Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations.

Morquio A (Mucopolysaccharidosis IVA; MPS IVA) is an autosomal recessive lysosomal storage disorder caused by partial or total deficiency of the enzyme galactosamine-6-sulfate sulfatase (GALNS; also known as N-acetylgalactosamine-6-sulfate sulfatase) encoded by the GALNS gene. Patients who inherit two mutated GALNS gene alleles have a decreased ability to degrade the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate, thereby causing GAG accumulation within lysosomes and consequently pleiotropic disease. GALNS mutations occur throughout the gene and many mutations are identified only in single patients or families, causing difficulties both in mutation detection and interpretation. In this study, molecular analysis of 163 patients with Morquio A identified 99 unique mutations in the GALNS gene believed to negatively impact GALNS protein function, of which 39 are previously unpublished, together with 26 single-nucleotide polymorphisms. Recommendations for the molecular testing of patients, clear reporting of sequence findings, and interpretation of sequencing data are provided.

Relationship between Subclinical Hypothyroidism and Uremic Pruritis in Hemodialysis Patients.

BACKGROUND AND AIM: Uremic pruritus (UP) is one of the most distressing symptoms in hemodialysis (HD) patients. Subclinical hypothyroidism (SCH) is a biochemical condition with high prevalence in HD patients. The present multicentric study aimed to assess the relationship between UP and SCH in HD patients. METHODS: The present cross-sectional study included 328 HD patients. All patients were submitted to careful history through clinical examination and standard laboratory assessment. Pruritis was evaluated using the pruritis visual analog scale (VAS). Patients were diagnosed with SCH if they had TSH levels above the upper limit of the normal reference range in association with normal free thyroxine (FT4) levels. RESULTS: Among the studied patients, there were 196 patients (59.8 %) with UP. Comparison between patients with UP and patients without revealed that patients in the former group had significantly longer HD duration (median (IQR): 47.5 (27.0-72.5) versus 36.0 (23.0-50.5) months, p < 0.001) and lower Kt/v (median (IQR): 1.4 (1.09-1.7) versus 1.54 (1.12-1.91), p = 0.009). Moreover, they had significantly higher ferritin (median (IQR): 653.0 (526.0-800.0) versus 628.0 (470.8- 716.0) ng/mL), hsCRP (median (IQR): 12.0 (8.0-14.0) versus 8.0 (6.0-9.0) mg/dL, p < 0.001) and TSH levels (median (IQR): 4.34 (1.98-5.2) versus 3.34 (1.9-4.85) µIU/ml) with a significantly higher frequency of SCH (45.9 % versus 28.8 %, p = 0.002). Logistic regression analysis identified hemodialysis duration (OR (95%) CI): 1.02 (1.009-1.028), p < 0.001), ferritin levels (OR (95% CI): 1.002 (1.001-1.003), p < 0.001), and SCH (OR (95% CI): 0.54 (0.32-0.89), p = 0.016) as significant predictors of UP. CONCLUSION: The present study suggested a possible link between SCH and the development of UP in HD patients.

Relation between erythropoietin resistance and metabolic syndrome in hemodialysis patients: A multicentric propensity score matched analysis.

Erythropoietin (EPO) resistance is frequently reported in hemodialysis (HD) patients. Metabolic syndrome (MetS) is a common biochemical condition that comprises central obesity, dyslipidemia, hypertension, and hyperglycemia. The present study aimed to assess the relation between MetS and EPO resistance in HD patients. The present multicentric study included 150 patients with EPO resistance and 150 patients without EPO resistance. Short-acting EPO resistance was diagnosed if the erythropoietin resistance index is ≥1.0 IU/kg/gHb. Comparison between patients with EPO resistance and patients without resistance revealed that the former group had significantly higher body mass index, lower hemoglobin levels, lower albumin levels, higher ferritin levels, and higher high-sensitivity C-reactive protein (hsCRP) levels. In addition, patients in the EPO resistance group had significantly higher frequency of MetS (75.3% vs 38.0%, p < 0.001) and higher number of MetS components (2.7 ± 1.3 vs 1.8 ± 1.6, p < 0.001). Multivariate logistic regression analysis identified lower albumin levels (OR (95% CI): 0.072 (0.016-0.313), p < 0.001), higher ferritin levels (OR (95% CI): 1.05 (1.033-1.066), p< 0.001), higher hsCRP levels (OR (95% CI): 1.041 (1.007-1.077), p = 0.018), and MetS (OR (95% CI): 36.68 (2.893-465.05), p = 0.005) as predictors of EPO resistance in the studied patients. The present study identified MetS as a predictor of EPO resistance in HD patients. Other predictors include serum ferritin, hsCRP, and albumin levels.

