Nitric oxide mediation of chemoregulation but not autoregulation of cerebral blood flow in primates.

The authors sought to develop a model for assessing in vivo regulation of cerebral vasoregulation by nitric oxide (NO), originally described as endothelial-derived relaxing factor, and to use this model to establish the role of NO in the regulation of cerebral blood flow (CBF) in primates. By using regional intraarterial perfusion, the function of NO in cerebral vasoregulation was examined without producing confounding systemic physiological effects. Issues examined were: whether resting vasomotor tone requires NO; whether NO mediates vasodilation during chemoregulation and autoregulation of CBF; and whether there is a relationship between the degree of hypercapnia and hypotension and NO production. Twelve anesthetized (0.5% isoflurane) cynomolgus monkeys were monitored continuously for cortical CBF, PaCO2, and mean arterial pressure (MAP), which were systematically altered to provide control and experimental curves of chemoregulation (CBF vs. PaCO2) and autoregulation (CBF vs. MAP) during continuous intracarotid infusion of 1) saline and 2) an NO synthase inhibitor (NOSI), either L-n-monomethyl arginine or nitro L-arginine. During basal conditions (PaCO2 of 38-42 mm Hg) NOSI infusion of internal carotid artery (ICA) reduced cortical CBF from 62 (saline) to 53 ml/100 g/per minute (p<0.01), although there was no effect on MAP. Increased CBF in response to hypercapnia was completely blocked by ICA NOSI. The difference in regional (r)CBF between ICA saline and NOSI infusion increased linearly with PaCO2 when PaCO2 was greater than 40 mm Hg, indicating a graded relationship of NO production, increasing PaCO2, and increasing CBF. Diminution of CBF with NOSI infusion was reversed by simultaneous ICA infusion of L-arginine, indicating a direct role of NO synthesis in the chemoregulation of CBF. Hypotension and hypertension were induced with trimethaphan camsylate (Arfonad) and phenylephrine at constant PaCO2 (40 +/- 1 mm Hg). Autoregulation in response to changes in MAP from 50 to 140 mm Hg was unaffected by ICA infusion of NOSI. In primates, cerebral vascular tone is modulated in vivo by NO; continuous release of NO is necessary to maintain homeostatic cerebral vasodilation; vasodilation during chemoregulation of CBF is mediated directly by NO production; autoregulatory vasodilation with hypertension is not mediated by NO; and increasing PaCO2 induces increased NO production.

Clearance of gadolinium chelates by hemodialysis: an in vitro study.

Although the gadolinium (Gd)-chelates currently approved for clinical use in the United States are considered "readily dialyzable," the actual clearance rates have not been published. The purpose of this study was to establish in vitro dialysis clearance rates of Gd-chelates to develop rational strategies for removing the agents with dialysis. Three agents, Gd-diethylenetriaminopentaacetic acid (Gd-DTPA), Gd-HP-DO3A and Gd-DTPA-BMA were diluted separately in plasma and saline and were dialyzed by using a clinical dialyzer unit with a commercially available capillary filter at rates of 0-300 cc/min. Predialyzer and postdialyzer concentrations were determined by inductively coupled atomic emission photometry. Urea and creatinine clearance rates also were determined. The clearance rate for Gd-chelates were considerably lower than that of urea and creatinine, which are generally considered benchmarks of dialysis efficiency. At 300 cc/min flow rates, the clearances were (clearance in cubic centimeters per minute with 95% confidence interval): Gd-DTPA-74 cc/min (68-80 cc/min) delta-HP-DO3A 67 cc/min (63-71cc/min); and Gd-DTPA-BMA 67 cc/min (63-71cc/min). In comparison, urea and creatinine were 180 cc/min (178-181 cc/min) and 142 cc/min (124-131 cc/min), respectively. There was no difference between clearance rates of Gd-chelates in saline and plasma, implying there was no protein binding. By using a first order kinetic model of dialysis time, more than 12.2 to 14.7 hours of dialysis would be necessary to remove 97% of the injected dose of Gd-chelate.(ABSTRACT TRUNCATED AT 250 WORDS)

Variability of ischemia during spermatic cord torsion in the rat.

