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gamma-Aminobutyric acid (GABA) concentrations in cerebrospinal fluid (CSF) were measured in 20 neonates with various gestational and postnatal ages. These concentrations varied between 9 and 45 nmol/ml which is approximately 20-100 times the concentrations found in adults. CSF GABA concentrations tended to decrease with advancing gestational age. No apparent alterations were noted with increasing postnatal age (until 6 weeks of age). Asphyxia but not neonatal sepsis was accompanied by an increase in CSF GABA concentrations compared to respective controls.

Twenty-three moderately obese middle-aged men with previously untreated hypertension (World Health Organization classification 1-2) were evaluated to assess the effects on blood pressure (BP) of a diet restricted in energy (fats and carbohydrates) but unrestricted in sodium (Group 1) compared to a diet restricted in energy and sodium (Group 2). The patients were randomly allocated to either of the two groups and were comparable in age, sex, weight, and BP. The same energy- and sodium- restricted diet was given to both groups, but the intake of Group 1 (n = 13) was supplemented with dietary sodium. The average urinary output for Group 1 was 192 +/- 39 mmol/24 hr at baseline and 200 +/- 56 mmol/24 hr during the diet. For Group 2 (n = 10), which remained on the initial diet, urinary sodium excretion changed from 188 +/- 53 mmol/24 hr at baseline to 97 +/- 32 mmol/24 hr (p less than 0.001). Intraarterial BP, cardiac output (CO), plasma volume, circulating norepinephrine (NE), and urinary NE were measured at baseline and at the end of the dieting periods. Before the dietary sodium supplement while on the initial diet, the patients in Group 2 showed a reduction in body weight from 97.3 +/- 10.5 kg to 88.6 +/- 9.9 kg (p less than 0.001). Heart rate (HR) and urinary NE output were significantly reduced in comparison with baseline, but intraarterial BP was unchanged. No change in cardiopulmonary blood volume, CO, or stroke volume (SV) was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

The respiratory performance was studied after intraperitoneal administration of the adenosine agonists N6-phenyl-isopropyl-adenosine (PIA) and adenosine- 5-ethylcarboxamide to preterm (gestational age 29–30 days) newborn halothane-anesthetized rabbits. Both agonists induced marked hypo ventilation and irregular breathing by decreases in the breathing frequency as well as the tidal volume. Expiratory time was markedly prolonged, resulting in a decrease in the respiratory duty cycle (inspiratory time/total cycle duration). Analysis using the occluded-breath technique revealed that the adenosine analogues altered the time setting of the expiratory (inspiratory) neuronal circuits and lowered the inspiratory off-switch level, while inspiratory drive and the bulbopontine setting of the inspiratory phase were unaltered. The ventilatory response to CO2 was blunted after both adenosine analogues studied. Theophylline almost completely reversed the hypoventilation and irregular breathing seen after PIA injection. It is concluded that activation of central nervous adenosine receptors induced a marked respiratory depression in the preterm rabbit. Furthermore, our data imply that an overactivity of central adenosine mechanisms may have a pathophysiological significance for the irregular breathing or apnea of prematurity sometimes seen in the human neonate.

Ten obese men (20-40% overweight) with previously untreated arterial hypertension (WHO stages I and II) were examined before and during sodium-restricted isocaloric diets. The mean (± s.d.) daily sodium excretion was reduced from 199 ± 65 to 65 ± 25 mmol/24 h. Intra-arterial blood pressure (BP), cardiac output (CO), plasma volume, circulating and urinary noradrenaline (NA), plasma renin activity (PRA) and urinary aldosterone were measured. Vascular reactivity was assessed with intravenous bolus injections of 50, 100 and 200 µg phenylephrine, and baroreflex sensitivity was assessed with the R-R interval response to pressure elevations on electrocardiogram. Significant reductions in systolic BP from 163 ± 18 to 147 ± 17 mmHg and in diastolic BP from 97 ± 7 to 88 ± 9 mmHg occurred during salt restriction. Blood pressure reductions were correlated with changes of urinary sodium excretion (r=0.71; P

Muscle nerve sympathetic activity was recorded in six patients with the sleep apnoea syndrome (SAS). Compared with age- and sex-matched control patients, an increased activity during wakefulness was found. Sleep apnoic events were associated with sequencies of progressively increasing sympathetic activity followed by a sudden reduction of activity. The high sympathetic activity associated with SAS may be important in the development of the systemic hypertension commonly seen in these patients.

Acute as well as chronic treatment with ketanserin but not with ritanserin reduced the blood pressure in the spontaneously hypertensive rat, indicating that 5-HT2-receptor blockade alone does not have antihypertensive properties. Whereas the blood pressure reduction to acute administration of ketanserin was directly related to its ability to shift the dose-response curve of phenylephrine (alpha 1-adrenergic blockade), the same relationship was not apparent following chronic treatment with ketanserin. This suggests that the 5-HT2- and alpha 1-blockade may complement each other in reducing the blood pressure, a conclusion supported by the observation that in the conscious rat, 5-HT2-receptor blockade by ritanserin enhanced the hypotensive response to prazosin. However, ritanserin did not influence the ability of prazosin to antagonize pressor responses to phenylephrine in the pithed rat.

