Palms of the past: can morphometric phytolith analysis inform deep time evolution and palaeoecology of Arecaceae?

BACKGROUND AND AIMS: Palm fossils are often used as evidence for warm and wet palaeoenvironments, reflecting the affinities of most modern palms. However, several extant palm lineages tolerate cool and/or arid climates, making a clear understanding of the taxonomic composition of ancient palm communities important for reliable palaeoenvironmental inference. However, taxonomically identifiable palm fossils are rare and often confined to specific facies. Although the resolution of taxonomic information they provide remains unclear, phytoliths (microscopic silica bodies) provide a possible solution because of their high preservation potential under conditions where other plant fossils are scarce. We thus evaluate the taxonomic and palaeoenvironmental utility of palm phytoliths. METHODS: We quantified phytolith morphology of 97 modern palm and other monocot species. Using this dataset, we tested the ability of five common discriminant methods to identify nine major palm clades. We then compiled a dataset of species' climate preferences and tested if they were correlated with phytolith morphology using a phylogenetic comparative approach. Finally, we reconstructed palm communities and palaeoenvironmental conditions at six fossil sites. KEY RESULTS: Best-performing models correctly identified phytoliths to their clade of origin only 59 % of the time. Although palms were generally distinguished from non-palms, few palm clades were highly distinct, and phytolith morphology was weakly correlated with species' environmental preferences. Reconstructions at all fossil sites suggested that palm communities were dominated by Trachycarpeae and Areceae, with warm, equable climates and high, potentially seasonal rainfall. However, fossil site reconstructions had high uncertainty and often conflicted with other climate proxies. CONCLUSIONS: While phytolith morphology provides some distinction among palm clades, caution is warranted. Unlike prior spatially restricted studies, our geographically and phylogenetically broad study indicates phytolith morphology may not reliably differentiate most palm taxa in deep time. Nevertheless, it reveals distinct clades, including some likely to be palaeoenvironmentally informative.

Selective intraoperative cholangiography and risk of bile duct injury during cholecystectomy.

BACKGROUND: Whether intraoperative cholangiography can prevent iatrogenic bile duct injury during cholecystectomy remains controversial. METHODS: Data from the national Swedish Registry for Gallstone Surgery, GallRiks (May 2005 to December 2010), were analysed for evidence of iatrogenic bile duct injury during cholecystectomy. Patient- and procedure-related risk factors for bile duct injury with a focus on the rate of intended intraoperative cholangiography were analysed using multivariable logistic regression. RESULTS: A total of 51 041 cholecystectomies and 747 bile duct injuries (1·5 per cent) were identified; 9008 patients (17·6 per cent) were diagnosed with acute cholecystitis. No preventive effect of intraoperative cholangiography was seen in uncomplicated gallstone disease (odds ratio (OR) 0·97, 95 per cent c.i. 0·74 to 1·25). Operating in the presence (OR 1·23, 1·03 to 1·47) or a history (OR 1·34, 1·10 to 1·64) of acute cholecystitis, and open surgery (OR 1·56, 1·26 to 1·94), were identified as significant risk factors for bile duct injury. The intention to perform intraoperative cholangiography was associated with a reduced risk of bile duct injury in patients with concurrent (OR 0·44, 0·30 to 0·63) or a history of (OR 0·59, 0·35 to 1·00) acute cholecystitis. CONCLUSION: Any proposed protective effect of intraoperative cholangiography was restricted to patients with (or a history of) acute cholecystitis.

Prognostic impact of inter-metastatic heterogeneity of viable tumour cells in colorectal liver metastases.

