Measurement of the vasoconstrictive substances endothelin,angiotensin II,and thromboxane B2 in cold storage solution can reveal previous renal ischemic insults

In a rat model, the left kidney was subjected to 60 min of normothermic ischemia followed by 15 min of reperfusion, whereas the right kidney, serving as a paired control, was not rendered ischemic. Both kidneys were then perfused in situ with either Euro-Collins (EC) solution (n=12) or University of Wisconsin (UW) solution (n=6) for 10 min. Each kidney was then harvested and stored at 4°C in its respective solution. After 24 and 48 h of cold storage, the following vasoactive substances were measured in the preservation media: endothelin (ET), angiotensin II (A-II), thromboxane (B₂) (TxB₂), and prostaglandin I₂ (PGI₂). After 24 h in EC solution, left kidneys uniformly produced significantly higher concentrations of each vasoactive substance than right kidneys: ET 1.64±0.3 pg/ml vs 0.82±0.1 pg/ml (P0.009); A-II 20.8±6.2 pg/ml vs 7.75+2.3 pg/ml (P0.007); TxB₂ 100.8±17.7 pg/ml vs 40.1±11.7 pg/ml (P0.04); PGI₂ 638.3±41.1 pg/ml vs 318.3±36.4 pg/ml (P0.001), respectively. At 48 h, a similar pattern of results was obtained as the kidney continued to produce TxB₂ and prostacyclins during the 24–48 h period. In the UW solution, basal levels of ET and A-II were lower than those in EC solution, but similarly increased after initial ischemia. At 24 h, the concentrations produced by the left and right kidneys were as follows: ET 0.66±0.1 pg/ml vs 0.48±0.1 pg/ml (P0.14); A-II 10.36±3.7 pg/ml vs 2.14±0.7 pg/ml (P0.006); TxB₂ 178±53 pg/ml vs 52±23.1 pg/ml (P0.001); and PGI₂ 448.3±49 pg/ml vs 323±44.3 pg/ml (P0.01), respectively. After 48 h, the range of concentrations of each substance was similar to that obtained after 24 h. In further studies, the concentrations of ET and A-II were measured in solution previously used to preserve human kidneys (n=7). The mean concentration of ET and A-II in these samples was 3.82±1.14 pg/ml and 21.3±9.2 pg/ml, respectively, whereas in control media both substances were below the limits of detection. These results demonstrate that vasoconstrictive substances can be measured in the preservation media after a kidney has been stored cold and that higher concentrations are found when the organ has been subjected to prior normothermic ischemia. The measurement of these vasoactive substances before transplantation may reveal that the kidney has been subjected to previous ischemic events. Moreover, these vasoactive substances could be involved in the early recovery of renal function after kidney transplantation.     

Early desensitization of somato-dendritic 5-HT1A autoreceptors in rats treated with fluoxetine or paroxetine

Electrophysiological and autoradiographic approaches were used to assess possible changes in 5-hydroxytryptamine (serotonin) 5-HT_1A receptors in the rat dorsal raphe nucleus after a subchronic treatment with fluoxetine or paroxetine, two specific serotonin reuptake inhibitors with antidepressant properties. Fluoxetine or paroxetine were injected daily (5 mg/kg, i.p.) for various time periods up to 21 days. Electrophysiological recordings performed 24 h after the last injection showed that the potency of the 5HT_1A receptor agonist, 8-OH-DPAT, to depress the firing of serotoninergic neurons in the dorsal raphe nucleus within brain stem slices was significantly reduced as early as after a 3-day treatment with either drug. The proportion of recorded neurons showing desensitization of somatodendritic 5-HT_1A autoreceptors increased along the treatment from 40% on the 3rd day to 60–80% on the 21st day. At no time during the treatment, was the specific binding of [³H]8-OHDPAT (agonist radioligand) or [³H] WAY-100 635 (antagonist radioligand) to 5-HT_1A receptors modified in the dorsal raphe nucleus or in other brain areas, suggesting that neither the density nor the coupling of these receptors to G-proteins were probably altered in rats injected with fluoxetine or paroxetine for up to 21 days.These results show that adaptive desensitization of somatodendritic 5-HT_1A autoreceptors within the dorsal raphe nucleus can already be detected after a 3-day treatment with selective serotonin reuptake inhibitors. Rather than the desensitization per se, it may be the progressive increase in the number of serotoninergic neurons with desensitized 5-HT_1A autoreceptors which plays a critical role in the (slowly developing) antidepressant action of these drugs.     

