cross-sectional areas at the target lesion site (i.e., smallest lumen site) and the (distal) reference site. Angiographic follow-up was performed in 42 patients. Preintervention and postintervention angiographic measurements and IVUS lumen cross-sectional area measurements were similar in both groups. However, at follow-up, the angiographic minimum lumen and reference diameters were significantly smaller in group A compared with group B (1.71 ± 0.47 mm vs 2.14 ± 0.73 mm, p <0.03, and 2.97 ± 0.29 mm vs 3.39 ± 0.76 mm, p <0.02; group A vs B). The data of this observational study suggest that lesions with inadequate compensatory enlargement, as determined by IVUS before intervention, may have less favorable long-term lumen dimensions after directional coronary atherectomy procedures.

Relation of Exercise-Induced Myocardial Ischemia to Cardiac and Carotid Structure

There is a strong relation of carotid atherosclerosis to coronary artery disease and left ventricular hypertrophy. In addition, abnormalities of carotid structure are strongly associated with abnormal left ventricular geometry and structure. However, little is known regarding the relation of exercise-induced ST depression to carotid atherosclerosis, carotid, or left ventricular structure in the absence of apparent coronary disease. The relationship of exercise ECG myocardial ischemia to the presence of carotid atherosclerosis and to carotid and left ventricular structure was assessed in 204 asymptomatic subjects free of clinical evidence of cardiovascular disease. Myocardial ischemia on the exercise ECG, defined by a chronotropically adjusted ST/HR slope of >3.47 microV/bpm, was associated with a nearly threefold greater likelihood of discrete carotid atherosclerosis (50% [6 of 12] versus 17% [29 of 192], P=.007) and with older age, male sex, higher systolic and diastolic blood pressures, greater left ventricular mass and mass index, and greater common carotid artery intimal-medial thickness and cross-sectional area index. Stepwise logistic regression analyses, including standard risk factors, revealed that only carotid artery cross-sectional area index (P=.0007) and systolic blood pressure (P=.005) independently predicted an abnormal chronotropically adjusted ST/heart rate slope. Moreover, among 132 subjects with > or = 10 microV of ST-segment depression, only left ventricular mass index and carotid artery cross-sectional area index were significant predictors of the chronotropically adjusted ST/heart rate slope response. Subendocardial ischemia on the exercise ECG is strongly associated with the presence of carotid atherosclerosis and is related to systolic blood pressure, carotid artery cross-sectional area index, and left ventricular mass index, independent of age, sex, and other cardiac risk factors. These findings provide additional insights into the relation between coronary and carotid atherosclerosis and suggest that an association among ischemia and left ventricular and carotid structural abnormalities may contribute to the pathogenesis of coronary events.

Longitudinal association of ambulatory pulse pressure with left ventricular mass and vascular hypertrophy in essential hypertension.

To determine the longitudinal relationship between clinic and ambulatory blood pressures and subsequent left ventricular and carotid artery structure. A retrospective follow-up study. A large district general hospital in Harrow, UK. One hundred and forty patients who had been subjected to 24 h ambulatory intra-arterial blood pressure monitoring on the basis of their having an elevated clinic blood pressure were followed up randomly a mean of 9.4 +/- 3.4 years later. The ambulatory blood pressure parameters measured were the mean systolic, mean diastolic and mean pulse pressures. Follow-up variables assessed included the clinic blood pressure, body mass index, total cholesterol, number of years of follow-up, left ventricular mass index, carotid intima-media thickness and carotid artery cross-sectional area. The left ventricular mass index, carotid intima-media thickness and carotid artery cross-sectional area. The mean pulse pressure and mean systolic blood pressure were correlated significantly with the left ventricular mass index (r = 0.46, P < 0.001 and r = 0.36, P < 0.001, respectively), carotid intima-media thickness (r = 0.45, P < 0.001 and r = 0.37, P < 0.001, respectively) and carotid artery cross-sectional area (r = 0.46, P < 0.001 and r = 0.41, P < 0.001, respectively). The mean pulse pressure was associated independently with all three outcome measures. In addition, the body mass index was an independent determinant of the left ventricular mass index, whereas the serum cholesterol level was associated independently with the carotid artery cross-sectional area; the number of years of follow-up was related independently to the left ventricular mass index and carotid intima-media thickness, but not to the cross-sectional area. These findings suggest that ambulatory blood pressure monitoring can play a role in guiding the choice of doses in drug therapy to limit potential target organ damage.