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.

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.

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.

Isolation, purification and determination of the amino acid sequences of biologically active atrial peptides were performed in 1983–84 by several groups. By that time the existence of such a humoral diuretic/natriuretic factor had been proposed for many years. The main, and perhaps the only, circulating form of atrial natiuretic peptide (ANP) is a 28 amino acid peptide structure with a disulphide bridge. This peptide is distributed mainly peripherally in the right and left cardiac atria. Smaller amounts are found in neonatal cardiac ventricles as well as in autonomic ganglia. In the central nervous system, high concentrations are found in hypothalamus, while lower concentrations are found in midbrain and brain stem regions. The amino acid sequence of ANP in the brain may be shorter than the form originating from cardiac atria. A 1-126 amino acid prohormone is present in granulae of atrial myocytes. After atrial distention the circulating 28 amino acid form is cleaved off. The main actions of this hormone include a diuretic/natriuretic effect, relaxation of vascular smooth muscle, and inhibition of basal or stimulated aldosterone secretion from the adrenal cortex. In the central nervous system, ANP has antidipsogenic actions, decreases salt appetite and lowers blood pressure. ANP may be of pathophysiological importance in several cardiovascular disorders such as congestive heart failure, paroxysmal supraventricular tachycardia and possibly also arterial hypertension. ANP seems to be a circulating hormone as well as a putative neurotransmitter with important regulatory actions on salt and water homeostasis as well as blood pressure regulation.

Administration of gammahydroxybutyric acid (GHBA) to 4 days old animals caused a dose dependent decrease in locomotor activity. GHBA also induced a marked hypoventilation, irregular breathing and finally apnea, while heart rate was slightly increased. Changes in monoamine neurotransmitter turnover indicated an inhibition of dopamine (DA) neurotransmission. It is concluded that GHBA mechanisms in the neonatal rat brain are biochemically as well as functionally mature at an early age and that the effects on locomotor activity and respiratory regulation at least partly may involve interactions with central DA neurotransmission.

Ketanserin is a new antihypertensive agent with affinity to serotonin (5-HT)2 receptors and at higher concentrations also to alpha 1-adrenoceptors. The present study was designed to evaluate the relative functional importance of the antagonism of alpha 1-adrenoceptors and 5-HT2-receptors in the antihypertensive mechanism of action of ketanserin and analogues after acute administration. In the spontaneously hypertensive rat, ketanserin and the two ketanserin analogues, R56413 and R55667 (which have relatively weaker alpha-adrenolytic properties) were studied with regard to their ability to reduce the blood pressure after acute administration in the conscious rat and their ability to shift the dose response curves for 5-HT and phenylephrine in the pithed rat. The agents tested reduced the blood pressure only in a dose range where they blocked alpha 1-adrenoceptors and there was a striking correlation between the degree of hypotension and the degree of inhibition of the phenylephrine induced pressor responses. 5-HT2-receptor blockade alone did not influence basal blood pressure. However, following pretreatment with R55667 in a low dose the blood pressure reduction to prazosin was enhanced. It is concluded that following acute administration in the rat the major portion of the antihypertensive response to ketanserin is due to an alpha 1-adrenoceptor blockade but that the 5-HT2-receptor blockade contributes.

