Tissue resident C reactive protein in degenerative aortic valves: correlation with serum C reactive protein concentrations and modification by statins.

OBJECTIVE: To assess aortic valve probes for valvar C reactive protein (CRP) presence, the relation between valvar and serum CRP, and a possible modification of CRP by statin medication. SETTING: Tertiary referral centre. PATIENTS AND DESIGN: End stage, degenerative valve tissue was taken from 81 patients, 57 with non-rheumatic aortic valve stenosis (AS) and 24 with degenerative aortic valve bioprosthesis (BP). Five non-stenosed valves served as controls. Tissue from four non-implanted bioprostheses was also examined. The presence and location of CRP was analysed by use of immunostaining and morphometry. Serum CRP concentrations were measured preoperatively. RESULTS: The majority of AS and BP valves exhibited CRP labelled cells, predominantly localised to the valvar fibrosa. The expression of CRP was much higher in BP than in AS (by a factor of 3.7, p = 0.03). Notably, non-stenosed aortic valves and non-implanted bioprostheses did not have CRP signalling. Serum CRP was also increased with BP (by a factor of 2.5, p = 0.02) and was significantly correlated with valvar CRP expression (r = 0.54, p < 0.001). The main finding in patients with (n = 26) and without statin treatment (n = 55) was that both valvar CRP expression (p = 0.02) and serum CRP concentrations (p = 0.04) were lower in the statin treated group. CONCLUSIONS: CRP was found in a large series of degenerative aortic valves, more often in bioprostheses than in native cusps. Serum CRP concentrations may reflect inflammatory processes within the aortic valve. The association of statin treatment with decreases in both valvar and serum CRP concentrations may explain known pleiotropic effects of statins in patients with aortic stenosis.

Do we still need CK-MB in coronary artery bypass grafting surgery?

AIM: The aim of this study was to evaluate the role of cardiac Troponin I (cTnI) and CK-MB for early prediction of outcome of patients undergoing coronary artery bypass grafting (CABG) surgery. METHODS: In 134 consecutive patients undergoing CABG-surgery blood samples were analyzed for cTnI concentration and CK-MB activity. ECG, hemodynamic parameters and the need for inotropic support, were continuously registered. Patients were divided into group A (uneventful course), group B (ischemia by ECG, hemodynamic stability) and group C (ischemia by ECG and IABP). RESULTS: After removal of X-clamp an increase cTnI and CK-MB was observed in all patients. Five hrs after stop of CPB group A (8.3+/-4.2 microg/L) had lower cTnI values compared to group B (14.8+/-5.3 microg/L) (p=0.035) and C (54+/-22.8 microg/L) (p=0.023). The cut off value was 14.8 microg/L. Sensitivity and specificity (99%/97%) was higher for cTnI than for CK-MB (90%/30%). The positive predictive value of outcome was better for cTnI (86%) than for CK-MB (33%). CONCLUSION: CTnI is a specific and sensitive marker for evaluation of perioperative myocardial ischemia (PMI). Additional determination of CK-MB activity does not provide further clinical information. CTnI should be the marker of first choice in CABG surgery.

[Chlamydia pneumoniae and cytomegalovirus in degenerative aortic valve stenoses]. / Chlamydia pneumoniae und Zytomegalie-Virus in degenerativen Aortenklappenstenosen.

Recent evidence suggests a causal relationship between inflammatory as well as infectious pathomechanisms and valvular degeneration. Based on the concept of chronic Chlamydia pneumoniae and cytomegalovirus (CMV) infections, and of variable stressors working on valvular microecology, the present study sought to assess the presence of the specific chlamydial heat shock protein (cHSP) 60, of CMV, of macrophages and of the human homologue hHSP60. Serial sections of high-grade degenerated native (n = 16) and prosthetic (n = 6) aortic valves were analyzed by immunohistochemistry for the presence of these determinants. Degenerated aortic valves revealed prevalence of Chlamydia pneumoniae in 41% (10 of 22) and CMV in 73% (16 of 22), while immunoreactive hHSP60 was present in 64% (14 of 22) and CD68 in 86% (19 of 22). Chlamydial HSP60, CMV and hHSP60 were predominantly found in valvular fibrosa; CMV showed a second predilection site at the ventricular luminal border. Both microorganisms revealed a strong correlation between each other (r = 0.73; p < 0.001) as well as with hHSP60 (cHSP60: r = 0.74; p < 0.001; CMV: r = 0.80; p < 0.001). Macrophage infiltration correlated with cHSP60 (r = 0.78; r < 0.001), CMV (r = 0.78; r < 0.001) and hHSP60 (r = 0.56; r = 0.007). Of note, the frequency of cHSP60, CMV and CD68 signaling was increased more than 5-fold in prosthetic valves compared to native valves (p = 0.017, p = 0.002 and p = 0.005). In summary, valvular infections of Chlamydia pneumoniae and of cytomegalovirus are frequently seen in degenerated aortic valves, irrespective of native or prosthetic origin. Colocalization of both HSP60 homologues and cytomegalovirus within macrophages in valvular fibrosa points to regional stressor effects that might be at least partly attributable to chronic persistent pathogen burden and molecular mimicry.