Comparison of Intravascular Ultrasound Measurements at the Sites of Balloon Dilatations of Femoral Arteries With Measurements of Postmortem Gross Arterial Segments at the Same Sites

Intravascular ultrasound measurements of arterial cross-sectional area at the site of balloon dilatation are quantitatively accurate and consistent with measurements by digital planimetry. Lumen cross-sectional area determinations are virtually the same and the minor differences in total arterial cross-sectional area are probably related to the dehydration of each specimen, which occurred during the interval between studies. Thus, arterial disruption by balloon angioplasty does not interfere with the quantitative accuracy of intravascular ultrasound measurements.

In vivo role of glucocorticoids in barotrauma vascular repair and fibrosis.

To determine the important repair events leading to vascular collagen accumulation following barotrauma, in vivo changes were assessed during dexamethasone (DEX) treatment, as well as physiological healing. Hypercholesterolemic rabbits underwent bilateral iliac artery endothelial denudation, followed by angioplasty. Messenger ribonucleic acid (RNA) (procollagen types I, III and transforming growth factor [TGF]beta1), and bio-histometric composition of iliac arteries of animals treated with DEX (2, 7 and 7 days; 1 mg/kg1/day1), were compared to that in controls 2, 7 and 30 days after angioplasty. Type I and III procollagen mRNA transcripts were up-regulated following injury in either group. Similarly, TGFbeta1 mRNA levels were also elevated; however, treatment with DEX led to down-regulation at day 30 post-angioplasty. Linear regression and correlation of the densitometric ratios of procollagen alpha1(I) and TGFbeta1 mRNA during repair were observed significantly in either group (DEX-treated, r2= 0.84; non-treated, r2=0.79). Biochemically derived total vascular RNA concentration decreased transiently (7 days), with DEX-treatment (P = 0.003). Arterial lumen cross-sectional area was reduced between days 2 and 30 (P=<0.02), accompanied by an increase in fibrillar collagen concentration in both groups of animals post-angioplasty. These results suggest that during barotrauma repair, administration of DEX (approximately 1 week), does not affect vascular intimal hyperplasia or fibrosis, and that despite treatment, significant production of type I procollagen mRNA continues, influencing subsequent collagen deposition. The data also confirm a strong correlation between TGFbeta1 and type I procollagen mRNA expression, and modestly with type III procollagen during post-angioplasty repair.

INTRAVASCULAR ULTRASOUND INSIGHTS INTO MECHANISMS OF STENOSIS FORMATION AND RESTENOSIS

Using intravascular ultrasound (IVUS), stenosis formation and restenosis (or late lumen loss following coronary angioplasty procedures) can be subdivided into two distinct underlying components: tissue accumulation and arterial remodeling. Arterial remodeling is defined as a change in total arterial cross-sectional area over time; it can be adaptive (an increase in arterial cross-sectional area as a compensatory response to plaque accumulation) or pathologic (a decrease in arterial cross-sectional area or chronic arterial shrinkage). Adaptive arterial remodeling can delay the development of coronary artery stenoses and prevent restenosis; pathologic remodeling can contribute to de novo lesion formation and has been shown to be the dominant mechanism of restenosis following coronary intervention. Serial IVUS studies have also been used to study the natural history of the restenosis process; adaptive remodeling occurs early (within 1 month) and pathologic remodeling occurs late (between 1 and 6 months) after intervention. The residual plaque burden postintervention acts as an amplifier in this process.