BACKGROUND: Heterogenous response to neoadjuvant chemotherapy in patients with multiple colorectal liver metastases (CRLM) has been associated with an acquired resistance to systemic therapy. This study evaluated the occurrence of a heterogenous inter-metastatic tumour response with regards to the proportion of viable tumour cells, and its prognostic impact. METHODS: A retrospective cohort study was conducted, including all patients with CRLM surgically treated at Karolinska University Hospital, Stockholm, Sweden, from 2013 to 2018. Factors associated with the proportion of viable tumour cells and inter-metastatic heterogeneity were analysed with regression and survival analyses. RESULTS: Out of 640 surgically treated patients, 405 patients (1357 CRLM), received neoadjuvant chemotherapy. Multiple CRLM were present in 314 patients (78%), out of whom 72 patients (23%) presented with a heterogenous tumour response. The median overall survival (OS) for patients with a heterogenous inter-metastatic tumour response was 36 months, compared to 57 months for patients with a homogenous inter-metastatic tumour response (p < .001). Poor OS in patients receiving preoperative chemotherapy was significantly associated with a heterogenous inter-metastatic tumour response (hazard ratio (HR) 1.68 (1.02-2.78)), right-sided primary tumour (HR 2.01 (1.29-3.43)) and CRLM diameter >5 cm (HR 1.83 (1.06-3.17)). CONCLUSION: Outcome in patients with a heterogenous inter-metastatic tumour response, illustrated by the proportion of viable tumour cells, is inferior to that of patients with a homogenous response. These results suggest that heterogeneity in treatment response is an important marker of aggressive disease and could be of clinical value for decisions on post-operative therapy.

Nationwide study of the treatment of common bile duct stones in Sweden between 1965 and 2009.

BACKGROUND: Treatment of common bile duct stones has changed. Open surgery has gradually been replaced by endoscopic and laparoscopic procedures. The aims of this study were to see how common bile duct stones have been treated in Sweden, to establish whether there were differences in morbidity and mortality between these approaches, and to identify factors influencing mortality. METHODS: All persons undergoing inpatient common bile duct exploration or endoscopic retrograde cholangiopancreatography (ERCP) during 1965-2009 in the Swedish Hospital Discharge Registry, but without a diagnosis of malignancy in the Swedish Cancer Registry, were included. The outcome death was identified by cross-linkage to the Causes of Death Registry. Registry data on possible risk factors for mortality were collected. RESULTS: A total of 126 885 procedures were performed in 110 119 patients. Open surgery was initially the only available method, but during the 1990s ERCP became predominant. Later, laparoscopic bile duct clearance became an established but uncommon method. A 90-day mortality rate of 0·2 per cent after open surgery, 0·8 per cent after ERCP, 0 per cent after laparoscopic exploration and 0·7 per cent after combined procedures was recorded. After adjustment for confounding, there was no difference in mortality between open surgery and ERCP. Biliary reintervention within 90 days was identified as a risk factor for death, whereas a concomitant diagnosis of pancreatitis reduced the risk. CONCLUSION: The laparoscopic technique had the lowest mortality and morbidity rates. After adjustment for confounding factors, there was no difference in mortality after open surgery and ERCP. The favourable outcome for laparoscopy may have been due to selection bias, owing to treatment of younger, healthier subjects with less severe disease.

Treatment patterns and survival in patients with hepatocellular carcinoma in the Swedish national registry SweLiv.

BACKGROUND: Consistent data on clinical features, treatment modalities and long-term survival in patients with hepatocellular carcinoma (HCC) using nationwide quality registers are lacking. This study aimed to describe treatment patterns and survival outcomes in patients diagnosed with HCC using a national maintained database. METHODS: Characteristics and treatment patterns in patients diagnosed with HCC and registered in the national register of liver and bile duct tumours (SweLiv) between 2009 and 2016 were reviewed. Overall survival (OS) was estimated using Kaplan-Meier analysis and the log rank test to compare subgroups for clinical features, treatment modalities and outcomes according to the year of treatment. RESULTS: A total of 3376 patients with HCC were registered over 8 years, 246 (7·3 per cent) of whom underwent transplantation. Some 501 (14·8 per cent) and 390 patients (11·6 per cent) had resection and ablation as primary treatment. Transarterial chemoembolization and systemic sorafenib treatment were intended in 476 (14·1 per cent) and 426 patients (12·6 per cent) respectively; the remaining 1337 (39·6 per cent) were registered but referred for best supportive care (BSC). The 5-year survival rate was approximately 75 per cent in the transplantation group. Median OS was 4·6 (i.q.r. 2·0 to not reached) years after resection and 3·1 (2·3-6·7) years following ablation. In patients referred for palliative treatment, median survival was 1·4 (0·8-2·9), 0·5 (0·3-1·2) and 0·3 (0·1-1·0) years for the TACE, sorafenib and BSC groups respectively (P < 0·001). Median survival was 0·9 years for the total HCC cohort in 2009-2012, before publication of the Swedish national treatment programme, increasing to 1·4 years in 2013-2016 (P < 0·001). CONCLUSION: The survival outcomes reported were in line with previous results from smaller cohorts. The introduction of national guidelines may have contributed to improved survival among patients with HCC in Sweden.

