Cardiovascular profile of UDCG 115 BS-pimobendane and reversibility of catecholamine subsensitivity in severe congestive heart failure secondary to idiopathic dilated cardiomyopathy.

The pyridazoline derivative UDCG 115 BS (pimobendane) is a new, noncatecholamine, nonglycoside inotropic compound with potent vasodilative properties which exerts its stimulatory myocardial effect by increasing the Ca2+ affinity of cardiac contractile proteins and thus improving Ca2+ utilization. The aim of this study was to characterize and quantify the hemodynamic profile of oral UDCG 115 BS in 25 patients suffering from idiopathic congestive cardiomyopathy (NYHA III) and compare these effects with the action of the beta 1-receptor agonist dobutamine. UDCG 115 BS 5 mg p.o. increased cardiac output, cardiac index, and stroke volume index by approximately 60%. With only minor changes in heart rate, ventricular filling pressures decreased by 40%. A decline in pulmonary and systemic vascular resistance (-50%), as well as in systolic, diastolic, and mean pulmonary artery pressures (-35%) were also observed. The effects of 5 mg UDCG 115 BS were comparable to those that occurred with the optimal dose of dobutamine, whereas 10 mg UDCG 115 BS induced significantly more pronounced hemodynamic changes. The effects of UDCG lasted for at least 12 h. No major side effects were observed. Continuous treatment with 10 mg UDCG 115 BS/day for greater than 5 days resulted in a significantly improved response in beta-adrenoceptor stimulation as well as a drop in endogenous plasma catecholamines to nearly normal values. We therefore conclude that UDCG 115 BS, with its unique receptor-independent mechanism of action, may represent a new therapeutic approach in the management of patients with congestive heart failure (CHF).

Beta-adrenergic receptors in nasal tissue with reference to their role in asthma and atopy.

Thirty-three samples of nasal tissue (turbinates and polyps) were collected and assayed for beta-adrenergic receptor (BAR) sites (radio-ligand assay). Patients were divided into groups: 1) nasal turbinates, 2) nasal polyps, both under the aspects of atopy and bronchial hyperreactivity. Different radiobinding was found in both groups: Patients A with high BAR and patients B with low BAR numbers. There was no correlation between BAR numbers--clinical symptoms and bronchial hyperreactivity. Generally the BAR numbers were higher in turbinates (p less than 0.01) than in polyps and in nonatopic compared to atopic patients (p less than 0.005). "Affinity state 1" BAR are equal in all groups; however, "affinity state 2"BAR are significantly less in polyps (p less than 0.05). In 50% of the examined cases there was a combination of polyps, asthma and atopy putting foreward a common line of pathogenesis in this entity. It is discussed that the underlying inflammation (allergic and non-allergic) is the cause for reduced BAR numbers in the effected tissue. So far nasal tissue seems to be like a mirror compared to the results from lower respiratory tract tissue with respect to beta-adrenergic receptors.

[Cyclic nucleotides in experimental glaucoma]. / Tsiklicheskie nukleotidy pri éksperimental'noi glaukome.

cAMP and cGMP contents were studied in various eye tissues of rabbits with experimental glaucoma induced by chronic intravenous adrenaline administration. Cyclic nucleotide level was measured in the retina, choroid, iris and ciliary body. An increase in the tissue cAMP level was found especially in the iris and ciliary body. An increase in tissue cAMP content is explained by an enhanced beta-adrenergic regulation in the eyes of rabbits with experimental glaucoma. No consistent changes were found in cGMP content in eye tissues.

Nonneural beta-adrenergic vasodilating mechanism in temperature biofeedback.

Although finger temperature feedback has been used to produce digital vasodilation in normal persons and those with Raynaud's disease, the mechanism and site of this effect have not been studied. In the present investigation, feedback-induced vasodilation was attenuated by brachial artery infusions of propranolol in infused, but not contralateral, hands and was not affected by digital nerve blockade. Quantitative measurements of finger blood flow demonstrated that this vasodilation occurred in arteriovenous shunts in normal persons and in the finger capillary bed in those with Raynaud's disease. Raynaud's disease patients who received finger temperature feedback reported 80 fewer percent symptoms 1 and 2 years after treatment and retained the ability to increase finger temperature and capillary blood flow at these times. These effects were not shown by patients given autogenic training, a relaxation procedure.

Neuromechanisms of asthma.

Autonomic nervous system abnormalities may indeed underlie bronchial hyperreactivity. Imbalances between excitatory (parasympathetic, alpha-adrenergic and noncholinergic excitatory) and inhibitory (beta-adrenergic and non-adrenergic inhibitory) nervous systems at one or more loci could lead to airway hyperreactivity. The current data, however, do not clearly identify any single abnormality in the autonomic nervous system that is ubiquitous in all asthmatic patients. Rather, it appears that bronchial hyperreactivity results from many factors and that distinct autonomic nervous system abnormalities may occur in individual subjects. Future studies of how autonomic control of airway function in asthma may be disordered should prove useful in gaining a better understanding of the pathophysiology of asthma and in designing new treatment modalities.

