A comparative study of nicardipine and pindolol as second-line treatments in essential hypertension.

A controlled, randomized, single-blind, parallel-group study compared the effects of nicardipine hydrochloride/hydrochlorothiazide (HCTZ) with those of pindolol/HCTZ in treatment of essential hypertension. The study included 43 patients aged 30-64 years with supine diastolic blood pressures between 95 and 125 mmHg at baseline. Patients initially received 50 mg/day HCTZ for 6 weeks and those patients whose diastolic blood pressure remained at or above 90 mmHg at week 6 (n = 29) completed a 6-week comparative phase in which they were given, in addition, either 30 mg nicardipine hydrochloride or 5 mg pindolol three times daily. Nicardipine was more effective than pindolol as a second-line treatment in controlling blood pressure but, because patients who were treated with nicardipine/HCTZ had higher baseline blood pressures, significance was lost when results were adjusted for the baseline blood pressure values. Treatment was described as 'very good' by 71.4% of patients in the nicardipine/HCTZ group and by 53.9% of those in the pindolol/HCTZ group; thus, both second-line antihypertensives were well accepted. Although 45% of patients in of each treatment group reported treatment-related adverse events, none experienced postural hypotension and no adverse event was unexpected.

Adrenergic innervation of the human liver. A fluorescence histochemical analysis of clinical liver biopsy specimens.

Liver biopsy specimens from 34 consecutive patients undergoing laparoscopy were processed for glyoxylic acid-induced fluorescence histochemical analysis. Most of the adrenergic nerves were located in the interlobular spaces and confined to blood vessels; no direct functional adrenergic innervation of the hepatocytes could be demonstrated. In eight cases of intrahepatic cholestasis, however, fluorescing varicose adrenergic axons were observed in patchy areas of accumulations of bile pigments. Otherwise the results were analogous in histologically normal liver tissue and in liver disease regardless of the underlying pathology. Methodological difficulties may explain some earlier contradictory results.

Multi-score estimation of catecholamine fluorescence for clinical purposes.

Experience accumulated at multi-score semiquantitation of catecholamine fluorescence of glyoxylic acid-treated stretch preparations of human clinical specimens is presented. The methodology and criteria of quantitation are described in detail. For an example, comparison between 3 different methods for analyzing neural-bound noradrenaline in human myocardial tissue in various heart diseases (obtained during the course of cardiac surgery) is presented: Biochemical determination of tissue noradrenaline content multi-score estimation of catecholamine fluorescence of glyoxylic acid-treated stretch preparations microfluorimetric analysis of the same stretch preparations. The results show that the multi-score estimation method gives a reliable concept of the relative amounts of noradrenaline stored in the intrinsic adrenergic nerve net (corresponding closely to the individual and group differences observed at biochemical noradrenaline determination). In addition, possible regional differences, alterations in the structural integrity of the inbuilt intrinsic nerve net, and other structural changes (e.g. pathological catecholamine accumulations) are easily recognized, whereas biochemical estimation cannot give information on structural aspects, which may have important clinical repercussions. Microfluorimetry does not seem suitable for studies on human myocardial specimens for several reasons which are discussed. The method of multi-score estimation of catecholamine fluorescence described and discussed is recommended for other similar and related studies on human clinical materials.

Taurine in human auricular myocardium and blood platelets.

Blood platelets have been used as a model for the aminergic neurones. In the hypertrophied left ventriles and platelets of spontaneously hypertensive rats the taurine content increases simultaneously. The main purpose of this work was to compare the taurine contents of human platelets and heart tissue. The taurine content was estimated from blood platelets and from the right atrial appendage removed during open heart surgery in 43 patients suffering from ischaemic heart disease. The results indicate that the taurine content increases in the hypertrophied right atrium of the patients with atrial septal defect, as it had previously been shown to increase in the hypertrophied left ventricle in patients who died of congestive heart failure. No correlations were found: 1) between the heart and platelet taurine contents of different groups, 2) between the atrial and platelet taurine in the pooled total results, 3) between the diastolic blood pressure and atrial or platelet taurine levels. Thus the increased taurine content of the auricular tissue is not reflected in the taurine content of the platelets.

