RETRACTED: Differing attenuation coefficients of normal and infarcted myocardium.

There are significant differences in attenuation coefficients between normal and infarcted myocardium measurable with a computerized transaxial tomographic scanner. Additionally, iodinated contrast material administered prior to killing the tests animals resulted in excellent visualization of the blood-myocardial interface at a time when standard radiographs detected no differences between the ventricular cavity and the myocardial wall. These natural and induced changes in attenuation coefficients offer a new approach to evaluating and understanding the processes of tissue injury and death. Their clinical relevance lies in application to the twin problems of myocardial infarction and the structure and function of the cardiac wall.

Reciprocal influence of salt intake on adrenal glomerulosa and renal vascular responses to angiotensin II in normal man.

The adrenal glomerulosa cell and the renal vasculature respond to similar arterial angiotensin II (A II) levels. We have assessed the effect of decreased sodium intake on their responses to A II in man. Studies were performed in 42 normal subjects in balance on a daily intake of 100 meq potassium and either 200 or 10 meq sodium/day. Renal blood flow was measured with (133)Xe and arterial A II, renin and aldosterone concentrations by radioimmunoassay. A II was infused intravenously (1, 3, or 10 ng/kg/min) for 40-60 min; 14 subjects received graded doses. The A II level increased linearly with dose and plateaued within 3 min; blood pressure and renal vascular resistance showed a similar time-course. Aldosterone rose within 10 and plateaued within 20 min. Dose-response relationships were established between the rate of A II infusion and the adrenal, the renal vascular, and pressor responses. Sodium restriction reduced the pressor (P < 0.01) and the renal vascular response (P < 0.01), but potentiated the adrenal response to A II (P < 0.01). An excellent correlation was found between the plasma A II and aldosterone levels, but the slope of their regression relationship on a high (y = 0.13x + 6) and low salt intake (y = 0.32x + 14) differed significantly (P < 0.0005). Thus, sodium intake reciprocally influences vascular and adrenal responses to A II: salt restriction blunts the vascular response and potentiates the adrenal's, a physiologically important influence in view of aldosterone's role in sodium conservation.

Blockade and stimulation of renal, adrenal, and vascular angiotensin II receptors with 1-Sar, 8-Ala angiotensin II in normal man.

We have assessed the capacity of an analogue of angiotensin II (A II), 1-Sar, 8-Ala A II (P113) in normal man to stimulate and block responses to A II in four systems: blood pressure was monitored directly from an arterial catheter, and renal blood flow was measured with 133Xe and arterial renin and aldosterone concentrations by radioimmunoassay. The 31 normal subjects were in balance on a daily intake of 200 meg sodium and 100 meq potassium to suppress endogenous renin. P113 administered intravenously induced a dose-related renal blood flow reduction, with a threshold dose of 0.1 mug/kg/min. This dose also induced a small but significant increase in arterial blood pressure and plasma aldosterone as well as a reduction in plasma renin activity. In contrast to its effect on the renal vasculature, no tendency to a progressive response in the latter three parameters was noted as the P113 dose was increased 30-fold, to 3.0 mug/kg/min. P113 also reduced the clearance of para-aminohippurate, creatinine, sodium, and potassium, a pattern similar to that induced by A II. P113 at 0.1 mug/kg/min reduced significantly the blood pressure and renal vascular and aldosterone responses to graded doses of A II. Higher P113 doses totally obliterated all three responses to A II infused at 10 ng/kg/min, a dose that provides arterial A II concentrations in the range found in angiotensin-mediated hypertension. When A II was infused first, to induce a pressor, renal vascular, and aldosterone response, P113 induced a dose-related reversal of the response in each system. In conclusion, P113 is a partial agonist in normal man, inducing an angiotensin-like response in settings in which endogenous A II is not playing a tonic role, and displaying dominant antagonist activity in settings in which A II is active. Moreover, the studies suggest that the receptors mediating the responses to A II are different in the renal vasculature and other systemic vascular beds. The adrenal receptor must also differ. This agent should be useful in dissecting the role of A II in diseases characterized by hypertension or abnormalities of renal and adrenal function.

