[Necrotizing cervico-facial cellulitis of dental origin in a developing country]. / Les cellulites cervico-faciales nécrosantes d'origine dentaire dans un pays en voie de développement.

INTRODUCTION: Necrotizing cellulitis of dental origin is a serious disease and requires prompt and effective management to avoid adverse outcomes. The purpose of this work is to describe the diagnostic and therapeutic difficulties encountered in this condition. METHODS: This was a prospective study in the thoracic surgery department of Mali Hospital from January 2011 to February 2015. We collected consecutively 19 cases of complicating cervico-facial cellulitis of dental origin. The anatomical and clinical aspects, therapeutic modalities and difficulties are described. RESULTS: Dental pain and fever were the predominant symptoms followed by cervical edema. Chest CT-scan was the basis for the diagnosis in all cases. Cervicotomy with debridement was the most performed surgical procedure. Pleural drainage was performed in 6 cases. Three patients (15.8%) died. CONCLUSION: Necrotizing cellulitis of dental origin is a serious disease with high morbidity and mortality. The key radiological examination is the thoracic CT-scan. Early medico-surgical management by emergency care, tailored antibiotic therapy, removal of necrotizing tissues and drainage of collections are required to deliver a good outcome.

New insight into the effects of heparinoids on complement inhibition by C1-inhibitor.

Complement activation is of major importance in numerous pathological conditions. Therefore, targeted complement inhibition is a promising therapeutic strategy. C1-esterase inhibitor (C1-INH) controls activation of the classical pathway (CP) and the lectin pathway (LP). However, conflicting data exist on inhibition of the alternative pathway (AP) by C1-INH. The inhibitory capacity of C1-INH for the CP is potentiated by heparin and other glycosaminoglycans, but no data exist for the LP and AP. The current study investigates the effects of C1-INH in the presence or absence of different clinically used heparinoids on the CP, LP and AP. Furthermore, the combined effects of heparinoids and C1-INH on coagulation were investigated. C1-INH, heparinoids or combinations were analysed in a dose-dependent fashion in the presence of pooled serum. Functional complement activities were measured simultaneously using the Wielisa(®) -kit. The activated partial thrombin time was determined using an automated coagulation analyser. The results showed that all three complement pathways were inhibited significantly by C1-INH or heparinoids. Next to their individual effects on complement activation, heparinoids also enhanced the inhibitory capacity of C1-INH significantly on the CP and LP. For the AP, significant potentiation of C1-INH by heparinoids was found; however, this was restricted to certain concentration ranges. At low concentrations the effect on blood coagulation by combining heparinoids with C1-INH was minimal. In conclusion, our study shows significant potentiating effects of heparinoids on the inhibition of all complement pathways by C1-INH. Therefore, their combined use is a promising and a potentially cost-effective treatment option for complement-mediated diseases.

[Heller myotomy by transthoracic procedure, a single center experience in Mali with 21 cases]. / Myotomie de heller par voie transthoracique : une experience monocentrique au mali de 21 cas.

AIMS: To evaluate the midterm results of myotomy for achalasia by thoracotomy procedure with the introduction of anti-reflux system by diaphragmatic flap. PATIENTS AND METHODS: This was a prospective study involved 21 patients (14 women and 7 men) operated for idiopathic megaesophagus during a period of 3 years. All the patients were operated by thoracotomy procedure. An anti-reflux system was performed using a diaphragmatic flap over the entire length of the myotomy. RESULTS: The mean age was 32 years (range 16 and 68 years). After the surgery we have seen a complete disappearance of dysphagia in 21 patients (100 %) (p <0.001) and a significant weight regain. Short term outcomes were marked by the occurrence of clinical gastroesophageal reflux disease in 1 patient (4.76%) who has received the anti-reflux system (p> 0.05). CONCLUSION: Oeso-cardio-myotomy of Heller by transthoracic procedure associated with the establishment of an anti reflux system by diaphragmatic flap has goods results.

