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The chronic pain (CP) and chronic multi-site pain (CMP) condition is a highly prevalent health problem. Several studies have reported a high (31-64%) prevalence of co-morbid restless legs syndrome (RLS) in patients with fibromyalgia, one specifically defined form of chronic widespread pain. The current study explored the association between CMP and RLS.The study included 4040 respondents to a postal questionnaire sent to 10,000 women in the age range of 18-64 years and randomly selected from the general population. Complete questionnaire data on type (acute/chronic), degree (mild to severe) and spreading (0-5 body zones) of pain, as well as RLS symptoms (validated questionnaire), were obtained from 3060 subjects. Information on lifestyle, anthropometrics, co-morbidities and medication was collected.RLS prevalence increased from 9.6% in subjects with no report of pain to 23,9%, 26.4%, 39.2%, 44.9% and 54.8% in those reporting one, two, three, four and five pain areas, respectively (p0.001). Further, RLS prevalence increased from 9.6% (no pain) to 27.9%, 37.9% and 42.4% in subjects with mild, moderate and severe chronic pain (p0.001). Multi-site pain, pain localized in the leg, extended pain duration and co-morbid psychiatric disorder were all independently associated with a RLS diagnosis in a multiple regression analysis.The prevalence of RLS increased progressively with pain severity and even more sharply with the degree of pain spreading in women recruited from the general population. Both acute and chronic pain was associated with RLS-related symptoms.

The effects of substance P (SP) and the naturally occurring met-enkephalin and the synthetic mu-specific opioid agonist, DAGO (Tyr-D-Ala-Gly-N-Methy-Phe-Gly-ol) and the delta-specific opioid agonist DADL (Tyr-D-Ala-Gly-Phe-D-Leu) on basal ventilation were investigated in halothane-anaesthetized rats. Local injections of SP (0.75-1.5 nmol) in the ventrolateral medulla oblongata (VLM), e.g. nucleus paragigantocellularis, and nucleus reticularis lateralis increased ventilation because of an elevation of tidal volume. Met-enkephalin induced a short-lasting ventilatory depression mainly because of a depression of tidal volume. Activation of delta- and mu-opioid receptors in the VLM by local application of DADL and DAGO, respectively, induced ventilatory depression, which was later in onset and more long-lasting. Local administration of met-enkephalin into the VLM also produced a long-lasting inhibition of the SP-induced ventilatory excitation. A similar blockade of the SP-induced excitatory ventilatory response could be elicited by DADL but not by DAGO. This antagonistic effect was attenuated by local application of the delta-opioid receptor antagonist ICI 154. 129. We conclude that the naturally occurring met-enkephalin as well as synthetic mu- and delta-specific enkephalin analogues (DAGO and DADL, respectively) in VLM depress basal ventilation by an effect on inspiratory drive. There is a functional antagonism between activation of delta-opioid receptors and SP receptors into the VLM in respect to respiratory regulation.

Acute intermittent repetitive hypoxia simulating sleep apnoea syndrome is responsible for acute rises in blood pressure (BP). In the rat, the BP rises are enhanced by added hypercapnia. To investigate the role of the autonomic nervous system (ANS) in acute hypertension during repetitive hypoxia alone, FiO2 (inspiratory fractional concentration of oxygen) 2 to 5%, or combined with hypercapnia FiCO2 (inspiratory fractional concentration of carbon dioxide) 2 to 5%, we used autonomic blockade by atropine (1 mg kg-1) + propranolol (1 mg kg-1)-phentolamine (1 mg kg-1). Seven Wistar male rats were chronically instrumented with two aortic and venous catheters. Repetitive administration of N2 and N2 + CO2 for 10s followed by 20s compressed air was repeated for 4-5 min before (control) and after autonomic blockade. After autonomic blockade there was no significant difference in mean blood pressure (MBP) during severe hypoxia (SHO) (14.9 +/- 0.5 mmHg) compared to control (10.5 +/- 0.9 mmHg), while MBP was significantly decreased in severe hypoxia + hypercapnia (SHOHC) (14.1 +/- 0.4 mmHg) compared to control (26.8 +/- 0.3 mmHg) (p0.001). We conclude that the acute BP rise observed during hypoxic breathing is not due to the activation of ANS, but when hypercapnia is added to the hypoxic stimulus about half of pressor response is caused by ANS.

