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L Hein

Publications and source records attributed to L Hein.

At least 37 records · Page 2Linked to original sources
PubMed2001

Alpha2-adrenoceptors modulating neuronal serotonin release: a study in alpha2-adrenoceptor subtype-deficient mice.

1. The release-inhibiting alpha2-adrenoceptors of cerebral serotoninergic axons were studied in mice. Slices of the hippocampus or the occipito-parietal cortex from NMRI mice, from mice lacking the alpha2A/D-, the alpha2B-, the alpha2C- or both the alpha2A/D- and the alpha2C-adrenoceptor, and from mice sharing the genetic background of the receptor-deficient animals (WT) were preincubated with [3H]-serotonin and then superfused and stimulated electrically, in most experiments by trains of 8 pulses at 100 Hz. 2. The concentration-response curves of the alpha2-adrenoceptor agonist medetomidine were virtually identical in hippocampal slices from NMRI and WT mice, with maximally 70% inhibition and an EC50 of about 2 nM. In hippocampal slices from NMRI mice, phentolamine and rauwolscine were equipotent antagonists against medetomidine. 3. The effect of medetomidine was greatly reduced, with maximally 20% inhibition, in hippocampal slices from alpha2A/D-adrenoceptor-deficient mice; was slightly reduced, with maximally 59% inhibition, in hippocampal slices from alpha2C-adrenoceptor-deficient mice; was not changed in hippocampal slices from alpha2B-adrenoceptor-deficient mice; and was abolished in hippocampal slices from mice lacking both the alpha2A/D- and the alpha2C-adrenoceptor. 3. Similar results were obtained in: (i) occipito-parietal slices from NMRI and alpha2A/D-adrenoceptor-deficient mice and (ii) hippocampal slices that were preincubated with [3H]-serotonin in the presence of oxaprotiline to rule out cross-labelling of noradrenergic axons. 5. The serotoninergic axons of the mouse brain possess both alpha2A/D-heteroreceptors, which predominate, and alpha2C-heteroreceptors but lack alpha2B-adrenoceptors. The situation resembles the coexistence of alpha2A/D- and alpha2C-autoreceptors but lack of alpha2B-autoreceptors at the noradrenergic axons of mice.

Animals↗
PubMed2001

Can we use vertical bore magnetic resonance scanners for murine cardiovascular phenotype characterization? Influence of upright body position on left ventricular hemodynamics in mice.

High resolution magnetic resonance (MR) imaging is uniquely suited for cardiovascular phenotype characterization in transgenic mice. Experimental MR scanners with the high magnetic field strength are commonly built with a vertical bore design. The hemodynamic consequences of a prolonged upright body position in anesthetized mice are, however, unknown. Thus, the purpose of this work was to investigate the influence of a vertical body position on murine systemic blood pressure and left ventricular (LV) hemodynamics over time. We studied six C57Bl/6 mice at 14-16 weeks of age (body weight, 24-28 g) under isoflurane anesthesia. Positioned supine on a 37 degrees C warming pad, a microtip catheter was advanced via the right carotid artery into the left ventricle. Continuous registration of LV hemodynamics was performed at rest and after tilting of the table to a 90-degree vertical position. After tilting, there was a transient decrease of LV systolic pressure to 96% of initial values immediately after tilting with return to baseline level within 6 min. Tilting to vertical position had no influence on LV end-diastolic pressure, heart rate, maximal rate of left ventricular pressure increase, and maximal rate of left ventricular pressure decrease. Over a follow-up period of 60 min in vertical position, there were no significant changes in murine hemodynamics. An acute change of body position is fully compensated by a normal orthostatic response in anesthetized mice. Prolonged upright body position exerts no significant changes in murine LV hemodynamics. Hence, high resolution MR studies for cardiovascular phenotype characterization in transgenic mice performed on vertical bore MR scanners allow measurements under physiologic conditions.

Animals↗
PubMed2001

Differential distribution of beta-adrenergic receptor subtypes in blood vessels of knockout mice lacking beta(1)- or beta(2)-adrenergic receptors.

