Biomedical subjects

T Hedner

Publications and source records attributed to T Hedner.

At least 361 records · Page 20Linked to original sources

PubMed1984

Short-term effects of felodipine, a new dihydropyridine, in hypertension.

Felodipine, a dihydropyridine, is a new vasodilating calcium antagonist which lowers blood pressure (BP) by selective action on vascular smooth muscle, especially in the resistance vessels. The effects on BP, heart rate (HR) and tolerance of different single oral doses of felodipine were studied in two series of hypertensive patients. When felodipine was given as single drug to 14 previously untreated hypertensives in a single-blind manner, BP was rapidly reduced by about 15% while HR increased by 25%. Felodipine given in a double-blind manner to eight patients on chronic beta-adrenoceptor blockade reduced BP by some 15-20% compared to placebo, while HR did not change. There was a significant correlation between the pre-treatment mean arterial BP (MAP) and the maximal relative change in MAP, i.e. the higher the initial BP the greater the reduction after felodipine. A significant correlation was also found between the plasma concentration of felodipine and the relative change in MAP. Felodipine was generally well tolerated. When given alone felodipine caused the side effects expected from a pure vasodilator, i.e. headache, flushing and palpitations. When given together with a beta-adrenoceptor blocker, the side effects were much less apparent.

Adult↗

PubMed1984

Ketanserin in combination with beta-adrenergic receptor blocking agents in the treatment of essential hypertension.

The antihypertensive properties of ketanserin, a 5-HT2 receptor antagonist, was investigated in combination with beta-adrenoceptor blockade. Ketanserin was given 40 mg twice daily to 10 hypertensive patients during 4 weeks in a double-blind placebo-controlled trial. Ketanserin significantly reduced supine and erect blood pressure compared to double-blind placebo, while no changes in heart rate were seen. When the blood pressure was assessed during 24 h at steady state conditions, the blood pressure reduction was maximal 1-2 h after tablet intake, corresponding to peak plasma concentrations of ketanserin. The blood pressure remained significantly reduced until next tablet intake (12 h). At steady state, on a 40 mg twice daily regimen, Css was 41.6 +/- 4.22, 36.9 +/- 5.19 and 39.8 +/- 4.81 ng/ml, Cmax 102.4 +/- 15.64 ng/ml and tmax 1.6 +/- 0.32 h. A slight sedation was observed in six patients. This side effect occurred 1-2 h after tablet intake and tended to subside with continued treatment.

Adrenergic beta-Antagonists↗

PubMed1984

An analysis of the mechanism by which gamma-aminobutyric acid depresses ventilation in the rat.

Intracerebroventricular administration of gamma-aminobutyric acid (GABA) or intraperitoneal injection of the GABA transaminase A inhibitor aminooxyacetic acid (AOAA) depressed ventilation in halothane-anesthetized rats. The depression was due to changes in both respiratory frequency (f) and tidal volume (VT) after GABA, whereas AOAA decreased only f. Intracerebroventricular GABA decreased inspiratory drive (VT/TI; intrapulmonary pressure at 100 ms) but did not change the bulbopontine setting of inspiratory duration (TI). Moreover, respiratory duty cycle (TI/TT) was decreased, and the ventilatory response to CO2 exposure was blunted. The ventilatory depression induced by GABA was reversed by the GABA antagonist bicuculline. The GABA content measured 45 min after AOAA administration was significantly increased in the whole brain, the hemispheres, striatum, and lower spinal cord regions. Whole-brain GABA content was significantly correlated to the changes in f, minute ventilation, TI, expiratory duration (TE), and total cycle duration. Furthermore, there was a significant negative correlation between brain stem GABA content and TI/TT but not VT/TI. In summary, GABA seems to interact with the central regulation of respiration at different levels in the brain. The main effect of increased endogenous concentrations of GABA is, however, a decrease in respiratory frequency due to a prolongation in TE.

Aminooxyacetic Acid↗

PubMed1984

Experience with ketanserin, a serotonin (S2) antagonist, in longterm treatment of essential hypertension.

