Twenty years with diabetes and amputations: a retrospective population-based cohort study.

AIM: To investigate the trends in non-traumatic lower limb amputation in people with and without diabetes. METHODS: From the Danish National Patient Register, all people with either type 1 or type 2 diabetes (n = 462 743) as well as a group of people without diabetes from the general population (n = 1 388 886) were identified and separated into three groups based on diabetes type. Among these, 17 265 amputations were identified between 1997 and 2017 and stratified into trans-femoral amputations, trans-tibial amputations and amputations below the ankle using surgical codes. Annual changes were described using least-squares linear regression. RESULTS: The yearly mean decrease in incidence rate of amputation per 1000 person-years was -0.032 [95% CI: -0.062, -0.001], -0.022 [-0.032, -0.012] and -0.006 [-0.009, -0.003] for trans-femoral amputation, -0.072 [-0.093, -0.052], -0.090 [-0.102, -0.078] and -0.015 [-0.016, -0.013] for trans-tibial amputation, and -0.055 [-0.080, -0.020], -0.075 [-0.090, -0.060] and -0.011 [-0.014, -0.007] for amputation below the ankle in people with type 1 diabetes, people with type 2 diabetes and people without diabetes, respectively. CONCLUSIONS: Over recent decades, the incidence of amputation has decreased significantly in people with diabetes and in the general population without diabetes.

Cardiovascular effects of antidiabetic drugs.

Type 2 diabetes mellitus is a common and severe chronic metabolic disease, which confers increased risk of cardiovascular disease and mortality. During the last decade a large number of new drugs within the classes dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4Is), glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) and sodium/glucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2Is) have been developed and tested in nine large-scale cardiovascular outcome trials (CVOTs). Here we review the evidence behind antihyperglycemic treatment of patients with type 2 diabetes with a particular focus on compiling and summarizing the evidence of hard clinical endpoints stemming from these large CVOTs.

Circulating levels of platelet α-granule cytokines in trauma patients.

OBJECTIVE AND DESIGN: To elucidate whether platelets differentiate cytokine release following trauma, we prospectively measured three major platelet-derived cytokines in 213 trauma patients on hospital arrival. METHODS: We measured plasma levels of the anti-inflammatory ß-thromboglobulins (ßTGs), transforming growth factor-ß1 (TGFß1) and the pro-inflammatory platelet factor 4 (PF4) cytokines. We also measured soluble glycoprotein VI (sGPVI), procoagulant platelet microparticles (PMPs) and white blood cell (WBC) counts, and evaluated in vitro platelet function in primary and secondary haemostasis by aggregometry and thromboelastometry, respectively. We evaluated associations of each cytokine by multivariate regression including injury severity score (ISS), WBC counts, sGPVI and platelet counts as explanatory variables. RESULTS: Severely injured patients (ISS > 15) had higher levels of ßTGs and TGFß1 (both p < 0.01) but lower levels of PF4 (p = 0.02). GPVI and PMPs levels correlated with TGFß1 and PF4 whereas we found no significant association between cytokine levels and measures of haemostasis. By multivariate regression, a high WBC count was associated with high levels of TGFß1 (p = 0.01) and ßTGs (p < 0.01) but with low levels of PF4 (p = 0.03). CONCLUSION: Severely injured patients had higher levels of ßTGs and TGFß1 but lower levels of the PF4; a high WBC count predicted this anti-inflammatory profile of platelet cytokines.

Local anaesthesia versus intravenous regional anaesthesia in endoscopic carpal tunnel release: a randomized controlled trial.

We carried out a prospective randomized trial in 38 patients to compare intravenous regional anaesthesia with local anaesthesia in endoscopic carpal tunnel release using the Agee single-portal technique. There was no significant difference in reported pain during surgery. Immediately after surgery, patients in the local anaesthesia group reported significantly less pain in the hand and at the tourniquet. Two hours after surgery, patients in the local anaesthesia group reported significantly less hand pain. Moreover, significantly fewer patients in the local anaesthetic group required additional analgesics during the first 2 hours after operation. We conclude that local anaesthesia reduces post-operative pain in endoscopic carpal tunnel release compared with intravenous regional anaesthesia.

Rapid sequence induction and intubation with rocuronium-sugammadex compared with succinylcholine: a randomized trial.