ANTECEDENTES: Se carece datos consistentes acerca de las características clínicas, modalidades terapéuticas y supervivencia a largo plazo en pacientes con carcinoma hepatocelular (hepatocellular carcinoma, HCC) basados en registros de calidad de ámbito nacional. El objetivo de este estudio fue describir los patrones de tratamiento y los resultados de supervivencia en pacientes diagnosticados de HCC usando una base de datos nacional. MÉTODOS: Se revisaron las características de los pacientes y los patrones de tratamiento en pacientes con un diagnóstico de HCC incluidos en el registro nacional de tumores de hígado y vías biliares (SweLiv) entre 2009 y 2016. La supervivencia global (overall sirvival, OS) se analizó mediante el método de Kaplan-Meier y test de log-rank para la comparación de subgrupos según las características clínicas de los pacientes, las modalidades de tratamiento y los resultados en función del año de tratamiento. RESULTADOS: Durante un periodo de 7 años, se incluyeron en el registro un total de 3.076 pacientes con HCC, 246 de los cuales recibieron un trasplante (7,2%). Se practicó resección y ablación como tratamiento primerio en 501 (14,8%) y 390 (11,6%) pacientes, respectivamente. La quimioembolización (TACE) y el tratamiento sistémico con sorafenib se efectuó en 476 (14,1%) y 426 (12,6%) pacientes, respectivamente; los 1.337 pacientes restantes (40,0%) fueron incluidos en la base de datos pero se derivaron para recibir el mejor tratamiento de soporte. La tasa de supervivencia a los 5 años fue del 75% en el grupo trasplantado. La mediana de OS fue de 4,6 años (rango intercuartílico, interquartile range, IQR 2,0-no alcanzado) tras la resección y de 3,1 años (IQR 2,3-6,7) tras la ablación. En los pacientes derivados para tratamiento paliativo, la mediana de supervivencia fue de 1,4 años (IQR 0,8-2,9), 0,5 años (IQR 0,2-1,2) y 0,3 años (IQR 0,1-1,0) para los grupos de TACE, sorafenib y mejor tratamiento de soporte, respectivamente (P < 0,001). La mediana de supervivencia para toda la cohorte de HCC en 2009-2012 fue de 0,9 años antes de la publicación del programa de nacional de tratamiento sueco, aumentando a 1,4 años en 2013-2016 (P <0,001). CONCLUSIÓN: Los resultados de supervivencia referidos eran consistentes con resultados previos obtenidos en cohortes más pequeñas; la introducción de guías nacionales puede haber contribuido a mejorar la supervivencia de los pacientes con HCC en Suecia.

Balloon angioplasty enhances the expression of angiotensin II AT1 receptors in neointima of rat aorta.

Angiotensin II is a vasoactive peptide and may act as a growth factor in vascular smooth muscle cells. Experimental injury of the rat aorta causes rapid migration of medial smooth muscle cells and their proliferation resulting in the formation of neointima. We have examined, using quantitative autoradiography, the expression of angiotensin II receptor subtypes AT1 and AT2, and angiotensin-converting enzyme, in the neointima formed in the rat thoracic aorta 15 d after balloon-catheter injury. In contrast to the normal aortic wall, which contained both AT1 and AT2 receptors (80% and 20%, respectively), neointimal cells expressed almost exclusively angiotensin II AT1 receptors. The apparent number of these receptors was fourfold higher in the neointima compared to that in the normal aortic wall. The affinities of the neointimal receptors to angiotensin II or to the AT1 receptor antagonist, losartan, were not different from those in the normal aortic wall. Angiotensin-converting enzyme binding in the neointima was not different from that in the media of the uninjured aorta. Our data suggest that angiotensin II AT1 receptors may have a significant role in injury-induced vascular smooth muscle proliferation and migration.

