[Changing the frequency of administration of darbepoetin alfa (from weekly to fortnightly) maintains the haemoglobin levels in patients undergoing peritoneal dialysis]. / El cambio en la frecuencia de administración de darbepoetin alfa (de semanal a quincenal) mantiene los niveles de hemoglobina en pacientes en diálisis peritoneal.

SUMMARY BACKGROUND: Less frequent dosing regimens during anemia treatment could benefit Peritoneal Dialysis (PD) patients. We investigated the effectiveness of darbepoetin alfa dosed every-other-week (Q2W) for maintaining hemoglobin (Hb) levels (11-13 g/dL). PATIENTS AND METHODS: One hundred and nine PD patients from 14 centers participated in an 8-month observational, prospective study. Patients (Hb 11-13 g/dL) receiving weekly (QW) darbepoetin alfa switched to Q2W dosing at the investigator's discretion. Doses were adjusted according to published guidelines. RESULTS: Sixty-nine percent (75 out of 109) of patients switched to Q2W dosing. Thirty-three percent maintained the g/week, equivalent to twice the previous mean weekly dose (26.1-25.8 g/week, QW dose). Forty-seven percent received a dose reduction (35.8-20.2 equivalent to the previous QW dose). More patients in the maintenance dose group 11 g/dL than those receiving a reduced weekly dose (80% vs. had Hb levels 51.4%, respectively, p = 0.0236). During the Q2W phase, the mean Hb level ranged from 12.0-12.5 g/dL for the maintenance dose group and 11.5-12.0 g/dL for the reduced dose group. From the switch to the end of the study, the mean (SD) change in Hb was -0.7 g/dL (0.98 g/dL, p = 0.0557) and -0.6 g/dL (1.6 g/dL, p = 0.1296) for the maintenance and reduced dose groups, respectively. The Q2W darbepoetin alfa was well tolerated. Only a single treatment-related adverse event (polycythemia) occurred. CONCLUSION: The majority of PD patients receiving QW darbepoetin alfa can be effectively switched to Q2W and still maintain their Hb level.

Health effects classification and its role in the derivation of minimal risk levels: immunological effects.

The Agency for Toxic Substances and Disease Registry (ATSDR) derives health-based guidance values known as minimal risk levels (MRLs). By definition, an MRL is a substance-specific estimate of the daily human exposure to a substance that is likely to be without an appreciable risk of adverse, noncancer effects over a specified duration of exposure. MRLs are preferentially derived from human studies, if available, or from the most sensitive animal species and the endpoint that is most relevant for humans. To date, the agency has derived 346 MRLs. Fifteen MRLs were derived for 11 different chemicals where the database has identified the immune system as the most sensitive target of toxicity. The chemicals include benzene, chlorfenvinphos, endosulfan, heptachlor, gamma-hexachlorocyclohexane, dibutyl tin, tributyl tin, PCBs, 2,3,4,7,8-pentachlorodibenzofuran, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and 2,4-dichlorophenol. The agency's rationale for classification of immunological endpoints is discussed and a brief description given of the critical studies selected for MRL development using immune system endpoints.

[Multicenter study of darbepoetin alfa in the treatment of anemia secondary to chronic renal insufficiency on dialysis]. / Estudio multicéntrico de darbepoetin alfa en el tratamiento de la anemia secundaria a insuficiencia renal crónica en diálisis.

