Increased sympatho-adrenal tone and adrenal medulla reactivity in DOCA-salt hypertensive rats.

Sympatho-adrenal tone and reactivity were evaluated in anaesthetized normotensive and DOCA-salt hypertensive rats, by measuring arterial plasma concentrations of norepinephrine and epinephrine under basal conditions and following bilateral carotid occlusion. Baseline norepinephrine levels were significantly higher in DOCA-salt hypertensive animals than in their respective normotensive controls, whether they were studied with intact vagi or following bilateral vagotomy. The possibility of a relationship between the increased basal sympathetic fibres and the maintenance of DOCA-salt hypertension is strongly suggested by the finding of a significant correlation between mean arterial pressure (MAP) and basal circulating norepinephrine values in those animals. Furthermore, the epinephrine increase following carotid occlusion was found to be markedly potentiated in hypertensive animals (intact or vagotomized), suggesting adrenal medullary hyperreactivity to baroreflex activation in this model of hypertension. In normotensive rats the epinephrine increase induced by the carotid occlusion was greatly potentiated by the administration of an alpha 2-antagonist (yohimbine), and completely abolished by administration of an alpha 2-agonist (clonidine). In contrast, the epinephrine response to carotid occlusion, which is already enhanced in hypertensive animals, was unaffected by the same treatments. These results therefore suggest that adrenal medullary hyperreactivity observed in DOCA-salt hypertensive rats may be due to a dysfunction of an alpha 2-adrenergic mechanism modulating adrenal medullary secretion.

Altered adrenergic activity in coronary arterial spasm: insight into mechanism based on study of coronary hemodynamics and the electrocardiogram.

To elucidate the pathophysiologic mechanism of coronary arterial spasm, the hypothesis was examined that underlying alterations in sympathetic activity may account for this syndrome in some patients. Observations were directed to alterations in coronary arterial hemodynamics and the electrocardiogram. Spasm of the left anterior descending coronary artery produced a mean increase in coronary vascular resistance of 107 percent (P less than 0.05) in four patients in whom coronary sinus blood flow was measured with the thermodilution technique. The alpha adrenergic blocking agent phentolamine, given intravenously, acutely reversed coronary spasm and its clinical manifestations in eight patients and reduced coronary resistance. In four patients, administration of the long-acting oral alpha blocking agent phenoxybenzamine (20 to 80 mg/day) caused disappearance of symptoms during a follow-up period of 3 to 12 months. Transient prolongation of the corrected Q-T interval preceded spontaneous or ergonovine maleate-provoked coronary spasm in 11 patients with variant angina pectoris, whereas no significant change in the Q-T interval followed ergonovine administration in 27 control patients with atypical chest pain who did not have coronary spasm. T wave inversions in the resting electrocardiogram were normalized by isoproterenol infusion in one patient and by long-term phenoxybenzamine treatment in four patients with variant angina pectoris. These Q-T and T wave changes are analogous to those described with unilateral or asymmetric stellate ganglion stimulation in animals. These observations suggest that alterations in the sympathetic nervous system that are consistent with asymmetric stellate ganglion activity and transient alpha adrenergic receptor stimulation can presage the development of coronary arterial spasm in some patients with variant angina pectoris.

Evidence for pain modulation by pre- and postsynaptic noradrenergic receptors in the medulla oblongata.

Activation of neurons in nucleus raphe magnus (NRM) produces hypoalgesia which most likely results from inhibition of spinal cord pain transmission pathways. Previous reports from this laboratory suggest that noradrenergic (NA) neurons modulate the activity of NRM neurons. More specifically, NA projections to NRM neurons appear to be inhibitory since iontophoretically applied norepinephrine (NE) inhibits the activity of NRM neurons. Furthermore, blockade of NA receptors in the NRM by the microinjection of alpha-adrenergic antagonists produces potent analgesia. Thus, the NA input to the NRM appears to increase pain sensitivity by tonically inhibiting NRM neurons. Pharmacological and physiological studies have differentiated alpha-adrenergic receptors into alpha-1 and alpha-2 subtypes. The present study was designed to examine the nature of the alpha-adrenergic receptor subtypes in the NRM and their role in the modulation of pain sensitivity. The results of these experiments are consistent with the classical model of postsynaptic alpha-1 receptors and presynaptic alpha-2 receptors which modulate NE release. Both the alpha-1 antagonist, prazosin, and the alpha-2 agonist, clonidine, produced an increase in nociceptive threshold. Conversely, both the alpha-1 agonist, phenylephrine, and the alpha-2 antagonist, yohimbine, produced a decrease in nociceptive threshold. Thus, in the region of the NRM, both presynaptic alpha-2 and postsynaptic alpha-1 noradrenergic receptors may be involved in the modulation of nociception.