Essential hypertension: abnormal renal vascular and endocrine responses to a mild psychological stimulus.

We have assessed the influence of a mild emotional stimulus on arterial blood pressure, heart rate, renal blood flow, plasma renin activity (PRA), and plasma aldosterone concentration in 24 normal subjects, eight of who had a parent with hypertension, and in 15 patients with essential hypertension. A nonverbal IQ test, Raven's Progressive Matrices, was employed as the stimulus. In 11 of the 15 hypertensives, arterial blood pressure rose transiently by 7 mm Hg or more, but in only three of 16 normal subjects (x2 = 7.23, p less than 0.01). Transient moderate increases in heart rate were also more common in the hypertensives (p less than 0.01). Renal blood flow rose in 11 of 16 normal subjects and fell in each of the 15 patients with essential hypertension (x2 = 15.1; p less than 0.005). As opposed to the transient changes in arterial pressure and heart rate, the fall in renal perfusion was sustained. The PRA fell in 10 of the 16 normal subjects with a negative family history and rose in 14 of 15 patients with essential hypertension (p less than 0.005). Changes in plasma angiotensin II concentration and in plasma aldosterone were in accord with the changes in PRA, but plasma cortisol did not change. Both the renal vascular response and the change in PRA were intermediate in normal subjects in whom family history was positive for hypertension. For the entire group of 39 subjects there was statistically significant agreement between the direction of the renal vascular response and the directional change in PRA: renal blood flow rose when PRA fell and fell when PRA rose (p less than 0.005). We conclude that there is an abnormality in the control of both the renal circulation and of renin release in patients with essential hypertension in response to psychological provocation, and that a similar process is present in some normotensive subjects whose parents have hypertension.

Renal vascular tone in essential and secondary hypertension: hemodynamic and angiographic responses to vasodilators.

The renal vascular response to graded doses of acetylcholine, dopamine and phentolamine, assessed by xenon washout and selective arteriography was used to define the relative contribution of fixed and reversible vascular abnormalities to increased renal vascular resistance in patients with essential or secondary hypertension. The increase in blood flow induced by acetylcholine and dopamine was blunted strikingly in patients with advanced nephrosclerosis, chronic pyelonephritis and polycystic kidney disease and was normal in the kidney contralateral to a significant renal artery stenosis. Conversely, the response to both was potentiated in 9 of 13 (69%) patients with mild essential hypertension. Equivalent potentiation of the response to acetylcholine was induced in normal subjects by increasing renal vascular tone pharmacologically with angiotensin. Phentolamine infused into the renal artery also increased renal blood flow significantly in 6 of 9 (67%) patients with mild essential hypertension, but in none of 15 normal subjects, over a dose reange that paralleled that for alpha-adrenergic blockade. Changes in the selective renal arteriogram were in excellent accord: potentiated response to acetylcholine, phentolamine or dopamine was associated with reversal of the small vessel abnormalities visualized in the arteriogram. The reduced blood flow response in advanced nephrosclerosis or parenchymal disease was associated with a reduced angiographic change during dilator infusion. The results suggest a quantitatively important, functional renal vascular abnormality--perhaps mediated by the sympathetic nervous system--in many patients with mild essential hypertension. Conversely the renal vascular abnormality associated with advanced nephrosclerosis or renal parenchymal disease is largely fixed and is probably due to organic changes.

The renal circulation in hypertensive disease.

The pivotal role of the kidney in sustaining hypertension from any source or etiology is becoming increasingly clear. The possibility that the renal vasculature participates not only in the pathogenesis of renal vascular hypertension, but also in that of essential hypertension, has been the subject of continuing interest for 40 years. Evidence that a functional abnormality resulting in increased renal vascular tone is present in about two-thirds of patients with uncomplicated essential hypertension is reviewed, along with more circumstantial evidence that sympathetic nervous system activity operating on the renal vasculature is responsible. Two additional groups of patients in whom a characteristic abnormality of the renal vasculature is present have also been identified. In one group there is severe hypertension which is resistant to most forms of antihypertensive therapy but which is especially responsive to propranolol. In these patients renal blood flow and glomerular filtration rate are reduced, renin secretion rate is increased and the renal vessels are resistant to vasodilators, suggesting the presence of advanced organic arteriolonephrosclerosis, as a complication of long-standing, severe hypertension. The renal lesion, in turn, contributes to the increasing severity of the process. In a second group of patients, generally young and with uncomplicated hypertension, renal blood flow is inappropriately increased. In these patients a number of observations on their renal vasculature, renin and aldosterone responses to a volume challenge suggest an abnormality in the perception of extracellular fluid volume. A perfectly normal renal arterial tree, free of organic abnormality or an increase in tone due to active vasoconstriction, is distinctly unusual in essential hypertension.