Ketanserin ia a quinazoline derivative which acts selectively on serotonin (S2) receptors. The compound has been shown to possess antihypertensive properties. BP and HR were measured blindly on 14 patients with essential hypertension during one year. Ketanserin 40 mg, once or twice daily, reduced BP (and HR to a slight extent) largely unchanged from 14 days after initiation of therapy. Response rate varied from 57-77% at the regular control visits. During the one year follow up period the reduction in supine SBP was 9 +/- 3% (p less than 0.001) and DBP was 12 +/- 1% (p less than 0.001). The only side effect was a slight sedation that passed with time. It is concluded that ketanserin is effective in the chronic treatment of hypertension and may offer a new alternative to existing pharmacotherapy.

Adult↗

PubMed1984

Interaction of substance P with the respiratory control system in the rat.

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.

Animals↗

PubMed1984

Transfer of terbutaline across the human placenta in late pregnancy.

Placental transfer of terbutaline was studied in 22 women in late pregnancy who were delivered by elective Caesarian section. A single i.v. dose of terbutaline (0.25 or 0.5 mg) was given at various times (13-295 min) before delivery. Immediately after delivery, one blood sample was drawn from the placental side of the umbilical vein and one from the mother's antecubital vein. By use of gas chromatography plus mass spectrometry terbutaline was assayed in maternal plasma and in plasma and whole blood from the umbilical vein. Plasma concentrations in the mothers (Cmv) were initially 7 micrograms/L, while the highest umbilical venous level ( Cuv ) recorded was 3.5 micrograms/L. The ratio Cuv /Cmv increased continuously during the time interval studied and approached unity after 2-3 h. The blood:plasma concentration ratio in venous umbilical blood was initially low. It reached unity after about 60 min, but increased steadily to about 1.5 during the time of study. Thus there was a continuous uptake of terbutaline from plasma into the erythrocytes. The slow in vivo equilibration of terbutaline between plasma and erythrocytes is probably due to the low lipophilicity of the drug. However, the latter characteristic did not seem to impede its diffusion across the placenta to any great degree.

Adult↗

PubMed1984

Effects of theophylline on adenosine-induced respiratory depression in the preterm rabbit.

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.

Adenosine↗

PubMed1984

Weight-reducing diets: role of carbohydrates on sympathetic nervous activity and hypotensive response.

Two groups of obese, normotensive men were put on weight-reducing diets in an outpatient study. The groups were comparable with regard to age, weight, heart rate, blood pressure, energy and salt intake during a four-week control period. In a four-week dieting period, Gp I (n = 12) received an energy-reduced diet (1370 kcal, 5.7 MJ) with 24 energy per cent carbohydrates. Group II (n = 11) had an isocaloric diet (1400 kcal, 5.8 MJ) with 59 energy per cent carbohydrates consisting of mainly mono- and disaccharides. Significant decreases in systolic blood pressure, heart rate, plasma noradrenaline and urinary excretion of noradrenaline were observed in Gp I but not in Gp II. Weight reduction and decrease of urinary sodium output was equal in both groups. No difference in alcohol consumption was recorded. We conclude that in obese normotensive patients a high proportion of mono- and disaccharides counteracts the expected hypotensive response of weight reduction. On the other hand, and judged from the present data, the blood pressure decrease observed in the group on a low carbohydrate diet seems to be secondary to an effect on the sympathetic nervous system.

Adult↗

PubMed1983

Effects of taurine and a taurine antagonist on some respiratory and cardiovascular parameters.

Respiratory performance, heart rate and blood pressure were studied in halothane anesthetized rats after administration of taurine and the putative taurine antagonist 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1, 1-dioxide hydrochloride (TAG). Intracerebroventricular (i.c.v.) taurine depressed ventilation due to decreased inspiratory neural drive and depression of respiratory timing mechanisms. I.c.v. administration of 1-100 micrograms TAG caused no changes in the respiratory and circulatory parameters studied except at the highest dose interval where respiratory frequency and minute ventilation were depressed. The respiratory depression induced by taurine (0.2 mg) or beta-alanine (1 mg) was antagonized by administration of TAG (100 micrograms). However, TAG did not antagonize the respiratory effects induced by i.c.v. glycine or gamma-aminobutyric acid (GABA) in equipotent respiratory depressant doses. The decline in inspiratory neural drive as well as in "respiratory timing" after i.c.v. taurine was restituted toward control values by TAG. The hypotension and bradycardia induced by taurine were also antagonized by TAG. It is concluded that TAG seems to antagonize the depressant action of taurine and beta-alanine but not of GABA and glycine on respiratory performance. TAG might also possess some partial agonist activity in higher doses.