BUT: Evaluer les résultats à mi-parcours de l'œsocardiomyotomie de Heller par voie transthoracique avec la mise en place du système anti-reflux par un lambeau diaphragmatique pour le mégaoesophage idiopathique. PATIENTS ET MÉTHODES: Il s'agissait d'une étude prospective ayant concerné 21 patients (14 femmes et 7 hommes) opérés pour un mégaoesophage idiopathique durant une période de 3 ans. La voie d'abord a été la voie transthoracique gauche pour tous nos patients. Un système anti-reflux avait été réalisé en utilisant un lambeau diaphragmatique sur toute la longueur de la myotomie de l'œsophage thoracique. RÉSULTATS: L'âge moyen était de 32 ans (extrêmes : 16 et 68 ans). Les suites immédiates étaient simples. Après l'intervention nous avons assisté à une disparition complète de la dysphagie chez 21 patients (100 %) (p < 0,001) et une reprise pondérale conséquente. Les suites à court terme étaient marquées par la survenue d'un reflux gastro-œsophagien clinique chez 1 patient (4.76 %) qui avait bénéficié d'un système anti-reflux (p > 0,05). CONCLUSION: L'œsocardiomyotomie de Heller par voie transthoracique associée à la mise en place systématique d'un système anti-reflux par lambeau diaphragmatique donne de bons résultats.

Myotomie de Heller par voie transthoracique : une experience monocentrique au Mali de 21 cas

But : Evaluer les resultats a mi-parcours de l'osocardiomyotomie de Heller par voie transthoracique avec la mise en place du systeme anti-reflux par un lambeau diaphragmatique pour le megaoesophage idiopathique. Patients et methodes : Il s'agissait d'une etude prospective ayant concerne 21 patients (14 femmes et 7 hommes) operes pour un megaoesophage idiopathique durant une periode de 3 ans. La voie d'abord a ete la voie transthoracique gauche pour tous nos patients. Un systeme anti-reflux avait ete realise en utilisant un lambeau diaphragmatique sur toute la longueur de la myotomie de l'oesophage thoracique. Resultats : L'age moyen etait de 32 ans (extremes : 16 et 68 ans). Les suites immediates etaient simples. Apres l'intervention nous avons assiste a une disparition complete de la dysphagie chez 21 patients (100 %) (p 0;001) et une reprise ponderale consequente. Les suites a court terme etaient marquees par la survenue d'un reflux gastro-osophagien clinique chez 1 patient (4.76 %) qui avait beneficie d'un systeme anti-reflux (p 0;05). Conclusion : L'osocardiomyotomie de Heller par voie transthoracique associee a la mise en place systematique d'un systeme anti-reflux par lambeau diaphragmatique donne de bons resultats

DPC 681 and DPC 684: potent, selective inhibitors of human immunodeficiency virus protease active against clinically relevant mutant variants.

Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of many highly active antiretroviral therapy regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross-resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate to suppress preexisting resistant mutant variants and/or to inhibit de novo-generated resistant mutant variants. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at the trough. We have optimized a series of substituted sulfonamides and evaluated the inhibitors against laboratory strains and clinical isolates of HIV type 1 (HIV-1), including viruses with mutations in the protease gene. In addition, serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC(90)). Two compounds resulting from our studies, designated DPC 681 and DPC 684, are potent and selective inhibitors of HIV protease with IC(90)s for wild-type HIV-1 of 4 to 40 nM. DPC 681 and DPC 684 showed no loss in potency toward recombinant mutant HIVs with the D30N mutation and a fivefold or smaller loss in potency toward mutant variants with three to five amino acid substitutions. A panel of chimeric viruses constructed from clinical samples from patients who failed PI-containing regimens and containing 5 to 11 mutations, including positions 10, 32, 46, 47, 50, 54, 63, 71, 82, 84, and 90 had mean IC(50) values of <20 nM for DPC 681 and DPC 681, respectively. In contrast, marketed PIs had mean IC(50) values ranging from 200 nM (amprenavir) to >900 nM (nelfinavir).

The discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1 ,5-a]-pyrimidine: a corticotropin-releasing factor (hCRF1) antagonist.