Testicular torsion affects prepubertal males and causes testicular infarction and subfertility. Animal models of spermatic cord torsion have been used in an attempt to study the mechanism of testicular injury from torsion. Although standardized animal models of torsion have been proposed, their reliability in producing testicular ischemia has not been documented. Dynamic enhanced magnetic resonance imaging (MRI) of the testis was used in a rat model with surgically induced, unilateral, 720 degrees torsion to quantify the severity of ischemia. Intravenous dysprosium diethylenetriaminepentaacetic acid-bis methylamide (Dy-DTPA-BMA) was injected as a bolus followed by serial dynamic Turbo GRASS images. Region of interest (ROI) measurements were obtained within the testicular parenchyma during contrast enhancement and washout. Perfusion abnormalities ranging from minimal delay in contrast enhancement in the torqued testicle to complete absence of intraparenchymal blood flow were documented with dynamic enhanced MRI. Reperfusion scans 1 hour after surgical reduction of torsion showed normalization of testicular blood flow in all animals. Dynamic enhanced MRI appears to be a useful method of documenting the perfusion deficit arising from torsion of the testis. Standard animal models of torsion produce inconsistent results because they do not reliably reproduce testicular ischemia. The ability of MRI to quantify perfusion abnormalities in the testis may provide additional information in the evaluation of human patients with symptoms of testicular torsion.

Dynamic enhanced magnetic resonance imaging of testicular perfusion in the rat.

Magnetic Resonance Imaging (MRI) has several theoretical advantages in the evaluation of spermatic cord torsion and testicular ischemia. The technique uses no ionizing radiation, has both excellent spatial and temporal resolution and, when used with an intravenous bolus of a paramagnetic contrast agent, provides a semiquantitative assessment of tissue perfusion and vascular injury. In clinical instances of testicular torsion, accurate estimates of tissue perfusion are desirable since testicular salvage is inversely related to the duration of torsion and the degree of tissue ischemia. Perfusion imaging of the rat testis was used as a model to demonstrate the potential use of MRI in the experimental and clinical analysis of disorders that affect blood flow to the testis.

Hydrated clearance of gadolinium-DTPA as a measurement of glomerular filtration rate.

Technetium (99mTc)-diethylene triamine pentaacetic acid (DTPA) hydrated clearance studies are accurate for determining GFR but require special facilities for handling and measuring samples. We investigated the potential of a non-radioactive paramagnetic analog, Gadolinium (Gd)-diethylene triamine pentaacetic acid (DTPA), an approved NMR contrast agent, as a glomerular filtration marker. Instead of relying on the radioactivity of technetium, this test is based on the fact that gadolinium induces alterations in the NMR T1 relaxation times in blood and urine samples. Ninety patients underwent simultaneous determinations of GFR using 1 mCi of Tc-DTPA and 0.05 mmol/kg Gd-DTPA (Berlex Labs) IV. The patients were hydrated with oral and intravenous fluid. Following a one hour equilibrium period, three or four consecutive urine collections were obtained; plasma samples were acquired at the beginning and end of each approximately 20-minute interval. 99mTc-DTPA radioactivity was determined with a scintillation counter. T1 relaxation times were measured on a 10 MHz NMR spectrometer. These were converted to Gd-DTPA concentration by comparison with standard solutions. The Gd-DTPA derived GFR closely approximated the 99mTc-DTPA derived GFR which ranged from 15 to 147 ml/min. The equation and correlation coefficient of the regression line is y = 1.04 x -2.2, r = 0.94. Thus, Gd-DTPA is a safe, non-radioactive indicator of GFR that may provide an alternative renal clearance method for clinical studies of progressive renal disease and nephrotoxicity.

Functional MR of the kidney.

A bolus injection of Gadopentetate Dimeglumine with dynamic gradient echo MR imaging has allowed for the visualization of normal and abnormal renal function. Following an injection of gadopentetate dimeglumine, NMR T1 relaxation times obtained on serial collections of serum and urine at timed intervals were used to derive the glomerular filtration rate. The merger of dynamic contrast-enhanced MRI with an in vitro NMR-derived GFR provides for assessment of renal function without the use of radioactive agents.

A novel testis-stimulating factor in familial male precocious puberty.