Novel mutation in GLRB in a large family with hereditary hyperekplexia.

Hereditary hyperekplexia (HH) is a disorder of the inhibitory glycinergic neurotransmitter system. Mutations in five genes have been reported to cause the disease. However, only single mutation in GLRB, the gene encoding beta-subunit of the glycine receptor, in a singleton patient with HH has been found to date. In this study, 13 patients with HH were identified through neurology and genetic clinics. Formal clinical examinations, linkage analysis, homozygosity mapping, in-mutation screening of GLRB and in silico functional analyses were carried out. A novel mutation in GLRB among nine patients was identified. This c.596 T>G perturbation results in the change of the highly conserved methionine at position 177 to arginine. Besides the classical HH phenotype, seven patients had esotropia and few of them had behavioral problems. This study presents a large family with HH as a result of homozygous mutation in GLRB and expands the clinical spectrum of HH to include eye misalignment disorder. Moreover, the report of these familial cases supports the previous evidence in a single patient of an autosomal recessive inheritance of HH because of defects in GLRB.

Clinical, biochemical and molecular characterization of peroxisomal diseases in Arabs.

Peroxisomes are single membrane-bound cellular organelles that carry out critical metabolic reactions perturbation of which leads to an array of clinical phenotypes known as peroxisomal disorders (PD). In this study, the largest of its kind in the Middle East, we sought to comprehensively characterize these rare disorders at the clinical, biochemical and molecular levels. Over a 2-year period, we have enrolled 17 patients representing 16 Arab families. Zellweger-spectrum phenotype was observed in 12 patients and the remaining 5 had the rhizomelic chondrodysplasia punctata phenotype. We show that homozygosity mapping is a cost-effective strategy that enabled the identification of the underlying genetic defect in 100% of the cases. The pathogenic nature of the mutations identified was confirmed by immunofluorescence and complementation assays. We confirm the genetic heterogeneity of PD in our population, expand the pool of pathogenic alleles and draw some phenotype/genotype correlations.

Zellweger syndrome caused by PEX13 deficiency: report of two novel mutations.

Peroxisomal biogenesis disorders represent a group of genetically heterogeneous conditions that have in common failure of proper peroxisomal assembly. Clinically, they are characterized by a spectrum of dysmorphia, neurological, liver, and other organ involvement. To date, mutations in 13 PEX genes encoding peroxins have been identified in patients with peroxisomal biogenesis disorders. Mutations in PEX13, which encodes peroxisomal membrane protein PEX13, are among the least common causes of peroxisomal biogenesis disorders with only three mutations reported so far. Here, we report on two infants whose clinical and biochemical profile was consistent with classical Zellweger syndrome and whose complementation analysis assigned them both to group H of peroxisomal biogenesis disorders. We show that they harbor two novel mutations in PEX13. One patient had a genomic rearrangement resulting in a 147 kb deletion that spans the whole of PEX13, while the other had an out-of-frame deletion of 14 bp. This represents the first report of a PEX13 deletion and suggests that further work is needed to examine the frequency of PEX13 mutations among Arab patients with peroxisomal biogenesis disorders.

Testing combinations of protease inhibitor and preservation solution to improve islet quality and yield.

UNLABELLED: Pancreas preservation using an oxygenated two-layer method (TLM) has been reported to improve islet yields, as has supplementation of Liberase with Pefabloc. We hypothesized that using both TLM and Pefabloc could enhance islet yield as compared with preservation in University of Wisconsin (UW) or Histidine-Tryptophan Ketoglutarate (HTK) solution. METHODS: Ninety-eight pancreata with no significant differences of age, body mass index, or cold ischemia time preserved randomly with UW (n = 40), TLM (n = 48), or HTK (n = 10) were processed with (n = 36) or without (n = 66) Pefabloc. RESULTS: The total islet equivalent (IEQ) from TLM-preserved pancreata processed with Pefabloc (n = 12) showed lower yields versus those processed without Pefabloc (n = 36): 216,120 +/- 27,906 vs. 301,427 +/- 21,447 IEQ (P < .05). Islets from 1 of 12 (8.33%) pancreata processed with Pefabloc in TLM were transplanted, in contrast with 15/36 TLM (41.67%) pancreata processed without it. Islet yields were not significantly different among pancreata preserved in UW and processed with Pefabloc (n = 17) versus without Pefabloc (n = 23): 342,693 +/- 45,588 versus 266,609 +/- 29,006 IEQ (P = .149). The number of transplants from UW-preserved pancreata was 3/17 (17.65%) when processed with Pefabloc and 4/23 (17.39%) without. Among the HTK group, there was no significant difference in islet yields between pancreata processed with (n = 7) versus without Pefabloc (n = 3): 248,227 +/- 65,294 versus 483,555 +/- 144,070 IEQ (P = .118). CONCLUSIONS: Pefabloc showed no benefit to improve islet yields. Pancreata preserved in TLM provided better transplant quality islets when processed in the absence of Pefabloc.

