Synergistic effects of ethanol and hyperthermia on carotid artery vasoconstriction.

BACKGROUND: Heatstroke is a serious condition and clinical studies indicate that vascular stroke increases with excessive consumption of alcohol (ethanol). It was our objective to test the influence of ethanol on cerebral perfusion at normal and higher temperatures. METHODS: Recording of isometric tension in rabbit carotid artery strips in organ baths with different concentrations of ethanol at 37 degrees C and during hyperthermia (39-43 degrees C) and scintigraphic cerebral imaging of a radioactive isotope in the control situation and during hyperthermia. RESULTS: Stepwise heating induced reproducible reversible graded contraction, proportional to temperature. At high concentrations (toxic levels), ethanol induced an increase in tension and heating potentiated these responses. Extracellular Mg(2+) potentiated both heat-induced contraction and ethanol-induced contraction while extracellular Ca(2+) had no effect on these responses. During hyperthermia and ethanol scintigraphic isotope uptake was reduced in cortical and cerebellar regions. CONCLUSIONS: Carotid artery vasomotor tone is temperature dependent and heating induces vasoconstriction. Alcohol (ethanol) at 37 degrees C elicited carotid artery contraction at high concentrations (toxic levels) but at any concentration during elevated temperature (39-43 degrees C). Ethanol potentiated the effect of hyperthermia-induced vasoconstriction and reduced cerebral perfusion as shown by radionuclide imaging. The synergistic effect of ethanol and hyperthermia may induce heat stroke and brain damage.

Hyperthermia-induced vasoconstriction of the carotid artery, a possible causative factor of heatstroke.

Clinical and experimental studies indicate that hyperthermia can cause heatstroke with cerebral ischemia and brain damage. However, no study has examined the direct effects of heating carotid artery smooth muscle and tested the hypothesis that hyperthermia induces arterial vasoconstriction and, thereby, decreases cerebral blood flow. We recorded isometric tension of rabbit carotid artery strips in organ baths during stepwise temperature elevation. The heating responses were tested at basal tone, in norepinephrine- and KCl-precontracted vessels, and after electrical field stimulation. Stepwise heating from 37 degrees C to 47 degrees C induced reproducible graded contraction proportional to temperature. The responses could be elicited at basal tone and in precontracted vessels. Heating decreased the contractile responses to norepinephrine and electrical field stimulation but increased contraction to KCl. These responses were not eliminated by pretreatment with the neuronal blocker tetrodotoxin. Our results demonstrate that heating carotid artery preparations above 37 degrees C (normothermia) induced a reversible graded vasoconstriction proportional to temperature. In vivo this reaction may lead to a decrease in cerebral blood flow and cerebral ischemia with brain damage as in heatstroke. The heating-induced contraction is not mediated by a neurogenic process but is due to altered transcellular Ca2+ transport. Cooling, in particular of the neck area, therefore, should be used in the treatment of heatstroke.

Is oscillometric ankle pressure reliable in leg vascular disease?

The objective of the study was to evaluate the validity of oscillometric systolic ankle pressure in symptomatic leg arterial occlusive disease. Ankle pressure measurements using oscillometric curves obtained using a standard 12-cm cuff with a specially designed device for signal processing were validated against the continuous wave (CW) Doppler technique. Thirty-four subjects without signs or symptoms of peripheral vascular disease (68 legs) and 47 patients with leg ischaemia (85 legs) varying from moderate claudication to critical ischaemia were examined. The oscillometric curves were analysed using several algorithms reported in the literature, based on the assumption that maximum oscillations are recorded near mean arterial pressure. In normals, reasonable agreement between CW Doppler and oscillometric methods was seen. When an algorithm that determined the lowest cuff pressure at which maximum oscillations occurred, and a characteristic ratio for systolic pressure of 0.52 was used, the mean difference between CW Doppler and oscillometry was 1.7 mmHg [range -19 to +27, limits of agreement (2 SD) 21.1 mmHg]. In ischaemic legs, oscillometry overestimated systolic ankle pressure by a mean of 28.8 mmHg [range -126 to +65, limits of agreement 82.8 mmHg]. The difference was more pronounced among patients with critical ischaemia compared with claudicants, and also more evident among diabetics. The error of oscillometric pressure determination in subjects with leg arterial disease inversely increased with CW Doppler ankle pressure. In 39% of the recordings in legs with a CW Doppler systolic pressure below 100 mmHg, the oscillometric mean arterial pressure was higher than the recorded CW Doppler systolic pressure. In conclusion, the oscillometric method to determine systolic ankle pressure, based on the concept of maximum cuff oscillations occurring near mean arterial pressure, is not reliable in leg arterial disease, usually overestimating ankle pressure.

