Prophylaxis of restenosis with (186)re-labeled stents in a rabbit model.

BACKGROUND: Intraluminal beta-irradiation has been shown to decrease neointimal proliferation after angioplasty in experimental models. The purpose of this study was to test the technical feasibility and biological effects of (186)Re-labeled stents. METHODS AND RESULTS: Thirty-four New Zealand White rabbits were fed a 0.5% cholesterol diet before balloon angioplasty and insertion of Palmaz stents in the infrarenal aorta. The animals were killed 7 weeks after stent implantation. Two of 34 animals died prematurely (aortic leak, pneumonia). Control stents (n=7) were compared with (186)Re stents (2.6 MBq [n=6], 8.1 MBq [n=5], 16.0 MBq [n=6], and 25.3 MBq [n=8]). Stent application was successful in all cases. No thrombus occlusion was observed. After 7 weeks, neointima formation was 2.2+/-0.2 mm(2) in the control group. In the treatment groups, a dose-dependent neointima reduction was detectable (0.5+/-0.5 mm(2) [2.6 MBq], 0.4+/-0.4 mm(2) [8.1 MBq], and 0 mm(2) [16.0 MBq, 25.3 MBq]). No induction of neointimal formation was observed at the edges of the stents. Radiation resulted in delayed reendothelialization. CONCLUSIONS: (186)Re stents were capable of reducing neointima formation in a dose-dependent fashion. (186)Re stents did not cause late thrombosis or neointimal induction at the stent margins in the observation period of 7 weeks.

Use of near-infrared reflection spectroscopy to study the effects of X-ray contrast media on renal tolerance in rats: effects of a prostacyclin analogue and of phosphodiesterase inhibitors.

RATIONALE AND OBJECTIVES: Use of near-infrared reflection spectroscopy (NIR-RS) as a new model to assess renal tolerance of contrast agents and determination of the effects of a prostacyclin analogue and of two phosphodiesterase inhibitors on renal tolerance. MATERIALS AND METHODS: NIR-RS was used to measure total hemoglobin, oxygenated hemoglobin and tissue oxygen saturation in the renal cortex of rats and the effect of diatrizoate, iopromide and iotrolan injected at 1 g iodine/kg alone or together with the prostacyclin derivative, iloprost, or the phosphodiesterase inhibitors, rolipram and mesopram, on these parameters. RESULTS: Injection of the contrast media alone resulted in a 10% to 35% depression of total hemoglobin, oxygenated hemoglobin, and tissue oxygen saturation approximately 40 to 100 seconds after administration, whereas saline showed no effect and mannitol solution only a minor effect. Coadministration of iloprost or pretreatment with the phosphodiesterase inhibitors, rolipram or mesopram, significantly attenuated the contrast media-induced effects. CONCLUSION: NIR-RS might be useful for the determination of contrast media-induced side effects. Stable prostacyclin analogues or phosphodiesterase inhibitors have the potential to mitigate these side effects.

Prevention of the hemodynamic effects of iopromide-carrying liposomes in rats and pigs.

RATIONALE AND OBJECTIVES: Intravenous injection of liposomes is able to trigger allergy-like reactions that affect the cardiopulmonary system. The mechanism of these effects is still not totally clear. Because prediction of adverse reactions and the consequent exclusion of reactive patients do not seem feasible, prevention might have a considerable impact. METHODS: Two small, multilamellar liposome batches with the encapsulated contrast agent iopromide, which differed by size and buffer composition, were injected into anesthetized rats (n = 5 per group) and pigs (n = 6 per group). Blood pressure (BP), cardiac output (CO), contractility (dP/dt; in rats), total peripheral resistance (TPR; in rats), pulmonary vascular resistance (in pigs), and pulmonary arterial pressure (PAP; in pigs) were monitored. Saline, mannitol solution, the two buffers, and the contrast medium were used as controls. RESULTS: Significant changes in hemodynamic parameters were observed not only between liposomes and controls but also between the two liposome preparations. In rats, a significant decrease in BP followed by its normalization and subsequent increase, a decrease in CO followed by an increase, a decrease in TPR, and a decrease in dP/dt followed by an increase were observed. In pigs, the effects were different both in quality and in quantity (more intense) compared with those in rats. In this species, an increase in BP, a decrease in CO, an increase in TPR, and an increase in PAP were found. Pretreatment with acetylsalicylic acid was able to prevent the hemodynamic changes induced by the liposomes. CONCLUSIONS: Allergy-like side effects induced by liposome injection strongly depend on the size, electric charge, and composition of the particles. The mechanism triggered by liposome injection probably is complex and can be effectively blocked by pretreatment with acetylsalicylic acid.