Structure activity relationship studies led to the discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazo lo-[1,5-a]-pyrimidine 11-31 (DMP904), whose pharmacological profile strongly supports the hypothesis that hCRF1 antagonists may be potent anxiolytic drugs. Compound 11-31 (hCRF1 Ki = 1.0+/-0.2 nM (n = 8)) was a potent antagonist of hCRF1-coupled adenylate cyclase activity in HEK293 cells (IC50= 10.0+/-0.01 nM versus 10 nM r/hCRF, n = 8); alpha-helical CRF(9-41) had weaker potency (IC50 = 286+/-63 nM, n = 3). Analogue 11-31 had good oral activity in the rat situational anxiety test; the minimum effective dose for 11-31 was 0.3 mg/kg (po). Maximal efficacy (approximately 57% reduction in latency time in the dark compartment) was observed at this dose. Chlordiazepoxide caused a 72% reduction in latency at 20 mg/kg (po). The literature compound 1 (CP154526-1, 30 mg/kg (po)) was inactive in this test. Compound 11-31 did not inhibit open-field locomotor activity at 10, 30, and 100 mg/kg (po) in rats. In beagle dogs, this compound (5 mg/kg, iv, po) afforded good plasma levels. The key iv pharmacokinetic parameters were t1/2, CL and Vd,ss values equal to 46.4+/-7.6 h. 0.49+/-0.08 L/kg/h and 23.0+/-4.2 L/kg, respectively. After oral dosing, the mean Cmax, Tmax t1/2 and bioavailability values were equal to 1260+/-290 nM, 0.75+/-0.25 h. 45.1+/-10.2 h and 33.1%, respectively. The overall rat behavioral profile of this compound suggests that it may be an anxiolytic drug with a low motor side effect liability.

4-(1,3-Dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2, 4-dichlorophenyl)pyrazolo[1,5-a]-1,3,5-triazine: a potent, orally bioavailable CRF(1) receptor antagonist.

Structure-activity studies in the pyrazolo[1,5-a]-1,3,5-triazine series led to the discovery that compound 11i (DMP696) is a potent hCRF(1) receptor antagonist (K(i) = 1.7 nM vs 7.5 nM for alpha-hel-CRF(9-41), hCRF(1) adenylate cyclase IC(50) = 82 nM vs 286 nM for alpha-hel-CRF(9-41)). Compound 11i has excellent oral pharmacokinetic profiles in rats and dogs (37% and 50% oral bioavailabilities, respectively). This compound displays good activity in the rat situational anxiety model (MED = 3 mg/kg (po)), whereas a literature standard 1 (CP154526-1) was inactive (MED > 30 mg/kg (po)). Analogue 11i reduced stereotypical mouth movements in rhesus monkeys by 50% at 21 mg/kg (po) using the human intruder paradigm. Overall, the profile of pyrazolotriazine 11i indicates that hCRF(1) receptor antagonists may be anxiolytic agents, which have reduced motor side effect profiles.

Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1.

A research program targeted toward the identification of expanded-spectrum nonnucleoside reverse transcriptase inhibitors which possess increased potency toward K103N-containing mutant human immunodeficiency virus (HIV) and which maintain pharmacokinetics consistent with once-a-day dosing has resulted in the identification of the 4-cyclopropylalkynyl-4-trifluoromethyl-3, 4-dihydro-2(1H)quinazolinones DPC 961 and DPC 963 and the 4-cyclopropylalkenyl-4-trifluoromethyl-3, 4-dihydro-2(1H)quinazolinones DPC 082 and DPC 083 for clinical development. DPC 961, DPC 963, DPC 082, and DPC 083 all exhibit low-nanomolar potency toward wild-type virus, K103N and L100I single-mutation variants, and many multiply amino acid-substituted HIV type 1 mutants. This high degree of potency is combined with a high degree of oral bioavailability, as demonstrated in rhesus monkeys and chimpanzees, and with plasma serum protein binding that can result in significant free levels of drug.

Two new potent neurotransmitter release enhancers, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone and 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone: comparison to linopirdine.

Linopirdine (3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one, DUP996) is an extensively studied representative of a class of cognition enhancing compounds that increase the evoked release of neurotransmitters. Recent studies suggest that these agents act through the blockade of specific K+ channels. We have recently identified more potent anthracenone analogs of linopirdine: 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE991) and 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone (DMP 543). Although linopirdine possesses an EC50 of 4.2 microM for enhancement of [3H]ACh release from rat brain slices, XE991 and DMP 543 have EC50S of 490 and 700 nM, respectively. In addition to greater in vitro potency relative to linopirdine, both compounds show greater in vivo potency and duration of action. Although 5 mg/kg (p.o.) linopirdine does not lead to statistically significant increases in hippocampal extracellular acetylcholine levels, 5 mg/kg (p.o.) XE991 leads to increases (maximal effect > 90% over baseline) which are sustained for 60 min. Moreover, DMP 543 at 1 mg/kg causes more than a 100% increase in acetylcholine levels with the effect lasting more than 3 hr. At doses relevant to their release-enhancing properties, the only overt symptom consistently observed was tremor, possible via a cholinergic mechanism. These results suggest that XE991 and DMP 543 may prove to be superior to linopirdine as Alzheimer's disease therapeutics. In addition, these agents should be useful pharmacological tools for probing the importance of particular ion channels in the control of neurotransmitter release.