Significance of reduced regional myocardial blood flow in asynergic areas evaluated with intervention ventriculography. Results of studies combining washout of xenon-133 and postextrasystolic potentiation.

Nineteen patients with coronary artery disease were studied to determine the significance of reduced regional myocardial blood flow (50 ml/min per 100 g or less) in areas of abnormal wall motion. Regional myocardial blood flow was measured in four regions of the left ventricle with an Anger camera after the injection xenon-133 into the left main coronary artery. Abnormal wall motion was evaluated with biplane left ventriculography at rest and during postextrasystolic potentiation, a potent inotropic stimulus. Abnormal wall motion was defined as hemiaxis shortening of less than 20 percent. Four hemiaxes were designated as corresponding to the four regions of myocardial blood flow. Of 76 hemiaxes evaluated in the 19 patients, 54 manifested normal wall motion and 22 abnormal wall motion; 8 of the 22 hemiaxes had reduced regional myocardial bood flow. In these 8, hemiaxis shortening increased 6 +/- 2 percent (mean +/- standard error of the mean) above values at rest during postextrasystolic potentiation (with normalization of hemiaxis shortening in only 1 of the 8), compared with an increase of 19 +/- 4 percent (P less than 0.001) in the 12 hemiaxes with borderline regional myocardial blood flow (with normalization of hemiaxis shortening in 9 of the 12, P less than 0.05). These results indicate that the presence of reduced regional myocardial blood flow in areas of abnormal wall motion usually predicts a poor response to post-extrasystolic potentiation, whereas abnormal wall motion without reduced regional myocardial blood flow usually predicts a good response. The combination of reduced regional myocardial blood flow and abnormal wall motion suggests scarred and nonviable myocardium.

Comparison of observer performance with 16 mm cinefluorography and 70 mm camera fluorography in coronary arteriography.

Clinical 16 mm cinefluorography and 70 mm camera fluorography were compared in 30 unselected patients undergoing coronary arteriography. Accuracy in detecting coronary arterial stenosis and collateral vessels and in assessing the degree of stenosis was similar with the two techniques. With both methods, there were significant inter- and intraobserver differences in estimating the degree of stenosis. These differences indicate that coronary arteriography is only a semiquantitative method for making decisions about treatment, prognosis and follow-up of patients. The use of more than one observer increases the likelihood that stenotic lesions will be detected. Interobserver variation in detecting collateral circulation is small.

Regional myocardial blood flow during hyperemia induced by contrast agent in patients with coronary artery disease.

Regional myocardial specific blood flow (regional specific flow) was measured at rest and during contrast hyperemia after the intracoronary injection of xenon-133. The changes in regional specific flow were transient, resulting in some compromise in one of the underlying restraints of the inert gas washout method, namely, the presence of a steady state. Therefore, to determine the clinical utility of this technique, regional specific flow values obtained with this method were correlated with the presence and severity of coronary artery disease as assessed from the coronary arteriogram and left ventriculogram. Regional specific flow during contrast hyperemia was 186+/- 11 (mean +/- 1 standard error of the mean) ml/min per 100 g in control patients and 115+/-5 in patients with coronary artery disease. There was an inverse relation between regional specific flow during contrast hyperemia and the percent coronary stenosis when the stenosis was 40 percent or greater (r = 0.70, P less than 0.001). Regional specific flow was significantly less in patients with asynergy (77 +/- 10 ml/min per 100 g) than in patients with normal ventricular function (105 +/- 5) distal to coronary stenoses of greater than 75 percent. Thus regional specific flow measured during contrast hyperemia using the xenon washout technique and the Anger camera differentiated patients with normal coronary arteriograms from those with coronary artery disease. With this technique, good correlation was shown between regional specific flow and the percent coronary stenosis and presence of ventricular wall abnormalities. The information obtained with this method may provide prognostic information concerning suitability for surgical intervention.