The impact of vessel orientation in space on densitometric measurements of cross sectional areas of coronary arteries.

Under ideal conditions, densitometric measurement of a coronary arterial cross section in biplane angiographic images should result in nearly equal cross sectional areas for both planes. However, quite appreciable discrepancies have been found by some authors in patients. In this study, the role of inadequate spatial orientation of the vessel axes relatively to the x-rays was assessed by use of a 3D technique applied to 60 stenoses (45 pre PTCA and 15 post PTCA) in simultaneously acquired digital biplane coronary angiograms of 27 CAD patients. The 3D technique yields two radius values per projection directly in mm at any arterial cross section of interest. This was used to determine the areas Ar(in mm2) of the reference cross sections. As with catheter calibration, these cross sections were thus assumed to be more or less circular, but out-of-plane effects and errors due to a catheter diameter determination in pixels were avoided. The areas of the stenotic sections were then determined densitometrically (in mm2) from the two projections (1 and 2) according to As1 = ArDs1/Dr1, resp. As2 = ArDs2/Dr2, where Dr1, Dr2, Ds1 and Ds2 are the conventional densitometric areas of the reference and stenotic cross sections measured in planes 1 and 2. As expected, the areas As1 and As2 correlated only moderately: As2 = 0.92 As1 + 0.7 mm2, r = 0.82, n = 60, SEE = 1.4 mm2. The 3D method also yielded the two spatial angles between the local vessel axis and the X-rays of both planes. These two angles were then used to correct each densitometric area for inadequate orientation. With the corrected densitometric areas As1c and As2c, the correlation improved to: As2c = 1.05 As1c + 0.03 mm2, r = 0.93, n = 60, SEE = 0.8 mm2. Inadequate orientation of the cross sections in space thus appears to be an important factor of inaccuracy in densitometric measurements of stenotic cross sections in patients.

Coronary artery restenosis after balloon angioplasty in humans is associated with circumferential coronary constriction.

Therapies that inhibit intimal hyperplasia do not prevent restenosis after coronary artery balloon angioplasty, suggesting that additional mechanisms may be responsible for restenosis in humans. Using an intravascular ultrasound (Hewlett-Packard Sonos Intravascular Imaging System). 3.5F, 30-MHz (Boston Scientific) monorail imaging catheter, we studied 17 patients with clinical and angiographic restenosis at an average (mean +/- SD) of 7 +/- 6 months after balloon angioplasty (13 men age, 71 +/- 10 years; 12 left anterior descending coronary arteries, 4 right coronary arteries, and 1 left circumflex coronary artery) The lumen area (L.A), vessel wall area (VWA), and total cross-sectional area (CSA) within the external elastic lamina were measured at the restenosis site and at proximal and distal reference sites, which were defined as adjacent segments with the least amount of plaque. Consistent with coronary angiography findings, decreased LA at the restenotic site was detected in all 17 patients. The unique finding was that total CSA at the restenotic site was significantly decreased compared with both proximal and distal reference sites (10.1 +/- 2.4 versus 14.8 +/- 3.2 mm2 and 10.1 +/- 2.4 versus 13.8 +/- 3.1 mm2, respectively, P < .001), whereas VWA (intima plus media) was slightly increased at the angioplasty site compared with both proximal and distal reference sites (8.0 +/- 2.3 versus 7.6 +/- 2.3 mm2 and 8.0 +/- 2.3 versus 6.7 +/- 2.3 mm2, respectively, P = NS). Eighty-three percent of the loss in LA at the restenotic site was due to constriction of the total CSA, while the increase in VWA at the restenotic site accounted for only a 17% loss in LA. We then compared these results with the morphology of coronary artery segments in 14 patients without restenosis. These coronary artery segments had been previously treated with balloon angioplasty (7 +/- 5 months). Unlike that in restenotic lesions, the total CSA within the external elastic lamina at the sites of previous angioplasty was similar to that in distal and proximal reference sites (P = NS). Significant and consistent reduction in arterial CSA, with a minor increase in VWA, characterizes human coronary lesions that cause angiographic restenosis. These data suggest that in humans, "recoil" and/or vascular contraction with healing in response to balloon injury is a major contributor to restenosis after balloon angioplasty.

