Steen Matzen

BRADYCARDIA DURING REVERSIBLE HYPOVOLAEMIC SHOCK: ASSOCIATED NEURAL REFLEX MECHANISMS AND CLINICAL IMPLICATIONS

1. Heart rate response to reversible central hypovolaemia can be divided into three stages. In the first stage (corresponding to a reduction of the blood volume by approximately 15%) a modest increase in heart rate (<100 beats/min) and total peripheral resistance compensate for the blood loss, and a near normal arterial blood pressure prevails (preshock). During the second stage, a reduction of the central blood volume by approximately 30% results in a decrease in heart rate, total peripheral resistance and blood pressure due to activation of unmyelinated vagal afferents (C‐fibres) from the left ventricle. In the third stage, blood pressure falls further as haemorrhage continues and tachycardia (> 120 beats/ min) is manifest. This stage may proceed into irreversible shock with death from cardiac arrest probably related to the formation of free oxygen radicals.

Histaminergic Mediation of the Stress-Induced Release of Prolactin in Male Rats

Histamine (HA) is likely to participate in the neuroendocrine regulation of prolactin (PRL) secretion. We, therefore, studied the possible involvement of HA in the stress-induced release of PRL in conscious male rats. HA (30 micrograms) infused intracerebroventricularly 15 min before decapitation elevated PRL plasma levels from 5 +/- 1 to 54 +/- 6 ng/ml (p less than 0.01). Intracerebroventricular infusion of the H2 receptor antagonists cimetidine (CIM: 100 micrograms) or ranitidine (RAN: 125 micrograms) abolished the PRL response to HA (p less than 0.01), while intracerebroventricular infusion of the H1 receptor antagonist mepyramine (MEP; 100 micrograms) inhibited the response only 40% (p less than 0.05). Intra-arterial infusion of CIM (2,000 micrograms) or RAN (2,500 micrograms) inhibited the HA-stimulated PRL secretion 52% (p less than 0.01) or 63% (p less than 0.01), respectively. The H1 receptor antagonists MEP (1,000 micrograms) and SKF-93944 (1,500 micrograms) had no effect following intra-arterial administration. Restraint stress increased the PRL level to 84 +/- 6 ng/ml (p less than 0.01 vs. control). This effect was prevented by intracerebroventricular infusion of CIM or RAN (p less than 0.01) and inhibited 75% by MEP (p less than 0.01). Intra-arterial infusion of CIM, MEP, and SKF-93944 inhibited the stress response about 50% (p less than 0.01), while RAN decreased the response only 25% (p less than 0.05). Ether stress elevated the plasma PRL concentration to 46 +/- 5 ng/ml (p less than 0.01 vs. control). When infused intracerebroventricularly CIM or RAN prevented the response (p less than 0.01), while MEP had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

A NEW AMORPHOUS HYDROCOLLOID FOR THE TREATMENT OF PRESSURE SORES: A RANDOMISED CONTROLLED STUDY

A randomised controlled study was carried out to compare the effect of a new amorphous hydrocolloid (hydrogel, Coloplast) with that of conventional treatment on the healing time of pressure sores. After initial debridement in the outpatient clinic of pressure sores located in the sacral (n = 21) or trochanteric (n = 11) area the patients were randomised to be treated with either hydrogel (n = 17) or wet saline compresses (n = 15). Once a week the healing was estimated by the same investigator. The relative volumes (from the initial 100%) of hydrogel-treated wounds were significantly less (26 +/- 20%, p < 0.02) than those of saline treated wounds (64 +/- 16%) in the last week of the study. The saline treated wounds needed more frequent weekly debridement than the hydrogel-treated wounds (21% compared with 7% of all weekly dressings, p < 0.03). We conclude that amorphous hydrocolloid increases current healing of pressure sores compared with conventional treatment. It is therefore a better choice for treating patients with pressure sores in their homes.