Are microbubbles free flowing tracers through the Myocardium? Comparison of indicator-dilution curves obtained from dye dilution and echo contrast using harmonic power Doppler imaging.

BACKGROUND: Harmonic power Doppler imaging (H-PDI) has been introduced into the field of contrast echocardiography as a contrast-specific imaging modality. However, there has been considerable skepticism as to whether H-PDI would be quantifiable, because it depends on the destruction of microbubbles and has more complex signal processing than gray scale imaging. The aim of the present study was to evaluate the relationship between the concentration of microbubbles and the resulting H-PDI signals even under conditions where bubble destruction is most likely. Furthermore, we evaluated whether microbubbles of Levovist freely pass the microcirculation, which is a prerequisite for the assessment of myocardial blood flow. METHODS AND RESULTS: A strong positive correlation was found between the H-PDI signals and the amount of microbubbles up to the onset of acoustic shadowing (r = 0. 968, P<0.001). Time-intensity curves for H-PDI of air-filled microbubbles were compared with time-concentration curves of indocyanine green (ICG) in both a flow phantom and a working heart setup. The mean transit times (MTTs) through the myocardium of both agents were compared after a bolus injection into the left coronary artery. A close correlation was observed between 1/MTT and flow in both setups (r>0.98, P<0.0001). However, at high flow rates, the MTTs of the microbubbles were slightly, albeit not significantly, faster than those of indocyanine green. CONCLUSIONS: We conclude that microbubbles fulfill the prerequisites of free flowing tracers through the myocardium. Furthermore, H-PDI technology allows a reliable assessment of time-concentration curves of air-filled microbubbles up to the onset of acoustic shadowing.

Species-specific pharmacological properties of human alpha(2A)-adrenoceptors.

On the basis of data obtained in rabbits, the imidazoline receptor ligand rilmenidine has been suggested to decrease blood pressure in humans by activating central alpha(2A)-adrenoceptors. A prerequisite for this hypothesis was the unproved assumption that rabbit and human alpha(2A)-adrenoceptors are equally activated by rilmenidine. Because alpha(2A)-adrenoceptors in the brain and on cardiovascular sympathetic nerve terminals are identical, the latter were used as a model for the former to confirm or disprove this assumption. Human atrial appendages and rabbit pulmonary arteries were used to determine the potencies of alpha(2)-adrenoceptor agonists in inhibiting the electrically (2 Hz) evoked [(3)H]norepinephrine release and of antagonists in counteracting the alpha(2)-adrenoceptor-mediated inhibition induced by moxonidine. In the rabbit pulmonary artery, rilmenidine and oxymetazoline are potent full agonists, whereas in the human atrial appendages they are antagonists at the alpha(2)-autoreceptors, sharing this property with rauwolscine, phentolamine, and idazoxan. In contrast, prazosin is ineffective. In addition, a partial nucleotide and amino acid sequence of the rabbit alpha(2A)-adrenoceptor (a region known to substantially influence the pharmacological characteristics of the alpha(2)-adrenoceptor) revealed marked differences between the rabbit and the human alpha(2A)-adrenoceptor. The sympathetic nerves of both the human atrial appendages and rabbit pulmonary artery are endowed with alpha(2A)-autoreceptors, at which, however, both rilmenidine and oxymetazoline exhibit different properties (antagonism and agonism, respectively). The antagonistic property of rilmenidine at human alpha(2A)-adrenoceptors indicates that in contrast to the suggestion based on rabbit data, the hypotensive property of the drug in humans is not due to activation of alpha(2A)-adrenoceptors but other, presumably I(1)-imidazoline receptors, are probably involved.

N-Type calcium channels control sympathetic neurotransmission in human heart atrium.

BACKGROUND: Because knowledge about the type of calcium channels involved in action potential-induced norepinephrine release from the human peripheral sympathetic nervous system is sparse, we investigated which types of calcium channels are functionally important in the sympathetic nerves of human cardiac tissue. METHODS AND RESULTS: In superfused segments of human right atrial appendages, the type of calcium channels that control [(3)H]norepinephrine release evoked by transmural electrical stimulation was determined. [(3)H]norepinephrine release was almost abolished by 0.2 micromol/L omega-conotoxin GVIA (a selective blocker of N-type channels) but was not modified by 0.1 micromol/L omega-agatoxin IVA (a selective blocker of P- and Q-type channels). Mibefradil (a T-type and N-type calcium channel blocker) at concentrations of 0.3 to 3 micromol/L reduced the evoked tritium overflow in a frequency- and calcium-dependent manner, whereas 0.1 to 10 micromol/L amlodipine, diltiazem, and verapamil (selective blockers of L-type channels) were ineffective. CONCLUSIONS: Norepinephrine release from cardiac sympathetic nerves is triggered by Ca(2+) influx via N-type but not L- and P/Q-type calcium channels. The inhibitory effect of mibefradil on norepinephrine release at clinically relevant concentrations is probably due to its blocking action on N-type Ca(2+) channels. This property of mibefradil is unique among the calcium channel blockers that have been or still are therapeutically applied and may considerably contribute to its slight negative chronotropic effect in vivo.