12 patients with primary hypertension not adequately controlled on combined treatment with diuretics, beta-adrenergic blocking drugs and hydralazine were included in the study. The patients were hospitalised and hydralazine discontinued. The diuretic and beta-blocking medication was given about 1 hour prior to the short term experiments and, following baseline measurements, an oral solution of felodipine (0.075-0.1 mg/kg) was ingested. Cardiac output was measured (dye dilution technique) and continuous monitoring of intra-aortic blood pressure (brachial artery) was performed. In 10 patients, changes in renal plasma flow (para-aminohippuric acid clearance) and glomerular filtration rate (51Cr-EDTA-clearance) were followed over a short period, and in 6 patients repeated after 5 to 7 months. Plasma renin activity (radioimmunoassay of angiotensin I) was followed, as was plasma concentration of felodipine. A significant hypotensive response was seen only 15 minutes after intake of felodipine. The maximal response occurred after 30 minutes when mean arterial blood pressure was reduced by 24% (from 132 to 102 mm Hg). There was a linear relationship between the change in mean arterial blood pressure and log plasma concentration of felodipine. Cardiac output increased from 5.1 +/- 1.5 to 6.6 +/- 2.6 L/min (p less than 0.01), partly because of increased heart rate from 56 +/- 7.9 to 65 +/- 9.5 beats/min (p less than 0.01) and partly due to increased stroke volume from 93 +/- 25 to 103 +/- 34 ml/beat (p less than 0.05). Renal plasma flow increased significantly (p less than 0.05) from 343 +/- 138 ml/min to 391 +/- 154 ml/min and 400 +/- 149 ml/min, while glomerular filtration rate did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Ketanserin is an agent whose main pharmacologic action is antagonism of serotonin (5-hydroxytryptamine, 5HT) receptors of the 5HT2 subtype. It also has weak alpha 1-adrenergic blocking properties, which may contribute to the acute blood pressure lowering effects seen in animal models of hypertension. During chronic treatment of hypertension in animals, the 5HT2 antagonistic properties, or a combination of 5HT2 and alpha 1-antagonistic effects, seems to be responsible for ketanserin's hypotensive action. Studies of patients with hypertension have demonstrated the therapeutic effects of ketanserin in monotherapy and combination therapy. In humans, the drug has a terminal half-life of 12-25 hours, and a twice daily dosage will lower blood pressure over the day. Ketanserin is a vasodilator that acts on both resistance and capacitance vessels. Chronic treatment with the drug causes minimal reflex changes in cardiovascular function, as well as sustained blood pressure reduction comparable with the effects of beta-adrenergic blockers or diuretics. In elderly patients, the therapeutic effects of ketanserin appear to be greater, and side effects are less frequent compared with beta-blockers and diuretics. In addition to its antihypertensive action, ketanserin also produces other effects that may be important in reducing cardiovascular morbidity and mortality in patients with hypertension. Some studies have shown a reduction in total and low-density lipoprotein (LDL) cholesterol, and a rise in high-density lipoprotein (HDL) cholesterol. Ketanserin also reduces ex vivo platelet aggregation and inhibits the serotonin-induced platelet release reaction. Worldwide experience with ketanserin in the treatment of hypertension indicates that it is a safe and effective agent for long-term therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphine concentrations in plasma and cerebrospinal fluid (CSF) were measured in 58 elderly patients after intramuscular administration of 10 mg morphine. The assay employed gas chromatography with electron capture detection. From 49 of the patients undergoing urological procedures plasma and lumbar CSF samples were obtained simultaneously as spinal analgesia was given, and in addition, repeated venous samples were obtained over 4 hours from 35 of the patients. A plasma-morphine concentration vs time plot was drawn from the mean values and a CSF-morphine vs time plot was calculated by pooling individual CSF concentrations and using the sliding mean technique. The individual CSF/plasma-morphine concentration ratio vs time was also plotted. In addition, 2 or 3 CSF and plasma samples were collected simultaneously from 3 patients undergoing thoracotomy. Large interindividual variation in the CSF concentration was found. The peak CSF level was reached after 3 h and, following pseudoequilibrium, CSF-morphine levels appeared only slightly lower than those found in plasma. The availability to spinal CSF amounted to no more than 0.005% of the administered dose. CSF-morphine concentrations were not related to plasma protein or albumin concentrations.

Preterm neonatal rabbits (gestational age 29 days) were given GABA (750 mg/kg) or the GABA-like drugs muscimol (2 mg/kg) and GHBA (375 mg/kg) intraperitoneally. Basal respiration and the ventilatory response to 10% CO2 were studied, before and after drug administration, in a whole body plethysmograph during halothane anesthesia. The three drugs tested all caused a decrease in minute volume. The decrease in minute volume was mainly due to a decrease in tidal volume after GABA and muscimol, while GHBA reduced minute volume due to a decrease in respiratory frequency. A decrease in respiratory frequency was also seen after muscimol administration. Changes in the respiratory time intervals were seen after muscimol and GHBA both causing significant increases in expiratory and respiratory time. ‘Inspiratory drive’ and ‘respiratory timing mechanisms’ were evaluated by Vτ/TI and Tι/TTOT, respectively. GABA and muscimol reduced both VT/TI and Tι/TTOT while GHBA only reduced TI/TTOT Addition of 10% CO2 to the inhalation gas caused an increase in tidal volume and minute volume during control conditions. This response to CO2 was abolished by GABA and GHBA treatment. Our findings demonstrate that GABA and GABA-like drugs cause respiratory depression in the preterm neonate. Central mechanisms are most likely involved in this response. These findings may be relevant to the irregular or apneic breathing sometimes seen in the preterm human infant.

The intravenous administration of 8−hydroxy−2(di-N-propylamino) tetralin, a selective 5−HT receptor agonist, caused a biphasic blood pressure response and bradycardia in Sprague-Dawley rats. The initial pressor response involved peripheral α1-adrenoceptors since it was present in pithed rats and was antagonized by prazosin. Though the intracerebroventricular route of administration was not more effective the hypotension and bradycardia were probably of central origin. The bradycardia was prevented by pretreatment with atropine and propranolol suggesting an involvement of vagal as well as sympathetic activity. These results support the view that central 5−HT receptor activation reduces the blood pressure and heart rate.

Chronic oral treatment (8 weeks) with the selective 5-hydroxytryptamine2 (5-HT2)-receptor blocking agent, ritanserin, did not reduce blood pressure in the spontaneously hypertensive rat (SHR) during basal conditions or during stress (jet air). In pithed rats the pressor responses to 5-HT but not to phenylephrine or sympathetic stimulation of the sympathetic outflow were completely antagonized. These observations indirectly suggests that the 5-HT2-receptor blocking properties of the antihypertensive agent ketanserin cannot alone account for the antihypertensive effects in SHR that are observed during chronic treatment with this agent.