BACKGROUND: An unanticipated difficult airway may arise during rapid sequence induction and intubation (RSII). The aim of the trial was to assess how rapidly spontaneous ventilation could be re-established after RSII. We hypothesized that the time period from tracheal intubation to spontaneous ventilation would be shorter with rocuronium-sugammadex than with succinylcholine. METHODS: This randomized and patient- and observer-blinded trial was approved by the regional Ethics Committee and the Danish Medicines Agency. We included elective surgical patients undergoing general anaesthesia for RSII using alfentanil (10 µg kg(-1)), propofol (2 mg kg(-1)), and either succinylcholine (1 mg kg(-1)) or rocuronium (1 mg kg(-1)). Sugammadex (16 mg kg(-1)) was given in the rocuronium group after tracheal intubation. The primary endpoint was the time from correct placement of the tracheal tube to spontaneous ventilation, defined as a respiratory rate of more than 8 bpm and a tidal volume of at least 3 ml kg(-1) for 30 s. RESULTS: We included 61 patients; of whom, 55 were evaluated for the primary endpoint. The median time from tracheal intubation to spontaneous ventilation was 406 s with succinylcholine and 216 s with rocuronium-sugammadex (P = 0.002). The median time from tracheal intubation to 90% recovery of the first twitch in train-of-four (T(1) 90%) was 518 s with succinylcholine and 168 s with rocuronium-sugammadex (P < 0.0001). Intubation conditions and time to tracheal intubation were not significantly different. CONCLUSIONS: RSII with rocuronium followed by reversal with sugammadex allowed earlier re-establishment of spontaneous ventilation than with succinylcholine.

High sCD40L levels early after trauma are associated with enhanced shock, sympathoadrenal activation, tissue and endothelial damage, coagulopathy and mortality.

BACKGROUND: Severe injury activates the sympathoadrenal, hemostatic and inflammatory systems, but a maladapted response may contribute to a poor outcome. Soluble CD40L is a platelet-derived mediator that links inflammation, hemostasis and vascular dysfunction. OBJECTIVES: To investigate the association between the sCD40L level and tissue injury, shock, coagulopathy and mortality in trauma patients. METHODS: A prospective, observational study of 80 trauma patients admitted to a Level I Trauma Center. Data on demography, biochemistry, Injury Severity Score (ISS) and 30-day mortality were recorded and admission plasma/serum analyzed for sCD40L and biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments [hcDNA], Annexin V, thrombomodulin and syndecan-1), coagulation activation/inhibition (PF1.2, TAT-complex, antithrombin, protein C, activated protein C, sEPCR, TFPI, von Willebrand factor [VWF], fibrinogen and factor [F] XIII), fibrinolysis (D-dimer, tissue plasminogen activator [tPA] and plasminogen activator inhibitor-1 [PAI-1]) and inflammation (interleukin-6 [IL-6] and sC5b-9). We compared patients stratified by median sCD40L level and investigated predictive values of sCD40L for mortality. RESULTS: High circulating sCD40L was associated with enhanced tissue and endothelial damage (ISS, hcDNA, Annexin V, syndecan-1 and sTM), shock (pH, standard base excess), sympathoadrenal activation (adrenaline) and coagulopathy evidenced by reduced thrombin generation (PF1.2), hyperfibrinolysis (D-dimer), increased activated partial thromboplastin time (APTT) and inflammation (IL-6) (all P < 0.05). A higher ISS (P = 0.017), adrenaline (P = 0.049) and platelet count (P = 0.012) and lower pH (P =0.002) were associated with higher sCD40L by multivariate linear regression analysis. High circulating sCD40L (odds ratio [OR] 1.84 [95% CI 1.05-3.23], P = 0.034), high age (P = 0.002) and low Glasgow Coma Score (GCS) pre-hospital (P = 0.002) were independent predictors of increased mortality. CONCLUSIONS: High early sCD40L levels in trauma patients reflect tissue injury, shock, coagulopathy and sympathoadrenal activation and predict mortality. As sCD40L has pro-inflammatory activity and activates the endothelium, sCD40L may be involved in trauma-induced endothelial damage and coagulopathy.

Continuous adductor-canal-blockade for adjuvant post-operative analgesia after major knee surgery: preliminary results.