[Persistence of Chlamydia pneumoniae in coronary plaque tissue. A contribution to infection and immune hypothesis in unstable angina pectoris]. / Persistenz von Chlamydia pneumoniae in koronarem Plaquegewebe. Ein Beitrag zur Infektions- und Immunhypothese bei instabiler Angina pectoris.

BACKGROUND AND OBJECTIVE: There is an increasing number of pointers towards a causative connection between Chlamydia pneumoniae and atherosclerosis. But the pathogenetic mechanism and intimal structures that are involved remain unclear. Starting with the hypothesis of a chronic infection, as demonstrated by the presence of the chlamydial stress (heat-shock) protein 60 (HSP 60), the presence and localization of these bacterial products in coronary atheromas was investigated. PATIENTS AND METHODS: Coronary atheroma tissue from primary stenoses in 42 patients (36 men, 6 women, mean age 60.2 +/- 7.3 years) was studied immunohistochemically in the course of a retrospective analysis for chlamydial HSP 60. The findings in clinically acute coronary syndrome (Braunwald's classification) present in 27 patients were compared with those in 15 patients with acute angina and evaluated in relation to expression and site of predilection. RESULTS: An immune reaction to chlamydial HSP 60 was demonstrated in 27 of 42 atheromas (64%). Intact, non-atherosclerotic vessels, such as the mammary artery and sphenous vein, showed no such signals. Chlamydial HSP 60 was localized in maximally 23% of all plaque cells, mostly in macrophages/foam cells, more rarely in smooth muscle cells. Chlamydia in foam cells most often revealed ultrastructural patterns that pointed to the persistence of the pathogen. Sites of predilection of chlamydial HSP were predominantly foam cell areas and cell-poor regions, more rarely inflammatory infiltrates and areas of rupture. When comparing both types of lesion, signals for chlamydial HSP 60 were present in 21 of the 27 atheromas (78%) with unstable angina or acute myocardial infarction, but in only 6 of the 15 atheromas (40%) with stable angina. Within the group with the acute coronary syndrome, the prevalence of chronic chlamydial infection was independent of a previous myocardial infarction. CONCLUSIONS: Chlamydial HSP 60 can often be demonstrated in primary coronary stenosis of symptomatic patients. It is most frequently found in macrophages/foam cells and is highly prevalent in the acute coronary syndrome. In-situ findings suggest a pathogenetically relevant role of chronic persistent infection of Chlamydia pneumoniae in unstable coronary plaques.

Presynaptic cannabinoid and imidazoline receptors in the human heart and their potential relationship.

Segments of human right atrial appendages preincubated with [3H]noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone were used to examine whether the cardiac sympathetic nerves are endowed with cannabinoid receptors and to further study pharmacological properties of presynaptic imidazoline receptors. The cannabinoid CB1 receptor agonists CP55,940, HU210 and anandamide inhibited evoked [3H]noradrenaline release. The inhibition by CP55,940 and anandamide was abolished by the CB1 receptor antagonists SR141716A (1 microM) and LY320135 (1 microM). Rauwolscine at the imidazoline receptor-blocking concentration of 30 microM abolished the inhibitory effect of CP55,940 and anandamide. After blockade of alpha2-adrenoceptors with 1 microM rauwolscine, the imidazoline binding site ligand S23230, which is the (-)-enantiomer of the racemic oxazoline derivative S22687, exhibited low potency in inhibiting electrically evoked [3H]noradrenaline release (pIC30%=4.96), whereas the (+)-enantiomer S23229 and the racemate S22687 were ineffective. In the presence of 30 microM rauwolscine, S23230 did not significantly inhibit evoked release. The imidazoline receptor-mediated inhibitory effect of BDF 6143 and aganodine on evoked [3H]noradrenaline release was abolished by 1 microM SR141716A and by 1 microM LY320135. The inhibitory effect of moxonidine on evoked [3H]noradrenaline release, which is exclusively mediated via activation of alpha2-autoreceptors, was not antagonized by 1 microM SR141716A. In conclusion, inhibitory cannabinoid CB1 receptors are present on the sympathetic axon terminals of human atrial appendages. Presynaptic imidazoline receptors share the property of other receptors in that they can be stereoselectively activated. The cross-antagonism of imidazoline receptor agonists/antagonists with CB1 receptor antagonists/agonists suggests that these receptors may have certain binding domains in common or that they interact with each other in an unknown manner.