Effect of sublingually administered nitroglycerin on regional myocardial blood flow in patients with coronary artery disease.

The effect of sublingually administered nitroglycerin on regional myocardial specific blood flow (in ml/min per 100 g tissue) was evaluated with a xenon-133 washout technique in 31 patients in a resting nonstressed state. Eight patients had normal coronary arteriograms (Group 1), 12 had coronary artery disease without collateral vessels (Group 2) and 11 had coronary artery disease with collateral vessels (Group 3). Although nitroglycerin caused a similar decrease in mean arterial blood pressure and blood pressure-heart rate product in all three groups, the decrease in regional myocardial blood flow was significantly less in Group 3 (-8+/-6% [mean+/-standard error of the mean]) than in Group 1 (-31+/-5%), P less than 0.05); an intermediary decrease occurred in Group 2 (-23+/-5%). Within Group 3, there was a mean increase in regional myocardial blood flow after nitroglycerin in the five patients whose collateral vessels were of a higher angiographic grade and arose from non-stenosed coronary arteries, whereas a reduction was observed in the six patients with none or only one of these findings (+10+/-7% versus -23+/-3%, P less than 0.001). This study suggests that even in the resting state, in some patients with coronary artery disease enhancement of regional myocardial blood flow can occur after sublingual administration of nitroglycerin and is probably mediated through well functioning collateral vessels. It is possible that the drug's effects on both the coronary and systemic circulation may relieve angina in some patients with coronary artery disease.

Magnetic resonance imaging of skeletal muscle. Prolongation of T1 and T2 subsequent to denervation.

The changes seen in the T1 and T2 relaxation times, water content and size of the extracellular fluid spaces of rat muscle samples following 15 days of denervation were studied by in vitro proton NMR spectrometry (10 MHz). Two different skeletal muscle groups (gastrocnemius and soleus) were studied. Denervation led to longer T1 values: 548 +/- 61 msec vs. 486 +/- 16 msec (P less than .05) for the gastrocnemius and 581 +/- 27 msec vs. 521 +/- 25 msec (P less than .05) for the soleus. Similar increases in T2 were measured. The sizes of the extracellular fluid spaces of denervated muscle were significantly larger despite a minor increase in total water content. Overall, the relaxation times of skeletal muscle correlated better with the size of the extracellular fluid space than with the total water content.

NMR of skeletal muscle. Differences in relaxation parameters related to extracellular/intracellular fluid spaces.

The relationships between the T1 and T2 relaxation times, tissue water content and extracellular fluid space of two types of skeletal muscle groups were studied in rabbits and rats by means of NMR proton spectroscopy (10 MHz). Although there was no significant difference in the total water content between muscles rich in type I (74.5 +/- .8%; soleus) or type II (75.0 +/- .7%; gastrocnemius) fibers, the respective T1 (521 +/- 25 vs. 486 +/- 16 millisecond; p less than .01) and T2 (39.5 +/- 1.8 vs. 36.5 +/- 1.0 millisecond; p less than .01) relaxation times were consistently prolonged. The longer relaxation times of the soleus as compared with the gastrocnemius muscle were related to a larger extracellular fluid space as measured by (35S) sulfate +34.5%; p less than .01). For this reason, it seems likely selective changes in these spaces will be detectable by NMR proton imaging.

The production and evaluation of contrast-carrying liposomes made with an automatic high-pressure system.