Animals↗

PubMed1983

Central respiratory and cardiovascular effects in the rat of some putative neurotransmitter amino acids.

Respiratory performance was studied in halothane anesthetized rats after intracerebroventricular (i.c.v.) injection of beta-alanine, taurine or glycine (0.01--1 mg). The amino acids induced a marked decrease in both respiratory frequency (f) and tidal volume (VT), which was immediate and longlasting. The respiratory depressant action of glycine could readily be reversed by strychnine, a glycine antagonist. Measurement of respiratory time intervals, inspiratory time (TI), expiratory time (TE) and total cycle duration (TTOT), after administration of the putative neurotransmitter amino acids revealed that the effects on f were due to prolongation of the duration of expiration. The duration of inspiration was principally unaltered, but mean inspiratory flow (VT/TI) and respiratory timing (TI/TTOT) decreased. In experiments employing the occluded breath technique, P0.1 was reduced in the same magnitude as the mean inspiratory flow (VT/TI). The results also showed a change in central (bulbopontine) setting for TE, while the setting to TI was unaltered. An inert amino acid, valine, which was administered i.c.v. in the same doses, had no effects on respiratory parameters. Apart from the effects on basal ventilation of beta-alanine, taurine and glycine, the CO2 induced respiratory response was blunted. These three amino acids also depressed heart rate and mean arterial pressure. Although relatively high doses were used to induce the respiratory effects, it may be hypothetised that the putative neurotransmitters beta-alanine, taurine and glycine may have a physiological role in the central regulation of breathing.

Amino Acids↗

PubMed1983

Felodipine--a new vasodilator, in addition to beta-receptor blockade in hypertension.

In a double-blind, cross-over trial, 10 men with primary hypertension, not adequately controlled with a beta-blocker alone, were also given felodipine or placebo for periods of one week. Placebo was administered single-blind for 2 weeks and 1 week, respectively, before randomization and between treatments. The dose of felodipine ranged from 6.25 mg to 25 mg. The addition of felodipine resulted in a pronounced (20%), statistically significant reduction in blood pressure (BP) and a small but significant increase in heart rate (HR). The effects were seen within 1-2 h and were maximal after 3-4 h. During steady state treatment the duration of BP reduction was at least 12 h. No orthostatic reaction was seen. There was a significant correlation between the plasma concentration of felodipine and change in BP. The most frequently reported side-effects were headache and ankle oedema, the latter probably being due to pronounced pre-capillary vasodilatation. There was no weight increase and thus no indication of general water retention. No clinically significant change in laboratory variables and no influence on the P-Q time were seen. Thus, felodipine in combination with a beta-blocker seems to be a useful addition to the treatment of hypertensive patients whose BP is not adequately controlled with a beta-blocker alone.

Adrenergic beta-Antagonists↗

PubMed1983

Ketanserin in essential hypertension: effects during rest and exercise.

Ketanserin is a new, specific serotonin receptor blocking agent, which causes vasodilatation, presumably by an action on the vascular wall. The antihypertensive response to ketanserin 40 mg twice daily as monotherapy was assessed in 8 patients with essential hypertension. The investigation was an 8 week, double-blind, cross over study, which also included measurements during isometric (handgrip) and dynamic exercise (bicycle ergometry), as well as determination of plasma catecholamines and ketanserin. Ketanserin caused a reduction of supine and standing systolic and diastolic blood pressure (BP) during rest and a slight bradycardia. Although there was attenuation of the pressor response to handgrip, treatment with ketanserin did not really affect the changes in BP or heart rate during exercise, i.e. the base-line differences remained the same. There was no significant correlation between the effect on BP and the plasma level of ketanserin. The changes in BP produced by ketanserin showed little correlation with the initial levels of plasma catecholamines or with alterations in those levels. Although the results did not indicate direct interference by ketanserin with sympathetic tone, the lack of reflexogenic tachycardia, as well as the lack of increase in plasma noradrenaline during hand grip, indicates at least some modulation of autonomic function. It is concluded that ketanserin lowers BP in essential hypertension without interference with cardiovascular reflexes during standing or exercise, and that the compound may offer an alternative approach in the treatment of hypertension.