We wanted to assess whether benzodiazepines worsen sleep apnoea, since their use in such patients has been controversial. Fourteen male patients with mild to moderate obstructive sleep apnoea were investigated in a placebo-controlled, double-blind study evaluating the influence of nitrazepam (NIT) on apnoea frequency and severity. Each patient was given oral nitrazepam 5 or 10 mg, or corresponding placebo, in a randomized order on three separate nights. Wash-out time was one week. A complete sleep study was undertaken at each study night. Eleven patients completed the study. Although there were individuals with marked variability in apnoea index between the three study nights, there was no significant change in apnoea index or minimum arterial oxygen saturation with any of the two nitrazepam dosages studied. Only 3 out of 11 patients had a higher apnoea index after both nitrazepam doses compared to placebo, and in these patients the increase in sleep-disordered breathing was of marginal clinical significance. Nitrazepam caused a modest increase in total sleep time and a decrease in rapid eye movement (REM) sleep. These results demonstrate that nitrazepam does not worsen sleep apnoea in patients with mild to moderate sleep apnoea. The previously reported sleep apnoea promoting effects of benzodiazepines may be restricted to a small subgroup of patients with sleep-disordered breathing.

The effectiveness of diclofenac 50 mg t.i.d. as additive treatment to parenteral patient-controlled administration therapy (PCAT) with morphine in cancer pain has been investigated in a double-blind study. In the fifteen patients who completed the study, morphine i.v. was titrated to optimal pain relief over 5 days. The mean total morphine consumption was significantly reduced during diclofenac administration (82.8 mg morphine per day) compared to placebo (95.0 mg morphine per day). The reduction in mean morphine consumption during active treatment with diclofenac was independent of the initial dose of self-titrated morphine. Pain, self-assessed according to VAS, tended to be lower during the diclofenac period, although the difference did not reach statistical significance. No adverse events were recorded among the 15 patients who completed the study. The present findings show that a non-steroidal anti-inflammatory agent, such as diclofenac, has a morphine-sparing effect in morphine-treated patients with cancer pain.

Diclofenac sodium suppositories 150-200 mg day-1 were compared with placebo in a double-blind study during the first 3 days after uvulopalatopharyngoplasty in 40 patients with habitual snoring or obstructive sleep apnoea syndrome. Consumption of rescue analgesics (paracetamol suppositories) and pain assessed by a visual analogue scale were significantly less in the diclofenac group. Bleeding time (modified Ivy's test) and reported side effects did not differ between the two groups.

In 14 patients on hemodialysis who received kidney grafts from living related donors, plasma levels of immunoreactive atrial natriuretic factor (Ir-ANF) were determined in a sequence covering the last hemodialysis treatment, the day of transplantation, and a follow-up period of 6-12 months. The geometric mean value before dialysis was 196 pg/ml, the range 32-634. Weight loss during dialysis was 1.5 +/- 1.1 kg (mean +/- SD), but only a nonsignificant reduction in Ir-ANF levels occurred. On the day of transplantation, plasma Ir-ANF levels increased from 143 pg/ml before to 391 post-transplantation (P = 0.02, n = 12), probably in response to deliberate volume expansion. Post-transplant Ir-ANF levels correlated significantly to diuresis during the first 24 h, which ranged from 3.7 to 17.81 (mean 6.6; r = 0.65, P = 0.02). On day 2, mean 24 h diuresis decreased to 3.3 +/- 1.41. Most patients had reached their true dry weight by day 5, but Ir-ANF levels remained high, the geometric mean being 180 pg/ml. During further follow-up and preserved graft function (GFR range 34-88 ml/min per 1.73 m2 body surface area), Ir-ANF levels declined to a geometric mean of 63 pg/ml by 2-6 months and to 36 at 12 months post-transplant. We conclude that plasma Ir-ANF levels are chronically elevated in patients with chronic renal failure but may be further stimulated by acute overhydration. Transplanted kidneys initially respond to the increased levels but adapt within a day. Even with good graft function, normalization of plasma Ir-ANF requires several weeks or months.