beta-Adrenergic receptors (beta-AR) are essential regulators of cardiovascular homeostasis. In addition to their prominent function in the heart, beta-AR are located on vascular smooth muscle cells, where they mediate vasodilating effects of endogenous catecholamines. In this study, we have investigated in an isometric myograph different types of blood vessels from mice lacking beta(1)- and/or beta(2)-adrenergic receptor subtypes (beta(1)-KO, beta(2)-KO, beta(1)beta(2)-KO). In wild-type mice, isoproterenol induced relaxation of segments from thoracic aorta, carotid, femoral and pulmonary arteries, and portal vein. The relaxant effect of beta-receptor stimulation was absent in femoral and pulmonary arteries from beta(1)-KO mice. In aortic and carotid arteries and in portal veins, the vasodilating effect of isoproterenol was reduced in mice lacking beta(1)- or beta(2)-receptors. However, in these vessels the vasodilating effect was only abolished in double KO mice lacking both beta(1)- and beta(2)-receptors. Vessel relaxation induced by forskolin did not differ between wild-type and KO mice. Similar contributions of beta(1)- and beta(2)-receptors to isoproterenol-induced vasorelaxation were found when vessels from KO mice were compared with wild-type arteries in the presence of subtype-selective beta-receptor antagonists. These studies demonstrate that beta(1)-adrenergic receptors play a dominant role in the murine vascular system to mediate vasodilation. Surprisingly, beta(2)-receptors contribute to adrenergic vasodilation only in a few major blood vessels, suggesting that differential distribution of beta-adrenergic receptor subtypes may play an important role in redirection of tissue perfusion.

Animals↗
PubMed2000

The incidence of transient neurologic symptoms (TNS) after spinal anaesthesia in patients undergoing surgery in the supine position. Hyperbaric lidocaine 5% versus hyperbaric bupivacaine 0.5%.

BACKGROUND: The incidence of TNS after spinal anaesthesia is a problem. Especially the use of hyperbaric lidocaine in patients placed in the lithotomy position during surgery has been associated with a high incidence of TNS. The present study was performed to investigate whether TNS is present more frequently in patients undergoing surgery in the supine position with use of hyperbaric lidocaine compared with hyperbaric bupivacaine. METHOD: Seventy patients were included and randomised to receive either hyperbaric lidocaine or hyperbaric bupivacaine. All patients were contacted on the first and third postoperative days by an anaesthesiologist blinded to the local anaesthetic used. The patients were asked about symptoms of TNS, pain not associated with the operation area, and asked to grade the complaints after a verbal analogue score from 0 to 10. RESULTS: We found a total of ten patients who showed signs of TNS. There were nine patients in the lidocaine group (26%) who showed signs of TNS compared to only one patient in the bupivacaine group (3%) (P<0.01). The average score of TNS complaints was 3.5. A total of 13 patients (19%) complained of back pain. There were no significant differences with regard to which local anaesthetic was used. The average score of back pain was 3.3. CONCLUSION: TNS is a significant problem in patients having spinal anaesthesia with hyperbaric lidocaine compared to hyperbaric bupivacaine, both in the supine position. For day-case surgery, TNS would start after dismissal from hospital. The use of hyperbaric lidocaine is therefore questionable, even though these problems are of an order that the majority of patients would still choose spinal anaesthesia for future operations.

Adult↗
PubMed2000

The effects of atropine on dynamic compliance in healthy intubated adults.

In order to compare the effect of atropine and sodium chloride on the dynamic compliance of the respiratory system after tracheal intubation, we studied 20 patients allocated randomly into two groups to receive either: atropine after 5 min of steady state and sodium chloride after 10 min (group A) or in reverse order (group B) intravenously. The study was conducted in a randomized double-blinded manner. The patients were anaesthetized with thiopental 5 mg kg(-1) followed by thiopental 50 mg intravenously, as required. Intubation was facilitated by atracurium 0.5 mg kg(-1) intravenously and fentanyl 200 microg intravenously. During fixed volume ventilation (100 mL kg(-1), f=10), compliance and end-tidal carbon dioxide were measured every 10 s by a Datex AS/3-respiratory module connected to a portable IBM-pc. Five minutes was allowed to establish a steady state then either atropine or sodium chloride was administered according to the protocol. Respiratory dynamic compliance increased significantly after intravenous administration of atropine (P < 0.05). We conclude that atropine 1.0 mg given intravenously provides protection against an intubation-induced decline in respiratory dynamic compliance.

Adolescent↗
PubMed1999

Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission.

The sympathetic nervous system regulates cardiovascular function by activating adrenergic receptors in the heart, blood vessels and kidney. Alpha2-adrenergic receptors are known to have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system; however, the individual roles of the three highly homologous alpha2-adrenergic-receptor subtypes (alpha2A, alpha2B, alpha2C) in this process are not known. We have now studied neurotransmitter release in mice in which the genes encoding the three alpha2-adrenergic-receptor subtypes were disrupted. Here we show that both the alpha2A- and alpha2C-subtypes are required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons. Alpha2A-adrenergic receptors inhibit transmitter release at high stimulation frequencies, whereas the alpha2C-subtype modulates neurotransmission at lower levels of nerve activity. Both low- and high-frequency regulation seem to be physiologically important, as mice lacking both alpha2A- and alpha2C-receptor subtypes have elevated plasma noradrenaline concentrations and develop cardiac hypertrophy with decreased left ventricular contractility by four months of age.