Pharmacology of XR510, a potent orally active nonpeptide angiotensin II AT1 receptor antagonist with high affinity for the AT2 receptor subtype.

The angiotensin II (Ang II) type 1 receptor (AT1) mediates all known physiological effects of ANG II, whereas functions of the type 2 (AT2) receptor are not clear. Should undesirable AT2 effects be identified, it may be advantageous to combine antagonism of AT1 and AT2 receptors. XR510 was shown to inhibit the specific binding of [125I]Sar1,Ile8-Ang II for AT1 and AT2 subtype binding sites in rat adrenal membranes with IC50 of 0.26 and 0.28 nM, respectively, and in human tissues with subnanomolar binding affinity. In isolated rabbit aorta, XR510 exerted insurmountable Ang II antagonism with a Kb value of 4 nM. In conscious renal hypertensive rats, XR510 decreased blood pressure (BP) with intravenous (i.v.) and oral (p.o.) ED30 of 0.08 and 0.27 mg/kg, respectively. In spontaneously hypertensive rats (SHR), repeated daily oral dosing of XR510, losartan, and enalapril at 30 mg/kg/day decreased BP similarly. In conscious furosemide-treated dogs, XR510, given either intravenously or orally, decreased BP. These results suggest that XR510 is an orally active and selective Ang II receptor antagonist with equal binding affinities for AT1 and AT2 receptor binding sites.

Localization of angiotensin peptide-forming enzymes of 3T3-F442A adipocytes.

We have demonstrated that angiotensinogen is synthesized by 3T3-F442A cells and is hydrolyzed to angiotensins I and II (ANG I and II) by this model adipocyte system. This study was designed to determine whether ANG I is generated by renin or some other enzyme and where the formation of ANG I and/or II occurs in 3T3-F442A cells. Renin mRNA was not detected by Northern blot analysis of poly(A)(+)-selected RNA from cultures of fully differentiated adipocytes nor by the more sensitive polymerase chain reaction, implying that renin is not synthesized in this model adipocyte system. Hydrolysis of angiotensinogen to ANG I and II was demonstrated to be associated with the cell but not the media. Inhibitors, including EDTA, aimed at inactivating enzymes belonging to the serine, acid, or aspartyl proteases, and metalloproteases were ineffective in preventing the formation of either ANG I or II. Therefore the model adipocyte 3T3-F442A cell system forms ANG I and II in the absence of renin and angiotensin-converting enzyme. The unidentified enzymes responsible for peptide formation are associated with the cell itself.

Polymerase chain reaction analysis of renin in rat aortic smooth muscle.

Controversy exists whether vascular smooth muscle cells in vivo synthesize renin, thereby providing a critical component of the hypothesized vascular renin-angiotensin system. To examine this question, we enzymatically isolated and pooled the medial layer of thoracic aortas from Sprague-Dawley rats that were either untreated or enalapril treated for 3 days, isolated messenger RNA (mRNA), and performed Northern blot analysis with rat complementary DNA (cDNA) probes for renin, cathepsin D, and cathepsin E. Renin mRNA was detected in kidney but was not detected in aortic smooth muscle from the untreated or enalapril-treated groups. Cathepsin E mRNA was detected in enalapril-treated aorta and kidney, and cathepsin D mRNA was detected in all tissues examined. cDNA was synthesized and subjected to polymerase chain reaction analysis by using primers corresponding in sequence to regions conserved throughout the aspartic proteinases. Cathepsins D and E were amplified from kidney and aortic cDNA. Renin was less consistently amplified from the aortic cDNA and was much less abundant than cathepsin E or cathepsin D. These results suggest that 1) renin mRNA is present in aortic smooth muscle cells in vivo in quantities detectable only after multiple rounds of polymerase chain reaction amplification, 2) renin mRNA is not upregulated in aortic smooth muscle after converting enzyme inhibition, and 3) cathepsins D and E are the predominant aspartic proteinases in aortic smooth muscle.