Brain regulation of renin secretion involves central histaminergic neurons

The possible involvement of histamine (HA) in the stress-induced increase in plasma renin activity (PRA) was investigated in male rats. Intracerebroventricular (ICV) infusion of histamine (HA; 3.8-60 micrograms) increased PRA dose-dependently, and the Kd (dissociation konstant) of HA was estimated to approximately 30 micrograms. ICV infusion of HA (30 micrograms) as well as 5 min of restraint stress increased plasma renin activity (PRA) 2- and 3-fold, respectively (p less than 0.01). These effects were abolished by prior ICV infusion of the H2-receptor antagonists cimetidine (100 micrograms) and ranitidine (125 micrograms) (p less than 0.01), which reduced the PRA to subbasal levels (p less than 0.05). When administered alone the H2-receptor antagonists had no effect on PRA. In contrast, the H1-receptor antagonist mepyramine (100 micrograms) increased the basal PRA level (p less than 0.01) and slightly augmented the HA- and stress-induced increase in PRA (p less than 0.05). HA as well as restraint stress increased the plasma levels of dopamine, norepinephrine and epinephrine almost 2-fold (p less than 0.01). The effect of the two stimuli was prevented by prior ICV infusion of mepyramine or cimetidine (p less than 0.01). Pretreatment with the beta-adrenergic receptor blocker propranolol (7 mg/kg i.p.) abolished the HA-induced and inhibited by 70% the stress-induced PRA increase. The results indicate that histaminergic neurons participate in the cerebral regulation of renin secretion. The H2-receptor-mediated PRA-increasing effect of HA involves activation of sympathetic nerves. In addition, HA seems to exert a minor inhibiting effect on PRA via H1-receptors.

Involvement of Histamine in the Mediation of the Stress-Induced Release of Alpha-Melanocyte-Stimulating Hormone in Male Rats

The involvement of histaminergic neurons in the neuroendocrine regulation of the release of the pro-opiomelanocortin-derived peptides adrenocorticotropin (ACTH; anterior pituitary lobe) and alpha-melanocyte-stimulating hormone (alpha-MSH; intermediate pituitary lobe) was studied in conscious male rats. Pretreatment with the histamine (HA) synthesis inhibitor (S)-alpha-fluoromethylhistidine (100 mumol/kg i.p. at -6 h or 400 mumol/kg i.p. at -20 and -6 h) had no effect on basal ACTH release but decreased basal alpha-MSH release. The two doses of (S)-alpha-fluoromethylhistidine inhibited by 35 and 50% the ACTH response to inhibited the ACTH and alpha-MSH response to ether stress by 50 and 70%, respectively. Intracerebroventricular administration of the HA metabolism inhibitor SKF91488 (400 or 800 nmol at -15 min) stimulated basal secretion of ACTH and alpha-MSH dose-dependently and augmented slightly the restraint- and ether-stress-induced release of ACTH and alpha-MSH. Intracerebroventricular infusion of the H1 receptor antagonist mepyramine (0.37 mumol) or the H2 receptor antagonists cimetidine (0.40 mumol) or ranitidine (0.40 mumol) inhibited or prevented the alpha-MSH response to intracerebroventricular administration of HA (0.27 mumol), restraint or ether stress. Pretreatment with the dopamine receptor agonist bromocriptine or the beta-adrenergic receptor antagonist propranolol inhibited the alpha-MSH response to HA or stress. The results indicate that hypothalamic histaminergic neurons participate in the neuroendocrine regulation of the pro-opiomelanocortin-derived peptides from the anterior (ACTH) and intermediate (alpha-MSH) pituitary lobe of male rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Histaminergic Stimulation of Prolactin Secretion Mediated via H1- or H2-Receptors: Dependence on Routes of Administration