Cooling-induced gastrointestinal smooth muscle contractions in the rat.

The aim of this study was to assess the effect of cooling on smooth muscle contraction in various parts of the gastrointestinal tract (esophagus, stomach, duodenum, jejunum and colon) and to investigate the basic mechanism underlying cooling-induced (CIC) tonic and rhythmic contractions. Recordings of isometric tension from smooth muscle strips of different parts of the rat gastrointestinal tract were performed using organ-bath techniques, and stepwise cooling was applied. Cooling was tested before and after the addition of various standard agents interfering with known neurogenic (autonomic blockers, tetrodotoxin, capsaicin) and myogenic mechanisms of contraction (calcium channel blockers, Sarcoplasmatic and Ca2+-ATPase pump inhibitors). Step-wise cooling (37 degrees C to 5 degrees C) of all gastrointestinal smooth muscle preparations induced reproducible graded tonic contractions, inversely proportional to temperature. CIC was most pronounced in the jejunum. Cooling abolished rhythmic smooth muscle activity. CIC was not dependent on a neural mechanism nor the release of neurotransmitters, but linked to translocation of calcium. It was reduced by incubation in Ca2+-free solution. Blockage of the Ca2+-ATPase pump, which inhibits the extrusion of calcium, plays a significant role in the process and enhances CIC. Cooling of gastrointestinal smooth muscle preparations induces graded myogenic contractions inversely proportional to the temperature. The mechanism is not dependent on local nervous control but related to a temperature-sensitive process of calcium translocation.

Cooling is a potent vasodilator of deep vessels in the rat.

The objectives of this study were to determine the effect of cooling on smooth muscle tone of the pulmonary artery and aorta and to clarify the basic mechanism of these responses. We recorded isometric tension in smooth muscle strips of rat pulmonary artery and aorta in organ baths during stepwise cooling. Cooling responses were tested before and after the addition of various standard agents that interfere with known neurogenic (autonomic blockers, tetrodotoxin) and myogenic mechanisms (calcium channel blockers) of relaxation. We also examined the hypothesis of the presence of a cooling-released substance. Stepwise cooling (37degrees C to 4 degrees C) of aortic smooth muscle induced reproducible graded relaxations that were inversely proportional to temperature. Cooling-induced relaxation was not dependent on a neural mechanism nor the release of neurotransmitters or a cooling-released substance such as NO or CO. Cooling of pulmonary arterial and aortic smooth muscle preparations induced a graded myogenic relaxation inversely proportional to the cooling temperature. The mechanism is not dependent on local nervous or known mediators but related to a direct physico-chemical effect of cooling.

Blood pressure and cardiovascular autonomic function in healthy children and adolescents.

OBJECTIVES: To investigate the relationship between blood pressure levels and cardiovascular autonomic function in adolescents and preadolescents. STUDY DESIGN: We measured variability of beat-to-beat arterial pressure and R-R intervals using power spectral analysis in 56 adolescents (aged 13-16 years; mean age, 9.0 +/- 1.4 years) and 71 preadolescents (6-12 years; mean age, 13.5 +/- 1.1 years) in the supine and standing positions. RESULTS: Adolescents had higher levels of systolic arterial pressure and lower high-frequency power of RR intervals than preadolescents. Correlation between the basal level of arterial pressure and autonomic function was observed in adolescents but not in preadolescents. In adolescents, multivariate analysis indicated that the basal level of arterial pressure was inversely related with the high-frequency power of RR intervals and positively with the ratio of low-frequency and high-frequency power. No significant relation was found in preadolescents. During standing, adolescents had a more marked increase in diastolic arterial pressure, heart rate, low frequency of R-R intervals, and low frequency of arterial pressure compared with those of preadolescents. Changes in diastolic pressure showed a significant negative correlation with changes in high frequency of R-R intervals. CONCLUSION: Cardiovascular autonomic function plays an important role in increasing blood pressure levels associated with increased modulation of vagal tone of the heart after puberty but does not in the preadolescent.