This Spanish single-arm, multicenter, prospective clinical trial assessed the maintenance of hemoglobin concentrations (Hb) between 10-13 g/dL with unit doses of darbepoetin alfa and the safety of the treatment in dialysis patients. Eight-hundred twenty-six patients with chronic renal failure (CRF) (94% receiving haemodialysis and 6% receiving peritoneal dialysis) previously maintained on stable recombinant human erythropoietin (r-HuEPO) therapy with stable hemoglobin (Hb) concentrations (mean Hb concentration = 11.7 g/dL) were switched to darbepoetin alfa at a reduced dosing frequency for 24 weeks (a 20-week titration phase plus a 4-week treatment evaluation phase). Subjects receiving r-HuEPO two or three times weekly were switched to darbepoetin alfa once weekly, and those. who were receiving r-HuEPO once weekly were switched to darbepoetin alfa once every two weeks. The initial dose of darbepoetin alfa was determined from the r-HuEPO dose at inclusion into the study using a formula equating the peptide mass of the two molecules and rounding to the nearest available prefilled syringe dose. Overall, 86.8% of patients completed the 24-weeks of study. Changing the treatment from r-HuEPO to darbepoetin alfa and increasing the dose interval did not result in any clinically significant change in the Hb concentration. From base-line to the evaluation phase, the mean Hb fell 0.09 (95% CI, -0.2; -0.0) g/dl, with an increase of 0.19 (95% CI, 0.0;0.3) g/dL i.v. and a decrease of 0.22 (95% CI, -0.3; -0.1) g/dL s.c.). This maintenance of the mean Hb concentration was accompanied by a mean 9.8% reduction of the darbepoetin alfa dose (19.7% (95% CI, -24.9; -14.2) i.v. and 4.7% (95% CI, -8.5; -0.7) s.c. Treatment with darbepoetin alfa was well tolerated and no unexpected adverse events were reported. In conclusion, the replacement of previous r-HuEPO treatment by darbepoetin alfa in the therapy of anemia secondary to chronic renal failure in diaiyzed patients was effective, well tolerated, and decreased the frequency of dose administration compared with the previous r-HuEPO treatment. Darbepoetin alfa administered once weekly or once every two weeks maintained the baseline Hb levels whilst allowing dose reduction, which was higher in patients receiving i.v. darbepoetin alfa.

Estudio multicéntrico de darbepoetin alfa en el tratamiento de la anemia secundaria a insuficiencia renal crónica en diálisis / Darbepoietin treatment of anemia secondary to chronic renal failure in dialysis

Este ensayo clínico prospectivo, multicéntrico, de un solo brazo, evaluó el mantenimiento de las concentraciones de hemoglobina (Hb) entre 10-13 g/dL con darbepoetin alfa y la seguridad de este tratamiento, en pacientes con insuficiencia renal crónica (IRC) en diálisis (94% hemodiálisis, 6% diálisis peritoneal, concentración de Hb basal = 11,7 g/dL) tratados hasta el inicio de este estudio con eritropoyetina recombinante humana (r-HuEPO). Se incluyeron 826 pacientes con concentraciones de Hb y dosis de r-HuEPO estables (824 recibieron al menos una dosis de darbepoetin alfa y fueron evaluables para el análisis de seguridad). Los pacientes recibieron darbepoetin alfa durante 24 semanas (20 de titulación más 4 de evaluación). La dosis inicial de darbepoetin alfa se determinó a partir de la dosis previa de r-HuEPO, utilizando la equivalencia en masa peptídica entre ambas moléculas y ajustando a la jeringa precargada más próxima. Se administró darbepoetin alfa 1 × semana (en pacientes en tratamiento previo con r-HuEPO 2-3 × semana) o cada dos semanas (en los pacientes con r-HuEPO 1 × semana). El 86,8% de los pacientes completaron las 24 semanas de estudio. El cambio del tratamiento a menor frecuencia de dosificación no produjo modificaciones clínicamente significativas en la concentración de Hb [los cambios desde la visita basal al período de evaluación consistieron en un descenso de 0,09 (IC 95%, –0,2; –0,0) g/dL, con aumento de 0,19 (IC 95% 0,0; 0,3) g/dL en la vía iv y descenso de 0,22 (IC 95%, –0,3; –0,1) g/dL en la vía sc]. Este mantenimiento de Hb se acompañó de una reducción media de la dosis de darbepoetin alfa de un 9,8% (IC 95%, –12,9; –6,6) [19,7% (IC 95%, -24,9;-14,2) (vía iv) y 4,7% (IC 95%, –8,5; –0,7) (vía sc)]. El tratamiento con darbepoetin alfa fue bien tolerado, no observándose acontecimientos adversos inesperados. En conclusión, la sustitución de cér-HuEPO por darbepoetin alfa en la terapia de la anemia secundaria a IRC en pacientes en diálisis fue eficaz, bien tolerada y disminuyó la frecuencia de administración de dosis en comparación con el tratamiento previo con r-HuEPO. Darbepoetin alfa 1 vez por semana o 1 vez cada 2 semanas mantuvo los niveles de Hb basales a la vez que permitió una reducción de la dosis por ambas vías de administración, siendo mayor en los pacientes tratados por vía iv