Ketanserin is a serotonin (S2) blocker that reduces blood pressure (BP) in patients with essential hypertension preferentially by a reduction of peripheral vascular resistance. Heart rate is generally not affected or slightly reduced. When given in monotherapy on a 40 mg b.i.d. regimen, ketanserin reduces diastolic BP as effectively as metoprolol 100 mg b.i.d. or hydrochlorotiazide 25 mg b.i.d. The incidence of adverse reactions is low and comparable to these reference drugs. A satisfactory BP control is provided over a 24-h interval on a 40 mg b.i.d. dosage schedule, and the effect is maintained on a long-term basis, i.e., greater than 2 years. The response seems to be more marked in older patients, which may be due to an augmented platelet serotonin release and a vascular hypersensitivity in this age group. The future usefulness of ketanserin, as well as any other antihypertensive agent, will depend on its ability to prevent organ damage, as well as its ability to provide "quality of life" for the patient.

The acute antihypertensive effects of the dihydropyridine calcium antagonist, felodipine, were investigated in 12 male patients aged 43 to 64 years with uncontrolled blood pressure on combined treatment with a thiazide diuretic, a beta-blocker and hydralazine. Central and renal haemodynamics were monitored after acute oral administration (0.075 mg/kg) of felodipine in combination with the beta-blocker and diuretic. Six patients were continued on long term oral felodipine (mean dose 20 +/- 24 mg/day) in combination with the other drugs for 6 to 18 months. Ambulatory blood pressure was measured repeatedly and renal function re-examined once during long term felodipine therapy. In the 6 patients on long term therapy, systolic blood pressure was reduced from 190 +/- 17 to 149 +/- 24 mm Hg and diastolic blood pressure from 116 +/- 12 to 89 +/- 14mm Hg (p less than 0.001). No significant change in heart rate was observed (65 +/- 4 vs 62 +/- 10 beats/min). Renal plasma flow significantly increased from 284 +/- 97 to 425 +/- 131 ml/min/m2 (p less than 0.01) but glomerular filtration rate was unchanged (72 +/- 20 vs 80 +/- 22 ml/min/m2). Hence, the filtration fraction was significantly reduced and normalised in all patients (0.26 +/- 0.04 vs 0.20 +/- 0.03) [p less than 0.05]. Bodyweight was unchanged. It is concluded that felodipine is a highly potent vasodilator with a favourable effect on renal function and is suitable for long term therapy in patients with severe primary hypertension.

In order to investigate the potential role of atrial natriuretic peptide (ANP) in mild to moderate essential hypertension, a study was conducted in groups of normotensive and hypertensive middle-aged men born in 1926 and 1927. Venous plasma concentrations of immunoreactive ANP (irANP) were studied in relation to measurements of cardiac structure and function, urinary electrolytes as well as some cardiovascular hormones. Plasma irANP did not differ between normotensive controls (31 +/- 14 pmol l-1) and borderline or untreated hypertensive patients. However, irANP concentrations were slightly but significantly (P less than 0.05) lower in the borderline (26 +/- 8 pmol l-1) compared to the untreated established hypertensives (35 +/- 14 pmol l-1). No relationships were found between irANP and blood pressure, indices of left ventricular structure and function or hormone parameters in subgroups or the whole study group. Our data do not support the view that plasma irANP is increased in uncomplicated essential hypertension, since our groups of borderline or established hypertensive middle-aged men without major cardiac involvement did not differ in irANP concentrations compared to normotensive controls. Thus, during the development or in the early stages of essential hypertension, ANP secretion does not seem to be abnormal.

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.

The adenosine agonist N 6 -phenylisopropyladenosite e (PIA) was given intracerebroventricularly to halothane-anesthetized rats. Administration of 10 μg PIA caused a decrease in pulmonary ventilation due to effects on both respiratory frequency as well as tidal volume. The respiratory depression was accompanied by bradycardia and hypotension. The data indicate that central adenosine mechanisms might be involved in respiratory and circulatory regulation.

The rationale for ketanserin therapy in hypertension is reviewed against the background of known physiological and pathophysiological effects of serotonin. The usefulness of the serotonin (5-HT2) antagonist ketanserin in the treatment of hypertension is evaluated with respect to its known antihypertensive property as well as in relation to its effect on hypertension-induced cardiovascular changes, platelet hyperreactivity, and atheroma formation. Based on ketanserin's documented antihypertensive effect and also on its potentially positive effect on cardiovascular mortality via other mechanisms, it would appear that ketanserin could offer a highly rational approach to the treatment of hypertension and its risks in the future.