Functional characterization of beta-adrenoceptors mediating relaxation in sheep gallbladder.

The purpose of this study was to characterize beta-adrenoceptor subtype(s) mediating relaxation in smooth muscle strips of the sheep gallbladder. Experiments were performed on isolated smooth muscle strips suspended in tissue baths containing Krebs' solution. Isoprenaline (10(-8) M-10(-5) M) and salbutamol (10(-7) M-10(-4) M) produced concentration-dependent relaxation of carbachol (10(-7) M-3 x 10(-7) M) contracted smooth muscles of the sheep gall bladder. Isoprenaline-induced relaxation was significantly antagonized by propranolol with -logKB values of 7.81 +/- 0.11 (n = 7) and 7.73 +/- 0.12 (n = 6) in the fundic and ductal strips respectively. Atenolol (10(-5) M), a selective beta 1-adrenoceptor antagonist, also significantly antagonized isoprenaline-induced relaxation with -logKB values of 5.82 +/- 0.11 and 6.09 +/- 0.09 in the fundic and ductal strips respectively. However, ICI 118551, a selective beta 2-adrenoceptor antagonist, at concentrations up to 10(-6) M had little or no effect on isoprenaline-induced relaxation in either of these preparations. BRL 37344A, a selective beta 3-adrenoceptor agonist produced concentration-dependent relaxation of carbachol-precontracted fundic and ductal strips. BRL 37344 was approximately 9-fold more potent in the ductal than fundic strips. In both preparations, BRL 37344-induced relaxation was not significantly (p > 0.05) antagonized by propranolol (3 x 10(-7) M). This would confirm that the response was mediated via beta 3-adrenoceptors. It was concluded that beta 1- and beta 3-adrenoceptors coexist in the sheep gallbladder and mediate smooth muscle relaxation.

Forskolin reverses tachyphylaxis to the bronchodilator effects of salbutamol: an in-vitro study on isolated guinea-pig trachea.

The objective of this study was to assess the relaxant responses of salbutamol, a beta2 agonist, and forskolin, an activator of adenylate cyclase, and the possible role of forskolin in reversing tachyphylaxis to salbutamol. The in-vitro bronchodilator effects of salbutamol and forskolin (10(-9)-10(-5) M) were tested on isolated guinea-pig tracheal rings precontracted with carbachol (10(-7) M). Both salbutamol and forskolin elicited concentration-dependent relaxation. Potency (EC50; the dose resulting in 50% relaxation) was determined from cumulative concentration-response curves. Salbutamol was more potent than forskolin in relaxing the tracheal preparations (-log molar EC50 7.68+/-0.14 and 6.3+/-0.17, respectively). Reproducible relaxant responses to salbutamol could be elicited after 24 h incubation in Krebs solution. Tachyphylaxis to the relaxant effects of salbutamol was experimentally induced by incubation (24h) of the preparations in Krebs solution containing salbutamol (10(-6) 3x10(-6) or 10(-5) M). This pretreatment of the tissues resulted in a significant reduction in the potency of salbutamol. The potency of salbutamol was reduced to 6.85+/-0.2, 6.8+/-0.1 and 5.9+/-0.27 after 24h incubation with salbutamol 10(-6), 3x10(-6) or 10(-5) M, respectively. The potency of salbutamol was increased from 7.35+/-0.2 to 7.76+/-0.28 by addition of forskolin (3x10(-7) M) under control conditions. Moreover, forskolin (3x10(-7) M) reversed the development of tachyphylaxis to salbutamol-induced relaxation in tissues pretreated with salbutamol. The potency of salbutamol was increased to 7.29+/-0.41, 7.37+/-0.17 and 7.23+/-0.35 after the addition of forskolin (3x10(-7) M) to preparations pre-incubated (24h) with salbutamol 10(-6), 3x10(-6) or 10(-5) M respectively. These results show that in guinea-pig tracheal ring preparations, forskolin shares with salbutamol the ability to relax airway smooth muscle and produces an apparent reversal of tachyphylaxis to the bronchodilator effects of salbutamol, particularly in the low concentration range. This effect could provide an alternative therapy for long term use, particularly with high doses of beta2 agonists in bronchial asthma.