BACKGROUND: Familial male precocious puberty is a gonadotropin-independent form of precocious puberty that occurs only in males. The cause of the disorder is unknown. To examine the hypothesis that the plasma of boys with familial male precocious puberty contains a novel stimulator of testicular testosterone production, we developed a bioassay using adult male cynomolgus monkeys. METHODS: We collected plasma from 12 boys with familial male precocious puberty, 7 normal prepubertal boys of similar ages and with similar plasma gonadotropin levels, and 1 boy with hypogonadotropic hypogonadism and infused it into the testicular artery of adult male cynomolgus monkeys that had been pretreated with gonadotropin-releasing-hormone antagonist to inhibit the endogenous secretion of gonadotropins. Testicular venous effluent was collected at 15-minute intervals for 3 or 5 hours for the measurement of testosterone. RESULTS: The mean (+/- SE) peak testosterone response, as compared with base line, was significantly greater in the monkeys infused with plasma from the 12 boys with familial male precocious puberty than in the monkeys infused with plasma from the 7 normal prepubertal boys and the boy with hypogonadotropic hypogonadism (385 +/- 51 vs. 184 +/- 25 percent, P less than 0.005) in the three-hour studies. Plasma from 92 percent of the boys with familial male precocious puberty and 12.5 percent of the normal prepubertal boys stimulated a response greater than 195 percent of base-line values. In the animals studied for five hours after receiving a second dose of antagonist, the mean peak testosterone response, as compared with base line, was significantly greater in the monkeys infused with plasma from three boys with familial male precocious puberty than in the monkeys infused with plasma from three normal prepubertal boys (363 +/- 81 vs. 115 +/- 6 percent, P less than 0.01). The mean area under the testosterone-response curve was significantly larger in the monkeys infused with plasma from the boys with familial male precocious puberty in the five-hour studies (154 +/- 34 vs. -58 +/- 10 percent, P less than 0.005), but not in the three-hour studies. CONCLUSIONS: These findings support the presence of a circulating testis-stimulating factor in the plasma of boys with familial male precocious puberty. The production of such a factor would explain the biologic nature of the disorder.

Gadopentetate dimeglumine clearance in renal insufficiency in rabbits.

The total body clearance of gadopentetate dimeglumine (Gd-DTPA) was evaluated in 17 normal rabbits and 11 rabbits with renal insufficiency induced by angioinfarction. Serial measurements of the serum spin lattice relaxation rate (1/T1) were compared with actual gadolinium concentrations as determined by mass spectroscopy. Gadopentetate dimeglumine concentrations measured by both mass spectroscopy and magnetic resonance (MR) relaxometry decreased by two logs in both normals and rabbits with renal impairment by 24 hours and were highly correlated with each other (r = .98). The estimated total body clearance of gadopentetate dimeglumine was 14.1 +/- 0.56 cc/minute for the normal animals and 3.78 +/- 0.19 cc/minute for the impaired rabbits. These results indicate that gadopentetate dimeglumine is excreted rapidly, usually within 24 hours, even in the presence of renal insufficiency.

Choice of contrast material for four-hour delayed contrast-enhanced computed tomography of the liver.

Four-hour delayed contrast-enhanced computed tomography (DCECT) shows promise for improved detection of focal liver lesions. No previous studies have examined the use of nonionic contrast materials for DCECT. The authors undertook a case-controlled study in monkeys to define the relative efficacies of iopamidol and diatrizoate for DCECT. In this model, diatrizoate made the liver significantly more opaque at four hours than did iopamidol (mean 126.5 vs 87.6 HU, P less than or equal to 0.05). Opacification of the gallbladder and biliary tract occurred more often and was denser with diatrizoate. The relative efficacies of biliary excretion correlate with similarities in molecular structure. While it has been shown that the increased density from DCECT with diatrizoate may allow detection of more metastatic lesions, the clinical utility of the inferior parenchymal density obtained with iopamidol, extrapolated to be approximately 11 to 14 HU in humans, remains to be-established.

Gadolinium-DTPA enhanced dynamic MR imaging in the evaluation of cisplatinum nephrotoxicity.

Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) enhanced dynamic magnetic resonance (MR) imaging was used to monitor the nephrotoxic effects of cis-platinum (cis-diamminedichloroplatinum; CDDP), a chemotherapeutic agent that produces damage in the proximal convoluted tubule. Ten New Zealand white rabbits (NZWs) were divided into two groups and were evaluated at two clinically relevant doses of CDDP. Group 1 (four NZWs) received CDDP intravenously at 125 mg/m2 over 1 h. Rabbits in Group 2 (six NZWs) were infused with CDDP at 40 mg/m2 each day for 5 consecutive days. Dynamic MR images were performed in the axial plane at 1.5 T using a gradient recalled acquisition in the steady state sequence with an echo time of 11 ms, a repetition time of 20 ms, and a flip angle of 10 degrees after a bolus injection of Gd-DTPA 0.1 mmol/kg. Thirty-two sequential post Gd-DTPA images (5.12 s/image) were obtained over 2 min 45 s at a single location. All rabbits underwent baseline normal and serial post CDDP Gd-DTPA enhanced dynamic MR scans. Analysis of the alterations in the normal pattern of renal enhancement caused by CDDP was facilitated by using a stacked profile image and quantitative region of interest measurements of signal intensity. Normally, after the injection of Gd-DTPA, a dark band promptly appears in the outer cortex of the kidneys and migrates centripetally toward the papilla, reflecting the tubular concentration of Gd-DTPA. In Group 1 rabbits, nephrotoxicity due to CDDP was observed as early as 9 h after administration of the drug, with a complete disappearance of the dark band by 7 days. In Group 2 rabbits, the band disappeared gradually and reappeared 2-10 days after the completion of CDDP treatment, indicative of tubular damage and recovery with return of the concentrating ability of the kidney. These results illustrate the feasibility of using Gd-DTPA dynamic MR as a sensitive monitor of drug induced alterations of renal function.

Dynamic Gd-DTPA-enhanced MR imaging of the kidney: experimental results.

To determine the normal appearance of dynamic enhanced renal magnetic resonance (MR) images, 25 rabbits were injected with Gd-DTPA and 32 consecutive gradient-recalled images were acquired. Several rabbits were also imaged in dehydrated (five animals) and overhydrated (seven animals) states. A reproducible renal enhancement pattern is observed that can be divided into three phases. During the first phase, a peripheral dark band appears, probably representing arrival of Gd-DTPA within the arterioles and vasa recta. The second phase begins as a second dark band migrating centripetally toward the medulla; this likely represents the concentration of Gd-DTPA in the descending limb of the loop of Henle. The third phase is characterized by a gradual darkening in the papilla, probably caused by concentration of Gd-DTPA within the collecting ducts. Hydration status influences the duration of these phases. These observations can be explained by the anatomy and physiologic characteristics of the nephron, as well as the MR characteristics of Gd-DTPA at different concentrations.

Magnetic resonance imaging versus computed tomography in the evaluation of soft tissue tumors of the extremities.

Twenty patients with extremity soft tissue tumors were prospectively evaluated with magnetic resonance imaging (MRI) and computed tomography (CT) scans with subsequent anatomic correlation of surgical findings. MRI and CT had a similar percentage of accuracy in assessing tumor relationship with major neurovascular (80% and 70%, respectively) and skeletal (80% and 75%, respectively) structures. MRI was significantly better than CT in displaying contrast between tumor and muscle when using the T2 weighted spin echo (SE) (p2 less than 0.002) and inversion recovery (IR) (p2 less than 0.005) pulse sequences. MRI and CT were comparable in demonstrating contrast between tumor and fat. The contrast between tumor and vessel was better displayed by MRI compared with CT when using the T1 weighted SE (p2 less than 0.001) and T2 weighted SE (p2 less than 0.001) pulse sequences. T1 and T2 values were measured on fresh tumor and normal tissue samples and were used to predict relative contrast on different MRI pulse sequences using isosignal contour plots. MRI appears to offer several advantages over CT in the evaluation of extremity soft tissue tumors.

Gadolinium cryptelates as MR contrast agents.

Gadolinium cryptelates are complexes of a lanthanide metal ion with amino acids of macrocyclic polyamines. These compounds are water soluble and possess reduced relaxation properties similar to Gd diethylene triamine pentaacetic acid (DTPA). Three Gd cryptelates (Gd NOTA, DOTA, TETA) were evaluated. Gadolinium DOTA is the most stable Gd complex with a dissociation constant of 10(-28) and appears to have a greater serum stability than Gd DTPA. Gadolinium NOTA and Gd TETA have lower dissociation constants than Gd DTPA at 10(-17) and 10(-19). Gadolinium DOTA has tissue distribution properties similar to Gd DTPA, is rapidly excreted by the kidneys, and provides a high degree of contrast enhancement on magnetic resonance (MR) images, both systemically and within the CNS. Hence, Gd DOTA is an alternative water-soluble MR contrast agent to Gd DTPA.