Myocardial catecholamines and their biosynthetic enzymes in various human heart diseases.

Myocardial noradrenaline (NA) content, together with the activities of the enzymes tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) was measured in biopsy specimens taken during cardiac surgery from patients with various heart diseases. Fluorescence histochemical studies were also performed on comparable specimens. The mean NA content in patients with symptomatic ischaemic heart disease (IHD) was significantly higher than that in patients with valvular heart disease (VHD), atrial septal defect (ASD) or congestive heart failure (CHF). The lowest mean NA content was found in patients with CHF. The activities of TH and DBH were highest in the IHD group, although the differences between IHD and VHD groups were not significant. Histochemical investigations of adrenergic structures showed less fluorescence intensity in the CHF than in the other 3 groups. On the other hand, the density of the adrenergic nerve net and the size and number of varicosities were greatest in patients suffering from IHD. The significance of these results is discussed in relation to the pathophysiological mechanisms underlying these various disease conditions. In IHD the high myocardial NA content creates local conditions for excessive NA release into the myocardial interstitium at the onset of ischaemia, which is known to result in several adverse local consequences.

Arthritis associated with Campylobacter jejuni enteritis.

Among 342 patients with infection due to Campylobacter fetus ss. jejuni, 8 cases (2.3%) of arthritis were found. Three patients had monoarthritis and 5 oligoor polyarthritis. The arthritis began 4 days - 4 weeks after the onset of diarrhoea; this interval and the synovial fluid findings suggest that the arthritis was reactive. The histocompatibility antigen HLA-B 27 was identified in 5 of the 7 patients tested.

Innervation of the human gastric wall.

The intrinsic innervation of the human gastric wall was studied by means of (1) demonstration of the acetylcholinesterase activity, (2) fluorescence microscopy, and (3) electron microscopy. The cholinergic innervation was rich: in the mucosa, a dense three dimensional network consisting of single delicate varicose acetylcholinesterase-positive axons and small nerve fascicles was observed in close relation to the gastric glands. In the submucosa, large nerve trunks and densely woven plexuses mainly consisting of single varicose axons (obviously perivascular plexuses)) were seen. In the muscularis external, a small-meshed net consisting of single varicose axons and nerve fascicles was observed. The ganglia of the myenteric plexus were small and scattered irregularly between and within the muscle layers. Most of the nerve cells exhibited moderate to intense acetylcholinesterase activity. In the serosa, only a few nerves were observed. By fluorescence microscopy, an abundance of brightly yellow fluorescing irregularly fusiform enterochromaffin cells was observed in the epithelial lining of the antral glands. The parietal cells of the fundic glands exhibited a granular, yellow to orange autofluorescence. Fluorescing axons were seen in intimate relation to some enterochromaffin cells, whereas most enterochromaffin cells and parietal cells did not receive any direct functional adrenergic innervation. In the other tissue layers, only a few fluorescing nerves were seen. The main ultrastructural characteristics of the intrinsic innervation of the mucosa were: (1) 'Innervation fasciculée'; (2) the axons were unmyelinated; (3) two main types of nerve terminals were identified according to their vesicle population(s): (a) nerve terminals containing only clear vesicles, (b) nerve terminals containing clear vesicles and large dense-cored vesicles. Most of the axons and nerve terminals within the nerve fascicles were acetylcholinesterase-positive. The nerve terminals were separated from the gastric glands (and the parietal cells, chief cells and endocrine cells of their epithelial lining) by a considerable gap so that it seems unlikely that the gastric glands, parietal cells, chief cells and endocrine cells receive a direct innervation in the sense of synaptic neurotransmission; the transmitter substance must diffuse across a wide gap. In contrast, the endocrine cells were in close contact with the parietal cells and chief cells, and occasional membrane specialization (desmosomes) reinforce the assumption that (also) direct local humoral interaction may be possible. In addition, a large number of mast cells was observed in the lamina propria, many lying as close to glandular cells (parietal cells, chief cells and endocrine cells) as were the nearest nerve terminals.

Platelet taurine in patients with arterial hypertension, myocardial failure or infarction.