The antihypertensive effects of the hydralazine-related compound cadralazine (2-(3-[6-(2-hydroxypropyl)ethylamino]pyridazinyl)ethyl carbazate, ISF 2469), were investigated in 16 patients with primary hypertension concurrently treated with beta-blockers and diuretics. The protocol included a double-blind placebo controlled haemodynamic evaluation after the first tablet and two 4-week double-blind placebo controlled cross-over periods followed by an open evaluation during 2 months. Cadralazine induced a moderate, prolonged fall in blood pressure that was associated with vasodilatation and slight increases in cardiac output (dye-dilution) and heart rate. Renal plasma flow (PAH) and glomerular filtration rate (51Cr-EDTA) were not significantly influenced, but the filtration fraction was reduced. Plasma concentrations of noradrenaline and adrenaline rose, whereas plasma renin activity was unchanged. The haemodynamic parameters were not correlated with the plasma concentrations of cadralazine. During chronic cadralazine treatment the supine blood pressure was significantly lower than during the double-blind placebo phase (160/93 vs 174/102 mmHg). The compound was generally well tolerated but the body weight increased slightly (1.1 kg), probably because of fluid retention. Several patients who had previously experienced side effects with hydralazine, including one with hydralazine-syndrome, tolerated cadralazine well. This suggests that cadralazine does not cross-react with hydralazine.

The effects of intraperitoneal administration of bupivacaine on pain and the sympathoadrenal response to surgery were studied in a double-blind randomized trial in 19 patients undergoing cholecystectomy. Bupivacaine (2 mg/kg) was dissolved in 300 ml isotonic saline and administered into the peritoneal cavity 10 min before the operation (n = 9). Saline was administered in a comparable group of patients (n = 10). There were no significant differences in pain scores between the groups during the first day after surgery (P greater than 0.05). Postoperative requirements of pethidine during the first 2 days after surgery did not differ significantly between the groups. Blood glucose levels were significantly lower in the bupivacaine-treated group 1 h (P less than 0.05) and 4 h (P less than 0.05) after skin incision. No significant differences were observed between the groups regarding plasma catecholamine and serum cortisol levels during and after surgery. Differences between the groups regarding urine output of catecholamines during the first and second postoperative days were not significant. Our results suggest that single administration of a local anesthetic intraperitoneally does not reduce pain or the sympathoadrenal response to upper abdominal surgery.

Eighteen moderately obese middle-aged men with untreated mild hypertension were randomized to two groups and placed on a low energy diet regimen for 9 to 11 weeks. In Group I (n = 10) the amount of sodium chloride in the diet maintained the urinary sodium excretion at the predieting level. Mean body mass was reduced by 9.1 +/- 0.7 (SEM) kg. Mean intra-arterial pressure showed no significant change. There were significant decreases in heart rate (p less than 0.05) and urinary norepinephrine excretion (p less than 0.05) but not in plasma concentration of norepinephrine. In Group II (n = 8) energy as well as sodium intake was restricted, with a 95 +/- 22 mmol/24 hour reduction of urinary sodium excretion. Body mass decreased by 9.3 +/- 1.1 kg, and mean arterial pressure decreased by -18.9 to -4.3 mm Hg (95% confidence interval). There were also significant reductions in heart rate (p less than 0.001) and plasma norepinephrine concentrations (p less than 0.01) but not in urinary norepinephrine excretion. The pressor response (mean arterial pressure) to norepinephrine infusion at different dose rates was significantly elevated (p less than 0.05) in Group I during dieting in comparison with baseline. The blood pressure response to norepinephrine during dieting in patients in Group II was not changed from baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

The selective 5-HT2-receptor-blocking agent ritanserin is an analogue of the antihypertensive agent ketanserin. By evaluating the antihypertensive effects of ritanserin the aim of this investigation was to indirectly elucidate the mechanism of action of ketanserin. Thirteen patients with essential hypertension were treated with placebo and ritanserin, 10 mg b.i.d., in a double-blind, cross-over design (4-week periods). At the end of the treatment periods blood pressure as well as plasma concentrations of ritanserin were evaluated for 24 hours. Despite high steady state and peak plasma concentrations of ritanserin the compound did not lower the blood pressure compared with placebo. Since chronic selective 5-HT2-receptor blockade by means of ritanserin did not lower the blood pressure, it is concluded that the 5-HT2 blocking properties of ketanserin cannot alone be responsible for the antihypertensive effects of ketanserin.

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.

The antihypertensive effects of guanfacine (0.5 to 4 mg daily) were investigated for 1 yr in 13 patients with essential hypertension. Blood pressure (BP) and heart rate (HR) response was measured during isometric exercise (handgrip) before starting the therapy, after 1 yr of treatment, and 2 wk after withdrawal. Guanfacine in once-daily dosage reduced BP during rest (supine BP: control, 175 ± 6/103 ± 4 mm Hg; 1 yr guanfacine, 161 ± 5/91 ± 3 mm Hg). Steady-state plasma concentrations after 1 yr were 4.1 ± 0.59 ng/ml. Resting plasma norepinephrine (NE) and epinephrine (E) levels were lower during active therapy than 2 wk after withdrawal (guanfacine and control: plasma NE, 0.27 ± 0.03/0.64 ± 0.13 ng/ml; plasma E, 0.09 ± 0.02/0.17 ± 0.05 ng/ml). The relative reduction of plasma catecholamines (guanfacine and withdrawal) was of the same order during handgrip exercise as during supine rest. During isometric handgrip exercise, BP was lower during guanfacine therapy than before treatment and 2 wk after withdrawal, but the increment in BP during handgrip exercise was not affected by the drug despite the lower BP values on therapy. Our data indicate that the central α2-agonist action of guanfacine reduces sympathoadrenal function equally during rest and isometric exercise. Clinical Pharmacology and Therapeutics (1984) 35, 604–609; doi:10.1038/clpt.1984.83

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.