Catheter entrapment by atrial suture during minimally invasive port-access cardiac surgery

PURPOSE: The port-access approach allows surgeons to perform heart operations through small intercostal openings, or "ports". This technique requires new skills for anesthesiologists. A pulmonary artery venting (PAV) catheter and, in some cases, a coronary sinus catheter (for administration of retrograde cardioplegia) are positioned with the aid of fluoroscopy and transesophageal echography (TEE). Both catheters have a wider diameter than the more commonly used conventional PA catheter and present distinctive features. We report a case in which a pulmonary artery venting catheter was entrapped by a suture during a port-access procedure. CLINICAL FEATURES: A 35-yr-old man with severe mitral valve insufficiency was scheduled for valve repair. After a successful bypass procedure, resistance was felt while attempting to withdraw the PAV catheter. On fluoroscopy, fixation of the catheter at the heart level was established and perforation by suture was confirmed after injection of a contrast agent. Because of the risk of cardiac wall rupture and tamponade, the thorax was reopened. After release of some atrial sutures, the catheter could be withdrawn easily. Transfixion by a suture was confirmed by visual examination. CONCLUSION: The more frequent use of a PAV catheter in minimally invasive cardiac surgery with the port-access technique should remind the anesthesiologist of the higher risk of entrapment by surgical sutures. Surgeons should be aware of the risk of accidentally transfixing this catheter during closure of the atriotomy via the port.     

Long-term enhancement of REM sleep by the pituitary adenylyl cyclase-activating polypeptide (PACAP) in the pontine reticular formation of the rat

In rats, rapid eye movement (REM) sleep can be elicited by microinjection of vasoactive intestinal polypeptide (VIP) into the oral pontine reticular nucleus (PnO). In the present study, we investigated whether this area could also be a REM-promoting target for a peptide closely related to VIP: the pituitary adenylyl cyclase-activating polypeptide (PACAP). When administered into the posterior part of the PnO, but not in nearby areas, of freely moving chronically implanted rats, PACAP-27 and PACAP-38 (0.3 and 3 pmol) induced a marked enhancement (60-85% over baseline) of REM sleep for 8 h that could be prevented by prior infusion of the antagonist PACAP-(6-27) (3 pmol) into the same site. Moreover, injections of PACAP into the centre of the posterior PnO resulted in REM sleep enhancement which could last for up to 11 consecutive days. Quantitative autoradiography using [125I]PACAP-27 revealed the presence in the PnO of specific binding sites with high affinity for PACAP-27 and PACAP-38 (IC50 = 2.4 and 3.2 nM, respectively), but very low affinity for VIP (IC50 > 1 microM). These data suggest that PACAP within the PnO may play a key role in REM sleep regulation, and provide evidence for long-term (several days) mechanisms involved in such a control. PAC1 receptors which have a much higher affinity for PACAP than for VIP might mediate this long-term action of PACAP on REM sleep.     

Promotion of cell growth by stimulation of cloned human 5-HT1D receptor sites in transfected C6-glial cells is highly sensitive to intrinsic activity at 5-HT1D receptors

5-Hydroxytryptamine (serotonin, 5-HT), essentially known as a neurotransmitter and vasoactive agent, also functions as a mitogen in various cell types through several different second messenger systems. Stimulation of cloned human 5-HT_1D receptor sites by sumatriptan in stably transfected rat C6-glial/5-HT_1D cells promotes cell growth (Pauwels et al. (1996) Naunyn-Schmiedeberg's Arch Pharmacol 353:144–156). In the present study, the pharmacology of this growth response was investigated using a broad series of 5-HT receptor ligands. The data were compared with the responses obtained by measuring inhibition of forskolin-stimulated cAMP formation. 5-HT (EC₅₀: 25 nM) promoted cell growth of C6-glial/5-HT_1D cells, and this in contrast to the absence of any measurable effect in pcDNA3-plasmid transfected and non-transfected C6-glial cells. The 5-HT effect could be mimicked by the following compounds (EC₅₀ in nM): zolmitriptan (0.41), 2-methyl-4-(5-methyl[1,2,4] oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (GR 127,935; 0.86), naratriptan (0.92), metergoline (1.9), sumatriptan (2.9), (N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-y)]ethylamine (MK-462; 3.0), and R(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R(+)-8-OH-DPAT; 30.7). These EC₅₀-values correspond to the compounds binding affinities at the human 5-HT_1D receptor site and, with the exception of GR 127,935 and metergoline, also to the EC₅₀-values found by measuring over 5 min inhibition of forskolin (100 M)-stimulated cAMP formation. Prolonged exposure of GR 127,935 (3 h) and metergoline (30 min) to cells yielded EC₅₀ values in the cAMP assay more close to those measured in the mitogenic response. The growth response to sumatriptan, 5-HT, GR 127,935 and metergoline was blocked by the apparently silent antagonists methiothepin, ritanserin and ketanserin with potencies similar to blockade of inhibition of stimulated CAMP formation. The 8-OH-DPAT effect also is likely mediated by 5-HT_1D receptors; stereoselectivity was found with its enantiomers at this receptor site and the effect was blocked by ketanserin (1 M) but not by spiperone (1 M). Micromolar concentrations of the 5-HT_1B receptor agonist 3-(1,2,5,6-tetrahydro)-4-pyridil-5-pyrrolo[3, 2-b]pyril-5-one (CP 93,129) and of the 5-HT₂ receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induced cell growth with a potency that accorded with the affinity of these compounds for the human 5-HT_1D receptor site. These effects were sensitive to ketanserin (1 M) antagonism, but not to blockade by -adrenergic blockers and the 5-HT₂ receptor antagonist 2-anilino-N-[2-(3-chlorophenoxy)-propyl] acetamidine hydroiodide (BW 501-C-67). The findings suggest that 5-HT_1A, 5-HT_1B and 5-HT₂ receptors are not implicated in 5-HT-stimulated C6-glial/5-HT_1D cell growth. In conclusion, human 5-HT_1D receptors are involved in the growth of C6-glial/5-HT_1D cells. This cellular response is highly sensitive to the intrinsic activity of compounds at 5-HT_1D receptors.     