Cardiac and hemodynamic tolerability of iopromide with or without sodium or iloprost and of ioversol in the anesthetized rat.

RATIONALE AND OBJECTIVES: In this study, the cardiac and hemodynamic effects of iopromide alone were compared with those of two combination preparations (iopromide plus sodium and iopromide plus the prostacyclin analog iloprost) and with ioversol after left ventricular bolus administration in rats. METHODS: The tracheae of anesthetized male Wistar rats were cannulated to facilitate spontaneous respiration. The animals were set up to allow recording or calculation of the following parameters: femoral arterial blood pressure (systolic, mean, and diastolic), left ventricular end-diastolic pressure, heart rate, and contractility. Iopromide (330 mg iodine/mL; 2 g iodine/kg) with or without sodium chloride (20 mmol/L) or iloprost (approximately 50 ng/mL; dose: 300 ng/kg) was injected into the left ventricle within 30 seconds. Ioversol (320 mg iodine/mL) was used at the same dose and injection rate. RESULTS: Iopromide and ioversol induced transient changes in blood pressure (decrease followed by an increase), left ventricular end-diastolic pressure (increase), heart rate (decrease), contractility (increase followed by decrease), and electrocardiogram (extrasystoles, ST depression). Ioversol exhibited more pronounced effects on contractility and ST depression. The differences were statistically significant. The addition of sodium to iopromide resulted in a slight, but not significant influence on cardiac or hemodynamic parameters. The addition of iloprost improved ST depression slightly and hemodynamics significantly resulting in less mean and end-diastolic blood pressure change and less heart rate decrease. Contractility was significantly increased compared with iopromide with or without sodium. CONCLUSIONS: The addition of sodium or iloprost to nonionic contrast media might be useful in the alleviation of cardiac and hemodynamic side-effects.

Cardiac and hemodynamic tolerability of iodinated contrast media in the anesthetized rat.

RATIONALE AND OBJECTIVES: The study was designed to compare the hemodynamic effects of 11 iodinated contrast media (CM), including ionic (diatrizoate, ioxaglate), nonionic monomeric (iohexol, iopromide, iopamidol, iopentol, ioversol, iomeprol, ZK 139129), and nonionic dimeric (iotrolan, iodixanol) compounds. METHODS: Following left ventricular bolus injection of 1.2 g I/kg body weight in anesthetized rats, cardiohemodynamic parameters were measured. RESULTS: Compared with the control group, except for blood pressure (BP), all CM showed a similar response regarding the direction of the cardiohemodynamic changes after CM injection. A biphasic change in BP was observed for diatrizoate and iodixanol, whereas all other CM showed a transient increase in BP being most pronounced for ioxaglate. No arrhythmias were detected. The increase in LVEDP was lowest for the isotonic dimeric CM iotrolan and iodixanol. CONCLUSIONS: Only mild transient side effects were observed. Low osmolar, especially isotonic, dimeric CM show a clear benefit regarding cardiovascular side effects.

Hemodynamic tolerance of intravascular contrast agents for magnetic resonance imaging.

RATIONALE AND OBJECTIVES: Intravascular contrast agents for magnetic resonance imaging (MRI) facilitate the quantification of tissue perfusion. The authors determined the hemodynamic tolerance of these agents. METHODS: Doses of 0.05, 0.15, and 0.45 mmol/kg of the polymeric intravascular contrast agent gadolinium-DTPA-polylysine, and di-nitrobenzyl-gadolinium-DTPA, a non-polymeric intravascular contrast agent with high protein binding, and gadolinium-DTPA dimeglumine, a paramagnetic contrast agent with extracellular distribution, were injected into 18 normal male rats as a peripheral intravenous bolus. Systolic, diastolic, and mean blood pressure, left ventricular end-diastolic and developed pressure, positive rate of pressure change (+dP/dt), dP/dt, the rate-pressure product, and heart rate were recorded during a period of 20 minutes. Hemodynamic effects were established by analysis of variance for repeated measurements. RESULTS: There was a transient increase of all blood pressure parameters and contractility for Gd-DTPA-polylysine at the dose of 0.45 mmol/kg only. Di-nitrobenzyl-Gd-DTPA increased blood pressure parameters at 0.45 mmol/kg only. At doses of 0.05 and 0.15 mmol/kg, no significant hemodynamic effects were observed. CONCLUSIONS: The authors conclude that Gd-DTPA-polylysine is hemodynamically safe at doses to 0.15 mmol/kg and acts like a plasma expander at higher doses after peripheral bolus injection in normal rats. Additional investigations are indicated to elucidate the mechanism of a nonsignificant and satiable transient hemodynamic depression after injection of 0.05 mmol/kg DNB-Gd-DTPA.