Relation of arterial structure and function to left ventricular geometric patterns in hypertensive adults

Objectives. The present study sought to determine whether conduit artery structure and function vary according to the pattern of left ventricular adaptation to hypertension.Background. Although left ventricular geometric pattern has been shown to predict cardiovascular events in hypertension, the arterial status in patients with the different patterns is unknown.Methods. We evaluated arterial structure and function by carotid ultrasound and applanation tonometry in 271 unmedicated hypertensive patients classified by echocardiography as having normal ventricular geometry (n = 176), concentric remodeling (n = 54), concentric hypertrophy (n = 16) or eccentric hypertrophy (n = 25).Results. All groups were similar in age, gender distribution and body size. Patients with concentric and eccentric hypertrophy had similar blood pressures (mean 173/100 and 171/99 mm Hg, respectively) and left ventricular mass, but compared with patients with normal left ventricular geometry and concentric remodeling, only those with concentric hypertrophy had increased arterial wall thickness (0.96 ± 0.20 vs. 0.80 ± 0.18 mm, p< 0.05), end-diastolic diameter (6.38 ± 0.97 vs. 5.76 ± 0.87 mm, p < 0.05), cross-sectional area (22.1 ± 5.71 vs. 16.6 ± 5.4 mm2, p < 0.05) and elastic modulus (713 ± 265 vs. 471 ± 241 dynes/cm2 × 10−6, p < 0.05). Patients with concentric remodeling and eccentric hypertrophy had similar values for these measures (0.85 ± 0.22 and 0.89 ± 0.21 mm, 5.67 ± 0.77 and 6.04 ± 0.44 mm, 17.2 ± 5.4 and 19.7 ± 5.9 mm2, 558 ± 263 and 614 ± 257 dynes/cm2 × 10−6, respectively), despite lower systolic blood pressures in the former group (156/94 mm Hg, p < 0.001). The prevalence of plaque was comparable in patients with concentric (56%) and eccentric (42%) hypertrophy and significantly greater in those with normal geometry (21%).Conclusions. Among patients with generally mild, uncomplicated systemic hypertension, arterial structure and function are most abnormal when concentric left ventricular hypertrophy is present and may contribute to the more adverse outcome associated with this geometric pattern.

Effects of chronic blockade of angiotensin II receptor on the maintenance of hypertension and vascular changes in spontaneously hypertensive rats

Previous studies have shown that chronic treatment of spontaneously hypertensive rats (SHR) with angiotensin converting enzyme inhibitors is effective in causing the regression of hypertension and vascular structural changes in adult SHR. The purpose of this study was to determine the involvement of angiotensin type 1 receptors in the maintenance of hypertension and vascular changes in adult SHR. Three groups of 15-week-old male SHR were treated with three different doses of the angiotensin type 1 receptor antagonist L-158,809. After 12 weeks of treatment, average systolic blood pressure was reduced in a dose-dependent manner from 206 +/- 2 mmHg (1 mmHg = 133.3 Pa) in the control SHR to 154 +/- 7 mmHg in the 0.6 mg/kg group, 172 +/- 3 mmHg in the 0.3 mg/kg group, and 196 +/- 8 mmHg in the 0.1 mg/kg group. Withdrawal of the treatment caused a rapid rise in blood pressure within 1 week, and 14-16 weeks after treatment had been withdrawn, blood pressure of SHR treated with the highest dose had increased to 169 +/- 8 mmHg. Blood pressure of the SHR treated with the two lower doses had increased to the level of the untreated SHR. Mean blood pressure, diastolic pressure, and pulse pressure were significantly reduced in the SHR treated with 0.6 mg/kg L-158,809. The arterial media cross-sectional area and media to lumen ratio were reduced by L-158,809 treatment (0.6 mg/kg dose). Treatment did not affect body weight or heart rate. Contractile response of the mesenteric arteries to nerve or norepinephrine stimulation was not affected by the treatment. However, arteries from treated SHR did not show an angiotensin II potentiation of nerve-stimulated response, as was observed in the control SHR. We conclude that persistent control of blood pressure by treatment with L-158,809 is associated with its effects on the structure and function of the arteries in the SHR.