The beta-adrenergic system of non-allergic patients with chronic airflow obstruction and early morning dyspnoea.

Lymphocyte beta-adrenergic receptor function and urinary excretion of catecholamines were measured in eight non-allergic patients with partially reversible chronic airflow obstruction (CAO) and early morning dyspnoea (EMD), and in eight matched healthy control subjects. In order to establish a possible relationship between the early morning dyspnoea and a reduced beta-adrenergic activity, these parameters were measured during the "morning dip" in FEV1 and in the afternoon, when lung function is maximal. No differences were observed for lymphocyte beta-adrenergic receptor characteristics (beta-receptor number, Kd, for 3H-dihydroalprenolol, and cAMP response to isoproterenol) between patients and controls, when determined at 8 AM or at 4 PM. Nor was there a significant circadian variation in these parameters present in both groups. By contrast, the patients showed a significantly reduced urinary excretion of epinephrine and norepinephrine, as measured in four-hourly urine portions collected between 8 and 12 AM and between 4 and 8 PM, respectively. In addition, the urinary excretion of epinephrine showed a significant circadian variation in the patients, which was correlated with the FEV1 (% predicted). Such a relationship was not found for norepinephrine. The results suggest that a (generalized) dysfunction of the beta-adrenergic receptor is not involved in the pathogenesis of CAO or EMD. However, reduced beta-adrenergic receptor stimulation due to decreased levels of catecholamines may contribute to the observed (variation in) airflow obstruction of the patients.

Observations in New England Deaconess Hospital rats harboring pheochromocytoma.

Pheochromocytomas are rare tumors, typically found in the adrenal medulla, which may secrete large quantities of catecholamines such as dopamine, norepinephrine, and epinephrine. Pheochromocytomas are usually associated with hypertension, which may be severe. Relatively little is known about the cardiovascular manifestations of pheochromocytoma because of the rarity of the disease and the difficulty of ethically studying patients with this explosive and potentially lethal disease. New England Deaconess rats (a Wistar-derived strain) harbor a transplantable pheochromocytoma which has many features reminiscent of the human disease. These rats develop markedly elevated concentrations of norepinephrine that are associated with severe hypertension, desensitization of alpha and beta adrenergically mediated responses, and catecholamine-induced cardiomyopathy. This paper briefly reviews work undertaken in the author's laboratory on the mechanisms of these alterations in the cardiovascular system of rats harboring pheochromocytoma.

Plasma melatonin concentrations in depression.

The pineal hormone melatonin was measured in midnight plasma samples from 11 depressed patients and 18 control subjects. Plasma melatonin concentrations were significantly lower in the depressed patients. The implication of these findings for beta-adrenoceptor subsensitivity in depression is discussed.

Pathophysiology of hypertension in the elderly.

Combined systolic and diastolic arterial hypertension and isolated systolic hypertension in the elderly are proven risk factors for stroke, sudden death, coronary artery disease, and congestive heart failure. Because hemodynamics, vascular and cardiac adaptations, fluid volume, and endocrine functions are distinctly altered in the elderly hypertensive patient compared with a younger patient, antihypertensive treatment should be individualized, and an unsophisticated regimen, such as a stepped-care approach, is too rigid to be as beneficial for elderly hypertensive patients as for young hypertensive patients.

Dynamics of the lymphocyte beta-adrenoceptor system in patients with allergic bronchial asthma.

It has been proposed that reduced beta-adrenergic responsiveness plays an important role in the increased airway reactivity of asthmatic patients. This hypothesis has been supported by studies showing reduced beta-adrenergic responsiveness in lymphocytes of asthmatic patients, predominantly during the occurrence of active and severe symptoms. Little is known about the mechanism underlying this relationship and its clinical relevance with respect to bronchial hyperreactivity. Therefore, in this study we assessed the status of the beta-adrenergic receptor-adenylate cyclase system in lymphocytes of allergic asthmatic patients in relation to parameters of bronchial hyperreactivity. This was performed before and after challenge with house-dust mite allergen, as a possible modulating factor of beta-adrenergic responsiveness. It was shown that lymphocytes of 'stable' allergic asthmatic patients with increased airway reactivity may have normal beta-adrenergic responsiveness and a normal beta-adrenergic receptor number. After allergen challenge, however, a group of 12 patients developed reduced beta-adrenergic responsiveness, which could be partially attributed to changes in the beta-adrenergic receptor number, while changes distal to the receptor also occurred. The results indicate that reduced beta-adrenergic responsiveness in lymphocytes of allergic asthmatic patients is a consequence of an active disease state rather than the reflection of a primary aetiological factor. A number of the patients concomitantly developed enhanced bronchial reactivity to propranolol after allergen challenge, which might indicate that reduced beta-adrenergic receptor function also occurs at the level of the bronchial tree. In five of the patients it was shown that beta-adrenergic hyporesponsiveness could be restored after environmental control in combination with drug treatment, thus indicating the dynamic character of the lymphocyte beta-adrenergic receptor system in asthmatic patients.