An automatic, high-pressure system (Microfluidizer) has been found useful for producing contrast-carrying liposomes on an industrial scale. The goal of this investigation was to determine the feasibility of using this new microemulsification process to manufacture contrast-carrying microemulsified liposomes (MELs). Seven contrast media (three ionic, four nonionic) were encapsulated into the MELs. Light and electron microscopy, light scattering, radioisotope, and CT scan techniques were used to characterize these MELs, and the contrast entrapments among the studied media were compared. The contrast-carrying MELs had good properties for imaging normal reticuloendothelial tissues, selectively. They had a narrow size range (0.1-3.0 micron), a single bilayer wall, high liver and spleen upake, and low leakage rates. The nonionic media were significantly more effectively entrapped in the MELs than the ionic media (P less than .05). The iodine-to-lipid weight ratio was about 1:16 for ionic media and 1:4 for nonionic media. Physical properties of the contrast media such as osmotic pressure and charge appeared to affect contrast entrapment. It was concluded that the microemulsification process is a useful system for producing contrast-carrying liposomes continuously, on a large scale and in a reproducible manner.

Imaging of complex NMR spectra.

The Point Spread Function (PSF) in NMR imaging is the result of both the line broadening due to magnet field inhomogeneity and the intrinsic spectrum of the nucleus at resonance. In the case of proton imaging, the line broadening dominates the small chemical shifts and the spectral lines are not resolved. This is not generally the case with other nuclei having strong chemical shifts and the PSF then has a complex structure. During imaging, the complex PSF is convolved with the spatial distribution of the nucleus at resonance and this leads to halo artifacts which are dependent on the imaging technique employed. The images due to the ensemble of spectral lines can be separated in principle by deconvolution of the data with the PSF before reconstruction. In the special case where the complex PSF is spatially independent, it can be obtained from the Free Induction Decay (FID) data produced in the absence of a spatially encoding gradient field. This technique has been successfully applied to in-vivo imaging of exogenous perfluorocarbon material.

The detection of inflammation in collapsed lung by alterations in proton nuclear magnetic relaxation times.

The purpose of this study was to establish the proton NMR relaxation times of collapsed but otherwise normal lung tissue and to determine whether an inflammatory process within a collapsed lung can be detected by alterations in relaxation times. The lungs of three groups of rabbits were studied: group A (n = 7) had a sterile collapse of one lung for two days. The two other groups also had one lung collapsed, but with bacterial (group B, n = 6) or chemically induced (group C; n = 6) pneumonitis superimposed. The contralateral lung, which was acutely deflated at the time of thoracotomy, served as a control in each animal. T1, T2 and the total water content were measured on freshly excised lung samples. In group A, there was no significant difference in T1 (606 +/- 14* ms vs. 595 +/- 18 ms;* = SEM) or T2 (80.6 +/- 1.7 ms vs. 78.4 +/- 2.6 ms) between the collapsed and the control lung tissue. In each animal in groups B and C, T2 was longer in the collapsed lung with superimposed pneumonitis than in the control lung tissue (group B: 116.8 +/- 6.9 ms vs. 82.9 +/- 1.8 ms, P less than .001; group C: 120.5 +/- 5.9 ms vs. 86.0 +/- 1.5 ms, P less than .001). T1 changes were similar, but less marked. There was a linear relationship between the relaxation times and the total water content of the lung samples (T1:r = 0.87; T2:r = 0.91). It is concluded that proton NMR may have a potential in detecting disease such as inflammation in collapsed lung tissue based on differences in relaxation parameters compared with normal lung areas.

Nuclear magnetic resonance spectroscopy of acute and evolving pulmonary hemorrhage. An in vitro study.

The proton NMR relaxation times of lung tissue were determined in a rabbit model of acute and evolving pulmonary hemorrhage (PH). Pure PH was simulated by injecting blood into a single lobe using endobronchial catheterization. In vitro spectroscopic measurements of T1 and T2 were made and total water content was determined on lung samples that were excised at regular intervals. T1 and T2 were markedly longer in lungs with acute PH than in normal lungs (T1: 818 +/- 44 vs. 643 +/- 4 msec; T2 164.0 +/- 16.3 vs. 88.1 +/- 3.4 msec). Within the first 24 hours, evolving PH was characterized by a rapid and progressive decrease in T1 (-50%) and T2 (-57%). Up to seven days after the instillation of blood, the T1 (450 +/- 43 msec) and T2 (69.7 +/- 1.9 msec) of lung with modeled PH remained below values of normal lung. The observed shortening of the relaxation times of lung disease with PH was closely paralleled by a decrease in tissue water content.