Controversy exists regarding the involvement of H1- or H2-receptors in the PRL-releasing activity of histamine (HA). This could be due to differences in the route of administration of HA and histaminergic compounds. Therefore, we studied the effect on PRL secretion of HA and HA-agonists infused intracerebroventricularly (ICV) or systemically (IA) either alone or in combination with HA-antagonists in male rats. HA administered ICV as well as IA stimulated PRL secretion dose dependently. The stimulatory effect of ICV-infused HA was blocked by the H2-receptor antagonist cimetidine (CIM) and mimicked by the H2-receptor agonists 4-methylhistamine (4-MeHA) and dimaprit (DIM). In contrast, the H1-receptor antagonist mepyramine (MEP) enhanced the PRL-releasing effect of HA while the H1-receptor agonist 2-thiazolylethylamine (2-TEA) had no significant effect. The stimulatory effect of IA-infused HA was blocked by the H1-receptor antagonist MEP and mimicked by the H1-receptor agonist 2-TEA, whereas the H2-receptor antagonist CIM enhanced the PRL-stimulatory effect of HA and the H2-receptor agonist DIM was without effect. 4-MeHA stimulated PRL secretion, but this effect was unrelated to stimulation of H2-receptors. The effect of ICV administered HA was unaffected by IA infused antagonists and the effect of IA administered HA was not altered by ICV infused antagonists. HA had no effect on the PRL release from isolated adenohypophyses, and HA did not stimulate PRL secretion in pituitary stalk-sectioned rats following IA infusion. The findings indicate that HA administered ICV exerts its PRL releasing activity via H2-receptors while HA administered IA stimulates PRL secretion via H1-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Neovaginal construction in vaginal aplasia and sex-reassignment surgery

During the period 1984-1994 33 patients were admitted to the department of plastic surgery for the purpose of neovaginal construction. They comprised 22 patients with vaginal agenesis or aplasia and 11 transsexual men. In most cases neovaginal construction was done by blunt dissection and lining with a split thickness skin graft from the thigh, and in the cases of sex-reassignment surgery genital skin was also used. The two groups differed as the patients with vaginal agenesis or aplasia had remarkably few complications compared with the transsexual group. The most common complications were defects in the skin grafts and vaginal stenosis. The transsexuals therefore had an extended recovery period including several admissions and visits to the outpatient clinic. The difference in genotype does not explain the high complication rate in the transsexual group as eight in the vaginal agenesis or aplasia group had Morris syndrome (testicular feminisation (XY)). However, the phenotype may be of importance in vaginal construction as the male (transsexual) pelvis is narrow and the levator muscles are stronger than those in the female pelvis.

Histaminergic Regulation of Prolactin Secretion: Involvement of Serotoninergic Neurons

The possible involvement of the serotoninergic system in histamine-induced PRL secretion was studied in urethane anesthetized male rats. Intracerebroventricular infusion of histamine (30 micrograms) stimulated PRL secretion 10-fold. This effect was mimicked by the H2-receptor agonist dimaprit (300 micrograms), while the H1-receptor agonist 2-thiazolylethylamine (140 micrograms) had no effect. Pretreatment with the serotonin receptor blockers methysergide (2.5 mg/kg i.p.) or ketanserin (2.5 or 10.0 mg/kg i.p.) reduced the PRL peak response to histamine 75, 54, or 58%, respectively. During serotonin receptor blockade, dimaprit had a stimulatory effect similar to that of histamine, while 2-thiazolylethylamine had no effect. Intraarterial infusion of histamine (420 micrograms) stimulated PRL secretion 6-fold. This effect was mimicked by the H1-receptor agonist 2-thiazolylethylamine (1,900 micrograms), while the H2-receptor agonist dimaprit (3,000 micrograms) had no effect. Pretreatment with methysergide (2.5 mg/kg i.p.) or ketanserin (2.5 or 10.0 mg/kg i.p.) reduced the peak response to histamine 54, 54, or 51% respectively. The effect of histamine was mimicked by 2-thiazolylethylamine, while dimaprit slightly inhibited the PRL secretion. The antiserotoninergic activity of methysergide and ketanserin was demonstrated by their ability to prevent the PRL-releasing effect to serotonin. The effects of methysergide and ketanserin were not due to dopamine-like activity, since none of the drugs affected basal PRL secretion and since the dopamine receptor antagonist pimozide did not prevent the inhibitory effect of methysergide on the histamine-induced PRL release. The findings indicate that histamine-stimulated PRL secretion is mediated in part by serotoninergic neurons.