The content of taurine in the hypertrophied left ventricle is increased in congestive heart failure an in spontaneously hypertensive (SH) rats. In SH rats the taurine content of and taurine uptake by the platelets are also increased. The present results indicate that, as in the heart, the taurine content may also increase in the platelets of those patients with congestive heart failure. The taurine content and uptake are not increased in the platelets of hypertensive patients as they are in the platelets of SH rats. It is likely that in acute myocardial infarction, a considerable amount of taurine is released from the heart into the plasma. However, there is no simultaneous increase in the platelet taurine content. From this work on can only conclude that platelets may reflect taurine changes in the heart in some pathological states, e.g. congestive heart failure.

Effect of cold ischaemic arrest and subsequent coronary reperfusion on the intrinsic adrenergic innervation and neural noradrenaline of the atrial myocardium during aortic valve replacement.

The effect of cold ischaemic arrest (aortic cross-clamping for 50-70 min during general hypothermia of +30 degrees C, associated with local cardiac cooling with +4 degrees C saline solution) and subsequent coronary reperfusion (20-30 min) on the intrinsic adrenergic innervation of the right atrial myocardium, was studied in 10 patients in the course of prosthetic aortic valve replacement using the glyoxylic acid-induced fluorescence histochemical method. No clear changes were observed: (a) the morphological integrity of the intrinsic adrenergic nerve net remained intact, (b) no obvious depletion occurred in the neural noradrenaline level, (c) the procedure did not affect the "droplet fibres" (i.e. huge axonal accumulations of noradrenaline). Thus, the common need for catecholamine support during and after weaning off from cardiopulmonary bypass does not seem to be explained by damage to the adrenergic axons or depletion of the adrenergic neurotransmitter noradrenaline.

Human chronic lymphocytic leukaemia. Surface markers and activation of lymphocytes.

Cell surface markers and the responses of lymphocytes to T- and B-cell mitogens were studied in 10 patients with CCL. T cells were identified as cells rosetting with sheep red blood cells (SRBC), and S-Ig was used as a marker for B lymphocytes. Most cells from all patients had a detectable amounts of S-Ig, and the percentage of cells rosetting with SRBC was low in all cases. Of the lymphocytes from these patients, 3-74% (mean 33%) were positive for the acid esterase (ANAE), which has been claimed to be a T-cell marker. However, some patients had cells that were positive for both S-Ig and ANAE. Acid esterase staining is therefore not a valid T-cell marker in chronic lymphocytic leukaemia. In cultures containing the T-cell mitogen leucoagglutinin (LA) and the T- and B-cell mitogen pokeweed mitogen (PWM) the reactivity of the lymphocytes was low. The cells responded vigorously to the T- and B-cell mitogen protein A (PA); however, the response was serum-dependent, being strong in a culture medium containing foetal calf serum (FCS), but impaired in the presence of human AB serum. Only 1 patient had cells that responded to the B-cell mitogen LPS.

Atrial acetylcholinesterase activity in various heart diseases of man.

Distribution and activity of the acetylcholinesterase enzyme in the human atrial myocardium was studied histochemically in a clinical series of patients subjected to cardiac surgery for (1) uncomplicated atrial septal defect (ASD), (2) ischaemic heart disease (IHD), (3) mitral and/or aortic valvular disease (VHD) necessitating replacement with a prosthetic valve, without major symptoms or signs of myocardial incompensation, or (4) clinically overt congestive heart failure (CHF) due to VHD prior to cardiac surgery. In all specimens, a rich distribution of acetylcholinesterase-positive single axons and small fascicles, constituting a three-dimensional nerve net, was observed within the myocardial tissue. This nerve net was obviously mainly parenchymatous, i.e. unrelated to the blood vessels. Small groups of acetylcholinesterase-positive small nerve cells were observed in some specimens, with loosely woven fascicles of axons emerging from one pole of the ganglia. No differences in the distribution of the acetylcholinesterase activity or in the pattern of the inbuilt intrinsic nervous apparatus were observed in the various groups of patients. All specimens were completely devoid of non-specific cholinesterase activity. It was concluded that (I) the human atrial myocardium is richly supplied with cholinergic intrinsic (post-ganglionic vagal) axons and (II) the acetylcholinesterase activity is not a major determinant of the parasympathetic abnormalities associated with cardiac diseases, especially with myocardial pump failure.