Angiotensin-II receptor subtypes in fetal tissue of the rat: autoradiography, guanine nucleotide sensitivity, and association with phosphoinositide hydrolysis.

Quantitative autoradiography revealed large numbers of angiotensin-II (AT) receptors in the 18-day-old rat embryo. The selective AT-1 antagonist DuP 753 readily competed for AT receptors in liver, lung parenchyma, and choroid plexus, and these receptors are classified as AT-1 receptors. The selective AT-2 displacers CGP 42112 A and/or PD 123177 competed with high affinity with AT bound to most receptors located in skeletal muscle, skin, diaphragm, bronchi, and stomach, and these receptors are classified as AT-2 receptors. The amount of AT-2 receptors in fetal tissue was more than 10-fold higher than that of AT-1 receptors. In skeletal muscle and skin, DuP 753 competed with AT in the presence of 10(-7) M CGP 42112 A, indicating the presence of small numbers of AT-1 receptors. In liver and lung parenchyma, binding to AT-1 receptors was sensitive to guanine nucleotides. AT binding to AT-2 receptors in fetal skin and skeletal muscle was insensitive to guanine nucleotides. AT stimulated phosphoinositide hydrolysis in liver (ED50, 64 nM) and in skin and skeletal muscle (ED50, 62 nM); this was inhibited by DuP 753 (liver IC50, 38 nM; skin and skeletal muscle IC50, 26 nM), but not by PD 123177 in concentrations up to the micromolar range. AT-1 receptors are probably coupled to G-proteins, and their stimulation increases phosphoinositide hydrolysis. AT-2 receptors may not be linked to G-proteins, their stimulation is not associated with phosphoinositide hydrolysis, and the nature of their second messenger system(s) is presently unknown.

Nonpeptide angiotensin AT1 and AT2 receptor ligands modulate the upper limit of cerebral blood flow autoregulation in rats.

We investigated the effect of angiotensin AT1 and AT2 receptor blockade on the upper limit of CBF autoregulation in pentobarbital-anesthetized rats. CBF was measured by laser-Doppler flowmetry from the parietal cortex and MABP was increased by intravenous phenylephrine infusion. Neither the AT1 antagonist losartan nor the AT2 ligand PD 123319 nor angiotensin II (ANG II) in the presence of losartan affected baseline CBF. When the blood pressure was increased in the control group, CBF remained fairly constant up to 145 mm Hg and increased steeply after 150 mm Hg. Both PD 123319 (7-10 mg/kg) and losartan (1-10 mg/kg) shifted the upper limit of CBF autoregulation toward higher pressures. Intravenous infusion of PD 123319 was more effective than bolus injection. The losartan effect was dose dependent. Selective stimulation of AT2 receptors with an intravenous ANG II infusion (0.54 micrograms/min) in the presence of losartan did not reverse the effect of losartan on CBF autoregulation, but, on the contrary, appeared to further shift the upper limit of autoregulation toward higher pressures. The results implicate a role for both AT1 and AT2 angiotensin receptors in the regulation of CBF.

Angiotensin IV reverses the acute cerebral blood flow reduction after experimental subarachnoid hemorrhage in the rat.

The effect of angiotensin (ANG) IV on CBF after experimental subarachnoid hemorrhage (SAH) was studied in rats using laser-Doppler flowmetry. ANG IV (1 microgram/kg/min i.v.) or saline treatments were started 20 min after SAH. ANG IV increased CBF (from 45 to 84% of baseline) by 60 min. In the saline group, CBF remained low (51%). Pretreatment with the specific ANG II antagonist Sar1, Ile8-ANG II did not antagonize ANG IV. Determination of nitric oxide synthase (NOS) activity in vitro or inhibition of NOS in vivo did not support a role for NO in the action of ANG IV.

Angiotensin II AT2 receptor stimulation extends the upper limit of cerebral blood flow autoregulation: agonist effects of CGP 42112 and PD 123319.