Histaminergic Regulation of Prolactin Secretion: Involvement of Tuberoinfundibular Dopaminergic Neurons

It has been shown that histamine (HA) stimulates prolactin (PRL) secretion via H2 receptors following intra-cerebroventricular infusion and via H1 receptors following systemic (intra-arterial) infusion. Since the effect of HA appears to be exerted at a suprapituitary level, we investigated the involvement of the tuberoinfundibular dopaminergic (TIDA) system in HA-induced PRL secretion in urethane-anesthetized male rats. HA infused intracerebroventricularly (30 micrograms) or intra-arterially (420 micrograms) decreased the dopamine (DA) concentration in pituitary portal blood by 30 and 23%, respectively. Blockade of DA receptors by pimozide did not prevent the stimulation of PRL secretion induced by intracerebroventricular infusion of HA or the H2 receptor agonist dimaprit. Furthermore, during DA receptor blockade intracerebroventricular infusion of the H1 receptor agonist 2-thiazolylethylamine inhibited PRL secretion. In contrast, pimozide prevented the stimulation of PRL secretion induced by intra-arterial infusion of HA and the H1 receptor agonist 2-thiazolylethylamine. In fact, under these conditions intra-arterial infusion of HA or the H2-receptor agonist dimaprit inhibited PRL secretion. During treatment with alpha-methyl-p-tyrosine, which reduced the hypothalamic DA content by 50%, HA infused intracerebroventricularly stimulated PRL secretion, while HA infused intra-arterially inhibited the secretion, which is in accordance with the results obtained during pimozide treatment. Cholinergic blockade by atropine did not prevent the HA-induced PRL release, excluding the possibility that the observed effect of pimozide is due to its anticholinergic property. We suggest that intracerebroventricular infusion of HA by activation of H2 receptors may stimulate PRL secretion partly via inhibition of the TIDA system and partly via other mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Arterial diameter during central volume depletion in humans

The luminal diameter of the radial artery was followed by high frequency ultrasound during 50° head-up tilt-induced central volume depletion in ten healthy subjects of whom six were tilted twice and pretreated with the serotonin receptor antagonist methysergide or placebo following a double-blind randomized design. Eight subjects without active treatment experienced presyncopal symptoms after 16–45 (mean 32 min). Central volume depletion was indicated by an increase in mean thoracic electrical impedance [from 31.5 (SEM 1.6) to 33.4 (SEM 1.7) ΩP < 0.05]. Cardiac output decreased [from 4.1 (SEM 0.3) to 2.2 (SEM 0.3) l · min−1] and heart rate [HR, from 64 (SEM 3) to 100 (SEM 7) beats · min−1], mean arterial pressure {MAP, from 77 (SEM 4) to 89 (SEM 2) mmHg [10.3 (SEM 0.53 to 11.9 (SEM 0.27) kPa]} and total peripheral resistance {TPR, from 19 (SEM 2) to 34 (SEM 4) mmHg · min · l−] [2.5 (SEM 0.27) to 4.5 (SEM 0.53) kPa · min−1]} increased; but with the appearance of presyncopal symptoms, HR, MAP and TPR were reduced to 65 (SEM 8) beats · min−1, 46 (SEM 4) mmHg [6.1(SEM 0.53) kPa] and 18 (SEM 3) mmHg · min · l−1 [2.4 (SEM 0.4) kPa · min−1 · l−], respectively (P < 0.05). Vascular resistance was reflected in the arterial diameter which decreased from 2.42 (SEM 0.17) to 2.27 (SEM 0.14) mm during head-up tilt and increased to 2.71 (SEM 0.14) mm with the appearance of presyncopal symptoms (P < 0.05). Methysergide reduced the resting radial (15 ± 2%) and temporal artery diameters (10 ± 3%) (P < 0.05); however, it affected neither tilt-tolerance nor the central cardiovascular response to tilt. The results suggested a serotonergic influence on arterial tone at rest, and demonstrated that vessels as large as the radial artery participated in vascular control during central volume depletion independent of such a serotonergic influence.