[Chlamydia pneumoniae in coronary plaques: Increased detection with acute coronary syndrome]. / Chlamydia pneumoniae in koronarem Plaquegewebe: Vermehrter Nachweis bei akutem Koronarsyndrom.

BACKGROUND AND OBJECTIVE: There is seroepidemiologic and experimental evidence for a link between Chlamydia (C.) pneumoniae and arteriosclerosis. However, the clinical importance and the pathogenic pathways implicated remain unclear. In the present study, we sought to evaluate the presence and the location of C. pneumoniae in coronary atheroma, as well as a potential prevalence with unstable versus stable angina. PATIENTS AND METHODS: Retrospectively, coronary plaque material of primary lesions from 51 consecutive patients (44 men, 7 women, mean age 59.6 +/- 9.4 years) was examined for the presence of C. pneumoniae by use of immuno-histochemistry and transmission electron microscopy. The findings associated with clinically acute coronary syndrome according to Braunwald's classification (n = 31) were compared to those with stable angina (n = 20) and regarded for potential relations to characteristic intimal features. RESULTS: Immunoreaction for C. pneumoniae was found in 32 of 51 (63%) coronary plaques. Signals (% prevalence of specific intimal features) were present with necrotic areas (40%), sparse cellularity (40%), neo-vascularization (29%), thrombi (20%), ruptured plaque areas (19%), and fields rich in foam cells and calcifications (13%). Intimal hyperplasia and inflammatory infiltrates showed no signals. As the central finding in this report, C. pneumoniae immunoreaction was more frequently (P < 0.001) found in 26 of 31 (84%) lesions associated with unstable angina or acute myocardial infarction, compared to 6 of 20 (30%) lesions with stable angina (P < 0.001). Intact vessels devoid of arteriosclerotic disease, such as mammarial arteries and saphenous veins, were without C. pneumoniae signals (negative controls). Ultrastructurally, chlamydial elementary bodies were found in foam cells and phagocytosing macrophages, also in fragmented extracellular matrix adjacent to apoptotic and necrotic intimal cells. CONCLUSIONS: Chlamydiae pneumoniae were detected in 32 of 51 (63%) coronary primary lesions of symptomatic patients. Most importantly, there was a highly significant prevalence of lesions associated with acute coronary syndrome. Predilection sites of C. pneumoniae were areas that revealed small healing activity and (or) propensity to plaque rupture. The present in situ findings indicate a pathogenic role of Chlamydiae pneumoniae in human (coronary) plaque rupture.

Modulation of noradrenaline release from the sympathetic nerves of human right atrial appendages by presynaptic EP3- and DP-receptors.

Strips of human right atrial appendages were preincubated with [3H]noradrenaline and then superfused with physiological salt solution containing inhibitors of uptake1 and uptake2. Tritium overflow was evoked by transmural electrical stimulation (standard frequency: 2 Hz). Prostaglandin E2 (PGE2) inhibited the electrically evoked tritium overflow; at the highest concentration investigated, tritium overflow was reduced by about 80% and the pIC50% value was 7.14. The effect of PGE2 was not affected by rauwolscine, which, by itself, increased the evoked overflow. Naproxen failed to affect the evoked tritium overflow and its inhibition by PGE2. The inhibitory effect of PGE2 on the electrically evoked tritium overflow was mimicked by prostaglandin E1, the EP1/EP3-receptor agonist sulprostone and the EP2/EP3-receptor agonist misoprostol with the rank order of potency (pEC50%): sulprostone (7.68) > misoprostol (7.10) > PGE1 (6.39). In contrast, PGF2alpha, the IP/EP1-receptor agonist iloprost and the stable thromboxane A2 analogue U46619 (9,11-dideoxy-11alpha,9alpha-epoxy-methanoprostaglandin++ + F2alpha) did not change evoked tritium overflow. PGD2 caused facilitation. These results suggest that the sympathetic nerve fibres innervating human atrial appendages are endowed with presynaptic inhibitory EP3 and facilitatory DP-receptors. The EP3-receptors appear not to be tonically activated and do not interact with the alpha2-autoreceptors.

[Spiral CT and MRT of the operated Stanford-type-A aortic dissection: its course and complications]. / Spiral-CT und MRT der operierten Stanford Typ A-Aortendissektion: Verlauf und Komplikationen.