This Spanish single-arm, multicenter, prospective clinical trial assessed the maintenance of hemoglobin concentrations (Hb) between 10-13 g/dL with unit doses of darbepoetin alfa and the safety of the treatment in dialysis patients. Eight-hundred twenty-six patients with chronic renal failure (CRF) (94% receiving haemodialysis and 6% receiving peritoneal dialysis) previously maintained on stable recombinant human erythropoietin (r-HuEPO) therapy with stable hemoglobin (Hb) concentrations (mean Hb concentration = 11.7 g/dL) were switched to darbepoetin alfa at a reduced dosing frequency for 24 weeks (a 20-week titration phase plus a 4-week treatment evaluation phase). Subjects receiving r-HuEPO two or three times weekly were switched to darbepoetin alfa once weekly, and those. who were receiving r-HuEPO once weekly were switched to darbepoetin alfa once every two weeks. The initial dose of darbepoetin alfa was determined from the r-HuEPO dose at inclusion into the study using a formula equating the peptide mass of the two molecules and rounding to the nearest available prefilled syringe dose. Overall, 86.8% of patients completed the 24-weeks of study. Changing the treatment from r-HuEPO to darbepoetin alfa and increasing the dose interval did not result in any clinically significant change in the Hb concentration. From baseline to the evaluation phase, the mean Hb fell 0.09 (95% CI, –0.2; –0.0) g/dl, with an increase of 0.19 (95% CI, 0.0;0.3) g/dL iv and a decrease of 0.22 (95% CI, –0.3; –0.1) g/dL sc). This maintenance of the mean Hb concentration was accompanied by a mean 9.8% reduction of the darbepoetin alfa dose (19.7% (95% CI, –24.9;-14.2) iv and 4.7% (95% CI, –8.5; –0.7) sc. Treatment with darbepoetin alfa was well tolerated and no unexpected adverse events were reported. In conclusion, the replacement of previous r-HuEPO treatment by darbepoetin alfa in the therapy of anemia secondary to chronic renal failure in diaiyzed patients was effective, well tolerated, and decreased the frequency of dose administration compared with the previous r-HuEPO treatment. Darbepoetin alfa administered once weekly or once every two weeks maintained the baseline Hb levels whilst allowing dose reduction, which was higher in patients receiving iv darbepoetin alfa

Hypertonic treatment reversibly increases the ratio of giant skew-miniature endplate potentials to bell-miniature endplate potentials.

