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Biomedical subjects

T Hedner

Publications and source records attributed to T Hedner.

At least 325 records · Page 18Linked to original sources
PubMed1986

Dissociation of renin and noradrenaline release in the renal circulation. Studies on patients with renal hypertension.

Plasma renin activity (PRA) and noradrenaline concentration (NA) were measured in the renal veins (V) and arterial blood (A) in 30 patients investigated for renin-mediated hypertension. Both PRA and NA concentrations in arterial blood were above our reference limits and they were positively correlated. In 18 of the patients renin secretion was unilateral from the diseased side. Their renal vein NA concentration was always higher on that side, compared to the contralateral one, but there were V-A gradients for NA on both sides in all but two cases. In 15 of the patients with such lateralisation of renin secretion the changes of PRA and NA V-A gradients were determined 30-60 min after an i.v. injection of dihydralazine. Both PRA and NA increased more markedly in the renal vein on the affected side where the estimated renal plasma flow was lower than on the contralateral side. The NA gradients increased less than the PRA gradients when changes on the renin secreting side were compared in patients with proven increase of renin secretion. We conclude that patients with renal hypertension have a high sympathetic nervous activity as evidenced by increased plasma NA concentrations and (V-A) gradients for NA on both sides. The release of NA into the renal circulation in renin mediated hypertension is thus not invariably accompanied by renin release. The higher renal vein NA concentration on the involved renin secreting side is explained by reduced RPF on this side.

Adult↗
PubMed1986

Blood pressure reduction and pharmacokinetics of ketanserin in hypertensive patients.

Pharmacokinetic and antihypertensive effects of the S2-serotonergic antagonist ketanserin were determined in 10 patients with essential hypertension (WHO stages I-II) after a single intravenous (0.15 mg/kg) and a single oral (40 mg) dose as well as during steady-state conditions on 40 mg once-daily dose regimen. The maximal plasma concentration (Cmax) of 99 +/- 14 and 97 +/- 14 ng/ml occurred approximately 1 h after single oral and chronic oral intake, respectively. The minimum steady-state concentration (Cssmin) was 13 +/- 2 ng/ml on a 40 mg once-daily regimen. Terminal half-lives (T1/2 beta) were 6.5 +/- 0.4 and 9.0 +/- 0.9 h after intravenous and single oral administration. During steady-state therapy the elimination half-life (24.7 +/- 2.6 h) was significantly increased compared to single dose administration. Bioavailability ranged between 15 and 60%, indicating a substantial first-pass effect. After intravenous ketanserin, mean supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) were maximally reduced after 30 min. A single oral 40 mg dose reduced mean supine SBP/DBP by 31 +/- 8/16 +/- 5 (P less than 0.01/P less than 0.05) at maximal plasma ketanserin concentrations. The SBP and DBP were reduced over 24 h during steady-state conditions on 40 mg once-daily treatment and the mean supine blood pressure reduction 24 h after dose intake was 23 +/- 7/16 +/- 4 mmHg compared to placebo control (P less than 0.05/P less than 0.01). The data from this study indicate that ketanserin monotherapy may lower blood pressure over 24 h in a once-daily regimen.

Aged↗
PubMed1986

Regional haemodynamics and antihypertensive effects during long-term ketanserin treatment.

The serotonin (S2) antagonist, ketanserin was given to 16 patients with essential hypertension on a single-blind basis. Ten patients were treated for 3 years with ketanserin 40-80 mg daily on a once or twice daily regimen. In this group supine blood pressure fell from 164 +/- 4/101 +/- 2 mmHg on placebo to 152 +/- 5/91 +/- 3 mmHg (NS/P less than 0.01) after 3 years of therapy. During treatment, total serum cholesterol remained essentially unchanged while serum triglycerides were significantly reduced. No side-effects were seen except for dry mouth or slight nasal congestion reported by two patients. In six patients regional haemodynamics were assessed by forearm plethysmography. After 3 months of ketanserin, resting vascular resistance was significantly reduced from 58.3 +/- 12 units on single-blind placebo to 47.0 +/- 12 units (P less than 0.005) on single-blind ketanserin, 40 mg twice daily. We conclude that ketanserin is an effective antihypertensive agent during long-term therapy with some beneficial effects on serum lipids. The antihypertensive effect seems to be mediated chiefly by a decrease in vascular resistance.

Female↗
PubMed1986

On the role of atrial natriuretic peptide in cardiovascular regulation in the spontaneously hypertensive rat.

Atrial natriuretic peptide ANP(1-23) reduced mean arterial pressure (MAP), cardiac output (CO), central blood volume (CBV) and stroke volume (SV) when given i.v. (100 pmol/min) to spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). In SHR, total peripheral resistance (TPR) was significantly lowered. The major cause of the fall in blood pressure in WKY was reduction in CO and in SHR reduction in TPR. Acute 20% volume expansion increased plasma immunoreactive ANP (IR-ANP) in WKY as well as in SHR. However, the ANP release in SHR was blunted compared with WKY. After chronic high salt intake, ANP release in SHR was even further reduced in relation to an acute volume load. We conclude that the release of ANP as well as the haemodynamic responses to exogenous ANP is altered in SHR.