Background: Sleep apnoea syndrome (SAS), one of the main medical causes of excessive daytime sleepiness, has been shown to be a risk factor for traffic accidents. Treating SAS results in a normalized rate of traffic accidents. As part of the COST Action B-26, we looked at driving license regulations, and especially at its medical aspects in the European region. Methods: We obtained data from Transport Authorities in 25 countries (Austria, AT; Belgium, BE; Czech Republic, CZ; Denmark, DK; Estonia, EE; Finland, FI; France, FR; Germany, DE; Greece, GR; Hungary, HU; Ireland, IE; Italy, IT; Lithuania, LT; Luxembourg, LU; Malta, MT; Netherlands, NL; Norway, EC; Poland, PL; Portugal, PT; Slovakia, SK; Slovenia, SI; Spain, ES; Sweden, SE; Switzerland, CH; United Kingdom, UK). Results: Driving license regulations date from 1997 onwards. Excessive daytime sleepiness is mentioned in nine, whereas sleep apnoea syndrome is mentioned in 10 countries. A patient with untreated sleep apnoea is always considered unfit to drive. To recover the driving capacity, seven countries rely on a physician's medical certificate based on symptom control and compliance with therapy, whereas in two countries it is up to the patient to decide (on his doctor's advice) to drive again. Only FR requires a normalized electroencephalography (EEG)-based Maintenance of Wakefulness Test for professional drivers. Rare conditions (e.g., narcolepsy) are considered a driving safety risk more frequently than sleep apnoea syndrome. Conclusion: Despite the available scientific evidence, most countries in Europe do not include sleep apnoea syndrome or excessive daytime sleepiness among the specific medical conditions to be considered when judging whether or not a person is fit to drive. A unified European Directive seems desirable. (C) 2007 Elsevier B.V. All rights reserved.

To investigate the sleep architecture and breathing as well as quality of life (QoL) in adults with GH deficiency (GHD) before and 6 months after GH replacement therapy.A prospective observational study.Nineteen consecutive adults with GHD (11 men, eight women; mean age 53, range 21-73 years) were studied.An overnight sleep study was performed and the Minor Symptom Evaluation Profile (MSEP), Functional Outcome of Sleep Questionnaire (FOSQ), Short Form 36 (SF-36) and Epworth Sleepiness Scale (ESS) questionnaires were applied at baseline and after the treatment period.For the whole group, there were no significant changes in mean total sleep time (TST; 370 min vs. 374 min), proportion of slow-wave sleep (SWS; 17.8%vs. 18.4%) and rapid eye movement (REM) sleep (12.1%vs. 13.9%) on GH replacement. Mean apnoea-hypopnoea index (AHI) was high and remained unchanged (28.2/h before vs. 28.0/h following GH replacement). Twelve patients (63%) were found to have obstructive sleep apnoea (OSA; AHIor= 10/h) at baseline. Compared with GH-deficient patients without OSA (AHI 3.9/h), the OSA patients (AHI 42.4/h) had less SWS (11.4%vs. 28.6%, P = 0.010) and REM sleep (10.1%vs. 15.5%, P = 0.036). A marginal increase was observed in REM sleep time (10.1% before vs. 12.7% after GH; P = 0.048) while SWS was unchanged in this group. Moreover, MSEP for General Well-being and Responsiveness, FOSQ scores for General Productivity, Activity Level and Vigilance as well as SF-36 domains for Vitality and Mental Health were improved.Contrary to some previous observations in a smaller group of patients, our data suggest that GH therapy does not induce or aggravate OSA in GH-deficient adults. Moreover, GH therapy may improve some of the QoL dimensions in these patients.

A large number of the population, especially the elderly, suffers from dry mouth. The aim of the present investigation was to stimulate the minor salivary glands by the topical application of the cholinesterase inhibitor physostigmine. In eight healthy subjects. 100 microl of the substance, in the concentration interval 2-8 mg/ml, was applied locally to the inside of the lower lip for 1 min. In a separate study comprising 12 dry-mouth patients. 10 ml of 0.4 1.6 mg/ml physostigmine was administered as a mouth rinse solution for 2 min. Secretion from the labial glands. assessed using the Periotron method, increased in a dose-dependent manner in response to physostigmine in both groups. Average peak secretion exceeded baseline by more than 50% throughout the 30- to 45-min observation period; from 1.71 to 2.62 microl cm(-2) min(-1) among the healthy subjects and from 1.17 to 1.84 microl cm 2 min among the dry mouth patients. No systemic effects were registered as reflected by ECG, heart rate or blood pressure. It is assumed that intraorally applied physostigmine diffuses through the oral mucosa and acts by preserving acetylcholine released from the cholinergic, parasympathetic nerves that innervate the minor salivary glands. The topical application of physostigmine to the oral mucosa may, therefore, be an interesting approach for the treatment of dry mouth.