Quantification of N-acetylaspartic acid in urine by LC-MS/MS for the diagnosis of Canavan disease.

Canavan disease is an autosomal recessive leukodystrophy characterized by excessive excretion of N-acetylaspartic acid (NAA) in urine. The disease is caused by deficiency of aspartoacylase, the enzyme responsible for the hydrolysis of NAA into acetate and l-aspartate. Patients, who are often asymptomatic in their early months, show a wide spectrum of clinical presentation thereafter that includes macrocephaly, poor head control, seizures, abnormal muscle tone, optic atrophy, significant developmental delay and death. In this work, we describe a simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of NAA in urine. The internal standard d3-NAA was added to untreated urine and the mixture was injected into the LC-MS/MS system operated in the negative ion mode. Detection was achieved in multiple reaction monitoring (MRM) mode by monitoring m/z 174 --> 88, 174 --> 130 and 174 --> 58 for NAA and 177 --> 89 for the internal standard. Separation was carried out on a C8 column (2.1 x 150 mm) using a mixture of acetonitrile and water (1:1 v/v) containing 0.05% formic acid at a flow rate of 0.25 ml/min. NAA was eluted at 1.6 min and the run time was approximately 2 min. Using spiked urine, the assay was linear up to 2 mmol/L with limit of quantification at 1 micromol/L (S/N = 12). NAA in patients' urine (n = 17) ranged between 366 and 21,235 mmol/mol creatinine compared to controls of <39 mmol/mol creatinine (n = 159). This LC-MS/MS method for NAA as described involved no extraction and no derivatization, showed no interference, and gave excellent recovery with low variability and short analytical time.

Management of the solitary cold thyroid nodule. A prospective study.

Forty-six patients with single cold thyroid nodules (SCTN) were studied prospectively to evaluate radio-iodine scans and fine needle aspiration biopsy (FNAB) as outpatient and preoperative diagnostic modalities and frozen section (FS) and paraffin section (PS) as excisional biopsies. In our series FNAB has a reasonable sensitivity (75%), good specificity (87%), a low positive predictive value of 38% and a high negative value of 97%. It has a false negative rate of 2.3% and a false positive rate of 56%.

[Amyloidosis of a coral reef infrarenal aorta]. / Amylose d'une aorte sous-rénale en pierre de corail.

This case concerns a 37-year-old woman with a cruro-gluteal claudication, from which she had been suffering since the age of 33, and which prevented her from walking more than 50 metres. The arteriographic examination revealed preocclusive coralliform proliferations of the infrarenal aorta, with a 30% stenosis of the right internal carotid artery. After 18 months, a straight aorto-aortic tube yielded excellent results. The results of the pathological examination led to the conclusion that this was a secondary aortic amyloidosis with no specific lesions of the aortic wall. This coral reef aorta is distinguished by its infrarenal location (fourth case worldwide), as well as by the major amylotic infiltrations of the endoaortic proliferations and of the aortic wall. In the absence of generalized amyloidosis, we suspect massive localized amyloidosis subsequent to an old inflammatory aortic process compatible with a juvenile atheroma opened in the aortic lumen or more probably a sequel of Takayasu's disease.

[Carotid-jugular fistula after an attempt at placement of a vena cava filter]. / Fistule carotido-jugulaire après tentative de placement d'un filtre cave.

A carotid-jugular fistula complicated the placement of a Green-field filter via the right internal jugular percutaneous passage: the local signs of an arterio-venous fistula were associated with right parietal infarction neurological symptoms. A crossography showed a carotid-jugular fistula and a limited dissection of the original carotid artery. An elective echo-guided compression failed. The surgical treatment eliminated the fistula, fixed the carotid dissection and placed a vena cava filter with an excellent result 34 months later. Percutaneous placement of vena cava filters can lead to rare vascular complications such as carotid-jugular fistulas which can, in certain cases, be treated with an elective external compression or endovascular procedures. Surgery offers a reliable technical solution that is complete and stable in time, particularly with recent fistulas and associated neurological symptoms.