Because both the saphenous nerve and in part the obturator nerve are traversing the adductor canal of the thigh, we hypothesised that repeated administration of a local anaesthetic (LA) into this aponeurotic space could be a useful option for post-operative analgesia after knee replacement surgery. A systematic search of the literature pertinent to the blockade of the saphenous and/or obturator nerves for pain relief after knee surgery was conducted. Further, pain and opioid requirements were evaluated in eight patients receiving a continuous blockade of the saphenous and obturator nerve (adductor-canal-blockade) after total knee arthroplasty (TKA). Finally, we performed cross-sectional MR scans of the adductor canal after injection of ropivacaine 30ml in one patient. The systematic literature search revealed only one controlled study, where selective blockade of the saphenous nerve was investigated for the purpose of clinical pain relief after knee arthroscopy. We located no studies reporting on saphenous and/or obturator nerve block for pain relief after TKA. Preliminary findings in eight patients demonstrated that a continuous adductor-canal-blockade for 48h after TKA was associated with low mean pain scores at rest and low mean requirements for supplemental morphine. MR scans in one patient demonstrated that 30ml of LA filled the adductor canal, including the distal part, where the posterior branch of the obturator nerve joins the vessels and the saphenous nerve. Continuous adductor-canal-blockade may be a valuable adjunct for post-operative analgesia after major knee surgery. These preliminary results should be confirmed in randomised, controlled trials.

Iatrogenic systemic air embolism treated with hyperbaric oxygen therapy.

Air embolism is a rare and potentially severe complication of surgical and invasive procedures. Emboli large enough to produce symptoms require immediate treatment because of the risk of 'gas lock' in the right side of the heart and subsequent circulatory failure. If air is transmitted to the arterial circulation through a shunt, it may cause cerebral emboli with neurological symptoms. We present two cases with venous air emboli and concurrent cerebral arterial emboli. Both patients were successfully treated with hyperbaric oxygen therapy.

Toxic encephalopathy and noise-induced hearing loss.

In several laboratory animal studies, it has been documented that the hearing, vision, and brain can be injured due to exposure to organic solvents. This finding formed the background for a pilot study (n=16) aimed at identifying new ways of qualifying diagnostics, treatment, and rehabilitation of patients suffering from brain injury due to exposure to organic solvents, also referred to as toxic encephalopathy. Diagnosing toxic encephalopathy is complicated because the symptoms of this type of diffuse brain injury are non-specific. So, it was initially hypothesised that some of the difficulties involved in diagnosing toxic encephalopathy could be minimized by extending the diagnostic procedure. Apart from clinical interviewing and neuropsychological testing, the diagnosis should include the examination of hearing and vision. This will help in achieving new measures that could improve in diagnosing toxic encephalopathy with more certainty. On the basis of ranking, only one patient in the pilot study was considered to have a normal neuropsychological test profile, which was defined as a test profile without any marked deviations when compared with a normal population. A total of 10 patients were considered to have "discrete problems." These patients had a test profile showing either a few strikingly negative results or an array of results slightly below the expected level when compared with a normal population. A total of four patients were considered to suffer from "moderate problems" and one patient from "severe problems." The patients with "moderate problems" and "severe problems" showed consistent negative results and an unambiguous negative test profile. However, the overall results of all neuropsychological examinations performed revealed a dispersed picture. Quite remarkably, all the 13 patients who had their hearing examined showed a loss of hearing, 7 patients complained about tinnitus, and all patients had a history of exposure to both noise and organic solvents, which had not been observed at the initial examination, but seemed to have serious implications for their prognosis and future life.

Intubation conditions after rocuronium or succinylcholine for rapid sequence induction with alfentanil and propofol in the emergency patient.

BACKGROUND AND OBJECTIVE: Previous studies mainly conducted on elective patients recommend doses of 0.9-1.2 mg kg[-1] rocuronium to obtain comparable intubation conditions with succinylcholine 1.0 mg kg[-1] after 60 s during a rapid-sequence induction. We decided to compare the overall intubating conditions of standard doses of rocuronium 0.6 mg kg[-1] and succinylcholine 1.0 mg kg[-1] during a strict rapid-sequence induction regimen including propofol and alfentanil. METHODS: Male and female patients (ASA I-III) older than 17 yr scheduled for emergency abdominal or gynaecological surgery and with increased risk of pulmonary aspiration of gastric content were randomized to a rapid-sequence induction with succinylcholine 1.0 mg kg[-1] or rocuronium 0.6 mg kg[-1]. Patients with a predicted difficult airway were excluded. A senior anaesthesiologist 'blinded' for the randomization performed the intubation 60 s after injection of the neuromuscular blocker. Intubating conditions were evaluated according to an established guideline. Tracheal intubation not completed within 30 s was recorded as failed. RESULTS: 222 patients were randomized. Three patients had their operation cancelled and 10 did not fulfil the inclusion criteria. Clinically acceptable intubation conditions were present in 93.5% and 96.1% of patients in the succinylcholine group (n=107) and the rocuronium group (n=102), respectively (P=0.59). CONCLUSIONS: During a rapid-sequence induction with alfentanil and propofol, both rocuronium 0.6 mg kg[-1] and succinylcholine 1.0 mg kg[-1] provide clinically acceptable intubation conditions in 60 s in patients scheduled for emergency surgery. Under the conditions of this rapid-sequence induction regimen rocuronium may be a substitute for succinylcholine.