Antihypertensive Agents↗

PubMed1983

Effect of gammahydroxybutyric acid on serotonin synthesis, concentration and metabolism in the developing rat brain.

5-HT synthesis, levels and degradation were investigated in the whole brain and regional brain areas in 4, 14, and 28 days old rats after administration of gammahydroxybutyric acid (GHBA). 5-HT synthesis was investigated by means of 5-HTP accumulation after decarboxylase inhibition by NSD 1015. 5-HTP accumulation increased in the 14 and 28 days old rats but decreased in the 4 days old animals 90 min after GHBA, 750 mg/kg. In the 28 days old rats a corresponding increase was also noted in the precursor amino acid tryptophan. Regional and whole brain 5-HT levels were not altered by GHBA treatment. Regional as well as whole brain levels of 5-HIAA increased in the 14 and 28 days old rats after GHBA administration. In conclusion, the present data indicate that GHBA increases the synthesis and degradation of 5-HT in adolescent rats. These effects of GHBA were not seen in the neonatal animals.

5-Hydroxytryptophan↗

PubMed1983

Pharmacokinetic aspects of epidural morphine analgesia.

Twenty patients undergoing thoracotomy were given 2, 4, or 6 mg morphine epidurally in a double-blind, randomized study for postoperative analgesia. Administration at T12-L1 or L1-L2 resulted in a dose-related analgetic duration (514 +/- 118 min, 778 +/- 207 min, and 938 +/- 155 min; means +/- SEM, respectively, for the groups). For the three groups, peak plasma morphine concentrations (range 19-34 ng/ml) were reached within 15 min. The plasma curves had a similar appearance as after an intramuscular injection and pharmacokinetic calculations showed an elimination half-life (mean +/- SEM) of 173 +/- 24 min, 200 +/- 60 min, and 213 +/- 57 min for the groups, respectively. The morphine concentrations in the CSF were considerably higher compared with plasma (45-100 times the plasma concentration at 1 h, 100-250 times at 3 h, and 125-175 times at 5 h) but the elimination half-life of morphine in the cerebrospinal fluid (CSF) was similar to that in plasma. The lumbar approach was used with similar efficacy as reported for thoracic administration. Side effects were few and nonsignificant. The authors conclude that epidural morphine administration results in a dose-dependent analgesia, as well as concentrations in the CSF that are considerably higher than in plasma. With similar elimination half-lives for morphine in CSF and plasma, the long analgetic duration probably depends on the locally high morphine concentrations achieved. For safety purposes, one may use the lumbar approach to the epidural space even for thoracic pain without reducing the efficacy.

Aged↗

PubMed1983

Circulatory effects of noise.

Thirteen patients with mild essential hypertension, mean age 44 years (range 21-59), were studied during "stress" before and after postsynaptic alpha-adrenoceptor blockade and combined postsynaptic alpha- and non-selective beta-adrenoceptor blockade. Loud broad band noise (100 dBA for 10 min) was used as the stress stimulus. Exposure to noise caused a significant increase in systolic (7%, p less than 0.05), diastolic (9%, p less than 0.01) and mean arterial pressure (6%, p less than 0.01). The blood pressure elevation was caused by an increase in total peripheral resistance (12%, p less than 0.05). There was no significant change in heart rate, stroke volume or cardiac output. The blood pressure response during noise stimulation was not affected by postsynaptic alpha-adrenoceptor blockade (prazosin, 2 mg orally). The hemodynamic reaction pattern, however, was totally reversed. Thus, the cardiac output increased significantly (9%, p less than 0.05), while the total peripheral resistance tended to decrease. Combined postsynaptic alpha- and non-selective beta-adrenoceptor blockade (labetalol, 200 mg orally) inhibited the increase in systolic blood pressure caused by noise, while the diastolic and mean arterial pressures still increased significantly (5%, p less than 0.01). Labetalol effectively blocked the stress-induced increase in total peripheral resistance and there was no significant increase in cardiac output after combined alpha- and beta-adrenoceptor blockade. Exposure to noise caused a significant increase in circulating noradrenaline (20%, p less than 0.05). Plasma adrenaline and plasma renin activity were not affected by noise stimulation. These results suggest that blood pressure elevation is essential during "stress" but that the hemodynamic pattern causing blood pressure elevation may vary and may be affected by pharmacological blockade of various parts of the sympathetic nervous system.