To investigate whether a dose-effect relationship exists between the severity of obstructive sleep apnea (OSA) and subclinical indicators of myocardial or vascular dysfunction.Cross-sectional study using correlation analysis.Twenty subjects referred to our sleep laboratory for screening or therapy of OSA but without regular medication and without known cardiovascular disease.Severity of OSA was quantified by polysomnography. Moreover, nocturnal excretion of norepinephrine was determined. Left ventricular (LV) myocardial function was assessed with Doppler echocardiography. Using ultrasonographic measurements, endothelium-dependent and endothelium-independent conduit artery dilation were measured as flow-mediated and glyceryltrinitrate-induced changes in brachial artery diameter.Worsening nocturnal hypoxemia, measured as nocturnal oxygen saturation nadir or percentage of sleep time spent in hypoxemia (90% hemoglobin oxygen saturation), predicted increased interventricular septum thickness (corrected for age and body mass index), prolonged isovolumetric relaxation time, decreased ratio between peak early and late mitral flow velocities, as well as reduced endothelium-dependent dilatory capacity of the brachial artery (all relationships corrected for cofactor age and with p0.05) were observed. Associations between these cardiovascular function markers and nocturnal excretion of norepinephrine followed the same trend, but relations with interventricular septum thickness and flow-mediated artery dilation missed significance (p = 0.064 and p = 0.061, respectively). LV posterior wall thickness, measures of LV systolic function, early mitral flow deceleration time, and endothelium-independent artery dilation were not significantly related to the degree of nocturnal hypoxemia or norepinephrine excretion. None of the correlations with apnea-hypopnea index were statistically significant.The severity of apnea-related hypoxemia is associated with a gradual deterioration of LV diastolic function as well as large-artery endothelial function.

Antinociception by nonsteroidal antiinflammatory drugs, notably diclofenac and S(+)-ibuprofen, has traditionally been attributed to peripheral tissue cyclooxygenase inhibition. This study investigates the potential role of the nitric oxide system for the central antinociceptive effects of diclofenac, S(+)-, and R(-)-ibuprofen. Diclofenac and S(+)- but not R(-)-ibuprofen inhibited the behavioral response dose dependently, "biting, scratching, and licking (BSL)," induced by the spinal application of N-methyl-D-aspartate, but not that of amino-methylisoxazole-propionic acid or substance P. Diclofenac and S(+)-ibuprofen induced a parallel shift in the number of BSL responses and in the duration of the response in the behavioral model at their approximate median effective doses (diclofenac 1 mumol and S(+)-ibuprofen 5 mumol). Pretreatment with L-arginine, the natural substrate for the nitric oxide synthetase, antagonized diclofenac, and S(+)-ibuprofen-induced suppression of the biting, scratching, and licking response evoked by intrathecal N-methyl-D-aspartate. D-arginine did not antagonize the diclofenac- and S(+)-ibuprofen-induced antinociception. The study results indicate that analgesia after diclofenac and S(+)-ibuprofen involves a central mechanism which may add to the peripheral antinociceptive effect of these agents. The central action of diclofenac and S(+)-ibuprofen is partly mediated by an interaction with the N-methyl-D-aspartate receptor and nitric oxide-generating mechanisms.

To determine if obstructive sleep apnea (OSA) is independently associated with cardiovascular risk factors and health status in subjects with severe obesity.Cross-sectional analysis of epidemiological data.3034 participants in the Swedish Obese Subjects (SOS) Cohort. Two sub-groups with a high and low likelihood for OSA based on questionnaire data were analysed in detail.General health questionnaires, anthropometric data including CT calibrated values for body fat distribution and lean body mass, blood pressure, fasting insulin, triglycerides, cholesterol, uric acid, glucose.Self-reported loud snoring and observed breathing pauses (high likelihood of OSA) was associated with increased frequency of WHO Grade 4 dyspnea, admissions to hospital with chest pain, myocardial infarction, blood pressure, fasting insulin, fasting triglyceride (women only), uric acid (women only) after adjustment for body fat distribution and other potential confounders.OSA may be another medical disorder which contributes to morbidity in severe obesity and is associated with some of the components of the metabolic syndrome observed in the centrally obese.