Gd(DOTA): an alternative to Gd(DTPA) as a T1,2 relaxation agent for NMR imaging or spectroscopy.

Methods have been devised for obtaining gadolinium(III) complexes of the ligands NOTA (1,4,7-triazacyclononane-N,N',N''-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), TETA (1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid), and DTPA (diethylenetriaminepentaacetic acid) as solids for use as pharmaceuticals. Their effectiveness as in vitro and in vivo contrast agents for NMR imaging or T1,2 relaxation agents for spectroscopy has been investigated. The Gd(DOTA) complex was shown to be a more stable alternative to Gd(DTPA) by serum stability studies and measurement of stability constants. Images of tumors grown in athymic mice were obtained by NMR after injection of Gd(DOTA) and Gd(DTPA).

Cerebrospinal fluid rhinorrhea: depiction with MR cisternography in dogs.

Canine cerebrospinal fluid rhinorrhea, which occurs frequently in purebred beagles, was demonstrated in two dogs on magnetic resonance images after cisternal introduction of gadolinium-DTPA dimeglumine.

Sequential MR studies of intracerebral hematomas in monkeys.

It is well recognized that the MR appearance of intracranial bleeding changes with the age of lesion. It is also well known that hemoglobin in stagnating blood undergoes oxidation to methemoglobin, a substance that lowers the relaxation times of surrounding water protons. To study these phenomena in a controlled way, about 3 ml of blood was injected into the right frontal lobe of two rhesus monkeys, and they were scanned sequentially for up to 2 months in a Picker NMR scanner (Bo = 0.25-0.5 T). The image intensity of the blood changed during the first week, consistent with the lowering of T1 and T2. On the inversion-recovery scans the initial appearance of the blood was less bright than was the contralateral white matter, reversing after 3-5 days. The opposite was true on spin-echo images. T1 and T2 values were calculated for all images. In parallel experiments, several milliliters of freshly drawn blood was placed in test tubes and relaxation times were measured in a bench-top analyzer at 0.25 T over a period of 10 days. The relaxation times dropped markedly, at a rate that depended on sterility, temperature, etc., closely approaching the expected result for complete conversion of hemoglobin to methemoglobin. Ten blood samples with different methemoglobin concentrations were prepared by adding varying doses of sodium nitrite. The change in 1/T1 was found to be roughly proportional to the methemoglobin concentration for values up to 40%, and the initial slope was consistent with published data.

Jet-directed catheter for interventional radiology.

A new catheter of dual lumen construction, suitable for clinical use, is capable of navigating acute vessel branches by selective retrojet fluid thrusts issuing from cowlings built into its distal sidewalls. Conventional radiopaque liquids can be used both to drive the system and to fluoroscopically locate its position relative to the vascular network. In vitro studies have shown the catheter to traverse straight vessels and negotiate difficult lateral turns over short radii in the process of entering progressively smaller branches. In vivo studies have verified these capabilities and suggest a means for embolizing tumors and arteriovenous malformations located at otherwise inaccessible regions. For arterial infusion of drugs to treat tumors, the turbulent jet action is utilized to enhance mixing within the blood stream to overcome the streaming phenomenon common to other catheters. The result is better distribution of the agent and increased opportunity for the drug to reach more of the tumor. The catheter system is undergoing clinical trials.

MR cisternography and myelography with Gd-DTPA in monkeys.

To enhance the contrast between cerebrospinal fluid (CSF), brain, spinal cord, and surrounding meninges and bone on magnetic resonance (MR) images, as well as to study CSF flow, gadolinium-DTPA was injected in the subarachnoid space of eight monkeys. Six doses of progressively higher concentrations (from .125 mmol to 250 mmol) were injected every 30-40 minutes. Images of head and spine were obtained at .26 T or .5 T in sagittal and axial planes, using both spin-echo and inversion-recovery sequences in 13 imaging experiments. Marked, consistent changes of signal intensity in the CSF cavities were observed following the injections. These changes were dose related and occurred at different times in the areas close to the injection site versus those distant, a disparity that obviously was related to CSF flow. Gd-DTPA cisternography and myelography may be valuable in MR imaging of central nervous system disease, such as tumors adjacent to the CSF cavities, abnormal CSF collections (e.g., arachnoidal cysts), CSF rhinorrhea and otorrhea, syringohydromyelia, and studies of hydrocephalus and CSF flow dynamics.