Renal vasodilatory effect of endothelial stimulation in patients with chronic congestive heart failure

Objectives. This study sought to examine the vasodilatory response of the renal circulation to endothelial stimulation in patients with chronic heart failure.Background. Renal blood flow is often reduced in patients with chronic congestive heart failure and may lead to deterioration of renal function. Stimulation of renal endothelium has been shown to cause renal vasodilation in animals and in isolated human renal artery. The vasoregulatory role of the renal endothelium in patients with heart failure has not been evaluated.Methods. Renal vasodilatory effect of endothelial stimulation with acetylcholine was assessed and compared with that of endothelial-independent vasodilation with nitroglycerin. Both drugs were infused into the main renal artery. Renal artery cross-sectional area was measured with intravascular ultrasound and renal blood flow velocity with the aid of an intravascular Doppler technique.Results. Both drugs caused a significant and comparable increase in renal artery cross-sectional area (maximal increase [mean ± SE] 14 ± 5% with acetylcholine, 15 ± 5% with nitroglycerin; both changes <0.05 vs. baseline). Acetylcholine also caused a significant reduction in renal vascular resistance (maximal reduction 55 ± 6%) and increase in renal blood flow (maximal increase 136 ± 54%). In contrast, nitroglycerin administration showed no significant effect on renal vascular resistance and blood flow.Conclusions. Stimulation of endothelium-derived nitric oxide with acetylcholine results in a significant vasodilatory effect on both conductance and resistance renal blood vessels and leads to a marked reduction in renal vascular resistance and enhancement of renal blood flow. Nitroglycerin, an exogenous nitric oxide donor, caused a selective vasodilatory effect on renal conductance but not on resistance blood vessels and failed to increase renal blood flow. These data suggest the possibility that stimulation of endogenous nitric oxide production in the kidney could be used as a therapeutic target for enhancement of renal flow in patients with heart failure.

Influence of suture technique and suture material selection on the mechanics of end-to-end and end-to-side anastomoses

Experiments were performed in dogs to evaluate the mechanics of 26 end-to-end and 42 end-to-side artery-vein graft anastomoses constructed with continuous polypropylene sutures (Surgilene; Davis & Geck, Division of American Cyanamid Co., Danbury, Conn.), continuous polybutester sutures (Novafil; Davis & Geck), and interrupted stitches with either suture material. After construction, the grafts and adjoining arteries were excised, mounted in vitro at in situ length, filled with a dilute barium sulfate suspension, and pressurized in 25 mm Hg steps up to 200 mm Hg. Radiographs were obtained at each pressure. The computed cross-sectional areas of the anastomoses were compared with those of the native arteries at corresponding pressures. Results showed that for the end-to-end anastomoses at 100 mm Hg the cross-sectional areas of the continuous Surgilene anastomoses were 70% of the native artery cross-sectional areas, the cross-sectional areas of the continuous Novafil anastomoses were 90% of the native artery cross-sectional areas, and the cross-sectional areas of the interrupted anastomoses were 107% of the native artery cross-sectional areas ( p < 0.05). At physiologic pressures, there were no differences in compliance among the three types of anastomosis. These data suggest that when constructing an end-to-end anastomosis in a small vessel, one should use an interrupted suture line or possibly continuous polybutester suture. Forty-two end-to-side anastomoses demonstrated no differences in cross-sectional areas or compliance for the three suture techniques. This suggests that, unlike with end-to-end anastomoses, when constructing an end-to-side anastomosis in patients any of the three suture techniques may be acceptable. (J T HORAC C ARDIOVASC S URG 1996;111:1063-72)