Adrenergic alpha-Agonists↗
PubMed1999

Gene substitution/knockout to delineate the role of alpha 2-adrenoceptor subtypes in mediating central effects of catecholamines and imidazolines.

Adrenergic receptors form the interface between the sympathetic nervous system and the cardiovascular system as well as many endocrine and parenchymal tissues. For the three alpha 2-adrenergic receptors (alpha 2A, alpha 2B, and alpha 2C), genetic mouse models have been developed that can be used to elucidate the physiologic function of each receptor subtype in vivo. Different strategies for homologous recombination in embryonic stem cells were applied to generate lines of mice with gene knockouts of the individual alpha 2-receptor subtypes (alpha 2A-KO, alpha 2B-KO, and alpha 2C-KO) or with a substitution of a mutant receptor at the wild-type locus (alpha 2-D79N). In these transgenic mice, the cardiovascular effects of alpha 2-agonists and imidazoline receptor agonists were tested. Stimulation of alpha 2B receptors in vascular smooth muscle produces hypertension and counteracts the clinically beneficial hypotensive effect of stimulating alpha 2A receptors in the central nervous system.

Adrenergic alpha-Agonists↗
PubMed1999

Progressive hypertrophy and heart failure in beta1-adrenergic receptor transgenic mice.

Stimulation of cardiac beta1-adrenergic receptors is the main mechanism that increases heart rate and contractility. Consequently, several pharmacological and gene transfer strategies for the prevention of heart failure aim at improving the function of the cardiac beta-adrenergic receptor system, whereas current clinical treatment favors a reduction of cardiac stimulation. To address this controversy, we have generated mice with heart-specific overexpression of beta1-adrenergic receptors. Their cardiac function was investigated in organ bath experiments as well as in vivo by cardiac catheterization and by time-resolved NMR imaging. The transgenic mice had increased cardiac contractility at a young age but also developed marked myocyte hypertrophy (3.5-fold increase in myocyte area). This increase was followed by progressive heart failure with functional and histological deficits typical for humans with heart failure. Contractility was reduced by approximately 50% in 35-week-old mice, and ejection fraction was reduced down to a minimum of approximately 20%. We conclude that overexpression of beta1-adrenergic receptors in the heart may lead to a short-lived improvement of cardiac function, but that increased beta1-adrenergic receptor signalling is ultimately detrimental.

Aging↗
PubMed1999

Occurrence, pharmacology and function of presynaptic alpha2-autoreceptors in alpha2A/D-adrenoceptor-deficient mice.

The occurrence, pharmacological properties and function of alpha2-autoreceptors were studied in hippocampal slices, occipito-parietal cortex slices, segments of heart atria and segments of the vas deferens of wildtype (WT) mice and mice in which the alpha2 A/D-adrenoceptor gene had been disrupted (alpha2 A/D(KO)). Tissues were preincubated with [3H]-noradrenaline and then superfused and stimulated electrically. Stimulation periods for brain slices consisted either of 1 pulse or of 2-64 pulses delivered at 1-s intervals; stimulation periods for peripheral tissues consisted either of 1 POP (pseudo-one-pulse; brief burst of 20 pulses/50 Hz) or of 2-4 POPs delivered at 1-s intervals. Single pulses or POPs were used to study the effect of medetomidine and its interaction with antagonists. One or more pulses or POPs per stimulation period were used to study alpha2-autoinhibition. Medetomidine decreased the evoked overflow of tritium in WT tissues. In alpha2 A/D(KO) tissues, the inhibition was slightly (peripheral tissues) or greatly (brain slices) attenuated but not abolished. Phentolamine, rauwolscine, spiroxatrine, 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101), tolazoline and prazosin antagonized the effect of medetomidine in all tissues. Their pKd values against medetomidine were compared with pKd values at prototypical alpha2 binding sites by means of a correlation analysis. For WT brain and atrial autoreceptors, the correlations indicated an alpha2D pharmacology, whereas for WT vas deferens autoreceptors they favoured an alpha2B pharmacology. In the KO tissues, any correlation with alpha2D was lost, and the non-alpha2 A/D-autoreceptors displayed alpha2B or alpha2C pharmacology. When 2 or more pulses or POPs were applied to WT tissues per stimulation period, the pulse number-overflow curve (POP number-overflow curve) was flat, indicating that overflow elicited by p pulses (POPs) was much smaller than p times the overflow elicited by a single pulse (POP); moreover, rauwolscine caused a pulse (POP) number-dependent and, at high pulse (POP) numbers, large increase in evoked tritium overflow. In alpha2 A/D(KO) tissues, the pulse (POP) number-overflow curve was much steeper, indicating that overflow elicited by p pulses (POPs) was closer to p times the overflow elicited by a single pulse (POP); moreover, rauwolscine caused no (atria) or only a small increase in overflow, and did so in brain slices only at high pulse numbers (16 and 64). In conclusion, the predominant alpha2D pharmacology of the autoreceptors in WT tissues supports the idea that the main mammalian presynaptic alpha2-autoreceptors belong to the alpha2 A/D subtype. However, alpha2 A/D-deficient animals also possess autoreceptors. As expected, these non-alpha2 A/D-autoreceptors display alpha2B or alpha2C pharmacology. In WT animals, alpha2B- or alpha2C-autoreceptors or both may coexist with alpha2 A/D-autoreceptors, at least in peripheral tissues. Little autoinhibition by released noradrenaline in trains of pulses remains when the alpha2 A/D-adrenoceptor is lacking, again in accord with a predominance of alpha2 A/D-autoreceptors.