Parieto-occipital hypoperfusion in late whiplash syndrome: first quantitative SPET study using technetium-99m bicisate (ECD)

Brain single-photon emission tomography (SPET) withN,N-1,2-ethylene-diylbis-l-cysteine diethyl ester dihydrochloride (ECD) was performed on ten patients with a clinically high grade late whiplash syndrome and on 11 controls. Two independent readers blinded to the clinical diagnosis were able to separate the ten patients from normal controls. All these patients had qualitative bilateral parieto-occipital hypoperfusion. To confirm this, the perfusion rate of parieto-occipital over global (perfusion index) was calculated after drawing elliptical regions of interest in transversal-oblique slices. The perfusion indices in patients were significantly lower than in controls as tested by the Mann-WhitneyU test. This quantitative study proves our recent qualitatively analysed observation (Lancet 1995; 345: 1513–1514).     

Evaluation of cellular viability by quantitative autoradiographic study of myocardial uptake of a fatty acid analogue in isoproterenol-induced focal rat heart necrosis

Previous studies led us to hypothesize that a fatty acid analogue, 15-p-iodophenyl--methyl pentadecanoic acid (IMPPA or BMIPP), which is taken up but not quickly metabolized by heart cells, would be a more suitable tracer of cellular viability than thallium-201. Biodistribution studies of 1-¹⁴C-IMPPA in conscious, freely moving rats showed that the concentration ratio of radioactivity in the heart with respect to the blood was about 8 for at least 60 min after intravenous administration, permitting its use as a putative tracer in these conscious, freely moving rats. Thereafter, the myocardial uptake of¹⁴C-IMPPA was studied in isoproterenol-treated rats (daily treatment for 10 days in order to induce cardiac hypertrophy and necrotic foci) with respect to control ones. Comparison of myocardial localizations by quantitative autoradiography of the uptake of²⁰¹Tl and¹⁴C-IMPPA with that of triphenyltetrazolium chloride (TTC) staining enabled comparative evaluation of nutritional blood flow, localization and uptake of¹⁴C-IMPPA and necrotic foci size. Distributions of¹⁴C-IMPPA and²⁰¹1 T1 in control rats' hearts were homogeneous, like TTC staining. In infarcted hearts, areas of decreased¹⁴C-IMPPA uptake were nearly the same (100%±5%) as those unstained by TTC. These areas were larger than those showing a decrease in thallium uptake (about 70%±5% of the total scar size). Therefore, IMPPA seems to be a more accurate and sensitive indicator of necrosis localization compared with thallium. It may be a useful agent for assessment of myocardial viability by single photon emission tomography (SPET) imaging.     

Iatrogenic Thyrotoxicosis: Causal Circumstances, Pathophysiology, and Principles of Treatment—Review of the Literature

Thyrotoxicosis is the clinical syndrome that results when tissues are exposed to high levels of circulating thyroid hormones. In most instances thyrotoxicosis is due to hyperthyroidism, a term reserved for disorders characterized by overproduction of thyroid hormones by the thyroid gland. Nevertheless, thyrotoxicosis may also result from a variety of conditions other than thyroid hyperfunction. The present report focuses on the etiologies, pathophysiology, and treatment of iatrogenic thyrotoxicosis. Iatrogenic thyrotoxicosis may be caused by (1) subacute thyroiditis (a result of lymphocytic infiltration, cellular injury, trauma, irradiation) with release of preformed hormones into circulation; (2) excessive ingestion of thyroid hormones (“thyrotoxicosis factitia”); (3) iodine-induced hyperthyroidism (radiologic contrast agents, topical antiseptics, other medications). Among these causes of iatrogenic thyrotoxicosis, that induced by the iodine overload and cytotoxicity associated with amiodarone represents a significant challenge. Successful management of amiodarone-induced thyrotoxicosis requires close cooperation between endocrinologists and endocrine surgeons. Surgical treatment may have a leading yet often underestimated role in view of the potential life-threatening severity of this disease, whereas others kinds of iatrogenic thyrotoxicosis are usually treated conservatively.