Significance of a terminal R wave in lead V1 of the electrocardiogram.

A terminal r wave in Lead V1 lower than 0.6 mV. was studied in the ECGs of four groups: (1) 104 healthy children, (2) 207 healthy young adults, (3) 171 patients with no autopsy evidence of a cardiopulmonary disease, and (4) 1,078 autopsy patients with a cardiopulmonary disease. Cases with a complete right bundle branch block were excluded. A terminal r wave occurred in 2.9 per cent healthy children, 1.4 per cent of healthy young adults, 0.6 per cent of patients without and in 5.9 per cent of patients with autopsy evidence of a cardiopulmonary disease. The occurrence of a terminal r wave was most common in pulmonary patients (10 per cent). But it was also found in patients with an anterior or a posterior myocardial infarction and in some cases of left ventricular hypertrophy. In the autopsy series RVH occurred in 57 per cent of patients with a Qr pattern, in 30 per cent of patients with a terminal r wave higher than the initial one, and in none of the patients with a terminal r wave lower than the initial one. It is concluded that the height of the terminal r wave has clinical significance. A terminal r wave higher than the initial one in Lead V1 is associated with a cardiopulmonary disease in subjects over 30 years of age, while an r wave lower than the initial one seems to be an innocent finding.

Auricular tyrosine hydroxylase and dopamine-beta-hydroxylase activities and noradrenaline content in ischaemic heart disease.

Assessments were made of the tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) activities as well as the noradrenaline (NA) content of samples excised from right auricular tissue during cardiac surgery on a total of 55 patients with ischaemic heart disease (IHD), valvular heart disease (VHD), uncomplicated atrial septal defect (ASD) or congestive heart failure (CHF). The NA content was significantly higher in the IHD group than in the other three groups. The TH activity was highest in the IHD group although the difference was statistically significant only compared with the ASD and CHF groups. The DBH activity was also highest in the IHD group, but again the difference was statistically significant only compared with the ASD and CHF groups. In the whole material there was a significant positive correlation between the NA content and TH or DBH activity, as well as between TH and DBH activity. In the IHD group there was a significant positive correlation between heart volume and TH activity. The results suggest that at least compared with ASD and CHF, the sympathetic tone is relatively high in IHD, possibly involving an enhanced NA turnover.

Effect of cessation of propranolol treatment on myocardial noradrenaline and acetylcholine content in the rat.

Cessation of long-term treatment of rats with propranolol 10 mg/kg/day subcutaneously produced no alteration in the myocardial noradrenaline content estimated 12, 24, 48 and 96 hours after the last propranolol injection; nor did the myocardial acetylcholine content change. These results do not support the idea that the withdrawal-rebound phenomenon caused by abrupt cessation of propranolol therapy is associated with an accumulation of the autonomic neurotransmitters in myocardial tissue.

Adrenergic innervation of the human gall bladder.

Adrenergic innervation of the human gall bladder was studied using two specific fluorescence histochemical methods. Blue-green fluorescing varicose nerves were scarce and mostly followed the course of blood vessels as typical perivascular plexuses. However, some adrenergic nerves not associated with the vessels were occasionally seen, as well as structures suggestive of a pericellular arrangement of varicose adrenergic nerve terminals on non-fluorescing ganglion cells. A few enterochromaffin cells were seen in the epithelial lining, also in the deep invaginations obviously representing the Aschoff-Rokitansky sinuses. Occasionally, small rounded cells with a rounded, relatively large nucleus, and exhibiting a weak yellow-green to blue-green granular cytoplasmic fluorescence, were observed in the wall of the gall bladder. The possible functional and evolutionary significance of these neural and endocrine elements was discussed against the data on physiological and pharmacological studies obtained from the literature. It was concluded that their significance is, in all probability, secondary to the influence of the intestinal polypeptide hormones, vagal innervation and circulating catecholamines upon the normal function of the gall bladder. The glyoxylic acid-induced fluorescence histochemical method was found to be superior to the conventional formaldehyde technique in studies on human tissue.