Adrenergic alpha-Agonists↗
PubMed1999

Modulation of vascular development and injury by angiotensin II.

OBJECTIVE: To examine the exact profile of expression and to determine the functional significance of the angiotensin II (Ang II), type I (AT1) and type 2 (AT2) receptors during rat aortic development and following rat carotid artery balloon injury. METHODS: AT1 and AT2 mRNA levels in rat aortae were measured using a quantitative reverse transcription polymerase chain reaction technique. Ang II receptor function was assessed by quantitating the effects of AT1 (DuP753) and AT2 (PD123319) receptor antagonists during these processes. RESULTS: During aortic development, AT1 expression was detected on gestational day 14, increased until embryonic day 16 (E16), after which, levels were similar throughout postnatal development. Conversely, AT2 mRNA first appeared at E16, reached maximal levels between E19 and neonatal day 1, and decreased thereafter. DNA synthesis rates decreased with aortic development (high at E15, 73.8 +/- 3.1%; dropping to 37.5 +/- 2.3% by E21). Whereas AT1 receptor antagonism accelerated this developmentally regulated decrease in DNA synthesis. AT2 receptor antagonism blunted this decrease. Because activated adult medial smooth muscle cells express a neonatal phenotype after vascular injury, we assessed Ang II receptor levels and function after carotid artery balloon injury. Both receptor subtypes increased; however, AT2 receptor mRNA expression peaked earlier than AT1 (48 to 72 h after injury). As with aortic development, DNA synthesis occurring between 24 to 48 h after injury (when AT2 receptors constitute 10% of the Ang II receptor population) decreased in DuP753-treated animals and increased in PD123319-treated animals. CONCLUSION: These results indicate that Ang II receptors play a role in vascular development by promoting opposing effects on vascular smooth muscle cell growth.

Angiotensin II↗
PubMed1999

Abnormal regulation of the sympathetic nervous system in alpha2A-adrenergic receptor knockout mice.

alpha2-Adrenergic receptors (ARs) play a key role in regulating neurotransmitter release in the central and peripheral sympathetic nervous systems. To date, three subtypes of alpha2-ARs have been cloned (alpha2A, alpha2B, and alpha2C). Here we describe the physiological consequences of disrupting the gene for the alpha2A-AR. Mice lacking functional alpha2A subtypes were compared with wild-type (WT) mice, with animals lacking the alpha2B or alpha2C subtypes, and with mice carrying a point mutation in the alpha2A-AR gene (alpha2AD79N). Deletion of the alpha2A subtype led to an increase in sympathetic activity with resting tachycardia (knockout, 581 +/- 21 min-1; WT, 395 +/- 21 min-1), depletion of cardiac tissue norepinephrine concentration (knockout, 676 +/- 31 pg/mg protein; WT, 1178 +/- 98 pg/mg protein), and down-regulation of cardiac beta-ARs (Bmax: knockout, 23 +/- 1 fmol/mg protein; WT, 31 +/- 2 fmol/mg protein). The hypotensive effect of alpha2 agonists was completely absent in alpha2A-deficient mice. Presynaptic alpha2-AR function was tested in two isolated vas deferens preparations. The nonsubtype-selective alpha2 agonist dexmedetomidine completely blocked the contractile response to electrical stimulation in vas deferens from alpha2B-AR knockout, alpha2C-AR knockout, alpha2AD79N mutant, and WT mice. The maximal inhibition of vas deferens contraction by the alpha2 agonist in alpha2A-AR knockout mice was only 42 +/- 9%. [3H]Norepinephrine release studies performed in vas deferens confirmed these findings. The results indicate that the alpha2A-AR is a major presynaptic receptor subtype regulating norepinephrine release from sympathetic nerves; however, the residual alpha2-mediated effect in the alpha2A-AR knockout mice suggests that a second alpha2 subtype (alpha2B or alpha2C) also functions as a presynaptic autoreceptor to inhibit transmitter release.