Cooling-induced bladder contraction: studies on isolated detrusor muscle preparations in the rat.

OBJECTIVES: Detrusor muscle contraction and uninhibited micturition after intravesical instillation of ice water is interpreted as a sign of upper motor neuron lesions. The basic mechanism of cooling-induced contraction (CIC) at the level of smooth muscle, however, has not been satisfactorily explained. We therefore designed model experiments with cooling of rat detrusor muscle. METHODS: We recorded isometric tension from strips of rat urinary detrusor muscle in organ baths during stepwise cooling. CIC was tested before and after addition of various standard agents interfering with known neurogenic (autonomic blockers, tetrodotoxin, capsaicin) and myogenic mechanisms of contraction (calcium channel blockers). RESULTS: Stepwise cooling (37 degrees to 5 degrees C) of detrusor muscle induced reproducible graded contractions, inversely proportional to temperature. CIC was not dependent on a neural mechanism (not blocked by tetrodotoxin or capsaicin) or the release of neurotransmitters but was linked to translocation of calcium. It was reduced by calcium channel blockers and Ca(2+)-free solution. Blockage of the Ca(2+)-adenosine triphosphatase pump, which inhibits the extrusion of calcium, also plays a significant role in the process and enhances CIC. CONCLUSIONS: Cooling of detrusor muscle preparations induces a graded myogenic contraction inversely proportional to the temperature. The mechanism is not dependent on local nervous control but is related to calcium translocation.

Postmastectomy lymphoedema. Treatment and a five-year follow-up study.

BACKGROUND: Lymphoedema of the arm is a common problem after mastectomy and radiotherapy of mammary cancer. In a prospective 5-year follow-up study we investigated the development of arm oedema and the effect of conservative compression treatment. METHODS: Two hundred and twenty-six patients who had undergone mastectomy were investigated. Oedema formation was estimated by recording displaced water volume of both arms preoperatively and six times post-operatively. One hundred fifty-seven patients (70%) could be followed for five years. An inter-arm difference of 100 ml or more was defined as oedema. Three types of treatment were given: (1) Compression with stockings in 28 patients, (2) intermittent compression (Flowtron) in 8 and (3) intermittent compression (Lympha-Press) and compression sleeves in 19 patients. RESULTS: A total of 46 patients (20%) developed post-operative oedema, 17 within six months and 29 one year postoperatively. The average oedema volume was 418 ml. Most patients with a moderate or severe oedema had irradiation therapy. Severe lymphoedema (750 ml or more) occurred in patients with irradiation postoperatively and lymph node engagement. There was no correlation between patient age and oedema formation. Compression therapy with stockings reduced oedema in 15 out of 28 patients (54%) and prevented further swelling. Therapy with stockings and Lympha Press reduced the arm volume in 13 out of 19 patients (68%). Four out of eight patients treated with Flowtron showed oedema reduction. In most patients cessation of treatment resulted in relapse of swelling to the same degree as before. CONCLUSIONS: Compression therapy is beneficial to control postmastectomy arm swelling. This applies to different modalities and prolonged periods of treatment are required to check progression. Application of stockings is the simplest way to treat postoperative oedema. In most cases postoperative oedema appeared during the first year after surgery and the most severe cases occurred after irradiation.

Neurogenic control of the ovine gallbladder: ultrastructural and functional study.

The purpose of this study was to investigate the ultrastructure of the local nerve supply of ovine gallbladders as well as the functional characteristics of inhibitory nerves. We used electron microscopy of thin sections of ovine gallbladders and in vitro isometric tension recording using gallbladder strips. Specifically, we measured contractile and inhibitory responses induced by transmural electrical field stimulation (EFS). We found a ganglionated plexus with intramural nerve cells and interconnecting axons. Clear and large dense-core vesicles colocalized in axons close to smooth muscle cells. EFS elicited gallbladder contractions which were converted to relaxation after atropine. EFS-induced relaxation was reduced by the nitric oxide (NO) synthase inhibitor, L-NOARG and blocked by propranolol and/or tetrodotoxin. In conclusion, enteric ganglia and neurones with synaptic vesicles (clear and dense core) were detected close to smooth muscle bundles. Neural inhibition of gallbladder contraction was mediated by beta-adrenoceptors coupled to NO generation.