The disposition of pethidine and its main metabolite, norpethidine, in cerebrospinal fluid (CSF) and plasma was studied in 11 thoracic surgery patients after lumbar epidural (100 mg;n=6) or lumbar intrathecal (25 mg;n=5) administration of pethidine. Pethidine appeared more slowly in plasma after intrathecal than after epidural administration (tmax 2.3 h and 14 min, respectively), but systemic bioavailability was similar. The CSF concentrations of pethidine were higher than those in plasma after both routes of administration. The maximal CSF/plasma concentration ratio was 6000 to 45000 after intrathecal administration but was only 26 to 97 after the epidural route. Pethidine was rapidly distributed in CSF; nine to ten h after the intrathecal and epidural injections the CSF/plasma concentration ratios were 12 to 89 and 2 to 33, respectively. The calculated bioavailability in CSF of epidural pethidine was 10.3%. The terminal elimination half-life of pethidine was 6.0 h (CSF) and 5.4 h (plasma) after intrathecal administration and 8.6 h (CSF) and 8.8 h (plasma) after epidural injection. The volume of distribution of unchanged pethidine in the subarachnoid space was 13 ml·kg−1 and clearance from the CSF was 15 µl·kg−1·min−1. In all patients receiving intrathecal pethidine and in some patients after epidural pethidine, CSF norpethidine concentrations were higher than those in plasma; the maximum CSF norpethidine was 102 to 1211 ng·ml−1 and 14 to 210 ng·ml−1 and the maximum CSF/plasma norpethidine concentration ratios were 21 to 652 and 0.6 to 14 times after intrathecal and epidural administration, respectively. Norpethidine was rapidly distributed and its level in CSF was about the same or lower than in plasma during the terminal elimination phase. The maximum CSF norpethidine level was 1.2±1.0% of that of pethidine after intrathecal injection. Thus, epidural pethidine enters the CSF more rapidly and to a greater extent than has been previously shown for epidural morphine, but pethidine is more rapidly redistributed from CSF. The terminal elimination half-life of pethidine was found to be long in relation to the reported duration of analgesia after a single spinal dose of pethidine, which suggests a potential risk of accumulation within the CSF on multiple spinal injections of pethidine. Pethidine is partly metabolised within the subarachnoid space by N-dealkylating enzymes in the CNS. After intrathecal injection of more than 25 mg pethidine, the concentration of the principle metabolite, norpethidine, in CSF may be higher than that associated with CNS toxicity in man.

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.

The pressure-volume relationship in preterm rabbit lung was studied at 28 days of gestation. Injection of 0.1 mg terbutaline, a selective beta2-receptor stimulating drug, significantly increased the volume of air at equivalent low transpulmonary pressures, compared to a saline treated group and an untreated group. These findings indicate an increased pulmonary distensibility of the fetal rabbit lung after terbutaline administration. The mechanism of action is discussed and surfactant mediated effects are suggested to be the probable explanation.

The sympathoinhibitory effects of ketanserin were investigated in the spontaneously hypertensive rat. In conscious rats ketanserin (0.1-10.0 mg/kg intravenously caused dose-related reductions in blood pressure and heart rate (carotid artery). The heart rate reduction was prevented by chemical sympathectomy (reserpine) and in anaesthetized rats the heart rate reduction was correlated to a reduction in the directly recorded preganglionic sympathetic activity in the left renal nerve. Ketanserin had no presynaptic effects on the sympathetic nerve terminals as evidenced by the lack of effect on the tachycardia induced by electrical stimulation of the sympathetic outflow in pithed rats. In rats, catecholamine-depleted by reserpine, the heart rate reduction was prevented, and in atropine-pretreated animals there was a partial blockade of the bradycardic effect. We conclude that the lack of reflexogenic tachycardia in response to the hypotension induced by ketanserin treatment is partly due to a preganglionic inhibition of sympathetic nerve activity.

A new hormonal system originating from cardiac atria has recently been discovered. These peptide hormones have important functions in the regulation of blood volume and fluid homeostasis. We have measured plasma concentrations of atrial natriuretic peptides (ANP) in two patients during acute volume expansion. ANP concentrations increased in relation to an increase in right atrial pressure, and significant diuresis/natriuresis was observed. We conclude that hormonal as well as neuronal mechanisms are activated by acute volume loading in man.