We wanted to assess whether benzodiazepines worsen sleep apnoea, since their use in such patients has been controversial. Fourteen male patients with mild to moderate obstructive sleep apnoea were investigated in a placebo-controlled, double-blind study evaluating the influence of nitrazepam (NIT) on apnoea frequency and severity. Each patient was given oral nitrazepam 5 or 10 mg, or corresponding placebo, in a randomized order on three separate nights. Wash-out time was one week. A complete sleep study was undertaken at each study night. Eleven patients completed the study. Although there were individuals with marked variability in apnoea index between the three study nights, there was no significant change in apnoea index or minimum arterial oxygen saturation with any of the two nitrazepam dosages studied. Only 3 out of 11 patients had a higher apnoea index after both nitrazepam doses compared to placebo, and in these patients the increase in sleep-disordered breathing was of marginal clinical significance. Nitrazepam caused a modest increase in total sleep time and a decrease in rapid eye movement (REM) sleep. These results demonstrate that nitrazepam does not worsen sleep apnoea in patients with mild to moderate sleep apnoea. The previously reported sleep apnoea promoting effects of benzodiazepines may be restricted to a small subgroup of patients with sleep-disordered breathing.

Circulating immunoreactive atrial natriuretic peptide, Ir ANP(99-126) and the N-terminal fragment of the prohormone, Ir ANP(1–98) were measured in two population samples from the general population of Gothenburg, Sweden. A group of 85-year olds (974 subjects) and a group of 40-year olds (191 subjects) were investigated in respect of cardiovascular, renal and metabolic disease. Ir ANP(99-126) and Ir ANP(1-98) were significantly higher in the 85-year olds compared to tile 40-year olds, and were significantly increased in subjects with congestive heart failure, ischaemic heart disease, atrial fibrillation and renal dysfunction but not in subjects with hypertension. Eighty-five-year-old subjects who were on treatment with digitalis, β-adrenergic-blockers, nitrates and diuretics had significantly increased Ir ANP(99-126) and Ir ANP(1-98). In multivariate analysis Ir ANP(99-126) concentrations were predictive for congestive heart failure, ischaemic heart disease, atrial fibrillation and treatment with β-blockers and anti-depressant drugs. Ir ANP(1–98) was predictive for congestive heart failure, ischaemic heart disease, atrial fibrillation, diabetes mellitus, renal failure and drug treatment with β-blockers and neuroleptics. We conclude that measurements of circulating concentrations of Ir ANP(99-126) and/or Ir ANP(1-98) may add valuable information in the diagnosis of congestive heart failure and ischaemic heart disease in an elderly population. It remains to be determined whether routine measurements of circulating Ir ANP(99–126) and Ir ANP(1–98) may be of value in predicting current cardiovascular disease for the individual patient.

Local injections of the tetradecapeptide somatostatin (SOM) into the brain stem region were performed in anesthetized and decerebrate rats. SOM administration (0.6-1.8 nmol) into the nucleus paragigantocellularis and the nucleus reticularis lateralis of the ventrolateral medulla oblongata induced ventilatory depression and apnea. The occurrence of apnea was dose dependent and attributed to the anesthetic depth, and it was seen within 60-240 s after injection. In anesthetized rats the apnea was seen as a termination or a continuous decrease in tidal volume while respiratory frequency remained unaltered. SOM-induced apnea was caused by depression of central inspiratory drive. SOM injections into the dorsal medulla were ineffective in eliciting apnea, although a ventilatory depression but no apnea was induced in the awake unanesthetized state. In addition to its effect on basal ventilation, SOM administration in the ventrolateral medulla resulted in a blunted ventilatory response to hypoxic and hypercapnic stimuli in anesthetized rats. We conclude that SOM has potent inhibitory effects on respiration that are specifically located in the nucleus paragigantocellularis and the nucleus reticularislateralis.