The effects of the angiotensin II AT2 receptor ligands CGP 42112 and PD 123319, the AT1 antagonist losartan, and the nonselective angiotensin II antagonist Sar1,Ile8-angiotensin II on the upper limit of CBF autoregulation were studied in pentobarbital-anesthetized rats. Blood pressure was increased by intravenous phenylephrine infusion, while CBF was measured continuously from the parietal cortex by laser-Doppler flowmetry. Intravenous infusions of CGP 42112 (0.1 and 1 mg kg-1 min-1) and PD 123319 (0.36 and 1 mg kg-1 min-1) shifted the upper limit of CBF autoregulation toward higher blood pressures without affecting baseline CBF. Sar1,Ile8-angiotensin II (4 micrograms kg-1 min-1) had no effect on baseline CBF or CBF autoregulation but antagonized the effect of CGP 42112 and PD 123319. Losartan (10 mg/kg i.v. bolus) reduced baseline blood pressure and CBF and shifted the autoregulation curve toward higher blood pressures. Sar1,Ile8-angiotensin II blocked the effect of losartan on baseline CBF but not on CBF autoregulation. These results suggest that both CGP 42112 and PD 123319 exert their effects on CBF autoregulation through stimulation of angiotensin II AT2 receptors. The mechanism by which losartan affects CBF remains unclear.

Exercise alters the pharmacokinetics of midazolam.

Six healthy volunteers received 15 mg midazolam, 50 mg ephedrine, or placebo orally before a 50-minute aerobic treadmill exercise and in a control session. Plasma drug concentrations for pharmacokinetic calculations were estimated from samples drawn up to 24 hours after drug intake. Heart rate, blood pressure, critical flicker fusion test, Maddox wing test, and visual analog scales relating to mood and feelings of tiredness were included in the sessions as pharmacodynamic measures. These tests were made at 35, 55, and 75 minutes and at 2, 2 1/2, 3 1/2, and 5 hours after drug intake. Exercise impaired the absorption of midazolam and counteracted the midazolam-induced decrement in flicker fusion threshold. Whether the effect on flicker fusion was caused mainly by the pharmacokinetic changes or by a general alerting effect of exercise cannot be verified by this experiment. The kinetics of ephedrine was not affected by exercise, but exercise enhanced the tachycardic response to ephedrine and abolished its pressor effect.

Angiotensin AT2 receptors regulate cerebral blood flow in rats.

LARGE cerebral arteries have been reported to contain angiotensin receptors that are exclusively of the AT2 subtype. We measured the effect of the AT2 receptor selective ligand PD 123319 on cerebral blood flow (CBF) in rats, using laser-doppler flowmetry. PD 123319 (1-10 mg kg-1) dose-dependently inhibited the increase in CBF, when the blood pressure was increased by a norepinephrine infusion. However, PD 123319 did not alter baseline CBF at normal blood pressures. Therefore PD 123319 appears to interfere with the autoregulatory mechanisms of CBF. The participation of AT2 receptors in the regulation of CBF confirms a physiological role for this receptor subtype, and may give clues for future treatment of various cerebrovascular disorders.

Angiotensin II AT1 receptor mediated contraction of the perfused rat cerebral artery.

The effect of angiotensin II on rat cerebral arteries was studied using isolated, perfused segments of anterior cerebral arteries. The infusion rate was set to maintain baseline intraluminal pressure at 75 mmHg. Angiotensin II (100 nM) increased the intraluminal pressure by 22.5 +/- 2.2 mmHg. Losartan, an AT1 antagonist, at 1 microM, completely blocked the effect of angiotensin II, whereas the AT2 ligands PD 123319 (1 microM) and CGP 42112 (1 microM) were ineffective. None of these AT1 or AT2 selective ligands alone displayed any agonist effects. The results show that angiotensin II induces contraction of the rat anterior cerebral artery by acting on AT1 receptors.

Characterization of angiotensin II receptor subtypes in the rat spleen.