Ytterbium- and dysprosium-EOB-DTPA. A new prototype of liver-specific contrast agents for computed tomography.

RATIONALE AND OBJECTIVES: A series of studies was conducted to determine whether metal complexes of the EOB-DTPA type are useful as contrast agents for computed tomography (CT). METHODS: Metal complexes using EOB-DTPA as ligand were synthesized with lanthanide metal ions (lanthanum [La], cerium [Ce], praseodyme [Pr], gadolinium [Gd], dysprosium [Dy], ytterbium [Yb], and lutetium [Lu]) and with nonlanthanides (lead [Pb] and bismuth [Bi]). Complex stability was assessed by measuring binding to bone meal. The physicochemical parameters partition coefficient, osmolality, viscosity, and protein binding were determined in vitro. Tolerability was tested both in vitro (thromboplastin time, effect on erythrocytes) and in vivo (acute, neural, and cardiovascular toxicities). Biliary excretion and tissue distribution, especially liver, kidney, and bone concentrations, were measured in rats after intravenous doses of 0.5 mmol/kg. Imaging performance using CT was investigated in vitro in a phantom model and, for Gd-EOB-DTPA, in vivo by injecting doses of 0.5 mmol/kg into healthy or tumor-bearing rats and rabbits. RESULTS: The kinetic stability of M-EOB-DTPA complexes differed widely. Nonlanthanide metals, especially Pb-EOB-DTPA, provided less stable complexes than lanthanides with an optimum of stability for the metals Gd, Dy, Yb, and Lu. Tolerability was good for all compounds, best results were obtained for Gd and Yb. Concentrations in rat liver after administration of Gd-EOB-DTPA, 0.5 mmol/kg intravenous, were approximately 1 mumol/g, resulting in CT enhancement of 16 Hounsfield units (HU). Tumor tissue was not enhanced. In rabbits, at the same dose level 30 HU was found. CONCLUSIONS: Metal complexes of the EOB-DTPA type, especially those of Gd and Yb seem to be useful as iodine-free liver-specific contrast agents for CT.

The haemodynamic effects of iodinated water soluble radiographic contrast media: a review.

All classes of iodinated water-soluble radiographic contrast media (RCM) are vasoactive with the iso-osmolar dimers inducing the least changes in the vascular tone. The mechanisms responsible for RCM-induced changes in the vascular tone are not fully understood and could be multifactorial. A direct effect on the vascular smooth muscle cells causing alterations in the ion exchanges across the cell membrane is thought to be an important factor in RCM-induced vasodilatation. The release of the endogenous vasoactive mediators adenosine and endothelin may also play a crucial role in the haemodynamic effects of RCM particularly in the kidney. In addition, the effects of RCM on blood rheology can cause a reduction in the blood flow in the microcirculation. The purpose of this review is to discuss the pathophysiology of the haemodynamic effects of RCM and to offer some insight into the biology of the endothelium and vascular smooth muscle cells as well as the pharmacology of the important vasoactive mediators endothelin and adenosine.

Hemodynamic response and effects on myocardial energetics of 3-cyano-2-morpholino-5-(pyrid-4-yl)pyridine (AWD 122-14) in anesthetized minipigs.

AWD 122-14, a new positive inotropic and vasodilating agent, was investigated in comparison to amrinone, milrinone and dopamine in anesthetized minipigs. AWD 122-14 (1.17.10(-7)-37.5.10(-7) mol/kg) increased dose-dependent left ventricular contractility (LV dp/dtmax) (122x5 +/- 11x3%; ED50 = 8.1x10(-7) to mol/kg). Dopamine (2.64x10(-8)-21x12 x 10(-8) mol/kg) in comparison increased contractility up to 153.1 +/- 44.9% of control value and is about 20 times more potent than AWD 122-14 at the ED50 value and about 10 times more potent at the ED30 value. Amrinone (1.60x10(-6)-16.90x10(-6) mol/kg) and milrinone (1.48x10(-7)-23.70x10(-7) mol/kg) only slightly increased contractility in anesthetized minipigs, but they appear to posses a similar pharmacological profile like AWD 122-14. The hemodynamic effects were associated with an increase in myocardial oxygen consumption (E1: 18.8 +/- 10.0%) due to the marked increases in LV dp/dtmax and heart rate. LVMW was unchanged and LVSW decreased (-29.0 +/- 10.2%) after application of AWD 122-14. The reduction in left ventricular work (LVMW, LVSW) and the increase in myocardial oxygen consumption led to a decrease of left ventricular external mechanical efficiency of the non-failing minipig heart (Etam: -21.1 +/- 9.4%). Additional hemodynamic effects of AWD 122-14 were studied under calcium channel blockade (verapamil, nifedipine). After pretreatment with verapamil the agent (1.17.10(-7)-18.75.10(-7) mol/kg i.v.) increased left ventricular contractility between 42.9 +/- 41.6% and 58.5 +/- 33.3%. After pretreatment with nifedipine the agent induced a dose-dependent increase in LV dp/dtmax between 11.1 +/- 7.7% and 47.8 +/- 23.7%.(ABSTRACT TRUNCATED AT 250 WORDS)