[Carotid surgery under loco-regional anesthesia. Early results of 100 recent cases]. / Chirurgie carotidienne sous anesthésie loco-régionale. Résultats précoces de 100 cas récents.

A prospective single-centre study was performed to evaluate the safety and efficacy of carotid revascularisation under local anesthesia. Between November 1, 1996 and March 30, 1998, 92 patients underwent surgery for 100 carotid artery stenoses under local cervical block anesthesia. Fifty-eight stenoses were asymptomatic and 42 were symptomatic. Duplex ultrasound scanning showed a tight (n = 17) or very tight carotid artery stenosis (n = 83); angiography showed 19 contralateral carotid artery stenosis and 30 hemodynamically significant stenosis of vertebral and/or subclavian arteries. Cerebral Magnetic Resonance Imaging (MRI) (N = 87) with circle of Willis Magnetic Resonance Angiogram (MRA) (n = 83) detected 29 ischemic defects (33%). Fifteen ischemic defects were found in 58 asymptomatic patients (26%). Circle of Willis was incomplete in 41%. Anesthesia was performed using superficial cervical block (n = 100). Endarterectomy was the most commonly used revascularisation technique in 86 cases with 5 eversion endarterectomies; carotid vein or prosthetic graft was used in 14%. In this study, there was no mortality, and no cardiac or neurologic complications, during the first postoperative month. Twelve patients experienced neurologic intolerance to carotid clamping. This clamping-related ischemia required 4 shunts. All patients with clamping intolerance had a good clinical outcome after revascularisation with no objective or MRI sequelae. Incomplete circle of Willis on MRA was a significant predictive test of clamping intolerance (p < 0.0001). Carotid artery surgery under local anesthesia reduces the cumulative mortality and morbidity rate (TCMM) to a very low level: 0% in this study. These recent results are the modern reference for current carotid artery surgery evaluation.

Detection and characterization of an ST97-SCCmec-V community-associated meticillin-resistant Staphylococcus aureus clone in a neonatal intensive care unit and special care baby unit.

A total of 29 meticillin-resistant Staphylococcus aureus (MRSA) isolates were obtained from 15 neonates and three healthcare workers (HCWs) in a neonatal intensive care unit (NICU) and special care baby unit (SCBU) and four patients in a medical ward of a Kuwait hospital between 10 and 30 April 2007. The isolates were characterized using antibiogram results, coagulase gene RFLP (coa-RFLP), PFGE, staphylococcal cassette chromosome mec (SCCmec) typing and multilocus sequence typing (MLST). All isolates were assessed for the carriage of Panton-Valentine leukocidin (PVL) and arginine catabolic mobile element (ACME) genes. The isolates belonged to three SCCmec types, six coa-RFLP types, six pulsotypes and six sequence types. One isolate was positive for PVL. None were positive for ACME. All MRSA isolates from the 15 neonates were phenotypically and genetically different from the MRSA isolates obtained from HCWs and those from patients in other wards. They were resistant to gentamicin, kanamycin and fusidic acid, had identical coa-RFLP and PFGE patterns, carried the type V SCCmec element and belonged to MLST sequence type ST97. The results showed the transmission of a rare clone of community-associated MRSA belonging to ST97 with the SCCmec-V genotype among neonates in a NICU and SCBU.

Results of treatment of displaced supracondylar humeral fractures in children by percutaneous lateral cross-wiring technique.

Seventy children with displaced type II and III supracondylar fractures of the humerus were managed with percutaneous lateral cross-wiring technique from January 2006 to January 2007. There were 54 boys and 16 girls with a mean age of 6.1 +/- 3.07 years. All patients were operated within 24 h after trauma using the Dorgans percutaneous lateral cross-wiring technique. Patients were followed up for a mean period of 6.1 +/- 2.6 months and assessed both radiologically for union; and functionally and cosmetically according to Flynn's criteria. All patients achieved solid union. Functionally, all patients achieved satisfactory results, while cosmetically, 91.4% of patients had satisfactory results and 8.6% had unsatisfactory results. The most frequently occurring complications were minor pin tract infection in six patients, deep infection in two patients, and 32 patients suffered excessive granulation tissue formation mostly around the proximal pin. There was no iatrogenic neurological injury either for the ulnar or for the radial nerves. The obtained results and minor complications reported signify this technique as a viable treatment method for displaced type II and III supracondylar fractures in children.