Changes in angiotensinogen messenger RNA in differentiating 3T3-F442A adipocytes.

Angiotensinogen messenger RNA (mRNA) has been identified in both brown and white adipose tissue. Recently we have shown that when 3T3-L1 cells were treated with isobutylmethylxanthine (IBMX) to accelerate differentiation, angiotensinogen mRNA increased markedly in adipocytes as compared with preadipocytes. To determine if a correlation existed between the regulatory events associated with the differentiation process, we compared the change in angiotensinogen mRNA in spontaneously differentiating 3T3-F442A cells with two established parameters of differentiation in adipocyte cell lines. Differentiation was assessed by visual examination of cells for lipid droplets, fluorescent staining of the F-actin fibers, and increases in glycerol phosphate dehydrogenase mRNA. F-actin fibers were highly structured in preadipocytes, becoming disassembled and very disorganized as cells differentiated into adipocytes. The quantity of angiotensinogen mRNA increased as the number of lipid-containing cells increased within a culture. Glycerol phosphate dehydrogenase mRNA accumulated in differentiated adipocytes to about the same extent as angiotensinogen mRNA. Thus, increases in angiotensinogen mRNA were associated with the morphological and biochemical changes that occur during the phenotypic modulation of 3T3-F442A cells.

Angiotensinogen gene expression in 3T3-L1 cells.

It has previously been established that angiotensinogen mRNA is present in brown and white adipose tissue of the rat. To determine whether angiotensinogen gene expression is present in adipocytes as compared with other cell elements, we have examined angiotensinogen mRNA in 3T3-L1 cells. These cells undergo adipocyte differentiation when the culture reaches confluence. To accelerate the differentiation process, cells were treated with dexamethasone and isobutylmethylxanthine for 3 days. On the 7th day after drug treatment, RNA was extracted from cells and was examined for angiotensinogen mRNA using a full-length rat angiotensinogen cDNA. Angiotensinogen mRNA was readily detected in differentiated 3T3-L1 cells. To determine when the gene is expressed, a 7-day time course from day 0 (before drug treatment) to day 7 was examined for the presence of angiotensinogen mRNA. In addition, C2 cells, a clonal cell line that does not differentiate into adipocytes, were examined. Angiotensinogen mRNA was detected on days 2-7 after drug treatment in 3T3-L1 cells, with no detectable levels in untreated 3T3-C2 cells. When 3T3-C2 cells were subjected to the same drug regimen, angiotensinogen mRNA levels increased in the same time course as 3T3-L1 cells. However, the increase in angiotensinogen message was greater in differentiating 3T3-L1 cells than in the nondifferentiating 3T3-C2 cells. Thus angiotensinogen mRNA is present in both adipocytes and in fibroblast-like cells and appears to be regulated by steroids.

Monograph support provided by the National Library of Medicine and its regional medical libraries in the medical behavioral sciences.

The National Library of Medicine's (NLM) monographic resources in the medical behavioral sciences (MBS) were examined to assess NLM's ability to support the needs of researchers writing in this area. A sample of 239 representative monographs derived from citations in MBS-related articles published in 61 journals in 1981 were evaluated. These monographs were limited to works published between 1978 and 1981, inclusive. The subject distribution of the sample included fourteen of the twenty-one main classes in the LC classification, although BF (psychology), H (social sciences), and R (medicine) constituted 80.3% of the sample. The study revealed that NLM held 48.5% of the sample. The holdings of ten research medical libraries, including six of the seven regional medical libraries, were also evaluated in order to gauge NLM's ability to support that element of the medical library network. The holding rates of these libraries ranged widely (9.6% to 36%), although NLM was found to have far more extensive holdings overall, and when assessed against classes BF, H, and R. Overall, NLM could have supplied from 28.8% to 44.5% of the monographs not held by the medical libraries. In only a few cases were the ten medical libraries able to provide access to monographs not held by NLM. The findings of the study indicate that, regardless of NLM's indication of support to the MBS area, the holdings of more general research and academic libraries are essential to support the monograph needs of MBS researchers.

Location and regulation of rat angiotensinogen messenger RNA.