Vascular reactivity in mesenteric resistance arteries following chronic nitric oxide synthase inhibition in Wistar rats.

1. Chronic inhibition of nitric oxide synthase (NOS) induces a sustained hypertension in rats. We studied the effects of chronic inhibition on the in vitro vasoreactivity of mesenteric resistance arteries in Wistar rats. We also investigated the effects of acute in vitro NOS inhibition in these vessels. 2. Acute NOS inhibition (N omega-nitro-L-arginine, L-NOARG, 10 microM) had no effect on the contractile response to KCl (125 mM), enhanced the response to the phorbol ester, phorbol dibutyrate (1 microM; 69 +/- 9% of KCl response, n = 6; 38 +/- 7% control, n = 6, P < 0.05), increased sensitivity to phenylephrine (EC50: 1.68 +/- 0.14 microM, n = 5; 2.35 +/- 0.23 microM control, n = 5, P < 0.05) and sodium nitroprusside (SNP; EC50 1.79 +/- 0.61 nM, n = 6; 20.44 +/- 6.87 nM control, n = 6, P < 0.05) and decreased sensitivity to acetylcholine (EC50 123 +/- 12 nM, n = 6; 45 +/- 10 nM control, n = 13, P < 0.05). 3. In contrast, contractile responses to KCl (125 mM; 170 +/- 12 mN mm-3, n = 10; 257 +/- 21 mN mm-3 in control, n = 13, P < 0.005) and phenylephrine (maximum response, 30 microM: 169 +/- 24 mN mm-3, n = 10; 295 +/- 19 mN mm-3 in control, n = 13, P < 0.001) were significantly reduced in magnitude following chronic NOS inhibition. Sensitivity to phenylephrine was not significantly altered. 4. The effects of chronic NOS inhibition (N omega-nitro-L-arginine methyl ester, L-NAME, 10 mg kg-1 daily for 3 weeks) were similar to those of acute NOS blockade with respect to the relaxant responses to SNP and acetylcholine, and also the contraction in response to protein kinase C activation. 5. Chronic inhibition of NOS significantly increased medial cross sectional area of mesenteric resistance arteries (0.013 +/- 0.002 mm2, n = 7; 0.009 +/- 0.0005 mm2 control, n = 15, P < 0.05). 6. Thus, in contrast to the acute effects of NOS inhibition, chronic NOS inhibition results in a down-regulation of the contractile responses to KCl and phenylephrine in mesenteric resistance arteries, despite an increase in medial cross sectional area. However protein kinase C-dependent contraction remains relatively enhanced. Endothelium-dependent relaxation is reduced and endothelium-independent relaxation is enhanced in a manner similar to the effects of acute NOS blockade.

Vagal modulation of epicardial coronary artery size in dogs. A two-dimensional intravascular ultrasound study.