Profiling of renal tubule Na+ transporter abundances in NHE3 and NCC null mice using targeted proteomics.

The Na+-H+ exchanger NHE3 and the thiazide-sensitive Na+-Cl- cotransporter NCC are the major apical sodium transporters in the proximal convoluted tubule and the distal convoluted tubule of the kidney, respectively. We investigated the mechanism of compensation that allows maintenance of sodium balance in NHE3 knockout mice and in NCC knockout mice. We used a so-called 'targeted proteomics' approach, which profiles the entire renal tubule with regard to changes in Na+ transporter and aquaporin abundance in response to the gene deletions. Specific antibodies to the Na+ transporters and aquaporins expressed along the nephron were utilized to determine the relative abundance of each transporter. Semiquantitative immunoblotting was used which gives an estimate of the percentage change in abundance of each transporter in knockout compared with wild-type mice. In NHE3 knockout mice three changes were identified which could compensate for the loss of NHE3-mediated sodium absorption. (a) The proximal sodium-phosphate cotransporter NaPi-2 was markedly upregulated. (b) In the collecting duct, the 70 kDa form of the y-subunit of the epithelial sodium channel, ENaC, exhibited an increase in abundance. This is thought to be an aldosterone-stimulated form of y-ENaC. (c) Glomerular filtration was significantly reduced. In the NCC knockout mice, amongst all the sodium transporters expressed along the renal tubule, only the 70 kDa form of the y-subunit of the epithelial sodium channel, ENaC, exhibited an increase in abundance. In conclusion, both mouse knockout models demonstrated successful compensation for loss of the deleted transporter. More extensive adaptation occurred in the case of the NHE3 knockout, presumably because NHE3 is responsible for much more sodium absorption in normal mice than in NCC knockout mice.

Increased natriuretic efficiency of furosemide in rats with carbon tetrachloride-induced cirrhosis.

The authors examined the natriuretic efficiency of furosemide in rats with cirrhosis induced by carbon tetrachloride (CCl(4)). Rats were treated for 17 weeks with intraperitoneal injections of CCl(4) in groundnut oil twice a week throughout the study. Control rats were treated with vehicle (groundnut oil). Studies in metabolic cages showed that sodium retention was present from week 14. Renal clearance experiments were performed in chronically, instrumented conscious rats at the end of week 14 and at the termination of the study (end week 16) when ascites and hyponatremia were present. After 14 weeks, cirrhotic rats had sodium retention along with increased renal plasma flow, normal GFR, normal renal lithium handling, and a significantly increased diuretic (+41% vs. control) and natriuretic (+56% vs. control) response to a test dose furosemide (7.5 mg/kg b.w., intravenously). The natriuretic efficiency of furosemide, i.e., the natriuresis expressed relative to the furosemide excretion rate (triangle upU(Na)V/U(FUR)V) was increased by 51% versus control. After 17 weeks, ascites and hyponatremia had developed, and significant decreases in renal plasma flow (-33%), GFR (-30%), and fractional lithium excretion (-44%) were observed. At this stage urinary recovery of furosemide was significantly decreased and the diuretic (-27% vs. Control) and natriuretic (-38% vs. control) responses to furosemide were significantly impaired. However, the increased natriuretic efficiency of furosemide was still present (+34% vs. control). Together these results suggest that increased sodium reabsorption in the thick ascending limb of Henle's loop is involved in the renal sodium retention in cirrhosis in rats that eventually results in decompensation with the formation of ascites.

Synthesis of conformationally restricted dinucleotides by ring-closing metathesis.

[reaction:see text] The ring-closing metathesis reaction has been used in the synthesis of conformationally restricted dinucleotides as well as a 3'-nucleotide analogue. From bis-allylic nucleoside phosphates obtained from simple nucleoside precursors, the synthesis of unsaturated cyclophosphates has been accomplished using either Grubbs' catalyst or an improved analogue. Hereby, the conformational freedom of the nucleic acid phosphordiester linkage has been efficiently constrained.