Miniature endplate potentials were recorded from single frog muscle fibers before, during and after treatment with hypertonic saline (200-500 mM NaCl or Na gluconate added to frog saline). Miniature endplate potential amplitude distributions were plotted from small muscle fibers so that the modes and ratios of the skew-miniature endplate potential to bell-miniature endplate potential classes could be defined. Muscle fibers were voltage clamped with two electrodes to determine the input resistance before, during and after treatment. Input resistance increased from two to 100 times during treatment and rapidly fell towards control values (no more than 30% greater) when preparations were returned to normal frog saline. Short duration treatments with 200-300 mM hypertonic salines immediately increased frequencies (100-fold) of both skew-miniature endplate potential and bell-miniature endplate potential classes. Preparations when returned to normal frog saline after a few minutes of treatment showed control miniature endplate potential distributions within minutes. One to two hour treatments left only the skew-miniature endplate potential class and with hour-long recovery periods bell-miniature endplate potentials reappeared and ratios of skew-miniature endplate potential to bell-miniature endplate potential classes returned to control values. Treatment with 500 mM NaCl added to frog saline immediately increased the percentage of skew-miniature endplate potentials (from 2 to 50%) with little or no increase in overall miniature endplate potential frequencies. The mode of the skew-miniature endplate potential class was unchanged after hypertonic treatment, whereas that of the bell-miniature end plate potential class either remained about the same size or decreased depending on the duration of treatment. The number and percentage of giant-miniature endplate potentials belonging to the skew-miniature endplate potential class increased as a function of the duration of 200-300 mM hypertonic saline treatments. Most giant-miniature endplate potentials had a slow rising phase with a foot and/or breaks demonstrating a composite structure. Sequentially recorded giant-miniature endplate potentials had similar initial slopes indicating either repetitive releases from single sites or releases from cooperative sites. After hypertonic treatment the bell-miniature endplate potential size was never more than that expected with the increase (under 30%) in input resistance. The results presented here are completely different from those of Yu and Van der Kloot [(1991) J. Physiol. 433, 677-704] who reported that the bell-miniature endplate potential amplitude was increased two- to four-fold after hypertonic treatment. The wide range of results in the ratio of skew-miniature endplate potential to bell-miniature endplate potential classes is discussed in regards to the quantal hypothesis which is based on a single class of immutable amounts of transmitter; and, a hypothesis based on a dynamical process that meters transmitter in subunit amounts to control miniature endplate potential size and class during release.

Immunocytochemical localization of alpha-actinin in frog muscle treated with the ionophore A23187.

Incubation of frog skeletal muscle with the ionophore A23187 induces severe damage in the muscle. At the level of the Z line, the ionophore induces redistribution and release of the protein alpha-actinin, as shown by immunocytochemical techniques. The ionophore does not induce damage in denervated preparations or in preparations pretreated with d-tubocurarine, which indicates that the effect is indirect and neurally mediated. It is concluded that the increase in spontaneous transmitter release produced by the ionophore induces Ca2+ influx through the acetylcholine receptor. Calcium ions activate neutral proteases which release alpha-actinin from the Z line.

Muscle damage induced by the ionophore A23187 can be prevented by prostaglandin inhibitors and leupeptin.

Frog skeletal muscle incubated in vitro with the ionophore A23187 shows extensive morphological alterations. Myofilament disruption, presumably mediated by excess intracellular calcium, can be partially prevented by preincubating the muscle with inhibitors of prostaglandin synthesis and the lysosomal thiol protease inhibitor leupeptin.

Neurogenic origin of an experimental myopathy induced by the ionophore A23187.

An experimental myopathy was induced in frog skeletal muscle incubated in vitro with the calcium ionophore A23187. This myopathy could be prevented if Ca2+ ions in the incubating medium were replaced by either Mg2+ or Co2+ ions. Similarly, preincubation of the preparation with acetylcholine (ACh) receptor blockers such as d-tubocurarine (d-TC) or alpha-bungarotoxin (alpha-BuTX) prevented the development of muscle damage. In muscles that had been previously denervated or treated with botulinum toxin (BTX) the ionophore failed to induce morphological alterations. These results suggest that spontaneous transmitter release, greatly increased by the ionophore A23187, triggers Ca2+ influx into the muscle fibres at the endplate region. Elevated levels of intracellular Ca2+ presumably activate proteolytic systems leading to myofilament disassembly.

Ultrastructural and physiological effects of the ionophore A23187 at identified frog neuromuscular junctions.

The physiological and morphological effects of the calcium ionophore A23187 (calimycin) at the frog neuromuscular junction in vitro were examined. Miniature endplate potentials were recorded intracellularly during exposure to the ionophore. Preparations fixed 15 or 30 min after adding the drug to the incubating medium, which exhibited a greatly increased miniature endplate potential frequency, showed no obvious morphological differences when compared to controls with regard to synaptic vesicle number or distribution of vesicles within the terminal. However, after 45-60 min of exposure to the ionophore, when miniature endplate potential frequency had declined almost to zero, most of the nerve endings appeared devoid of synaptic vesicles and other organelles while the plasma membrane was intact. It is suggested that the apparent depletion of vesicles from the terminal induced by the calcium ionophore is a consequence of irreversible changes at the terminal.