Adult↗

PubMed1983

Ketanserin, a novel 5-hydroxytryptamine antagonist: monotherapy in essential hypertension.

Blood pressure and heart rate, supine and standing, were studied in patients with essential hypertension during 8 weeks of oral therapy with two dosage schedules of ketanserin, 40 mg once and twice daily. Ketanserin caused significant reductions in both supine and standing blood pressure but no significant alterations in heart rate in both groups of patients. Measurements of blood pressure and heart rate over a 24 h period during steady state conditions revealed that maximal blood pressure reduction was correlated with time to peak plasma concentrations. Steady state plasma concentrations of ketanserin were significantly higher in the patients receiving 40 mg twice daily compared to 40 mg once daily. In the group with once daily treatment, tmax was 1.2 +/- 0.17 h, Css 13 +/- 4.3 ng/ml, Cmax 137 +/- 19.6 ng/ml and t1/2, z h. 9.6 +/- 1.27 h.

Adult↗

PubMed1983

Effect of terbutaline on lung mechanics and morphology in the preterm rabbit neonate.

Lung morphology, surface properties of fetal pulmonary fluid, and lung mechanics during spontaneous breathing were studied in preterm newborn rabbits after antenatal administration of terbutaline (0.1 mg). The histological evaluation of lung sections revealed increased amounts of granular eosinophilic and sudanophilic material in the terminal airspaces. The amount of fetal pulmonary fluid was decreased in terbutaline-treated animals; the fetal pulmonary fluid also showed improved surface properties, evaluated by the pulsating bubble technique. Increased dynamic lung compliance without altered air-way resistance was found in terbutaline-treated animals during the first 30 min after onset of breathing. This report demonstrates that terbutaline has an initial beneficial influence on the preterm neonatal lung, probably due to release of preformed surfactant into the alveolar spaces and to dehydration of the lung.

Animals↗

PubMed1983

Effects of TRH and TRH analogues on the central regulation of breathing in the rat.

Respiratory activity was studied in rats during light halothane anesthesia. Thyrotropin releasing hormone (TRH) and two TRH analogues: the desamidated form (TRH-OH) and gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN 1417) were administered intracerebroventricularly. TRH 0.5-5 micrograms induced a marked tachypnoea with a rapid onset and a duration of at least 20 min. DN 1417, a potent analogue of TRH with a very low TSH (thyroid stimulating hormone) releasing activity was more effective in stimulating respiratory frequency, while TRH-OH, regarded to have neither TSH releasing nor extra hypothalamic effects, at equimolar doses was unable to induce any changes in the respiratory pattern. When TRH was given into the fourth ventricle the dose response curve was slightly shifted to the left. In experiments employing the occluded breath technique, P0.1 was increased in the same magnitude as the mean inspiratory flow (VT/T1). The results also indicated an increase in the gain of the inflation reflex loop whereas the central bulbopontine setting for T1 and TTOT were not significantly changed. Local injection of TRH into the nucleus tractus solitarii induced a stimulation of respiratory frequency which was slower in onset compared to the response seen after injection into the lateral or fourth ventricles. Concomitantly to the respiratory changes, i.c.v. TRH injection induced a hypocarbia and an alkalosis. No changes in blood pressure or heart rate were seen. The respiratory stimulant effect of TRH could be potentiated by pretreatment with naloxone, methylatropine or a low dose of GABA. Haloperidol or propranolol did not significantly change the respiratory effects of TRH, while reserpine pretreatment seemed to blunt some of the ventilatory effects of TRH. It seems likely that TRH has few direct effects on brain stem neurones involved in the central regulation of respiration, but the main effects seem to be elicited in areas rostral to the brain stem. The respiratory stimulating effect of TRH is unrelated to TSH. Furthermore, other neurotransmitter systems might also be involved in modulation of the respiratory stimulation evoked by TRH.

Animals↗