The effect of indomethacin on cerebral blood flow and oxygen consumption in the rat at normal and increased carbon dioxide tensions

The effect of the fatty acid cyclo-oxygenase inhibitor indomethacin on cerebral blood flow (CBF) and the metabolic rate for oxygen (CMRO₂) was studied in paralyzed and artificially ventilated rats. In normocapnic animals, the drug (10 mg·kg^-1i. v.) reduced CBF to 50% of control without a measurable effect on CMRO₂. During hypercapnia (Pa_CO2 70–80 mmHg) the increase in CBF was reduced by about 80% but CMRO₂ remained unchanged. Autoradiographic evaluation of local CBF in 20 brain structures indicated that the reduction in CBF was relatively uniform throughout the brain. Dose response curves showed that an effect on CBF was evident already at an indomethacin dose of 1 mg·kg^-1 and maximal effects were obtained with 3–5 mg·kg^-1. Following i. v. injection of the drug reduction in CBF was observed already after 10 s and the full response occurred after 1–2 min. It is concluded that metabolites of arachidonic acid, possibly mainly prostacyclin, are powerful modulators of normal cerebrovascular tone, and help to mediate the CBF response to increased CO₂ tensions. However, since indomethacin does not modify the circulatory response in other conditions with increased CBF these substances do not qualify as general coupling factors controlling CBF in physiological or pathological states.     

A Comparative Study Between Laparoscopic Findings and Histological Stages in Primary Biliary Cirrhosis

Abstract: Histopathologically, early lesions of primary biliary cirrhosis (PBC) are focal within the liver and there is segmental involvement of the bile ducts. In addition, the development of PBC is variable within the liver. PBC is characterized by the following laparoscopic findings: reddish patch, mesh-like white marking and gentle undulation, etc. In the present study, we analyzed the correlation between the laparoscopic findings and the histological stage as per Scheuer's classification in 22 patients with PBC. The results of this study are summarized as follows: 1) Reddish patch was frequently observed in the early stage of PBC. 2) Mesh-like white marking was observed in cases of stage I, II and III. 3) Gentle undulation was seen in stage II and III. The absence of this finding is useful in the diagnosis of stage I. 4) In stage IV, these three findings were not observed. 5) From these three findings, it was difficult to differentiate stage II or III. But the presence of portal hypertension and increased vascularity of the liver capsule were observed in accordance with the progression of the disease. Indications of portal hypertension were seen even in the early stage and in some asymptomatic cases of PBC. In conclusion, the laparoscopic findings such as reddish patch, mesh-like white marking, gentle undulaion and portal hypertension are very valuable for stage diagnosis and the evaluation of prognosis in patients with PBC.     

Xanthine Oxidase Inhibition Prevents Atrial Fibrillation in a Canine Model of Atrial Pacing‐Induced left Ventricular Dysfunction

Allopurinol and Atrial Fibrillation . Aims: Oxidative stress could be a possible mechanism and a therapeutic target of atrial fibrillation (AF). Xanthine oxidase (XO) inhibition reduces oxidative stress, but the effects of XO inhibitor on AF have not been evaluated. Hence, we assessed the effects of XO inhibitor, allopurinol, on progression of atrial vulnerability in dogs associated with tachycardia‐induced cardiomyopathy. Methods and Results: The dogs were subjected to atrial tachypacing (ATP, 400 bpm) without atrioventricular block for 4 weeks. The dynamics of atrial‐tachycardia remodeling were evaluated in allopurinol‐treated dogs (ALO, n = 5), placebo‐treated controls (CTL, n = 6), and sham‐operated dogs (n = 6). In CTL dogs, 4 weeks of ATP significantly increased AF duration (DAF; from 0.2 ± 0.2 seconds to 173 ± 67 seconds, P < 0.05) and decreased atrial effective refractory period (ERP; from 152 ± 9 milliseconds to 80 ± 4 milliseconds at a cycle length of 350 milliseconds, P < 0.01). Allopurinol attenuated the ATP effects on ERP (118 ± 6 milliseconds, P < 0.01) or DAF (0.6 ± 0.3 seconds, P < 0.05). In CTL dogs, ATP‐induced rapid ventricular responses decreased left ventricular ejection fraction (LVEF; from 58.6 ± 0.1 to 23.5 ± 2.4%, P < 0.01), and increased left atrial diameter (LAD; from 17 ± 1 mm to 24 ± 1 mm, P < 0.01). ATP increased atrial fibrosis when compared with sham‐operated dogs (CTL 10.7 ± 0.8% vs Sham 1.1 ± 0.3%, P < 0.01). Allopurinol suppressed atrial fibrosis (2.3 ± 0.6%, P < 0.01 vs CTL) and eNOS reduction without affecting LVEF (20.6 ± 2.2%, ns) and LAD (23 ± 1 mm, ns). Conclusion: Allopurinol suppresses AF promotion by preventing both electrical and structural remodeling. These results suggest that XO may play an important role in enhancement of atrial vulnerability, and might be a novel target of AF therapy. (J Cardiovasc Electrophysiol, Vol. 23 pp. 1130‐1135, October 2012)     