The comparative bioavailability of cisapride as a 30 mg suppository and three 5 mg oral tablets was investigated in 12 non-smoking, healthy male volunteers. The two formulations were administered on two separate occasions following an overnight fast, according to a randomized cross-over design. The plasma concentration of cisapride was measured over 48 h after drug administration. The 30 mg suppository exhibited a mean time to the peak plasma concentration of 3.8 h, while the tablets showed a significantly earlier peak time of 1.5 h. The maximum plasma concentration of cisapride after the 30 mg suppository (50.3 ng · ml−1) was significantly lower than after the tablets (74.3 ng · ml−1). The AUCs following the two treatments did not differ significantly from each other. The comparative bioavailability of the 30 mg cisapride suppository in relation to the three 5 mg oral tablets was 85%, with a 95%-confidence interval of 67% to 102% (not adjusted for dose). Normalizing the mean AUC by dose, the relative bioavailability of the suppository was 43% of that of the tablet. The elimination half-life of cisapride was not significantly different following the administration of the two formulations (9.3 h for the suppository and 9.8 h for the tablet).

Atrial natriuretic peptide (ANP) induces potent diuretic/natriuretic, vasorelaxing and aldosterone inhibitory effects. Increased plasma levels in congestive heart failure (CHF) have been reported. The aim of this study was to investigate plasma immunoreactive ANP (ir-ANP) levels during acute treatment of CHF. Seven patients with CHF underwent cardiac catheterization. Ir-ANP plasma levels were followed up to two h after administration of an orally given phosphodiesterase inhibitor (Milrinone); a substance with positive inotropic and peripheral vasodilating properties. In all patients cardiac output increased and cardiac filling pressures decreased markedly. Initially high ir-ANP plasma levels decreased. Our patients did not have an increased blood volume. It is concluded that plasma ir-ANP levels in the pulmonary artery rapidly decrease when atrial pressure is reduced. These data suggest that atrial pressure is the major determinant for release of ir-ANP in man and that the ability to respond quickly to changes in cardiac filling pressures is maintained in patients with severe CHF. Plasma ir-ANP levels may also become useful as an index of the degree of heart failure and serve as a tool in monitoring response to drug therapy.

To investigate the antihypertensive effect of moderate sodium restriction, the sodium intake of 11 male outpatients was reduced by 120 mmol/day for 4-6 weeks. These patients and an untreated control group were slightly obese and had mild untreated hypertension (WHO 1-2). All subjects were examined before and at the end of the experiment. Diastolic blood pressure fell significantly in the diet group in comparison with the control group. Invasive haemodynamic examinations in the diet group showed an unchanged mean cardiac output and a reduction of mean total peripheral resistance. Plasma volume (Evan's Blue) did not change, neither did extracellular volume as calculated from determinations of tritiated water, total body potassium and body mass. During sodium restriction, plasma renin activity and urinary aldosterone excretion significantly increased. Noradrenaline and dopamine excretion in urine showed no significant changes during sodium restriction, neither did the plasma concentrations of atrial natriuretic peptides. The reduction in mean arterial blood pressure was correlated significantly with a decrease in 24-h sodium excretion and an increase in urinary aldosterone excretion. In conclusion, moderate dietary sodium restriction seems to lower blood pressure by diminishing the total peripheral resistance while cardiac output, extracellular and intravascular volumes are maintained.

Fistula formation between the appendix and adjacent organs is a rare condition. Cutaneous fistulas occur even more seldom. In this paper a case will be described where a fistula was formed between the appendix and the right buttock.

Spontaneously hypertensive rats (SHR) were subjected to right atrial appendectomy (ATRX) or sham operated. Five days after this procedure the rats were put on tap water or 1.5% NaCl as drinking water for 1 week. The blood pressure (carotid artery), 24 hours urinary sodium and kalium excretion, plasma levels of immunoreactive atrial natriuretic peptide (ir-ANP) and the rise in plasma ir-ANP concentrations after an acute volume expansion by homologous whole blood (10%) were evaluated after 1 week on the different diets. At the start of the dietary period the rise in plasma ir-ANP values was blunted in ATRX rats. After 1 week the salt loaded animals excreted tenfold more sodium than control rats. At this time basal ir-ANP values in plasma were not significantly influenced by the ATRX and/or the high salt diet but the rise in plasma ir-ANP concentrations to acute volume expansion was blunted in the salt loaded rats. However, the basal blood pressure was not influenced by the salt diet and/or the ATRX. These data do not support the notion that an alleged defieciency in ANP release mechanisms in the SHR is a major determinant for the blood pressure development in this rat strain.