Clinical and molecular diagnosis of Familial Mediterranean Fever in Egyptian children.

BACKGROUND: Familial Mediterranean Fever (FMF) is an autosomal inherited disorder affecting certain races including Arabs. Diagnosis depends mainly on clinical basis, but mild forms may remain undiagnosed. OBJECTIVES: This study aims at an accurate diagnosis of FMF in Egyptian children by detection of genetic mutations in addition to clinical assessment. SUBJECTS AND METHODS: Subjects included 66 Egyptian cases (37 males and 29 females) with a mean age of onset of 6.9 years. They had been referred from health centers and hospitals of the Delta region, Egypt. Analysis of the clinical manifestations was performed using Tel-Hashomer criteria in addition to 10 items clinical score system. For all these cases, DNA analysis was made for three common mutations M680I, M694V, and V726A using amplification refractory mutation system (ARMS-PCR) technique. RESULTS: Most of the cases had attacks ranging from 3-5 days duration with the mean of 3.6 days. Their rate of recurrence was variable but 47 % of them had suffered attacks 10-30 times/year. Abdominal pain was the most common symptom (87.9%) followed by fever (82%), arthritis or arthralgia (56.1%), chest pain (45%) and myalgia (6%). Laparotomy had been done during attacks for exploration or appen-dectomy in 27.7% of cases. Positive mutations were detected among 42 cases (63.6%), of them 14 (21.2%) were compound heterozygotes, 7 (10.6%) were had homozygotes while 21 (31.8%) were simple heterozygotes. Allele M694V was the most frequent one (18.8%) followed by V726A (17.4%) and M680I (12.1%). Taking positive mutation as a guide for diagnosis, a cutoff clinical score level was determined with =15 for unlikely, =20 for definite and 15-20 for probable diagnosis. CONCLUSION: Diagnosis of FMF among Egyptian children cases although based mainly on clinical suspicion requires to be confirmed through detection of the corresponding mutation which can be easily made using the simple ARMS-PCR technique.

Identification of a common novel mutation in Saudi patients with argininosuccinic aciduria.

We have identified a common novel mutation (Q354X) in the argininosuccinate lyase (ASL) gene in Saudi patients with argininosuccinic aciduria (ASAuria; McKusick 207900). The two index patients were siblings, had a neonatal onset of the disease and were diagnosed based on the clinical presentation and confirmed by analysis of their dried blood spots (DBS) by tandem mass spectrometry (MS/MS). The ASL gene was then analysed by direct sequencing. A further 28 patients with a confirmed diagnosis of ASAuria based on MS/MS of their DBS were tested by sequencing for the presence of the Q354X mutation. This mutation was found in 14 out of the 28 patients (50%) tested. Our work indicates that the Q354X allele is common, may account for 50% of the abnormal ASL genes in the Saudi population, and is likely to be associated with the neonatal form of the disease. We recommend that all patients diagnosed with ASAuria in Saudi Arabia or of Arab origin be tested for this mutation and for Q116X, which has been described previously. In addition, further analysis is needed to identify other underlying disease mutations for ASAuria in the Saudi population.

The optimum time for tumour imaging with thallium-201.

Following the intravenous injection of 75 MBq 201Tl-chloride we have assessed the uptake kinetics in the myocardium and in the primary tumour in 56 patients with lung cancer, 26 with breast cancer and 13 with mediastinal lymphoma. The time of maximal tumour uptake ranged from 8-20 min post-injection and did not differ significantly between lung cancer (mean +/- SD = 11.9 +/- 3.34 min), breast cancer (11.21 +/- 1.88 min) and lymphoma (11.76 +/- 3.25 min). The time of maximum cardiac uptake of 201Tl was 11.61 +/- 3.25 min. There was no significant washout of 201Tl from the tumours in the first hour after injection in the various malignant lesions studied. The time of maximal tumour to background activity was 18.3 +/- 0.59 min for lung cancer, 13.0 +/- 1.16 min for breast cancer and 16.7 +/- 1.04 min for lymphoma. The time course of 201Tl uptake in the tumours suggests that the mechanism of uptake is similar to that in the myocardium. The optimal time of 201Tl tumour imaging is from 20-60 min following injection and did not differ in various tumours studied.