Action of human interleukin-4 and stem cell factor on erythroid and mixed colony formation by peripheral blood-derived CD34+c-kithigh or CD34+c-kitlow cells

We studied the interaction of interleukin (IL)-4 and other burst-promoting activity (BPA) factors, such as IL-3, granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-9 and stem cell factor (SCF), on erythroid burst-forming unit (BFU-E) and erythrocyte-containing mixed (CFU-Mix) colony formation in serum-free culture. IL-4 alone did not support mixed colony formation in the presence of erythropoietin (Epo). However, IL-4 showed weak but significant BPA when peripheral blood (PB)-derived CD34⁺c-kit^low cells were used as the target population. The BPA of IL-4 was much weaker than that of IL-3, which exerted the most potent activity, as previously reported. When CD34⁺c-kit^high cells were used as the target, four factors known to have BPA, IL-3, GM-CSF, IL-9 and SCF, could express BPA. In contrast, IL-4 alone failed to support erythroid burst formation. Interestingly, IL-4 showed a remarkable enhancing effect with SCF in promoting the development of erythroid burst and erythrocyte-containing mixed colonies from CD34⁺c-kit^low and CD34⁺c-kit^high cells. Delayed addition of SCF + Epo or IL-4+Epo to the cultures initiated with either IL-4 or SCF alone clearly demonstrated that SCF was a survival factor for both BFU-E and CFU-Mix progenitors. In contrast, the survival effect of IL-4 was much weaker than that of SCF, and appeared to be more important for progenitors derived from CD34⁺c-kit^low cells than for those derived from CD34⁺c-kit^high cells. It was recently reported that CD34⁺c-kit^low cells represent a more primitive population than CD34⁺c-kit^high cells. Taken together, these results suggest that IL-4 helps to recruit primitive progenitor cells in the presence of SCF.     

ENFLURANE INCREASES THE ADRENALINE THRESHOLD FOR THE DEVELOPMENT OF SLOW RESPONSES IN ISOLATED CANINE TRABECULAE

To determine if enflurane has different effects on myocardialsensitivity to adrenaline than those previously reported forhalothane, we have studied the enflurane-adrenaline interactionin isolated canine trabeculae using doses of adrenaline necessaryto produce slow responses (adrenaline threshold for the developmentof slow responses, ATSR) as an indicator. The preparations weredepolarized in Tyrode's solution containing potassium chloride26 mmol litre^–1, then adrenaline concentrations in thesolution were increased stepwise. Enflurane 1% had no significanteffect, but 2% and 4% significantly increased the ATSR two-foldand sevenfold, respectively. To investigate the influence ofenflurane on the adrenaline—adrenoceptor interaction,we studied the effects on the ATSR of 2% enflurane alone orin combination with either prazosin 8 ng ml^–1 or metoprolol17 ng ml^–1. Compared with the ATSR obtained with 2% enfluranealone, alpha₁-block with prazosin did not alter, but beta₁-blockwith metoprolol significantly increased the ATSR (three-fold).These effects of enflurane are qualitatively as well as quantitativelysimilar to those reported previously for halothane. Thus, assumingthat the MAC value for enflurane is about 2–2.5 timesgreater than that for halothane, the effects of enflurane onslow channel conductance (antiarrhythmic effects of enflurane)might be about two to three times greater than those of halothaneat an equivalent depth of anaesthesia. Such differences mayexplain in part the clinical observation that ventricular arrhythmiasare less likely with enflurane than with halothane.     

CEREBRAL RESPONSES TO THE ADDITION OF NITROUS OXIDE TO HALOTHANE IN MAN

Cerebral responses to the substitution of 60% nitrous oxidefor nitrogen during halothane anaesthesia (0.84%, end-tidal)were studied in four patients during surgery. The mean (±SEM)cerebral blood flow equivalent and internal jugular venous oxygentension during halothane anaesthesia, 27±3 ml blood/mloxygen and 41±2 mm Hg respectively, increased significantlyto 45±3ml blood/ml oxygen and 54±3 mm Hg followingthe introduction of nitrous oxide. On the withdrawal of nitrousoxide, the mean cerebral blood flow equivalent and internaljugular venous oxygen tension returned gradually to the controlvalues. Cerebral perfusion pressure and blood-gas values, otherthan the internal jugular venous oxygen tension, did not changesignificantly. Marked slowing of the e.e.g. was observed followingthe addition of nitrous oxide to halothane. Upon the withdrawalof nitrous oxide the e.e.g. returned to the control pattern.These results indicate that cerebral blood flow was in excessof oxygen demand during nitrous oxide/halothane anaesthesiain man. This work was performed at the Department of Anaesthesiology,Yamaguchi University Hospital.