Adrenoceptors and the pharmacology of affective illness: a unifying theory.

Based on recent clinical and preclinical research, it is theorized that antimanic and antidepressant effects of clinically available drugs can be produced through their actions on alpha-1 adrenoreceptor-mediated neurotransmission in the central nervous system. The theory suggests that final effects on alpha-1 mediated neurotransmission may be produced not only by drugs which have direct effects on the alpha-1 receptor or its second messenger, but also by drugs having effects on neurotransmitter systems such as acetylcholine, GABA, and serotonin, among others, which modulate the activity of central norepinephrine neurons or, via feedback mechanisms, by drugs having effects on adrenergic receptors other than the alpha-1 receptor itself.

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.

[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.

Fever: pathogenesis, pathophysiology, and purpose.

Fever appears to have evolved in vertebrate hosts as an adaptive mechanism for controlling infection. This phenomenon is produced by certain exogenous (largely microbial) stimuli that activated bone-marrow-derived phagocytes to release a fever-inducing hormone (endogenous pyrogen). Endogenous pyrogen, in turn, circulates to the thermoregulatory center of the brain (preoptic area of the anterior hypothalamus) where it causes an elevation in the "set-point" for normal body temperature. Warm blooded animals produced fever by increasing heat production (through shivering) or reducing heat loss (by peripheral vasoconstriction), whereas cold blooded animals do so only by behavioral mechanisms (seeking a warmer environment). This paper discusses current concepts that involve the mechanism of endogenous pyrogen production, the role of central transmittors, and the probable function of fever in combating disease.

Alpha-adrenoceptors and alpha-adrenoceptor-mediated positive inotropic effects in failing human myocardium.

Experiments were designed to characterize cardiac alpha-adrenoceptors and the alpha-adrenoceptor-mediated positive inotropic effects in human myocardial tissue from patients with moderate New York Heart Association (NYHA) class II-III and severe (NYHA class IV) heart failure. The number of cardiac alpha-adrenoceptors was low but similar in moderate and severe heart failure (NYHA class II-III: 6.7 +/- 0.8 fmol/mg protein 3H-prazosin bound, n = 12; NYHA class IV: 7.4 +/- 0.9 fmol/mg protein 3H-prazosin bound, n = 9; NS). Correspondingly, the alpha-adrenoceptor-mediated positive inotropic effect (phenylephrine in the presence of propranolol) did not significantly differ in both groups. In the same hearts, the number of beta-adrenoceptors was measured. The number of beta-adrenoceptors was significantly reduced in severe heart failure (NYHA class II-III: 22.0 +/- 1.5 fmol/mg protein 3H-CGP 12177 bound, n = 12; NYHA class IV: 11.9 +/- 0.8 fmol/mg protein 3H-CGP 12177 bound, n = 9; p less than 0.05). The positive inotropic effect of isoprenaline was significantly reduced in NYHA class IV. The positive inotropic effect of Ca2+ was similar in both groups. In conclusion, cardiac beta-adrenoceptors and the beta-adrenoceptor-mediated positive inotropic effects were reduced in severely failing myocardium. Cardiac alpha-adrenoceptors and the positive inotropic effect resulting from their stimulation is unchanged. Therefore, down regulation in response to increased sympathetic stimulation or a compensatory increase of alpha-adrenoceptors does obviously not occur in the human heart.(ABSTRACT TRUNCATED AT 250 WORDS)

[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.