The presence of angiotensinogen messenger RNA (mRNA) was detected in rat vascular and adipose tissue. Angiotensinogen mRNA in rat aorta was localized in the adventitia and surrounding adipose tissue, and not in the vascular smooth muscle. Freshly dispersed and cultured endothelial and aortic smooth muscle cells did not contain detectable amounts of angiotensinogen mRNA. In addition to periaortic adipose tissue, angiotensinogen mRNA was present in other fat depots of both brown and white types. To examine regulation of angiotensinogen gene expression, Sprague-Dawley rats were treated with angiotensin converting enzyme inhibitor or underwent bilateral nephrectomy. Relative levels of angiotensinogen mRNA in brown adipose tissues increased dramatically by 48 hours after bilateral nephrectomy. However, only one source of brown adipose tissue showed increased angiotensinogen mRNA levels after animals were treated for 5 days with converting enzyme inhibitor. In addition, angiotensinogen was released into the medium from incubated adipose tissues with levels increasing over a 2-hour period. These results demonstrate that angiotensinogen is synthesized by adipose tissue in the rat and may play a role in the function of this tissue.

Endothelium-dependent relaxation is independent of arachidonic acid release.

Endothelium-dependent relaxation is mediated by the release from vascular endothelium of an endothelium-derived relaxing factor (EDRF). It is not clear what role arachidonic acid has in this process. Inhibition of phospholipase A2, and diacylglycerol lipase in cultured bovine aortic endothelial cells caused a marked reduction in agonist-induced arachidonic acid release from membrane phospholipid pools, and complete inhibition of prostacyclin production. EDRF release, assayed by measuring endothelium-dependent cGMP changes in mixed endothelial-smooth muscle cell cultures, was not inhibited under these conditions. In fact, EDRF release in response to two agonists, melittin and ATP, was actually increased in cells treated with phospholipase A2 inhibitors. In addition, pretreatment of rats with high-dose dexamethasone, an inhibitor of PLA2, did not attenuate endothelium-dependent relaxation in intact aortic rings removed from the animals, or depressor responses in anesthetized animals induced by endothelium-dependent vasodilators. In summary, inhibition of arachidonic acid release from membrane phospholipid pools does not attenuate endothelium-dependent relaxation in rats, or the release and/or response to EDRF in cultured cells.

Isolation of renin-rich rat kidney cells.

Enzymatic dispersion and density gradient (Percoll) sedimentation were used to isolate a population of renin-containing, granule-laden cells (density 1.067 g/ml) from rat kidney cortex. Using immunohistochemistry (light microscopy) and electron microscopy, we defined the presence and ability of these cells to store renin protein(s). A 1000 base pair rat renin complementary DNA was used to show that these cells express the renin gene. The reverse hemolytic plaque assay defined the functional properties of the renin-containing cell. The data are consistent with the postulated inverse relationship between calcium concentration and release of renin. Thus, we have isolated a population of functional rat kidney cells that synthesize, store, and release renin.

Angiotensin peptides and prostaglandin E2 synthesis: modulation of neurogenic responses in the rabbit vas deferens.

Isolated rabbit vasa deferentia were used to study the neuromodulation induced by angiotensins II and III (AII and AIII) upon both phases of the electrically stimulated contraction (ESC). AIII (10(-8)-10(-7) M) was shown to inhibit the ESC at low frequencies (2-10 Hz), while AII tended to potentiate both phases. Since AIII had no effect on contractions induced by exogenous ATP (twitch, putative transmitter), or norepinephrine (NE; tonic, neurotransmitter), AIII effects were presumed to be presynaptic. AIII neuromodulation was reversed by indomethacin, and prostaglandin E2 (PGE2) mimicked the inhibitory effects of AIII on ESC. The response to AIII was blocked by [Sar1,Ala8]AII (10(-6) M), an angiotensin antagonist. AIII (10(-9)-10(-5) M) stimulated PGE2 synthesis in a concentration-dependent manner. AII (10(-9)-10(-7) M) produced a dramatic rise in PGE2 synthesis, which declined sharply at higher AII concentrations. AII increased the overflow of [3H]NE approximately 50% (P less than 0.01; in the absence of indomethacin); similar concentrations of AIII did not affect [3H]NE release. However, 4 X 10(-8) M AIII in the presence of 26 microM indomethacin significantly (P less than 0.05) increased [3H]NE overflow. Thus, AIII inhibited ESC presynaptically by stimulating PGE2 synthesis, while AII potentiated these contractions presynaptically by enhancing NE release during nerve stimulation. Despite the greater inhibitory effect of AIII on force, AII was more potent than AIII in stimulating PGE2 production.