PURPOSE: To demonstrate normal postoperative spiral CT and MRI findings and typical complications in patients with aortic repair after Stanford type A aortic dissection. METHODS: 24 patients with aortic repair after Stanford type A aortic dissection were followed up by spiral CT and MRI (0.5 Tesla). Presence of persistent dissection, progressive or new dissection, proximal and distal anastomosis, periprosthetic space, supraaortic vessels, thrombosis and dilatation of the true and false lumen were evaluated. RESULTS: The following postoperative complications were seen: three pseudoaneurysms which developed at the proximal anastomoses of the Dacron prosthesis in two cases and at the insertion site of the reimplanted left coronary artery after implantation of a composite graft (Bentall procedure) in one case; one re-dissection; one perforation of the false lumen; periprosthetic flow in one patient after surgical repair of type A dissection by the graft inclusion technique; progressive dilatation of the false lumen in 4 cases; dilatation of the aortic root in a Marfan patient after replacement of the ascending aorta. CONCLUSION: Precise knowledge of the surgical technique performed is crucial to accurate postoperative imaging evaluation. MRI is the method of choice in the postoperative follow-up of clinically stable patients with aortic dissections.

Effects of selective h5-HT1B (SB-216641) and h5-HT1D (BRL-15572) receptor ligands on guinea-pig and human 5-HT auto- and heteroreceptors.

Human cerebral cortical slices and synaptosomes, guinea-pig cerebral cortical slices and human right atrial appendages were used to study the effects of SB-216641, a preferential h5-HT1B receptor ligand, and of BRL-15572, a preferential h5-HT1D receptor ligand, on the presynaptic h5-HT1B and h5-HT1B-like autoreceptors in the human and guinea-pig brain preparations, respectively, and on the presynaptic h5-HT1D heteroreceptors in the human atrium. The brain preparations, preincubated with [3H]serotonin ([3H]5-HT), and the segments of atrial appendages, preincubated with [3H]noradrenaline, were superfused with modified Krebs' solution and tritium overflow was evoked electrically (human and guinea-pig cerebral cortex slices and human atrial appendages) or by high K+ (human cerebral cortex synaptosomes). The electrically evoked tritium overflow from guinea-pig cerebral cortex slices was reduced by the 5-HT receptor agonist 5-carboxamidotryptamine (5-CT). This effect was not modified by BRL-15572 (2 microM; concentration 154 times higher than its Ki at h5-HT1D receptors) but was antagonized by SB-216641 (0.1 microM; concentration 100 times higher than its Ki at h5-HT1B receptors; apparent pA2 8.45). SB-216641 (0.1 microM) by itself facilitated, whereas BRL-15572 (2 microM) did not affect, the evoked overflow. In human cerebral cortex slices SB-216641 (0.1 microM) also facilitated, and BRL-15572 (2 microM) again failed to affect, the electrically evoked tritium overflow. In human cerebral cortical synaptosomes, 5-CT reduced the K+-evoked tritium overflow. This response was unaffected by BRL-15572 (300 nM) but antagonized by SB-216641 (15 nM; drug concentrations 23 and 15 times higher than their Ki at h5-HT1D and h5-HT1B receptors, respectively). Both drugs, given alone, did not modify the K+-evoked tritium overflow. In human atrial appendages, the electrically evoked tritium overflow was inhibited by 5-HT in a manner susceptible to antagonism by BRL-15572 (300 nM; 23 times Ki at h5-HT1D receptors) but not by SB-216641 (30 nM; 30 times Ki at h5-HT1B receptors). Both drugs by themselves did not change the electrically evoked tritium overflow. In conclusion, SB-216641 behaves as a preferential antagonist at native human 5-HT1B receptors and BRL-15572 as a preferential antagonist at native human 5-HT1D receptors. These compounds are clearly useful tools for the differentiation between human 5-HT1B and 5-HT1D receptors in functional studies.

Presynaptic imidazoline receptors and non-adrenoceptor [3H]-idazoxan binding sites in human cardiovascular tissues.