Because the role of tonic vagus nerve activity in regulating conduit coronary artery size remains undefined, we investigated the response of epicardial coronary artery size to changes in resting vagal tone resulting from vagotomy and muscarinic receptor blockade. Using intravascular ultrasound to measure left circumflex coronary artery cross-sectional area continuously, we examined the effects of vagotomy on left circumflex cross-sectional area in nine dogs. Lumen area decreased 20% from 8.70 +/- 2.81 to 6.92 +/- 1.97 mm2 after right vagotomy, 17% to 7.19 +/- 2.80 mm2 after left vagotomy (both P < .05 versus baseline), and 38% to 5.42 +/- 2.00 mm2 after bilateral vagotomy (P < .05 versus unilateral vagotomy). Vasoconstriction occurred despite increases in heart rate and an unchanged rate-pressure product. In six additional dogs, after acetylcholine (100 micrograms/kg i.v.), lumen area increased by 18%, although heart rate, blood pressure, and rate-pressure product were unchanged. Vasodilation was prevented by prior muscarinic blockade with glycopyrrolate. With glycopyrrolate administration and heart rate control by pacing, lumen area decreased by 26% (P = .011). When stellate stimulation was performed in a third group of eight dogs with heart rate, blood pressure, and rate-pressure product controlled by a combination of pacing and exsanguination, there was no change in coronary area, thus precluding reflex sympathetic activation as a contributor to the vasoconstriction produced by vagal withdrawal. Vagus nerve activity maintains tonic dilation of the left circumflex coronary artery by muscarinic receptor activation. Each vagus nerve contributes approximately equally to the tonically dilated state. Vagotomy-induced vasoconstriction occurs independently of local metabolic factors and coronary distending pressure and is a result of cholinergic withdrawal rather than reflex sympathetic activation.

Morphometry and Histochemistry of Pulmonary Arteries in a Hypoplastic Lung Model

Persistent pulmonary hypertension (PPH) is a common consequence of many neonatal respiratory diseases. The pathophysiology of PPH remains unknown. To study PPH, a rat model of pulmonary hypoplasia was used. Lung mass and body mass were recorded and lungs were prepared for frozen section examination and stained with hematoxylin and eosin, elastin, anti-Factor VIII, and nitro blue tetrazolium to identify nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase. The lungs were analyzed for air space volume, pulmonary artery wall thickness, total pulmonary arterial cross-sectional area, and density of tissue NADPH diaphorase staining. The mass of hypoplastic lungs was less than that of normal lungs (mean mass 85.93 mg vs 142.97 mg, P < 0.0001). The measured fraction of airspace volume was significantly less in hypoplastic lungs compared to controls (17.7% vs 30.8%, P < 0.0001). There was a significant difference in the pulmonary artery wall thickness ratio between the two groups (control 0.46 vs hypoplastic 0.487, P = 0.001). The arterial cross-sectional area was identical (control 1.25% vs hypoplastic 1.37%, P = 0.47). Staining density for NADPH diaphorase activity was determined using an intensity staining index (ISI). The experimental group showed increased staining for NADPH diaphorase (ISI = 54 in hypoplastic lungs vs 38 in controls, P < 0.01). Lung mass, appearance, and measured volume of airspace and tissue were all consistent with hypoplasia. In this model, arterial wall thickness was measurably greater in the hypoplastic group, while arterial cross-sectional area was not different. Staining for NADPH diaphorase showed significantly greater levels of enzyme in the hypoplastic lung. These data suggest that pulmonary hypertension in hypoplasia results in part from a biochemical mechanism. Precise characterization of pulmonary biochemical properties may lead to improved therapies for PPH of the newborn.

Histomorphometric and Biochemical Correlates of Arterial Procollagen Gene Expression During Vascular Repair After Experimental Angioplasty