Urothelial synthesis of prostanoids in the ovine ureter.

The purpose of this study was to investigate the site of production (urothelium/smooth muscle) and quantitative release of prostanoids in the ureter. Quantitative analysis of prostacyclin (PGI2) was by its metabolite, 6-keto PGFalpha, thromboxane (TXB2) and prostaglandin F2alpha. Synthesis by radiometry and radioimmunoassay was performed in vitro in sheep ureter specimens before and after removal of the inner epithelial layer and after addition of indomethacin. The major prostanoids present in the ureter were PGI2 and TXB2; PGI2 was quantitatively the largest component. Removal of the thin inner epithelial layer (urothelium) reduced mostly PGI2; addition of arachidonic acid significantly augmented PGI2 only in ureters with intact urothelium but did not alter TXB2 levels. The main source of prostanoid synthesis (PGI2) of the ureter is to be found in the urothelium. The functional role of the prostanoids may be related to coordination of peristalsis.

Tocolytic effect of the cyclooxygenase-2 inhibitor, meloxicam: studies on uterine contractions in the rat.

The objective of this study was to assess the tocolytic activity of meloxicam, a novel cyclooxygenase-2 inhibitor, in a comparative study with the non-steroidal anti-inflammatory drug, indomethacin. The in-vitro tocolytic effect of meloxicam and indomethacin (10(-9)-10(-5)M) was evaluated on spontaneously-contracting uterine strips from non-pregnant rats and from rats at various stages of pregnancy. The rhythmic motility of the strips was reproducibly maintained over several hours. The effect of drugs was evaluated from the extent of inhibition of the frequency and amplitude of contractions. Both indomethacin and meloxicam induced dose-dependent inhibitory effects, with meloxicam being slightly more potent in all groups studied, particularly in early pregnancy. These results suggest that meloxicam, which has fewer side-effects than cyclooxygenase-1 inhibitors, could be a potentially useful tocolytic agent in the treatment of premature labour.

Autonomic function in children with type 1 diabetes mellitus.

We investigated autonomic function in 58 children and young adults with Type 1 diabetes mellitus (aged 7-22 years, duration from 3 to 18, 8.6 +/- 3.4 years) and in 74 healthy controls (6-21 years) using power spectral analysis of blood pressure and heart rate in addition to conventional standard autonomic function tests: deep breathing, the Valsalva manoeuvre, and a standing test. None of the diabetic patients were symptomatic. Reproducibility of the tests was assessed by determining the coefficient of variation in 9 controls (7.8-37.7%). Thirteen per cent of the subjects had difficulty in adequately performing the Valsalva manoeuvre. After adjustment for age, sex, body mass index, and respiratory frequency, results of the Valsalva manoeuvre and deep breathing were not different between patients and controls and there was no significant postural reduction in systolic blood pressure (> or = 20 mmHg) in the patients. Heart rate variation in the supine position during natural breathing was low in patients, although power spectral analysis of heart rate variation did not show a significant decrease in the power density in the high and the low frequency in patients compared to healthy controls. Beat-to-beat blood pressure fluctuation was significantly lower in patients and correlated with metabolic control (mean annual haemoglobin A1c), but not with disease duration and was abnormal in 7 diabetic children (12%). In contrast, tests of vagal activity were not impaired in the patients in this age range. We concluded that vagal involvement in Type 1 diabetic patients determined by spectral analysis of R-R intervals in addition to conventional tests is uncommon, but that beat-to-beat blood pressure variation was more likely to be affected.

Psychosomatic and psychosocial symptoms are associated with low blood pressure in Swedish schoolchildren.

BACKGROUND: The relation between psychosomatic and psychosocial symptoms and blood pressure was studied in Swedish schoolchildren. METHODS: Blood pressure was measured in 122 healthy Swedish schoolchildren, aged 6-16 years. Psychosomatic and psychosocial symptoms, delinquent behaviour, parental health and employment status were assessed. RESULTS: Children with systolic blood pressure above + 1 SD of mean reported significantly less symptoms (x = 1.4) than children with blood pressure below -1 SD of the mean (x = 2.7; p < 0.05). Children with three or more self-reported symptoms had significantly lower blood pressure than children without symptoms both in the supine (110 +/- 12 vs. 120 +/- 18 mm Hg; p < 0.05) and in the standing position (117 +/- 17 vs. 127 +/- 18 mm Hg; p < 0.05). CONCLUSIONS: We conclude that psychosomatic and psychosocial symptoms in children might be associated with low blood pressure.