Neonatal rats were exposed to 20 or 30 min of total or partial oxygen deprivation. During asphyxia and subsequent recovery the endogenous levels of tryptophan and 5-hydroxytryptamine (5-HT, serotonin) were measured. The activity of tryptophan hydroxylase, the first and rate limiting enzyme in the 5-HT synthesis pathway, was studied in vivo by measuring the accumulation of 5-hydroxytryptophan (5-HTP) after inhibition of aromatic L-amino acid decarboxylase with NSD 1015. During asphyxia there was a decrease in tryptophan hydroxylase activity in the whole brain and various brain regions studied. The levels of tryptophan, 5-HTP and 5-HT all increased after 30 min of recovery from asphyxia. In the whole brain, 5-HTP and 5-HT levels were normal 2 h after anoxia while tryptophan levels normalized more slowly to reach control values after 6 h. In the regional brain study, the 5-HTP levels returned quickly to control levels after asphyxia in the striatum and midbrain but not in the brainstem and hemispheres regions. The whole brain 5-HTP and 5-HT levels did not differ from controls 24 and 48 h after the asphyxia. Although the neonatal nervous system exhibits a great resistance to asphyxia, the metabolism of the neurotransmitter 5-HT is affected already during a short period of asphyxia and subsequent recovery. As 5-HT is ascribed important neurotransmitter functions, this might be relevant to the neurological sequelae of human asphyxia neonatorum.

Peripheral venous plasma concentrations of immunoreactive atrial natriuretic peptide (irANP) were studied longitudinally in 12 women at the 12th, 24th, and 36th week of pregnancy as well as 3-5 days and 3 months post partum. Serial measurements of maternal hemodynamics were performed simultaneously with blood sampling for irANP determination. With advancing pregnancy there were significant increases (p less than 0.001) in cardiac output, stroke volume and heart rate, while total peripheral vascular resistance decreased (p less than 0.001). All these changes were normalized 3 months post partum. Plasma irANP increased (p less than 0.05) from 23.2 +/- 1.3 pM/l at week 12 to 25.9 +/- 1.5 pM/l at week 36 of pregnancy, and fell significantly (p less than 0.01) to 20.5 +/- 1.1 pM/l 3 months post partum. Changes in plasma irANP appear to be related to changes in maternal central hemodynamics. The changes in ANP release probably represent one of several mechanisms that maintain circulatory and volume homeostasis during normal pregnancy.

Rats lightly anesthetized with halothane were injected intracerebroventricularly (i.c.v.) with gamma aminobutyric acid (GABA) and the GABA-like drugs muscimol, baclofen, and gamma-hydroxybutyric acid (GHBA). Respiratory frequency (f) was reduced after GABA (1 mg) but increased after baclofen (0.5 microgram), while muscimol (0.5 microgram) or GHBA (1 mg) did no affect f. However, GHBA administered repeatedly caused a dose-dependent increase in f. Tidal volume (VT) decreased in a dose-dependent fashion after i.c.v. administration of all the drugs used. Taken together, these changes in f and VT resulted mainly in a dose dependent decrease in minute volume (VE) after GABA and muscimol while after baclofen and GHBA VE was increased due to the marked stimulation of f after repeated administration. Mean arterial pressure (MAP) decreased after GABA and muscimol while no effect or a slight increase was seen after baclofen and GHBA. Heart rate (HR) was unaltered after muscimol, decreased after gaba but slightly increased after GHBA and baclofen. No alterations were seen in blood gases except after administration of GABA which induced a slight hypoxia, hypercapnia and acidosis. The data indicate that an activation of GABA-ergic mechanisms results in a respiratory depression. Moreover, the effects of GABA and muscimol are probably due to a direct GABA-ergic receptor activation while the effects elicited by baclofen and GHBA are due to other mechanisms than direct GABA receptor activation or indirect effects via other system on respiratory regulating centers.

Eleven moderately obese women, aged 46-62 years, with a body mass index of 29-34 and with borderline hypertension (repeated diastolic blood pressure greater than 90 mmHg) fasted for 48 hours. Before the fast and after 48 hours of fasting, plasma noradrenaline, urinary noradrenaline, urine potassium, urine sodium and weight were measured. In six of the patients muscle nerve sympathetic activity was recorded from the peroneal nerve by tungsten microelectrodes for 15 min each time. The efferent muscle sympathetic activity (MSA) was expressed as the number of bursts/min. The recordings were done before the fast and after 48 hours of fasting. We found significant decreases in body weight from 88.4 +/- 2.5 kg to 86.4 +/- 2.5 kg. Systolic blood pressure (BP) was reduced from 158 +/- 3 mmHg to 146 +/- 5 mmHg (p less than 0.001) and diastolic BP from 96 +/- 3 mmHg to 89 +/- 3 mmHg (p less than 0.01) during the fast. MSA was significantly increased from 42.0 +/- 5.5 bursts/min to 44.5 +/- 5.8 (n = 6), while plasma and urine noradrenaline concentrations (n = 11) showed a non-significant tendency to increase. We conclude that the hypotensive response during the first days of extensive caloric reduction is not due to a decreased sympathetic activity. If anything, there may be weak increase of efferent sympathetic nerve activity and venous plasma levels of circulating noradrenaline. The mechanisms behind the acute hypotensive response to negative caloric balance are thus still unclear, but obviously different from long-term adaptation of the blood pressure.