The adenosine agonist N6-phenylisopropyladenosine (PIA) was given intraperitoneally to preterm rabbit neonates (29 days gestational age). 1 mg i.p. induced a marked respiratory depression and irregular breathing which could be prevented or antagonized by administration of theophylline. The results indicated a central nervous site of action and it is hypothesized that central adenosine overactivity may have a pathophysiological significance for the irregular breathing or apnea of prematurity sometimes seen in the human neonate.

Rats lightly anesthetized with halothane were treated with graded intraperitoneal doses of gamma-hydroxybutyric acid (GHBA), a GABA analogue. The drug induced a dose dependent decrease in minute ventilation, mainly due to reduced respiratory frequency. A reduced pH in arterial blood was recorded. GHBA also blunted or abolished the respiratory response to CO2 exposure in a dose-related way. Picrotoxin (0.25, 0.5 or 1.0 mg/kg intravenously), a presumed GABA antagonist did not significantly change the respiratory pattern when given alone but clearly antagonized the GHBA-induced respiratory depression. It is concluded that GABA-ergic mechanisms are involved in central respiratory control.

The effects of substance P (SP) on respiratory regulation were studied in halothane-anesthetized rats. Intracerebroventricular injections of SP in the dose range 3 to 30 micrograms (3 X 10(-9) to 3 X 10(-8) mol) induced a dose-dependent stimulation of minute ventilation due to an increase in tidal volume although respiratory frequency was slightly decreased. Inspiratory drive (tidal volume/inspiratory time; P0.1) increased whereas respiratory duty cycle (inspiratory time/total cycle duration) remained unchanged. Animals subjected to bilateral vagotomy showed a similar response to i.c.v. SP with the exception that the increase in tidal volume was less pronounced and inspiratory time/total cycle duration was decreased. When applying the occluded breath technique it was found that maximum pressure indicating inspiratory off-switch threshold mechanisms was increased in vagi-intact animals after SP. Furthermore, SP altered the vagally mediated control of the length of the inspiratory phase and induced a shortening of the bulbopontine setting for inspiratory time. A biphasic circulatory response with an initial depressor effect followed by a slight pressor effect was also seen after i.c.v. SP. It is concluded that SP interacts with the respiratory control system by at least two different mechanisms, bulbopontine time setting and inspiratory off-switch mechanisms. SP may also directly increase central inspiratory activity.

The atrial natriuretic peptides (ANP) are a family of newly discovered peptides which are released from atrial tissue and have potent diuretic/natriuretic, vasodilating and aldosterone inhibitory properties. Plasma concentration of ANP was measured and related to haemodynamic changes after acute blood volume expansion (10 and 20%) in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Acute blood volume expansion resulted in an increase in central (CBV) and peripheral blood volume (PBV), central venous pressure (CVP), stroke volume (SV) and cardiac output (CO), while total peripheral resistance (TPR) and heart rate (HR) were decreased. Mean arterial pressure (MAP) was unchanged. There were larger increases in CBV, CVP and CO in SHR than in WKY rats. In contrast, the increase in PBV and the decrease in HR were more marked in the WKY rats. Basal plasma ANP concentrations were similar in both groups. Blood volume expansion caused a linear increase in plasma ANP in the WKY rats, while the increase in plasma ANP concentration was attenuated in the SHR. It is concluded that acute blood volume expansion is more centralized in the SHR than in the WKY rats. Interestingly, the ANP release in response to blood volume expansion seems to be attenuated in SHR compared with WKY rats, as maximal plasma ANP concentrations were found at 10% volume load.

The respiratory activity in newborn preterm (29 days gestation) rabbits was studied after administration of thyrotropic releasing hormone. Intraperitoneal injection induced an increase in respiratory frequency (f) and a decrease in tidal volume (VT) resulting in a slight increase in pulmonary ventilation (VE). These effects were seen in parallel to a decrease in expiratory time (TE) and respiratory time (TTOT). An increase in the TI/TTOT ratio but (unaffected) VT/TI ratio indicates that thyrotropic releasing hormone affects "respiratory timing" mechanisms rather than "inspiratory drive." The changes in respiratory parameters are most probably due to an effect on the central respiratory controlling centers in the brain stem.