Quantitative autoradiography was used to determine the subtype of ANG receptors in the red pulp of the rat spleen. The AT1 antagonist DuP 753 competed for ANG binding with high affinity; binding was abolished by dithiothreitol. The AT2 competitor CGP 42112 A showed lower affinity, and the AT2 competitor PD 123177 did not affect binding at 10(-5) M. These data indicated the presence of only AT1 receptors. AT1 receptor number was similar in immature (2 weeks old) and adult (8 weeks old) rats. Binding was sensitive to guanine nucleotides, suggesting an association with G-proteins. Angiotensin II, at a dose of 10(-7) M, stimulated inositol phosphate formation 33% over control values in spleen from 8-week-old rats. This effect was significantly blocked by 10(-5) M DuP 753. We suggest a possible role of AT1 receptors in the regulation of splenic volume, blood flow, and lymphocyte function.

Angiotensin II AT2 receptor stimulation increases cerebrovascular resistance during hemorrhagic hypotension in rats.

The effects of the angiotensin II (ANG II) AT2 ligand PD 123319 and the AT1 antagonist losartan on cerebral blood flow (CBF) were studied during hemorrhagic hypotension in anesthetized rats using laser-Doppler flowmetry. In the control group CBF remained stable when mean arterial blood pressure (MABP) was lowered from 84 mmHg (baseline) to 45 mmHg, whereafter there was a pressure dependent decrease in CBF indicating inadequacy of autoregulation. Cerebrovascular resistance (CVR) was reduced until MABP 40 mmHg, where a maximum dilation was reached. PD 123319 dose-dependently (3-30 mg/kg i.v.) increased CVR through all blood pressures. Losartan 3 mg/kg i.v. had an effect similar to PD 123319. Selective stimulation of AT2 receptors with intravenous ANG II infusion, in the presence of AT1 receptor blockade by losartan, also increased CVR. As a result, reduced CBF was seen in the treatment groups. The effects of ANG II and PD 123319 30 mg/kg were antagonized by the nonselective ANG II antagonist Sar1,Ile8-ANG II (4 micrograms/kg/min i.v.). None of the treatments affected baseline CBF. The results confirm that ANG II contributes to cerebrovascular resistance and participates in the regulation of CBF apparently through AT2 receptors.

Hyperglycemia produced in mice by administration of acetazolamide and diphenylhydantoin.

Isolated mouse islets exposed to 3mM glucose released an increased amount of insulin in the presence of acetazolamide (AZM) (10 mM) and diphenylhydantoin (DPH) (0.35 or 3.5 mM), whereas insulin secretion due to 20 mM glucose was decreased in the presence of AZM (10 mM) and DPH (0.35, 0.70 or 3.5 mM). The serum insulin concentration was increased 1 h after AZM injection, but was not significantly altered 1 h after combined administration of AZM and DPH. A moderate transient hyperglycemia was found 1 and 2 h after DPH injection (100 mg/kg b.w.) in fed mice, and a slight, transient hyperglycemic response was observed 24 h after administration of AZM (1.5 g/kg b.w.) to fed mice. A steadily increasing, marked hyperglycemia was seen in both fed and starved mice when AZM was given shortly before or after DPH. All animals subjected to this kind of treatment died within 48 h after the injections. Ketones were found in urine and serum of the hyperglycemic animals, and the hyperglycemia was abolished and the survival of the animals was prolonged by insulin administration, suggesting that ketoacidosis contributed to the death. Light microscopy disclosed degeneration and necrosis of some B-cells, and occasionally insulitis after combined treatment with AZM and DPH. Pretreatment with AZM inhibited the hyperglycemic response to p-hydroxymercuribenzoate in fed mice, but did not affect the hyperglycemic response of fed mice to D-mannoheptulose. The findings indicate that AZM and DPH, when given to mice in combination and in sufficient amount, cause impaired B-cell function with an inhibited glucose-induced insulin release and a severe, fatal hyperglycemia. The B-cell changes are believed to be due to intracellular ionic alterations.

Type-1 and type-2 angiotensin II receptors in fetal rat brain.

Brain angiotensin II receptors were located in 18-day-old rat embryos by quantitative autoradiography. In the nucleus of the solitary tract and choroid plexus, binding was displaced by the type-1 antagonist DuP 753. In the inferior olive, paratrigeminal and hypoglossal nuclei, binding was displaced by the type-2 antagonist CGP 42112 A. Meninges and cephalic soft tissues contained predominantly type-2 angiotensin II receptors. Our results indicate a role for type-1 and type-2 angiotensin II receptors during brain development.