Atrial natriuretic peptide (ANP) is a recently discovered hormone, originating from atrial myocardium. The peptide (or family of peptides) induces potent diuretic/natriuretic, vasorelaxing and aldosterone inhibitory effects. We have investigated plasma concentrations of immunoreactive ANP in 10 patients with congestive heart failure (CHF). Mean plasma ANP concentrations were more than three times higher in CHF patients than in a matched control group. High plasma ANP concentrations in pathophysiological conditions with a high preload combined with salt and water retention is consistent with a physiological role of this hormone to correct hypervolemia by causing natriuresis and diuresis. It is concluded that ANP homeostasis is altered in patients with CHF and that this hormone may be of importance in the pathophysiology of CHF.

OBJECTIVE To investigate the cardiovascular effect of alpha-trinositol (D-myo-inositol-1,2,6-trisphosphate; PP56) in spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto (WKY) rats. alpha-Trinositol, a representative of a new group of pharmacological agents, is an inositol phosphate which seems to bind to a single population of binding sites, inhibiting, for example, agonist-induced vasoconstriction. In particular, alpha-trinositol seems to inhibit agonist-induced (e.g. neuropeptide Y-induced) elevations in intracellular Ca2+ levels in vascular smooth muscle cells. METHODS alpha-Trinositol was administered as a bolus injection (2-40 mg/kg body weight), followed by a continuous infusion (20-400 mg/kg body weight per h) for 40 min in freely moving SHR and WKY rats. RESULTS Acute intravenous bolus administration of alpha-trinositol reduced systolic and diastolic blood pressure, as well as heart rate, in a dose-dependent manner in SHR and WKY rats. After completion of the 40-min infusion the reduction in blood pressure was more pronounced in the SHR than in the WKY control rats. Heart rate did not change in the SHR, whereas it was significantly increased at the highest dosage (400 mg/kg) in the WKY rats. At this dosage, three out of eight SHR died from cardiac arrhythmias after completing the infusion. The lowest dose of alpha-trinositol administered (2 mg/kg bolus followed by 20 mg/kg per h infusion over 40 min) significantly inhibited the increase in mean arterial pressure induced by neuropeptide Y (2 micrograms/kg per min for 10 min) by approximately 30% in both the SHR and WKY rats. Furthermore, alpha-trinositol treatment completely inhibited the potentiation induced by neuropeptide Y (0.1 micrograms/min for 30 min) of the blood pressure responses to intravenous bolus injections of noradrenaline (20 ng), tyramine (40 micrograms) or angiotensin II (10 ng). CONCLUSIONS Our results demonstrate that alpha-trinositol antagonizes the direct postsynaptic pressor response to exogenous neuropeptide Y, as well as the potentiating effects of neuropeptide Y on other vasoconstrictors in SHR and WKY rats. However, in the SHR alpha-trinositol lowered basal blood pressure only in the dose range which was non-specific for neuropeptide Y inhibition. Thus, the present study indicates that neuropeptide Y is involved only slightly in the maintenance of high blood pressure in SHR.

We wanted to study the expression of P2-receptors at the mRNA-level in the heart and if it is affected by congestive heart failure (CHF). To quantify the P2 receptor mRNA-expression we used a competitive RT-PCR protocol which is based on an internal RNA standard. The P2 receptor mRNA-expression was quantified in hearts from CHF rats and compared to sham-operated rats. Furthermore, the presence of receptor mRNA was studied in the myocardium from patients with heart failure. In the sham operated rats the G-protein coupled P2Y-receptors were expressed at a higher level than the ligand gated ion-channel receptor (P2X1). Among the P2Y-receptors the P2Y6-receptor was most abundantly expressed (P2Y6 > P2Y1 > P2Y2 = P2Y4 > P2X1). A prominent change was seen for the P2X1- and P2Y2-receptor mRNA levels which were increased 2.7-fold and 4.7-fold respectively in the myocardium from the left ventricle of CHF-rats. In contrast, the P2Y1-, P2Y4- and P2Y6-receptor mRNA levels were not significantly altered in CHF rats. In human myocard the P2X1-, P2Y1-, P2Y2-, P2Y6- and P2Y11-receptors were detected by RT-PCR in both right and left atria and ventricles, while the P2Y4-receptor band was weak or absent. In conclusion, most of the studied P2-receptors were expressed in both rat and human hearts. Furthermore, the P2X1- and P2Y2-receptor mRNA were upregulated in CHF, suggesting a pathophysiological role for these receptors in the development of heart failure.

Neurohormonal changes in congestive heart failure (CHF) include an enhanced peripheral sympathetic nerve activity which results in increased release of noradrenaline, neuropeptide Y and ATP. To examine if such changes in CHF would modulate peripheral pre- and postsynaptic receptors of ATP and its degradation product adenosine, experiments were performed in a rat model of ischaemic CHF. In this model, ischaemia was induced in rats by ligation of the left coronary artery. Our results demonstrate that there is a selective downregulation of P2X receptor-mediated pressor effects, while the hypotensive effects mediated by the endothelial P2Y receptors are unaffected in CHF. Moreover, the adenosine-mediated inhibitory effects on heart rate and blood pressure were also attenuated in the CHF rats. The most important changes in adenosine and P2-receptor function induced by ischaemic CHF were the reduced pressor effect mediated by the P2X receptor and the increased heart rate due to an attenuated inhibitory effect of adenosine.