Histograms of the unitary evoked potential of the mouse diaphragm show multiple peaks.

1. Two classes of miniature end-plate potentials (m.e.p.p.s) were recorded from diaphragm neuromuscular junctions. Amplitude histograms of both classes had multiple peaks that were integral multiples of the smallest peak (s-m.e.p.p.s). The smaller m.e.p.p.s formed the first three or four peaks of histograms and the number of m.e.p.p.s (skew-m.e.p.p.s) in each peak decreased, forming an over-all skewed distribution. The larger m.e.p.p.s (bell-m.e.p.p.s) formed a more-or-less bell-shaped distribution. The distribution of m.e.p.p.s varied from mainly skew- to mainly bell-m.e.p.p.s. In young adult mice the number of subunits composing the classical m.e.p.p.s varied between ten and fifteen at room temperature; at higher temperatures the range was from three to ten subunits.2. End-plate potentials (e.p.p.s) were reduced with cobalt ions (ca. 4 mm) until most nerve impulses failed to release transmitter. The amplitudes of ;unitary evoked potentials' were of the bell-m.e.p.p. class and histograms show integral multiple peaks that correspond to the peaks in histograms of the bell-m.e.p.p.s.3. The peaks in both m.e.p.p. and unitary e.p.p. histograms remained in the same position throughout the recording period and became more distinct as the sample size increased.4. The variance of the s-m.e.p.p. was estimated from the noise and measurement error and the variance of all peaks in the histograms. Most variance of the first peak (s-m.e.p.p.) was due to noise and measurement error.5. The integral peaks in the m.e.p.p. and ;unitary evoked potential' histograms are predicted with a probability density model based on the estimated variance of the s-m.e.p.p. and the assumption that larger potentials are composed of subunits the size of s-m.e.p.p.s. The data and model support the hypothesis that m.e.p.p.s and unitary potentials are composed of subunits.

Effect of the Ca++ ionophore X-537A and a heat challenge on the distribution of mouse MEPP amplitude histograms.

Amplitude distributions of miniature endplate potentials (MEPPs) from the isolated mouse diaphragm neuromuscular junctions showed two classes of MEPPs at room temperature. The smaller MEPPs formed a skew distribution which composed about 15% of the MEPPs, the larger MEPPs formed a bell-shaped distribution and represented the classically studied MEPPs. In many MEPP amplitude histograms, both the skew part and bell-shaped part of the histogram showed integral peaks. The first peak is composed of s-MEPPs. The calcium ionophore (X-537A, 10(-5) M) blocked the generation of bell-shaped MEPPs leaving the s-MEPPs. There was little postsynaptic action at this low concentration. Heat challenges reversibly increased the percentage of s-MEPPs and reduced the mean of the bell distribution. Many MEPPs after either challenge had inflections on their rising phases. These observations are evidence that the larger classical MEPP is composed of subunits and the release of one subunit generates the s-MEPP.

A statistical model supports the subunit hypothesis of quantal relsease.

Successive frequency amplitude histograms of miniature endplate potentials (MEPPs) from mouse neuromuscular junctions show peaks at integral multiples of the smallest peak (s-MEPPs). The s-MEPPs are assumed to have normally distributed amplitudes and to represent the subunit size. A model has been derived from assumptions based on the hypothesis of MEPPs are generated by the synchronous release of transmitter subunits. The model was statistically tested on amplitude histograms and in the majority of cases the model produced extremely good fits to observed distributions.

Effects of adrenoceptor stimulating and blocking agents on carotid body chemosensory inhibition.