Angiotensin II AT1 receptors in rat superior cervical ganglia: characterization and stimulation of phosphoinositide hydrolysis.

Angiotensin II receptor number was higher in superior cervical ganglia of 2-week-old when compared to 8-week-old rats. In both young and adult rats, specific binding of [125I][Sar1]angiotensin II was displaced competitively by the AT1-receptor antagonist DuP 753 but not by the AT2-receptor competitor PD 123177. In ganglia from adult rats, DuP 753 competed with an IC50 of 113 nM. The stable guanine nucleotide GTP gamma S inhibited binding of [125I][Sar1]angiotensin II in young and adult rats by approximately 50% with IC50 values of 105 and 120 nM, respectively, suggesting that the angiotensin receptor is G-protein linked. Angiotensin II at a dose of 1 microM stimulated inositol phosphate formation 58% over control values in superior cervical ganglia from 8-week-old rats. This effect was totally blocked by 10 microM DuP 753 but not by 10 microM PD 123177. Our findings demonstrate that rat superior cervical ganglia contain AT1-type angiotensin receptors that are probably G-protein linked, and their stimulation results in increased inositol phospholipid metabolism.

Angiotensin II receptor subtypes and phosphoinositide hydrolysis in rat adrenal medulla.

Angiotensin II (ANG) receptor subtypes were characterized by quantitative autoradiography after incubation with the ANG agonist [124I]Sar1-ANG in rat adrenal medulla. ANG receptors are highly localized in adrenal medulla. Specific binding was displaced by 4% and by 95% with the AT, receptor blocker losartan and the AT2 receptor competitor CGP 42112A, respectively. Analysis of competition curves indicated relative binding potencies for the AT2 population of CGP 42112A>PD 123319> PD 123177. ANG stimulated +-nositol phosphate formation in a dose-dependent manner in rat adrenal medulla. Losartan at concentrations of 10(-9) to 10(-5) M antagonized the effect of ANG, whereas PD 123177 or PD 123319 had no antagonistic action. However, at a higher concentration (10(-5) M) PD 123177 or PD 123319 potentiated the effect of ANG on InsP1-accumulation. In the presence of PD 123319 (10(-5) M) ANG dose-response curve was shifted to the left with no change in the maximal effect. This affect was blocked by the addition of losartan (10(-5) M). On the contrary, the addition of CGP 42112A (10(-6) M) inhibited ANG-induced increase in InsP1-accumulation. On the other hand, ANG and CGP 42112A reduced basal cyclic GMP formation, this effect was partially reverted by sodium orthovanadate, a phosphotyrosine phosphatase inhibitor. Our results further demonstrate the presence of two ANG receptor subtypes in adrenal medulla: ANG binding to AT, receptor stimulates inositol phospholipid metabolism, whereas ANG binding to AT2 receptors decreases both inositol phosphate production and cGMP formation.

Ethanol antagonism by atipamezole on motor performance in mice.

The interactions of an alpha 2-adrenoceptor antagonist, atipamezole, and an alpha 2-adrenoceptor agonist, dexmedetomidine, with ethanol were studied in male NIH Swiss mice. The mice were given (i.p.) atipamezole 0.1, 0.3, 1, 3 and 10 mg/kg and dexmedetomidine 0.01, 0.03, 0.1, 0.3, 1, 3 and 10 mg/kg; the ethanol doses were 1, 2 or 3 g/kg. Motor performance was measured by spontaneous locomotor activity and rotarod test. Dexmedetomidine impaired performance in both tests. The effect of dexmedetomidine peaked at the dose of 1 mg/kg. Three mg/kg of atipamezole abolished totally the effects of 0.3 mg/kg of dexmedetomidine and partially those of 1 mg/kg of dexmedetomidine. Atipamezole counteracted and dexmedetomidine enchanced ethanol effects in both tests. The interactions were not of pharmacokinetic origin since blood and brain ethanol and dexmedetomidine levels were unaltered at the time of testing. The results suggest that ethanol effects on motor performance in mice are mediated in part via central noradrenergic mechanisms, and blockade of alpha 2-adrenoceptors by atipamezole leads to considerable antagonism of these ethanol effects.