Subsensitization of beta-adrenoceptors in airways and lymphocytes of healthy and asthmatic subjects.

Subsensitization of beta-adrenoceptors in airways and lymphocytes developing during 4 to 5 wk of orally administered terbutaline (a long-acting beta 2 selective bronchodilator) was compared in 10 healthy subjects and 11 subjects with mild asthma. The following results were obtained. Normal subjects developed a significant reduction in acute bronchodilator responsiveness to inhaled isoproterenol but not to subcutaneously administered terbutaline. The subjects with asthma failed to develop any alteration in responsiveness to either inhaled isoproterenol or subcutaneously administered terbutaline. None of 5 normal or 4 asthmatic subjects studied demonstrated any significant change in sensitivity to histamine-induced bronchospasm or any significant decrease in the acute protective effect of subcutaneously administered terbutaline against histamine-induced bronchospasm. Marked and significant decreases occurred in the density of lymphocyte beta-receptor sites in both groups. Maximal isoproterenol-stimulated cyclic AMP responses in lymphocytes from normal subjects were reduced, but in asthmatics, in whom the baseline values were lower to begin with, a similar decrease was not observed. In most instances, the number of receptor sites returned to normal within 2 wk after cessation of terbutaline. A single dose of methylprednisolone caused a return to normal values within 16 h. We conclude that chronic therapy with an oral beta 2-adrenostimulant, although producing striking and significant down-regulation of beta-adrenergic receptors of peripheral lymphocytes, does not lead to physiologically detectable beta-adrenoceptor subsensitivity in the airways of asthmatics or to consistent subsensitivity in the airways of healthy persons.

Enhanced beta-adrenergic-receptor responsiveness in hypoxic neonatal pulmonary circulation.

The influence of alveolar hypoxia on pulmonary vascular adrenergic receptors was studied in conscious newborn lambs. In control animals, pulmonary vessels were directly constricted by epinephrine and norepinephrine, but were unaffected by isoproterenol. Pulmonary resistance (PVR) was also unaffected by propranolol, thus implying minimal beta-receptor activity under normoxic conditions. Hypoxia raised PVR but also modified the pulmonary vascular responses to catecholamines: isoproterenol became a dilator, whereas the constrictor effects of epinephrine and norepinephrine were abolished. Although beta-blockade did not alter base-line PVR, propranolol increased the constrictor response to hypoxia, implying that hypoxia increases beta-adrenergic activity or reactivity in the pulmonary circulation. Consistent with this hypothesis are the following: 1) in alpha-blocked lambs, epinephrine was without local effects during normoxia, but caused vasodilation during hypoxia; 2) the absent constrictor response to epinephrine during hypoxia is fully restored by propranolol; and 3) although alpha-blockade blunts the hypoxic constrictor response, the full response is restored when beta-blockade is added. These results indicate that the hypoxic constrictor response is partially opposed by increased beta-mediated vasodilation. These enhanced beta-receptor effects are due, at least in part, to increased beta-receptor reactivity of unknown mechanism.

Clinical import of beta-adrenergic activity in the proximal urethra.

Beta-adrenergic activity of the proximal urethra was studied in 11 patients. Maximum urethral pressure was recorded before, and 20 and 60 minutes after the intravenous administration of 0.5 mg. orciprenaline sulfate. There was a 40 per cent or more decrease in the maximum urethral pressure in 6 of the 11 patients. Beta-adrenoreceptor agonists could prove useful in facilitating vesical emptying by reducing urethral resistance in patients with neurogenic bladder dysfunction.

[The hyper-reactive bronchial system. Pathophysiologic aspects and therapeutic consequences]. / Das hyperreagible Bronchialsystem. Pathophysiologische Aspekte und therapeutische Konsequenzen.

We talk about a hypersensitive bronchial system, when under certain endogen prepositions or exogen influences, upon which a healthy persons reacts hardly or not at all, it comes to a significant raise of the airway resistances. Probably this is the prestadium of a chronic obstructive airway disease, which often occurs with patients suffering from an existant bronchial disease. Therefore it is important for actual clinical practice to discuss those problems, which interfere with the raise of sensitivity of the bronchial airways. The discussion should be based on the actual state of science, because several therapeutic problems and consequences ensue.

[New aspects of catecholamin-receptor interactions. Pathophysiological and clinical implications (author's transl)]. / Neue Aspekte der Katecholamin-Rezeptor Wechselwirkung. Ihre Bedeutung in Pathophysiologie und Klinik.

The molecular aspects of catecholamine-receptor interactions are reviewed with respect to their clinical implications. Beta- and in some tissues alpha-adrenergic receptors are coupled to the membrane-bound adenylate cyclase. The adrenergic receptor sites are distinct membrane constituents. Their number and the ratio alpha-to beta-receptor site depend on the plasma concentration of catecholamines and are affected by diet and endocrinological factors. Recent clinical studies suggest that long-term treatment with beta-adrenergic agonists may induces desensitization of target tissues due to changes in the adrenergic receptor moieties.