[The cardiovascular effect of Cordemcura on various animal models in vivo]. / Zur Herz-Kreislaufwirkung von Cordemcura an verschiedenen Tiermodellen in vivo.

The cardiotonic activity of Cordemcura was investigated in anesthetized pigs, cats, and rats. Hemodynamic measurements were made under normal conditions and under drug-induced heart failure (hexobarbital, isoproterenol). Cordemcura caused significant positive inotropic effects with rapid onset and relatively short duration of action (0.2-3.2 mg/kg i. v.). In the pig dp/dtmax was increased by 31.4% (p less than 0.02) at 1.6 mg/kg, in the cat by 34.2% (p less than 0.05) at 0.5 mg/kg, and in the rat by 14.4% (ns) at 0.5 mg/kg. The inotropic response was associated with a significant reduction of total peripheral resistance (TPR) (pig: -21.4%, p less than 0.02; cat: -13.7), and relatively small changes in heart rate, cardiac output, and blood pressure. Under drug-induced heart failure there was no further increase in the cardiotonic activity of Cordemcura. The hemodynamic effects of Cordemcura were compared with the effects of dopamine (5-100 micrograms/kg i. v.) and ouabain (10-40 micrograms/kg i. v.).

Absolute and relative myocardial ischemia by isoproterenol overdosage.

Administration of greater than or equal to 10 mg/kg isoproterenol in rats absolutely diminished local myocardial blood flow within 0.5 min continuing up to 45 min. The blood flow reduction was followed by an increased lactate content and a decrease of both the intracellular redox potential and the content of high energy phosphates in the myocardium. The graduation of the initial lactate accumulation in different myocardial regions corresponds to the myocardial distribution of the infarct-like necroses occurring 24 h later. The very early alterations are comparable with an absolute (blood flow reduction), irreversible, and acute ischemia. In the dose range from 0.05 to 1 mg/kg of isoproterenol, an acceleration of the local myocardial blood flow was caused which, however, was accompanied by ischemia-like disturbances, too. Therefore, this condition is considered as a relative ischemia, an increased but insufficient blood supply.

Detection of myocardial ischemia by electron beam CT. Experimental studies.

PURPOSE: To determine if contrast-enhanced electron beam CT (EBCT) can detect areas of acute myocardial ischemia, and if pharmacological stress testing improves the diagnostic accuracy of EBCT. MATERIAL AND METHODS: We injected 0.5 ml/kg and 1.0 ml/kg b.w. of iopromide at a rate of 4 ml/s into the right atrium of 5 ventilated female minipigs at rest and after occlusion of the left anterior descending (LAD) coronary artery. Both ventricles were examined at six short axis levels with an EBCT unit. Myocardial perfusion was calculated from the time-density curves of four left ventricular myocardial segments and the aorta. We also tested the effect of the contrast agent on myocardial density after i.v. administration of 0.6 mg/kg dipyridamole before and after LAD occlusion. RESULTS: At rest, the contrast agent increased myocardial density by 28+/-2 HU, corresponding to a myocardial perfusion estimate of 67+/-7 ml/min/100 g. After dipyridamole, myocardial density increased by 29+/-4 HU. Following occlusion of the LAD, anteroseptal myocardium displayed 10+/-4 HU density increase. The area of non-enhancement corresponded to ischemic myocardium in stained pathologic sections. CONCLUSION: Contrast-enhanced stress EBCT can be used to detect areas of myocardial ischemia, and EBCT stress perfusion imaging may be necessary to consistently differentiate ischemic from non-ischemic myocardial tissue.