Neuropharmacological mechanisms in central regulation of respiration in anesthetized rats were studied in a whole body plethysmographic model. Neurotransmitter agonists and antagonists were administered intracerebroventricularly or locally into the brain and the respiratory pattern was analysed. The four anesthetics: enflurance (E), halothane (H), pentobarbital sodium (P) and urethane (U) were found to have different effects on central respiratory regulation. Respiratory frequency was higher after H and U compared to after E and P. Animals anesthetized with H exhibited a lower inspiratory drive and a slightly depressed sensitivity to CO2. The responses to the neuropeptides substance P and TRH as well as the amino acid neurotransmitter GABA were partly modified after the different forms of anesthesia. Apomorphine (i.c.v) induced a biphasic, haloperidol reversible, respiratory response in H- and U- (but not in E- and P-) anesthetized rats. The initial bradypnoic response might be due to a decreased sensitivity to afferent vagal signals, while the following tachypnoic phase might be elicited by dopaminergic mechanisms at posterior diencephalic and upper midbrain levels (hypoxic, hypercapnic tachypnea). The tachypnoic response was inhibited by a graded exposure to CO2. The effects of different neurotransmitters were further analysed in H-anesthetized animals. GABA and the GABA agonist muscimol exerted a depressant effect on ventilation in contrast to the GABA-like drugs GHBA an baclofen. Exogenous GABA depressed all respiratory parameters studied exept for inspiratory time and was found to affect mainly respiratory timing mechanisms. An increase in endogenous GABA levels induced by the GABA transaminase inhibitor AOAA blunted the respiratory response to CO2 and induced a ventilatory depression similar to that seen after exogenous GABA. A significance correlation between brain stem GABA levels and respiratory duty cycle was found. The tripeptide TRH induced a marked tachypnea due to the extrahypothalamic actions of the peptide. A delay in the response was seen after local injection into the nucleus tractus solitarius and the tachypnea was abolished by CO2 exposure. The ventilatory effects might be elicited by mechanisms similar to those involved in the tachypnoic response to apomorphine. The tachypnea was potentiated by GABA (possibly due to that both agents act on inspiratory off-switch lowering mechanism) and by methylatropine or naloxone (possibly due to secondary pertubation by cholinergic or enkephalinergic mechanisms). A stimulation of ventilation (increase in tidal volume) was seen after substance P (SP) due to an increase in inspiratory drive and o

The neuropharmacological effects of capsaicin (CAPS) (8-methyl-N-vanillyl-6-nonenamide) have been closely linked to the peptide neurotransmitter substance P (SP). In order to elucidate SP mechanisms in peripheral and central control of breathing we have studied the respiratory effects of CAPS and SP administration to neonatal and adult rats using a whole body plethysmographic method. CAPS (3 and 30 micrograms) induced an immediate apnea after intravenous injection. This effect could be reduced by vagotomy but not further changed by combined vagotomy and glossopharyngectomy. The apnoic periods were followed by periods of tachypnea. Intracerebroventricular (i.c.v.) administration of CAPS resulted in an increased tidal volume (VT) and a decreased respiratory frequency (f), i.e. a respiratory response similar to that seen after i.c.v. SP. No apnoic episodes were seen after i.c.v. injection. The respiratory pattern after acute i.c.v. CAPS administration was not significantly changed by neonatal CAPS pretreatment. However, while saline pretreated control animals responded to an i.c.v. injection of SP with an increase in VT and inspiratory drive (VT/TI), animals pretreated with CAPS responded with a shortening of inspiratory and expiratory time in combination with an increase in VT. Similar changes have been observed in vagotomized animals after SP administration. It is concluded that CAPS elicits apnea via mechanisms located outside the CNS, which cannot be fully deafferented by combined vagotomy and glossopharyngectomy. Furthermore, CAPS i.c.v. induces a stimulation of respiration by a central mechanism of action, possibly due to a release of SP. Neonatal pretreatment with CAPS modifies the respiratory response to i.c.v. SP. This effect might be due to an impairment in tonical afferent SP mechanisms to the central respiratory regulating system and possibly also to an impairment of central SP mechanisms involved in respiration.