Geographic assessment of breast cancer screening by towns, zip codes, and census tracts.

Early detection is the primary way to control breast cancer, and mammography screening can reduce breast cancer mortality 30 to 40 percent among women aged 50 years and older. Geographic areas with a high proportion of cases with late-stage diagnoses may reflect gaps in screening efforts. We used a spatial scan statistic, adjusting for the multitude of possible region locations and sizes, to test whether any particular region of Massachusetts had statistically significant excesses of late-stage diagnoses during the period 1982 to 1986. The novel geographic analysis technique utilized here can also be used in the control of other types of cancer.

Effects of chronic octreotide treatment on renal changes during cirrhosis in rats.

We examined the effect of a new long-acting release formula (LAR) of the somatostatin analogue, octreotide, on development of sodium retention and functional and structural changes in the thick ascending limb of Henle's loop (TAL) in rats with cirrhosis induced by common bile duct ligation (CBL). CBL and sham-operated control rats were treated with octreotide-LAR (10 mg/kg body weight subcutaneously, as a single dose) or vehicle at the time of CBL or sham-CBL. The rats were instrumented with chronic catheters, and sodium balance and renal function were examined 4 weeks after CBL or sham operation. Octreotide-LAR treatment significantly inhibited sodium retention in CBL rats and prevented renal vasodilatation without changes in glomerular filtration rate (GFR). The natriuretic response to a test dose of furosemide (7.5 mg/kg body weight intravenously) was significantly increased in CBL rats, and when expressed in terms of natriuretic efficiency (mmol Na/mg furosemide in urine), the natriuretic response was increased by 57% relative to sham-operated controls. Stereological examination of kidneys demonstrated a 53% increase in the volume of the inner stripe of the outer medulla and a 108% increase in the volume of TAL epithelium in cirrhotic rats relative to controls. The increased natriuretic efficiency of furosemide as well as the hypertrophy of the inner stripe and the TAL in this renal zone were absent in CBL rats treated with octreotide-LAR. These results suggest that octreotide-LAR treatment inhibits sodium retention in cirrhotic rats, partly by inhibition of increased furosemide-sensitive sodium reabsorption in the TAL.

Cyclodextrin inclusion complexes of miconazole and econazole--isolation, toxicity on human cells, and confirmation of a new interpretation of the drug supersaturation phenomenon.

Parameters that influence the precipitation of the beta-cyclodextrin (beta-CD) inclusion complexes of the antimycotics miconazole and econazole were investigated. The mechanistic reason for the superior antimycotic activity of the miconazole inclusion complex was studied. The toxicity of the complex was estimated. The temperature, the buffer strength, and the effect of the addition of hydrotropic agents on the CD solubility diagrams for the antimycotics were estimated. The miconazole and the CD dissolution rate for the complex was measured. The hemolytic activity of the miconazole inclusion complex, the physical mixture, miconazole, and the nitrate salt were compared. The toxicity on TR146 oral cell layers was measured. Lowering the temperature meant that both complexes precipitated at lower CD concentrations. Addition of hydrotropic agents and variation of the buffer strength affected the solubility diagrams. The dissolution medium was supersaturated with miconazole. The supersaturation was not disclosed by the traditional method to analyze for drug supersaturation. The miconazole complex was more toxic to erythrocytes than the physical mixture. On the other hand, the toxic effects of the two products on the TR146 cell layers were similar. Lowering the temperature eased the isolation of genuine CD inclusion complexes of miconazole and econazole. The miconazole supersaturation is likely to be the reason for the superior antimycotic activity of the complex. The complex and the physical mixture had about the same toxicity on TR146 cell layers.

Aldosterone receptor blockade inhibits increased furosemide-sensitive sodium reabsorption in rats with liver cirrhosis.