Studies on the cardiovascular depressant effects of N-ethyl- and N-benzyl-1,2-diphenylethanolamines in the rat: elucidation of the mechanisms of action.

The influence and mechanisms of action of N-ethyl- and N-benzyl-1,2-diphenylethanolamines (compounds E and B, respectively) on the arterial blood pressure and the heart rate of the rat together with their effects on CaCl2-induced arrhythmias in the rat were investigated. Both E and B in doses of (1.5-12 micromol/kg IV) decreased the arterial blood pressure and the heart rate in a dose-dependent manner. Studies with various receptor blockers, enzyme inhibitors and CaCl2 revealed that E-induced cardiovascular depressant effects were mainly due to CaCl2 channel blocking action and activation of cyclic guanylyl cyclase or release of NO whereas the cardiovascular effects of B seemed to involve both blockade of Ca2+ channels and activation of parasympathetic ganglia. Both compounds (12-14.5 micromol/kg) completely protected the rat against CaCl2 (60 mg kg(-1))-induced tachyarrhythmias. The B compound seemed to be several times more potent than the E compound in its cardiovascular depressant actions. The results suggest the potential usefulness of both compounds in the treatment of hypertension and supraventricular arrhythmias.

Studies on the spasmolytic and uterine relaxant actions of n -ethyl and n -benzyl-1,2-diphenyl ethanolamines: elucidation of the mechanisms of action.

The influence of N -ethyl- and N -benzyl-1,2-diphenyl ethanolamines (compounds E and B, respectively) was examined on the spontaneously contracting rabbit jejunum and the rat uterus together with their influence on the contractions induced by some spasmogens in the guinea-pig ileum and oxytocics and CaCl2in the pregnant rat uterus. Both E and B inhibited the spontaneous contractions of the rabbit jejunum with ID50values of 0.13 and 0.03 micromol ml-1. Their inhibitory activities were not antagonized by alpha- or beta-adrenoceptor blockers but significantly reversed by CaCl2(0.015 micromol ml-1). The compounds also antagonized nicotine, ACh-, histamine-, 5-HT- and CaCl2-induced contractions by 44-100%. Compound E seemed to be several times more potent than B in inhibiting the spontaneous uterine contractions with an ID50of (7 nmol ml-1). Their inhibitory effects were not antagonized by beta2-adrenoceptor or H2-receptor blocking drugs. Both compounds (40 nmol ml-1) antagonized in a competitive manner CaCl2-induced contractions in the K+-depolarised uterus and PGE2and oxytocin-induced uterine contractions. The ID50values were in the range of 1.6-10.7 nmol ml-1. The results suggest that E and B compounds may be considered as putative L-Ca2+channel blockers with certain selectivities. The E compound seemed to be more selective against uterine L-Ca2+channels and the B compound against intestinal smooth muscles. Thus, the compounds may be of potential value in treatment of some colics, the irritant bowel syndrome, dysmenorrhoea and premature deliveries.

Effects of two newly synthesized analogues of lidocaine on rat arterial blood pressure and heart rate.

Two new analogues of lidocaine were synthesized at the College of Pharmacy, King Saud University: compound I (Methyl-2-[2-(N,N-diethylamino) acetamido]-3-cyano-4,5-dimethylbenzoate) and compound II (Methyl-2-[2-(piperidino) acetamido]-3-cyano-4,5-dimethylbenzoate). Their influence on the arterial blood pressure and the heart rate of urethane-anaesthetized rats was studied and compared with the actions of lidocaine. Compounds I, II and lidocaine induced significant dose-dependent decreases in the arterial blood pressure and heart rate, which usually returned to basal values within 3-5 min. There were significant differences in the potency of the three compounds in producing their effects on blood pressure and heart rate (P< 0.0001, ANOVA). Compound II was 14 and 6 times more potent in reducing blood pressure and 8 and 2 times more capable of reducing the heart rate than lidocaine and compound I, respectively. The results of this study also indicated the ineffectiveness of antagonists of autonomic, histaminergic and 5-HT receptor, and various vasodilators in blocking the actions of the three compounds on blood pressure and heart rate. Pretreatment with CaCl(2)significantly reduced the hypotension and bradycardia induced by the three compounds, suggesting the involvement of calcium channels, probably of the L type. Several possible mechanisms are postulated. In conclusion, the results direct attention to the capability of the two new compounds to decrease blood pressure and heart rate; affects that may have clinical potential.