1 In segments of human right atrial appendages and pulmonary arteries preincubated with [3H]-noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone, the involvement of imidazoline receptors in the modulation of [3H]-noradrenaline release was investigated. 2 In human atrial appendages, the guanidines aganodine and DTG (1,3-di(2-tolyl)guanidine) which activate presynaptic imidazoline receptors, inhibited electrically-evoked [3H]-noradrenaline release. The inhibition was not affected by blockade of alpha 2-adrenoceptors with 1 microM rauwolscine, but antagonized by extremely high concentrations of this drug (10 and/or 30 microM; apparent pA2 against aganodine and DTG: 5.55 and 5.21, respectively). 3 In the presence of 1 microM rauwolscine, [3H]-noradrenaline release in human atrial appendages was also inhibited by the imidazolines idazoxan and cirazoline, but not by agmatine and noradrenaline. The inhibitory effects of 100 microM idazoxan and 30 microM cirazoline were abolished by 30 microM rauwolscine. 4 In the atrial appendages, the rank order of potency of all guidelines and imidazolines for their inhibitory effect on electrically-evoked [3H]-noradrenaline release in the presence of 1 microM rauwolscine was: aganodine > or = BDF 6143 [4-chloro-2-(2-imidazolin-2-yl-amino)-isoindoline] > DTG > or = clonidine > cirazoline > idazoxan (BDF 6143 and clonidine were previously studied under identical conditions). This potency order corresponded to that previously determined at the presynaptic imidazoline receptors in the rabbit aorta. 5 When, in the experiments in the human pulmonary artery, rauwolscine was absent from the superfusion fluid, the concentration-response curve for BDF 6143 (a mixed alpha 2-adrenoceptor antagonist/imidazoline receptor agonist) for its facilitatory effect on electrically-evoked [3H]-noradrenaline release was bell-shaped. In the presence of 1 microM rauwolscine, BDF 6143 and cirazoline concentration-dependently inhibited the evoked [3H]-noradrenaline release. 6 In human atrial appendages, non-adrenoceptor [3H]-idazoxan binding sites were identified and characterized. The binding of [3H]-idazoxan was specific, reversible, saturable and of high affinity (KD: 25.4 nM). The specific binding of [3H]-idazoxan (defined by cirazoline 0.1 mM) to membranes of human atrial appendages was concentration-dependently inhibited by several imidazolines and guanidines, but not by rauwolscine and agmatine. In most cases, the competition curves were best fitted to a two-site model. 7 The rank order of affinity for the high affinity site (in a few cases for the only detectable site; cirazoline = idazoxan > BDF 6143>DTG> or = clonidine) is compatible with the pharmacological properties of I2-imidazoline binding sites, but is clearly different from the rank order of potency for inhibiting evoked noradrenaline release from sympathetic nerves in the same tissue. 8 It is concluded that noradrenaline release in the human atrium and, less well established, in the pulmonary artery is inhibited via presynaptic imidazoline receptors. These presynaptic imidazoline receptors appear to be related to those previously characterized in rabbit aorta and pulmonary artery, but differ clearly from I1 and I2 imidazoline binding sites.

Presynaptic imidazoline receptors and alpha 2-adrenoceptors in the human heart: discrimination by clonidine and moxonidine.

The involvement of presynaptic alpha 2-autoreceptors and imidazoline receptors in the modulation of noradrenaline release was investigated in strips from human atrial appendages preincubated with [3H]noradrenaline and superfused with medium containing desipramine and corticosterone. Electrical impulses were applied transmurally at 2 Hz. The imidazoline derivatives moxonidine and clonidine reduced to evoked tritium overflow in a concentration-dependent manner. Moxonidine was 18-fold more potent than clonidine. The concentration-response curve for moxonidine, but not for clonidine was shifted to the right by the alpha 2-adrenoceptor antagonist rauwolscine. The apparent pA2 value of rauwolscine against moxonidine was 8.41. An inhibitory effect was also observed for the imidazoline derivative BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline), a mixed alpha 2-adrenoceptor antagonist/imidazoline receptor agonist; BDF 6143 was about 2-fold more potent than clonidine. Rauwolscine (1 microM) did not substantially shift the concentration-response curve of BDF 6143. It is concluded that noradrenaline release in the human atrium is inhibited not only via presynaptic alpha 2-autoreceptors but also via presynaptic non-I1, non-I2 imidazoline receptors. The failure of rauwolscine to antagonize the inhibitory effect of clonidine suggests that clonidine preferentially stimulates the presynaptic imidazoline receptors; the alpha 2-adrenoceptor component of its action is probably suppressed by an inhibitory interaction between the two receptors. In contrast, moxonidine acts via presynaptic alpha 2-autoreceptors, leaving the presynaptic imidazoline receptor unaffected.

Inhibition of noradrenaline release via presynaptic 5-HT1D alpha receptors in human atrium.

In segments of human right atrial appendages preincubated with [3H]noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone, we determined the effects of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on tritium overflow evoked by transmural electrical stimulation (2 Hz). Tritium overflow was inhibited by 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole succinate (RU 24969) and sumatriptan. Yohimbine and oxymetazoline (in the presence of idazoxan) also inhibited tritium overflow. The inhibitory potency of the drugs was significantly correlated with their affinity for 5-HTID receptors in human brain and for cloned human 5-HT1D alpha and 5-HT1D beta receptors, but not with their affinity for 5-HT1B, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5A, 5-HT5B and 5-HT7 receptors. The potency order 5-CT > 5-HT > 5-MeOT is opposite to the order of affinities reported for 5-HT6 binding sites. The preferential 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (up to 0.3 microM) and the selective 5-HT4 receptor agonist cisapride (up to 1 microM) failed to inhibit tritium overflow. L-694,247, a potent 5-HT1D beta receptor agonist, did not inhibit tritium overflow, but counteracted the inhibitory effect of 5-HT. Ketanserin at a concentration which should block 5-HT1D alpha but not 5-HT1D beta receptors and methiothepin at a concentration which may be assumed to block both 5-HT1D alpha and 5-HT1D beta receptors antagonized the inhibitory effect of 5-HT. Propranolol and ondansetron did not modify the 5-HT-induced inhibition of release. In conclusion, noradrenaline release in human right atrial appendages is inhibited via 5-HT receptors which are located on the noradrenergic axon terminals. These inhibitory presynaptic 5-HT receptors belong to the 5-HT1D subfamily. The ability of ketanserin to antagonize the inhibitory effect induced by activation of these receptors suggests that they can be subclassified as 5-HT1D alpha.