Animals↗
PubMed1985

A centrally elicited respiratory stimulant effect by bombesin in the rat.

The effects of the tetradecapeptide bombesin on respiratory regulation in the rat were studied using a whole body plethysmographic model. Application of the peptide was made intracerebroventricularly (i.c.v.) as well as via microinjections into specific brainstem areas. I.c.v. injection (0.1-5 micrograms) resulted in a dose-dependent increase in tidal volume while respiratory frequency was decreased only at higher doses. The respiratory duty cycle remained unchanged while the respiratory drive was significantly increased. The respiratory effects were blunted by bilateral section of the tenth cranial nerve. Studies employing the occluded breath technique indicated a change in the threshold to afferent vagal signals while the time-setting for inspiration remained unchanged. Similar ventilation changes were elicited when the peptide was injected into the area of the nucleus ambiguous but not in several other areas of the brainstem. Such bombesin sensitive areas are consistent with a recent immunohistochemical study describing a dense pattern of immunoreactive somata in this area of the brainstem. The ventilatory stimulant effect seems to depend on an intact afferent vagal innervation.

Animals↗
PubMed1985

Antihypertensive mechanism of action of ketanserin and some ketanserin analogues in the spontaneously hypertensive rat.

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.

Animals↗
PubMed1985

Acute and long-term antihypertensive effect of bopindolol--a nonselective beta-adrenergic blocker with ISA.

14 male hypertensive patients, mean age 53 years first took part in a 3 month, double-blind crossover comparison of 1-2 mg bopindolol, a nonselective beta-blocker with ISA, and 100-200 mg metoprolol. Effects on blood pressure and heart rate were followed. One patient dropped out after the initial phase and the remaining 13 patients were followed for 1 year on bopindolol. 8 patients measured blood pressure at home, and in them bopindolol 1 mg o.d. and 8 mg once weekly were compared in a double-blind fashion, for 3 weeks on each regimen. Finally, after 1 year on bopindolol, treatment was withdrawn and blood pressure and heart rate were followed in 10 of the initial patients. Bopindolol in a mean dose of 1.35 mg/day caused a significant reduction in blood in pressure (26/15 mmHg), as did metoprolol (24/13 mmHg) in a mean dose of 144 mg/day. No significant difference in antihypertensive response was observed. Supine and standing heart rate were reduced both during bopindolol and metoprolol treatment. During long-term therapy with bopindolol, satisfactory blood pressure control was maintained up to 1 year in all patients, the average supine blood pressure being reduced from 173/107 to 144/90 mmHg. During treatment with bopindolol 8 mg once weekly, the blood pressure control was satisfactorily maintained over the week and no significant difference was observed in comparison with daily administration (1 mg) of the drug. When active treatment was withdrawn, a gradual increase in blood pressure and heart rate was observed, the pretreatment values being reached 8 weeks after discontinuation of bopindolol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1985

CSF and plasma pharmacokinetics of intramuscular morphine.

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.

Aged↗
PubMed1985

Chronic 5-HT2 receptor blockade with ritanserin does not reduce blood pressure in the spontaneously hypertensive rat.

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.

Animals↗
PubMed1985

Capsaicin and regulation of respiration: interaction with central substance P mechanisms.

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.

Animals↗
PubMed1985

Acute administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT-receptor agonist, causes a biphasic blood pressure response and a bradycardia in the normotensive Sprague-Dawley rat and in the spontaneously hypertensive rat.

8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is a new serotonin (5-HT) receptor agonist that binds selectively to the 5-HT1A binding site. In the present paper we investigated the cardiovascular effects of 8-OH-DPAT in the normotensive Sprague-Dawley rat and in the spontaneously hypertensive rat. The acute i.v. administration of 8-OH-DPAT (5-150 micrograms/kg) was in both rat strains associated with a biphasic blood pressure response and a bradycardia. The initial pressor response was due to a direct vascular effect of 8-OH-DPAT involving activation of alpha-adrenoceptors since it was present in pithed rats and in reserpine pretreated rats and since it was attenuated by prazosin. The longer lasting hypotension was not due to a direct vascular relaxation or a presynaptic inhibition of transmitter release since the hypotension was not evident in pithed rats and since 8-OH-DPAT did not influence the pressor responses to electrical stimulation in pithed rats. Rather, the combination of hypotension and bradycardia would suggest a central site of action although the intracerebroventricular (lat. ventricles) route of administration was not more efficient (to induce hypotension) than i.v. administration. At least the bradycardia was mediated by changes in vagal as well as sympathetic discharge since it was prevented by pretreatment with atropine and propranolol in combination but not by pretreatment with either agent alone. The cardiovascular effects of 8-OH-DPAT were not prevented by pretreatment with methergoline, methiothepin, pirenperone or cianserine or by 5-HT depletion by means of p-chlorophenylalanine, which suggests that the putative 5-HT receptor that is responsible for the hypotension and bradycardia to 8-OH-DPAT is not of a presynaptic type and does not have the pharmacological characteristics of a general 5-HT1 receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1985

Development of dopamine autoreceptors in the postnatal rat brain.