Developmental changes in proton magnetic resonance relaxation times of cardiac and skeletal muscle.

Proton magnetic resonance relaxation time measurements were used to study developmental changes in rabbit cardiac and skeletal muscles during the last days of gestation and at several postnatal times. Tissue water content decreased steadily during late fetal and early postnatal stages of development. During this period T1 and T2 for cardiac and skeletal muscles also decreased. The relaxation times stabilized after the 20th postnatal day, and at this juncture the T1 and T2 values for myocardium remained consistently higher than for skeletal muscle. The developmental changes in proton relaxation time probably represent changes in water distribution and mobility as well as macromolecular structure during muscle maturation.

Balloon-occlusion superior mesenteric arteriography for improved visualization of the mesenteric and portal venous anatomy of dogs.

The superior mesenteric arteries of twelve dogs were occluded with an inflated balloon on the tip of an endhole catheter while diatrizoate meglumine and diatrizoate sodium (Renografin 76) was injected distal to the occlusion. The balloon was immediately deflated at the end of contrast injection. Films taken over a 33-second period showed consistently excellent visualization of the mesenteric arteries and veins as well as the portal veins. Comparison with studies performed by the conventional, nonocclusion technique confirmed the superiority of the films obtained with the balloon occlusion method. Histologic examination of the mesenteric artery at the site of balloon inflation and of the small and large bowel revealed no abnormalities.

Production and characterization of improved liposomes containing radiographic contrast media.

The authors have investigated liposomes prepared by the reverse-phase evaporation method (REVs) and a modification of this technique that employs a microemulsifier (MREVs), for the delivery of radiographic contrast media (RCM) to the liver and spleen. The modification entailed substituting a Microfluidizer (Microfluidics Inc., Newton, MA) for the sonication step of the REV technique. The MREV procedure is amenable to large-scale production and continuous-flow operation and yields products with high RCM encapsulation. Efficiently entrapped are ionic, high-osmolar diatrizoate (24.38 +/- 2.62% versus 8.35 +/- 0.55%; MREV versus REV), and nonionic, low osmolar Iotrolan (Schering AG, Berlin, FRG) (24.84 +/- 2.13% versus 7.25 +/- 1.19%) RCM with iodine-to-lipid ratio of 1.5:1. The MREV procedure, therefore, has practical advantages over the REV method. High liver and spleen uptakes of Iotrolan-containing vesicles were noted in normal rats. The diatrizoate MREVs lost their contents on contact with serum, resulting in urinary excretion of this agent. Computed tomography values of splenic and hepatic sections, 1 hour after intravenous injection of Iotrolan MREV (500 mgI/kg), are 0.78, and 0.08 Hounsfield Units (HU)/mgI/kg, respectively (versus 0.01, and 0.006 HU/mgI/kg for free Iotrolan).

Biodistribution and clearance of contrast-carrying MREV liposomes.

Contrast-carrying liposomes (CCLs) have been shown to increase the attenuation coefficient of the liver and spleen during computed tomographic (CT) imaging. A modification of the reverse-phase evaporation preparative technique ("MREV") led to production of CCLs that entrap contrast media efficiently. After intravenous injection, MREVs are phagocytized by the Kupffer cells of the liver and the macrophages of the spleen. The biodistribution and clearance of MREVs were studied to evaluate their potential for clinical use, MREVs carrying iodine-125-iotrolan were administered intravenously to 12 rats at doses of 400 mg lipid (containing 400 mg iodine) per kilogram body weight. Pairs of rats were anesthetized and scanned at 3 hours, and 1, 7, 14, 27 and 48 days; CT attenuation values of liver, spleen, blood, kidneys and bladder were measured. Immediately following CT, the rats were killed and tissue specimens were radioassayed. Maximum iodine content in liver and spleen was reached at one day and sustained at high levels for seven days. Biologic removal half-time of the agent in both the liver and spleen was six days. Maximum CT enhancements over baseline were observed at 24 hours and reached 210 delta HU in the liver and 880 delta HU in the spleen per gram iodine injected per kilogram body weight. It is concluded that MREVs have appropriate imaging characteristics, biodistribution, and clearance to be effective CT contrast agents.