Presynaptic 5-HT auto- and heteroreceptors in the human central and peripheral nervous system.

In view of the potential pathophysiological and therapeutic implications, presynaptic 5-HT auto- and heteroreceptors have been identified and characterized in isolated human tissues and their functional role has been determined. Such investigations have been carried out in different laboratories including that of the authors. Basic evidence for the involvement of inhibitory 5-HT receptors in modulation of 5-HT release in the cerebral cortex was obtained in slices: exogenous 5-HT inhibited 5-HT release in a manner susceptible to blockade by methiothepin, which given alone facilitated 5-HT release, probably by preventing endogenous 5-HT from activating the inhibitory receptors. The latter receptors are located on the 5-HT nerve terminals themselves, since 5-HT (and sumatriptan) also inhibited 5-HT release from cortical synaptosomes. Their pharmacological properties conform to those of the 5-HT1D class. Subclassification (5-HT1D alpha or 5-HT1D beta) has been tried with ketanserin which has an at least 60 times higher affinity for 5-HT1D alpha (pki = 7.1) than 5-HT1D beta receptors. Since ketanserin (0.32 microM) did not affect the concentration-response curve for 5-carboxamidotryptamine (5-CT), the presynaptic 5-HT autoreceptor may belong to the 5-HT1D beta rather than the 5-HT1D alpha subtype. The sympathetic nerve terminals of the human saphenous vein are endowed with inhibitory 5-HT1D beta heteroreceptors, as indicated by the potency ratio of several 5-HT receptor agonists in inhibiting noradrenaline release in strips of this blood vessels and by the ability of methiothepin, but not of ketanserin 0.3 microM, to act as an antagonist. Noradrenergic nerves in the dura mater, which probably innervate its microvasculature, may also be endowed with inhibitory 5-HT receptors, since 5-HT inhibited noradrenaline release from this tissue. In strips of atrial appendages, 5-HT receptor agonists (e.g. 5-HT, 5-CT and sumatriptan) inhibited noradrenaline release at potencies which are correlated with their ki values at 5-HT1D alpha and 5-HT1D beta receptors. Since this inhibitory effect was antagonized by ketanserin (0.3 but not 0.03 microM) and methiothepin, the presynaptic 5-HT receptor in this tissue may belong to the 5-HT1D alpha subtype. However, this conclusion needs further confirmation by experiments with more potent and subtype-selective antagonists of 5-HT1D alpha and 5-HT1D beta receptors.

Modulation of noradrenaline release from the sympathetic nerves of the human saphenous vein and pulmonary artery by presynaptic EP3- and DP-receptors.

1. Spirally cut strips of the human saphenous vein and pulmonary artery were used to determine the pharmacological properties of the presynaptic prostanoid receptors involved in the modulation of sympathetic [3H]-noradrenaline release. Strips preincubated with [3H]-noradenaline were superfused with physiological salt solution containing inhibitors of uptake1 and uptake2 and rauwolscine to eliminate involvement of presynaptic alpha 2-adrenoceptors. Tritium overflow was evoked by transmural electrical stimulation (standard frequency: 2 Hz). 2. In the saphenous vein, prostaglandin E2 (PGE2) inhibited the electrically-evoked tritium overflow; at the highest concentration investigated, tritium overflow was inhibited by more than 75% and the pEC50 value was 7.00. These effects were mimicked by prostaglandin E1, the EP1/EP3 receptor agonist, sulprostone and the EP2/EP3 receptor agonist, misoprostol with the rank order (pEC50): sulprostone (8.60) > PGE1 (7.25) > misoprostol (6.96). This rank order of potency suggests that the inhibitory effect of the drugs is mediated by presynaptic EP3-receptors. In contrast, PGF2 alpha did not inhibit evoked tritium overflow; the IP/EP1 receptor agonist iloprost and the stable thromboxane A2 analogue U 46619 (9, 11-dideoxy-11 alpha,9 alpha-epoxy-methanoprostaglandin F2 alpha) produced inhibition only at concentrations above 1 microM. 3. The EP1-receptor antagonist, AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) had no effect on the evoked tritium overflow nor did it modify the inhibitory effect of PGE2, further excluding involvement of inhibitory presynaptic EP1-receptors. 4. PGD2 caused a facilitation of evoked tritium overflow in the saphenous vein; this facilitation is probably mediated by presynaptic DP-receptors, since it was abolished by the selective DP-receptor antagonist, BW A868C (3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamino)hydantoin).5. In the pulmonary artery, sulprostone (pECm value 8.35), misoprostol (7.70) and PGE2 (6.80)inhibited electrically-evoked tritium overflow. This rank order of potency is consistent with the involvement of inhibitory presynaptic EP3-receptors.6. These results suggest that the sympathetic nerve fibres of both human saphenous vein and pulmonary artery are endowed with presynaptic inhibitory EP3 receptors. The EP3-receptors do not interact with the alpha 2-autoreceptors. In addition, the human saphenous vein seems to be endowed with presynaptic facilitatory DP-receptors.