To determine the transcriptional, biochemical, and histomorphometric correlates of neointimal procollagen accumulation during arterial repair after balloon angioplasty of atherogenic vessels, rabbit iliac artery collagen content and the induction of alpha 1(I) and alpha 1(III) procollagen mRNA were assessed in normal vessels and at 2, 7, and 30 days after angioplasty. Quantitative iliac artery histomorphometric neointimal collagen analysis was performed using a specific picrosirius red stain under polarized light. Arterial cross-sectional area reduction, total cellularity, and vascular smooth muscle cell density (per 10(4) mu2 of neointima) were quantified in routine and immunohistochemically stained sections (alpha-actin and RAM-11), from which biochemical concentrations of tissue protein, RNA, and DNA were also measured. Collagen comprised 0.23 +/- 0.1 mg/mg of total protein in the normal vessel wall and did not increase in vessels studied 2 and 7 days after angioplasty (0.26 +/- 0.06, 0.28 +/- 0.05 mg/mg of protein, P = NS). By 30 days after angioplasty, > 50% of the protein concentration was collagen (0.55 +/- 0.11 mg/mg of protein, P = .02). Collagen-positive histological staining also increased significantly from 17 +/- 2% of the neointima at day 2 to 32 +/- 5% by day 30 (P = .01). The transcript regulatory signal for alpha 1(I) procollagen mRNA was induced 2 days after angioplasty, peaking at 7 days for both alpha 1(I) and alpha 1(III), and returning to control levels 30 days after angioplasty. A significant luminal cross-sectional area reduction of the arterial wall was confirmed both by angiography and histomorphometry (P = .01). This was not associated with a significant change in alpha-actin (+) vascular smooth muscle cell density (38 +/- 7 nuclei per 10(4) mu2 at day 2 and at day 30) or tissue DNA concentration (P = NS). We conclude that procollagen genes are transcriptionally activated early (2 to 7 days) after angioplasty vessel injury and that collagen subsequently constitutes a major biochemical and histological component of the proliferative neointima by 30 days after angioplasty. Alterations in pathways regulating procollagen metabolism may also contribute to the accumulation of extracellular matrix and growth of the neointima in the late repair phase after vessel wall injury.

407-1 Cardio-Oesophageal Reflex: A Mechanism for “Linked Angina” in Patients with Angiographically Proven Coronary Artery Disease

We have shown previously that oesophageal acid stimulation can reduce coronary blood flow in syndrome X patients suggesting the presence of a cardio-oesophageal reflex in humans. The presence of such a reflex in patients with coronary artery disease could explain the mechanism of “linked angina”. To investigate this hypothesis we studied the effect of oesophageal acid stimulation on coronary blood flow in 14 patients with angiographically documented significant (&gt;50% stenosis) coronary artery disease (CAD) and 18 heart transplant patients (HT). A fine tube was introduced through the patient's nose in to the distal oesophagus. A 3.6F intracoronary Doppler catheter was positioned in the proximal left anterior descending coronary artery. Coronary blood flow was calculated from measurements of coronary flow velocities and arterial cross-sectional area from quantitative angiography. Oesophageal instillation of 0.1 M hydrochloric acid and 0.9% saline was performed in random, double-blind fashion (60 ml over 5 minutes) and the measurements were repeated after each infusion. Nine patients in the CAD group reported their usual chest pain on acid instillation but none experienced any pain after saline infusion. None of the patients in the HT group experienced any chest pain on acid or saline infusion. There were no significant difference in systemic haemodynamics after the infusions in both groups. The coronary blood flow (CBF) was significantly reduced by acid oesophageal stimulation in the CAD group [CBF pre-acid 70.4 ± 14.3, CBF post-acid 46.4 ± 19.1 ml/min (p &lt; 0.01)]. However, there was no significant difference in the CBF on saline infusion [73.5 ± 15.3 versus 72.5 ± 14 ml/min]. CBF in the HT group was unaffected by acid or saline infusion. In the 9 CAD patients who experienced angina on oesophageal acid infusion there was a significant reduction in CBF from 73.4 ± 12.9 to 34.6 ± 4.7 ml/min. However, in the 5 CAD patients who did not have any chest pain the CBF was unaffected by acid infusion [65.1 ± 16.7 versus 67.5 ± 16.7 ml/min] . Oesophageal acid stimulation can produce angina and significantly reduce coronary blood flow. The lack of any significant effect in the HT group, in whom the heart is denervated, suggests a neural reflex. The presence of such a reflex may be a mechanism for “Linked Angina” in patients with coronary artery disease.