1. The effects of alpha- and beta-adrenoceptor agonists and antagonists on chemosensory discharges originating from carotid bodies in situ were studied in anaesthetized cats.2. Noradrenaline (NA) injections commonly resulted in increased frequency of carotid nerve chemosensory discharge, an effect ascribed to reduced blood flow through the glomus, and reduced or eliminated by alpha-adrenergic block.3. NA injections occasionally produced an initial reduction of chemosensory discharge frequency, which was however less intense and of shorter duration than that caused by dopamine. This effect of NA is not mediated by alpha-adrenoceptors, since it is not blocked by dibenamine, but probably by low affinity for dopamine receptors.4. Dopamine and apomorphine-elicited chemosensory inhibition were not affected by low doses of phenoxybenzamine, which blocked NA-evoked hypertensive reactions.5. Higher doses of phenoxybenzamine and dibenamine produced a displacement to the right of dose-response curves for dopamine- and apormorphine-elicited chemosensory inhibition. However, this interference by alpha-adrenergic blockers was attributed to the resultant hypotension, since it was reversed upon restoration of blood pressure.6. Isoprenaline, a beta-adrenergic agonist, did not induce chemosensory inhibition, whilst beta-adrenergic blockers (propranolol and dichloroisoproterenol) did not modify dopamine- and apomorphine-elicited chemosensory inhibition.7. These results provide further support for the hypothesis that chemosensory inhibition could be mediated by specific dopamine receptors, distinct from alpha- and beta-adrenoceptors.

Effects of dopamine analogues and antagonists on carotid body chemosensors in situ.

1. The effects of dopamine, its analogues and antagonists on the chemosensory discharges originating from carotid bodies in situ were studied in anaesthetized cats. 2. Intracarotid (I.C.) injections of 100 ng or more of dopamine produced transient depression of the frequency of carotid nerve chemosensory discharges. Short term (1-5 sec) complete inhibition was usually elicited by 2 microgram dopamine. 3. I.V. injections of dopamine also produced inhibition of chemosensory discharges, an effect observed with doses which were still too low to produce changes in systemic arterial pressure. Half-maximal inhibition (ID50) of chemoreceptors was elicited with a mean dose of 84 ng.kg-1. 4. I.C. and I.V. injections of apomorphine and amantadine also produced transient inhibition of chemosensory activity. Higher doses of these analogues of dopamine were needed to produce this effect, and the resulting inhibition usually did not silence the nerve discharges. Apomorphine inhibition was slightly more prolonged than that with dopamine. 5. Large doses of amphetamine and tyramine, inducers of dopamine release, did not produce inhibition of chemosensory discharges. 6. The effects of two classes of dopamine antagonists were tested. Dose-response curves for dopamine and apomorphine inhibition were displaced to the right by administration of phenothiazines (chlorpromazine and perphenazine) and butyrophenones (haloperidol and spiroperidol). In animals treated with perphenazine or spiroperidol, dopamine became a stimulator of chemoreceptor activity. 7. It is suggested that dopamine present in carotid body may operate as a modulator of chemosensory activity.

Spontaneous subminature end-plate potentials in mouse diaphragm muscle: evidence for synchronous release.