[The influence of the new phosphodiesterase inhibitor enoximone in patients with an acute catecholamine-refractory heart insufficiency during open-heart surgery]. / Der Einfluss des neueren Phosphodiesterase-Inhibitors Enoximon bei Patienten mit einer akuten katecholamin-refraktären Herzinsuffizienz während Operationen am offenen Herzen.

19 patients in whom cardiopulmonary bypass (cpb) was performed during different types of cardiac operations, developed myocardial failure which remained refractory to inotropic support with increasing doses of adrenaline, dopamine and dobutamine, so that it was impossible to discontinue cpb. After changing the therapeutic approach to a new regime consisting of adrenaline, dopamine and enoximone, low-output syndrome (LCOS) could be successfully reversed in 12 of the 19 patients. In the 7 remaining patients blood pressure dropped in a clinically relevant way under treatment with enoximone. 5 of these patients needed intraaortic balloon pumping (IABP) inspite of the application of enoximone, before cpb could be successfully discontinued. In three patients receiving enoximone, persisting ventricular tachyarrhythmia appeared under treatment, and disappeared after discontinuation of the drug. One patient needed IABP and left heart bypass by means of the centrifugal pump before cpb could be duly discontinued. One patient died intraoperatively due to untreatable right ventricular failure and inability to discontinue cpb. It is concluded that enoximone represents a useful drug in a significant number of patients developing heart failure refractory to inotropic support, on emerging from cpb during cardiac surgery.

Inhibition of noradrenaline release from the sympathetic nerves of the human saphenous vein by presynaptic histamine H3 receptors.

The human saphenous vein was used to examine whether presynaptic histamine receptors can modulate noradrenaline release and, if so, to determine their pharmacological characteristics. Strips of this blood vessel were incubated with [3H]noradrenaline and subsequently superfused with physiological salt solution containing desipramine and corticosterone. Electrically (2 Hz) evoked 3H overflow was inhibited by histamine and the H3 receptor agonist R-(-)-alpha-methylhistamine. Histamine-induced inhibition of electrically evoked tritium overflow was not affected by alpha 2-adrenoceptor blockade by rauwolscine. S-(+)-alpha-methylhistamine (up to 10 mumol/l) as well as the histamine H1 and H2 receptor agonists 2-(2-thiazolyl)ethylamine (up to 3 mumol/l) and dimaprit (up to 30 mumol/l), respectively, were ineffective. The selective histamine H3 receptor antagonist thioperamide abolished the inhibitory effect of histamine. The histamine H2 and H1 receptor antagonists ranitidine and pheniramine, respectively, did not affect the histamine-induced inhibition of evoked tritium overflow. The present results are compatible with the suggestion that the sympathetic nerves of the human saphenous vein are endowed with inhibitory presynaptic histamine receptors of the H3 class.

[Scintigraphy with 123I-labelled fatty acids in coronary heart disease]. / Szintigraphie mit 123J-markierten Fettsäuren bei koronarer Herzkrankheit.

Forty-two patients (6 women, 36 men; mean age 55 [39-69] years), with one-, two- or three-vessel disease on coronary angiography, were studied using single-photon emission computer tomography with 15-p-123I-iodophenyl-pentadecanoic acid (IPPA), in order to evaluate this new method of demonstrating abnormalities of myocardial perfusion. The reference range for fatty acid turnover was determined in eleven controls (4 women, 7 men; mean age 41 [20-51] years) with no coronary stenosis. 185 MBq (5 mCi) of IPPA was administered intravenously during submaximal stress on a bicycle ergometer. Comparison between different regions of the tomograms revealed changes in fatty acid utilization typical of ischaemia. The sensitivity, specificity and predictive value of a positive result compared with coronary angiography were 95%, 89% and 93%, respectively, for the area supplied by the anterior interventricular artery, 92%, 91% and 93% for the circumflex branch and 89%, 91% and 90% for the right coronary artery. In 25 out of 31 patients (81%) with myocardial infarction, IPPA scintigraphy infarct localization agreed with the clinical findings. In two cases with unremarkable scintigrams left ventriculography showed hypokinesia, while in four cases neither method demonstrated any abnormality. There was one false-positive scintigram. IPPA scintigraphy has greater sensitivity and specificity than conventional nuclear medicine techniques in the demonstration of coronary heart disease.