Animals↗
PubMed1998

[Pericarditis and inflammatory bowel disease].

Extraintestinal manifestations of ulcerative colitis and Crohn's disease are well described in the literature. These may be diagnosed before, concomitantly or after the diagnosis of the specific type of inflammatory bowel disease. Between 25% and 36% of patients with either type of IBD will have at least one extraintestinal manifestation. Pericarditis and myocarditis are rare, but potentially serious complications. We report one such case.

Adult↗
PubMed1998

Genetic deletion and overexpression of angiotensin II receptors.

Angiotensin II receptors are essential components of the renin-angiotensin system transducing angiotensin II mediated signals across the plasma membrane of many cell types in the cardiovascular system. To date, three subtypes of angiotensin II receptors have been identified by molecular cloning, termed angiotensin II type 1 (AT1A, AT1B) and type 2 (AT2) receptors. This review focuses on recent transgenic animal models which have been generated to study the in vivo significance of angiotensin receptor diversity. AT1A receptors are the major blood pressure regulators and have a potent growth-stimulatory effect on cardiac myocytes in vivo. The AT1B receptor subtype may participate in the control of vascular tone if AT1A receptors are absent. AT2 receptors are abundantly expressed during embryonic development and may also play a role in blood pressure regulation by influencing vascular development and differentiation.

Angiotensins↗
PubMed1998

Ventricular tachycardia with ECT.

A case is presented in which a patient with ischemic heart disease developed episodic, nonsustained ventricular tachycardia (VT) during electroconvulsive therapy for major depression. The VT had a frequency of 200 beats/min and ceased spontaneously after 17 s. Altered autonomic discharge in the presence of ischemia is the probable cause. Predisposing factors, as well as management considerations, are discussed.

Major Depressive Disorder↗
PubMed1997

A dileucine motif in the C terminus of the beta2-adrenergic receptor is involved in receptor internalization.

The cytoplasmic C terminus of the beta2-adrenergic receptor and many other G protein-coupled receptors contains a dileucine sequence that has been implicated in endosome/lysosome targeting of diverse proteins. In the present study, we provide evidence for an essential role of this motif in the agonist-induced internalization of the beta2-adrenergic receptor. Mutation of Leu-339 and/or Leu-340 to Ala caused little changes in surface expression, ligand binding, G protein coupling, and signaling to adenylyl cyclase, when these receptors were transiently or stably expressed in CHO or HEK-293 cells. However, agonist-induced receptor internalization was markedly impaired in the L339,340A double mutant and reduced in the two single mutants. This impairment in receptor internalization was seen by using various approaches to determine internalization: binding of hydrophobic vs. hydrophilic ligands, loss of surface beta2-adrenergic receptor immunoreactivity, and immunofluorescence microscopy. The selective effects of these mutations suggest that the C-terminal dileucine motif is involved in agonist-induced internalization of the beta2-adrenergic receptor.

Amino Acid Substitution↗
PubMed1997

Overexpression of angiotensin AT1 receptor transgene in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block.

Previous studies have suggested that angiotensin II (Ang II) modulates cardiac contractility, rhythm, metabolism, and structure. However, it is unclear whether the cardiac effects are due to direct actions of Ang II on the myocardium or if they are due to secondary effects mediated through the hemodynamic actions of Ang II. In this study, we used the alpha-myosin heavy chain (alphaMHC) promoter to generate transgenic mice overexpressing angiotensin II type 1 (AT1a) receptor selectively in cardiac myocytes. The specificity of transgene expression in the transgenic offspring was confirmed by radioligand binding studies and reverse transcription-PCR. The offspring displayed massive atrial enlargement with myocyte hyperplasia at birth, developed significant bradycardia with heart block, and died within the first weeks after birth. Thus, direct activation of AT1 receptor signaling in cardiac myocytes in vivo is sufficient to induce cardiac myocyte growth and alter electrical conduction.

Animals↗