The behavioural and biochemical effects of racemic 3-PPP (3-[3-hydroxyphenyl]-N-n-propyl-piperidine) and its enantiomers was studied in developing rats, aged 1-28 days. All three compounds exhibit dopamine (DA) autoreceptor-stimulating properties. Moreover, the (+)-enantiomer displays agonist and the (-)-enantiomer antagonist actions, respectively, on the postsynaptic DA receptor. This means that the racemate has a DA autoreceptor stimulatory action with slight or no effects on the postsynaptic receptor. Locomotor experiments demonstrated that (+/-)-3-PPP inhibited spontaneous locomotor activity dosedependently in the 28 days old rats. No effects were seen in the age groups 14 days and younger. While the racemate and the (-)-enantiomer inhibited spontaneous locomotor activity in 28 days old rats, the (+)-enantiomer had no effects compared to saline. Interestingly, the (+)-enantiomer increased locomotor activity in the 4 days old rats, while the (-)-enantiomer and the racemate did not induce any effects. In the biochemical experiments, after blockade of DA neurotransmission with gamma-butyrolactone (GBL), (+/-)-3-PPP inhibited the increase in tyrosine hydroxylase activity (DOPA accumulation after NSD 1015) after GBL in the DA rich striatum region of the 28 days but not of the 4 days old rats. From these experiments it may be concluded that functional postsynaptic but not presynaptic DA receptors exist in the brain of 4 days old rats. Presynaptic DA receptors do not seem to be functionally mature until 28 days postnatally in the rat, i.e. during adolescent age.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Gammahydroxybutyric acid: central biochemical and behavioral effects in neonatal rats.

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.

Animals↗
PubMed1985

Treatment of arterial hypertension with ketanserin in mono- and combination therapy.

We evaluated the long-term antihypertensive effects of ketanserin, a selective serotonin2-receptor blocker with weak adrenergic receptor blocker properties. Ketanserin was given alone, 40 mg o.d. or b.i.d., for 2 years to 12 patients with essential hypertension. Systolic and diastolic blood pressures (BPs) were significantly reduced 14 days after the start of therapy and remained lowered during the 2-year follow-up period. In a larger group of patients who received ketanserin monotherapy for 2 to 3 months, the response to therapy varied considerably between subjects, with an overall response rate (BP less than 165/95 mm Hg) of 60% to 75%. During steady-state conditions, the maximum and minimum ketanserin plasma concentrations varied from threefold to fourfold between subjects and did not correlate with individual reductions in BP, but for each individual there was a positive correlation between BP reduction and ketanserin plasma concentration throughout a study day. In combination with beta-blockers, ketanserin effectively reduced BP in the supine and standing positions. The plasma concentration profile was not altered as much during combination therapy as when ketanserin was given alone. Side effects were few and tolerable. Ketanserin effectively reduces BP both alone and in combination with beta-blockers and may be still another drug useful in the treatment of essential hypertension.

Adrenergic beta-Antagonists↗
PubMed1985

Antihypertensive effects of ketanserin in the spontaneously hypertensive rat: mode of action.

In the spontaneously hypertensive rat (SHR), ketanserin and the ketanserin analogues R56413 and ritanserin were studied with regard to their ability to reduce the blood pressure in conscious rats and shift the dose-response curves for phenylephrine and serotonin (5-HT) in pithed rats after acute administration. 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 by ritanserin did not influence the blood pressure but it potentiated the hypotensive response to alpha 1-adrenoceptor blockade by prazosin. Thus, following acute administration in the SHR, the major portion of the antihypertensive response to ketanserin is due to an alpha 1-adrenoceptor blockade but the 5-HT2-receptor blockade may contribute.

Animals↗
PubMed1985

Chronic serotonergic blockade with ketanserin in the spontaneously hypertensive rat.

Spontaneously hypertensive rats were fed ketanserin-enriched (17 mg/100 g) or control chow for 6 weeks. After 6 weeks the blood pressure was reduced (16%). Pressor responses to phenylephrine were not different from control responses, which indicates that at this time the antihypertensive effect was not directly related to an alpha-adrenoceptor blockade. Cardiovascular responses to stress (jet air), baroreceptor sensitivity (bradycardia to phenylephrine), and central catecholamine turnover were unchanged, which supported the view that central mechanisms probably do not contribute to the antihypertensive effects of ketanserin.

Animals↗
PubMed1985

A comparative and long-term evaluation of ketanserin in the treatment of essential hypertension.

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.

Adrenergic beta-Antagonists↗