Multiple vasoactive factors in epidermal secretions of the Arabian Gulf catfish, Arius bilineatus (Valenciennes).

1. The Arabian Gulf catfish produces proteinaceous epidermal secretions when threatened or injured. 2. The soluble fraction of the catfish epidermal secretions (SES) has vasoconstrictor activities on sheep renal arteries, which can be inhibited by several antagonists, including atropine, indomethacin, prazosin, and verapamil. 3. Mepyramine, yohimbine, and ketanserin have negligible effects on SES-induced contraction. 4. SES exhibits a significant tachyphylaxis upon addition of a second (8.4% reduction) and third (47% reduction) dose of SES to the organ bath, which can be partially prevented by addition of a fresh arterial section prior to each addition. 5. A vasoconstricting activity has been partially purified from SES by gel filtration on Fractogel HW-65(F) and appears to be a protein with a pI near 7.3. This activity is affected only by verapamil and prazosin.

Haemodynamic changes during vasodepressor syncope in children and autonomic function.

We investigated postural haemodynamic changes in 24 boys and 30 girls, aged 8-16 years, with orthostatic intolerance. During the orthostatic test, nine boys and seven girls (30%) developed a vasodepressor attack (orthostatic-positive group). The orthostatic-positive group had a more marked increase in heart rate (HR) with slightly lower systolic blood pressure than the orthostatic-negative group during standing, with no significant difference in cardiac output (CO). The shift of blood volume from the intrathoracic region to the lower part of the body determined by electrical impedance and plasma catecholamines on rising were identical in the two groups. At the onset of the vasodepressor attack, CO did not change significantly, indicating that sudden arterial vasodilatation was the cause. In a pharmacological study on autonomic function, higher sensitivity of alpha-adrenoceptor in the resistance vessels was found in the orthostatic-positive group, but there was no significant difference in the basal level of cardiac vagal and sympathetic activity and in cardiac beta-adrenoceptor sensitivity between the two groups. The stepwise regression analysis showed that the magnitude of HR increment during standing was the most useful indicator in predicting the occurrence of a vasodepressor attack. These results suggest that low sympathetic activity in the resistance vessels together with an exaggerated rise in HR during upright posture is strongly associated with vasovagal and vasodepressor attacks in children.

Heterogeneous blood flow response in the foot on dependency, assessed by laser Doppler perfusion imaging.

The exact nature of the decrease in foot skin blood flow seen after a change in posture remains unsettled. This mechanism has previously been examined by non-invasive techniques such as the laser Doppler perfusion monitor (laser Doppler flowmetry). Taking into account the shortcomings of laser Doppler perfusion monitoring when applied to the determination of skin blood flow, which normally shows substantial heterogeneity, we have applied an emerging technology, the laser Doppler perfusion imager (LDPI). This technique provides a more comprehensive picture of the blood flow distribution in the skin, as it maps skin blood flow over a surface area (120 x 120 mm, 4096 measurement sites). It was used to examine if the reduction in tissue perfusion or the alterations in flow distributions seen after a change in posture (supine to dependency) could be fully explained by an increase in venous pressure (venous stasis of 50 mmHg) or if the data suggest a complementary mechanism. Skin blood flow of the forefoot decreased from 0.60 V (volt) (median) during rest to 0.40 and 0.38 V during venous stasis and dependency, respectively. Although almost identical median values were obtained during stasis and dependency, the flow distributions were different with a loss of high flow values during venous stasis. Biological zero was 0.24 V. As the LDPI technique readily records skin perfusion during variations in venous stasis and posture, as well as information on flow distribution changes. It appears promising for future application in stimuli-response studies of skin blood flow. The difference in flow distribution seen between increased venous pressure and dependency suggests an additive regulatory mechanism to the veni-vasomotor reflex during a change in posture.