We examined the role of chronic aldosterone receptor blockade on the altered furosemide-sensitive sodium reabsorption in rats with liver cirrhosis induced by common bile duct ligation. CBL and sham-operated control animals were treated with the aldosterone receptor antagonist canrenoate (20 mg/day i.v.) for 4 weeks. Untreated CBL and sham-CBL served as control groups. The plasma concentration of aldosterone was within the normal range in all groups. Sodium balance studies showed that aldosterone receptor blockade prevented sodium retention in cirrhotic rats. Clearance studies showed that the glomerular filtration rate was unchanged, whereas the renal plasma flow was increased in CBL rats. A test dose of furosemide (7.5 mg/kg b.wt. i.v.) produced significantly greater diuretic (+59%) and natriuretic (+56%) responses in CBL rats than in sham-operated controls. The urinary furosemide excretion rate (UFURV) reflects delivery of furosemide to the thick ascending limb. When the natriuresis was expressed relative to UFURV (i.e., the natriuretic efficiency), we found that natriuretic efficiency of furosemide was significantly increased in untreated CBL rats (+59%). However, the natriuretic efficiency of furosemide was normalized in CBL rats treated with canrenoate. The urinary excretion of furosemide was unchanged in untreated CBL rats, but it was significantly increased in cirrhotic rats treated with canrenoate (+43%). This suggests that in CBL rats, chronic canrenoate treatment increases the renal elimination of furosemide as a consequence of reduced metabolism. These data suggest that chronic aldosterone receptor blockade with canrenoate prevents sodium retention in cirrhotic rats partly by inhibition of increased sodium reabsorption in the thick ascending limb.

[Teratogenic effects of ACE-inhibitors and angiotensin II receptor antagonists]. / Fosterskadelige virkninger af ACE-haemmere og angiotensin II-receptorantagonister.

Since the introduction of angiotensin converting enzyme-inhibitors (ACE-inhibitors) in the 1980's, more than 50 cases of foetotoxic effects ascribed to intrauterine exposure to inhibitors have been published. Among the most commonly reported effects are: Hypotension, renal dysplasia, anuria/oliguria, oligohydramios, intrauterine growth retardation, pulmonary hypoplasia, unclosed ductus arteriosus, incomplete ossification of the skull, intrauterine og neonatal death. Recent animal studies have confirmed that intrauterine or neonatal exposure to ACE-inhibitors or the AT1-receptor antagonist losartan can cause death and serious, irreversible organ damage. These effects are similar to the complications previously reported in humans. Animal studies suggest that the foetotoxic actions are most common after exposure during the last trimester. However, due to the severity of these complications, the use of ACE-inhibitors and AT1-receptor antagonists should be avoided throughout pregnancy and in women who are breast feeding.

HIV-infected individuals with the CCR delta32/CCR5 genotype have lower HIV RNA levels and higher CD4 cell counts in the early years of the infection than do patients with the wild type. Copenhagen AIDS Cohort Study Group.

The relations among serum HIV RNA levels, CD4 cell counts, presence of the mutant CCR5-allele in heterozygous form, and clinical outcome was analyzed in 96 patients from the Copenhagen AIDS Cohort. In the early years of the infection, patients with the CCR5 delta32/CCR5 genotype had significantly lower HIV RNA levels (p = 0.005) and higher CD4 cell counts (p < 0.005) than did patients homozygous for the normal allele. The long-term clinical benefit of being heterozygous is small and cannot solely explain the large interpatient variation in progression rates. The beneficial effect of being heterozygous seems to be mediated by events in the early stages of the HIV infection.

Cardiovascular actions of chronic intracerebroventricular administration of metformin in normotensive rats.

Acute intracerebroventricular administration of the antihyperglycaemic agent metformin (0.25-1 mg) elicits sympathoinhibitory responses in spontaneously hypertensive rats. However, cardiovascular actions of chronic intracerebroventricular metformin administration are unknown. To define the dose-response relationship during chronic intracerebroventricular metformin administration, mean arterial pressure, heart rate, and locomotor activity were measured continuously by radiotelemetry in 40 normotensive rats. After a 10 day control period, an intracerebroventricular cannula was implanted and connected to an osmotic minipump which delivered metformin in the following doses: 0 [saline]. 0.01, 0.1, 1, and 10 mg/day. LD50 was 1.5 mg/day. Metformin, 1 mg/day attenuated the nocturnal, physiological increase in mean arterial pressure (-7.3 +/- 1.6% versus before metformin), produced behavioural changes and tended to increase locomotor activity. Lower doses of intracerebroventricular metformin (0.1 and 0.01 mg/day) did not affect mean arterial pressure, heart rate or locomotor activity. In conclusion, chronic intracerebroventricular administration of high dose metformin (1.0 mg/day) attenuates the nocturnal, physiological increase in mean arterial pressure. These findings are compatible with a toxic, sympathoinhibitory action of high doses of metformin intracerebroventricularly.