1. Miniature end-plate potentials (min.e.p.p.s) were recorded from small muscle cells of mouse diaphragms. Min.e.p.p. amplitude histograms showed successive peaks which were integral multiples of the smallest peak. The smallest potentials (submin.e.p.p.s) averaged 0-3-0-6mV and the mean of the larger min.e.p.p.s averaged 3-7 mV, depending on the muscle cell diameter. There was a positive correlation between time-to-peak and min.e.p.p. amplitude. Time-to-peak of the submin.e.p.p.s fell slightly below the regression line through the larger min.e.p.p.s. 2. Sometimes min.e.p.p. amplitude distributions changed spontaneously such that the mean of the major mode min.e.p.p.s decreased twofold during which time the mean of the submin.e.p.p.s did not change. Spontaneous decreases were most pronounced during low frequencies of release (10/min) achieved at 32 degrees C. 3. Small changes in temperature (2 degrees C steps in the range 32-40 degrees C) greatly altered the number of peaks of min.e.p.p. amplitude histograms without noticeably changing the position of the submin.e.p.p. peak. At 32 degrees C submin.e.p.p.s composed 5-20% of the histograms and the amplitude of the major mode peak was twelve to fifteen-times that of the submin.e.p.p.s. Over-all bell-shaped distributions were obtained at 37 degrees C which showed up to eight peaks with the major peak at the fourth to sixth peak. Temperatures slightly above 37 degrees C gave a flat distribution with the mean amplitude at the third peak. Min.e.p.p. amplitude histograms were initially skewed (mostly small min.e.p.p.s) after a 40 degrees C heat challenge. 4. Two to eight-times the normal concentration of Ca2+ in the saline reversibly increased the min.e.p.p. frequency and also decreased the mean of the major mode min.e.p.p.s (two to nine-times) without noticeably changing the mean of the submin.e.p.p.s. 5. Botulinum toxin A, 10(5) X intraperitoneal median lethal dose (10(5)I.P.LD50)/ml., almost abolished min.e.p.p.s in 30-90 min. The relative proportion of submin.e.p.p.s increased and the mean of the major mode min.e.p.p.s usually did not change during the initial decrease in frequency. Major mode min.e.p.p.s essentially ceased after 200-1000 were generated and remaining min.e.p.p.s of some cells showed skewed distributions with three small peaks that were integral multiples of the submin.e.p.p. peak. Smaller min.e.p.p.s were more resistant to block than the larger min.e.p.p.s and, although frequencies were low, small min.e.p.p.s were recorded after 4 hr of botulinum toxin incubation. 6. Colchicine (5 X 10(-4)M) within minutes reduced the major mode min.e.p.p.s by half (mean of major peak reduced to sixth or seventh peak). Additional colchicine (10(-3)M reduced the major mode min.e.p.p. amplitude to a fifth of that of control (mean of major mode min.e.p.p.s at the third peak) with no change in position of the submin.e.p.p. peak. Min.e.p.p. amplitudes slowly recovered to half control values after washing. 7...

Acute changes in ventilation and blood pressure induced by inhalation of tobacco smoke.

Inhalation of cigarette smoke through a tracheal cannula was induced in cats anesthetized with pentobarbital. Smoking of tobacco cigarettes produced increased ventilation and systemic hypertension, which were found to be due to their nicotine content. Respiratory stimulation and the increase in diastolic pressure were abolished by acute section of 'buffer nerves', but the mediation of carotid nerves was more important than that of the vagi for evoking reflex hyperventilation. Tobacco smoking induced a marked increase in the frequency of chemosensory impulses recorded from the carotid nerves, an effect due to its nicotine content.

Respiratory and circulatory reflexes induced by nicotine injections: role of carotid body chemoreceptors.

Intravenous and intracarotid injections of nicotine were delivered to cats anesthetized with pentobarbital. Low doses of nicotine were found to induce reflex hyperventilation and hypertension, mainly due to excitation of carotid body chemoreceptors. The frequency of discharge of carotid nerve chemosensory fibres was increased by nicotine in doses as low as 1 mug/kg when injected intravenously and 50 ng when injected into the carotid artery. Nicotine also activates vagal afferent fibres; some of them produce reflex excitation of the respiratory and vasomotor centres, but others provoke reflex inhibition. High doses of nicotine can act directly upon the medulla provoking acceleration or arrest of ventilation. Nicotine can also induce 'late' changes of b.p. (delay 5 sec or more) which are not mediated by the carotid or vagus nerves.

Dopamine-beta-hydroxylase activity in normal and sympathectomized carotid bodies.

Normal carotid bodies excised from cats showed DBH values of 5.04 + or - 0.53 nmol [(3)H]octopamine formed/h/100 mg tissue (x + or - S.E. ). Values from sympathectomized carotid bodies were not significantly different. While the ganglio-glomerular nerves, providing the sympathetic innervation of the carotid bifurcation, had a high DBH level, this was low in the carotid sinus nerve, providing its sensory innervation. Glomeral DBH may be contained in a special type of noradrenergic glomus cells, distinct from the most common dopaminergic glomus cells.