Acta pharmacologica et toxicologica最新文献

There is strong evidence that nitrate tolerance develops rapidly during repeated administration in the systemic resistance vascular bed and that there exists cross tolerance between different nitrates. There are divergent opinions on how tolerance in the systemic capacitance and the pulmonary vascular bed develops. This may be explained by real differences in tolerance development in ischemic heart disease and congestive heart failure but also by the use of several different preparations of nitrates in the studies performed. Available data on the pharmacokinetics of nitrates present a complex picture with highly variable bioavailability, clearance and apparent volume of distribution both inter- and intraindividually. It is suggested that nitrate tolerance should be studied in very homogeneous groups of patients with well defined hemodynamics. The nitrate used should have a very short half-life allowing for simulation of various modes of administration by intravenous infusion.

The muscarinic cholinergic receptors in the urinary bladders of man, guinea pig, rat and rabbit were studied by means of a receptor binding technique, with l-quinuclidinyl [phenyl 4-3H]benzilate, (-)3H-QNB, as radioligand. The potential role of the receptors in the supersensitivity of the rat bladder to muscarinic agonists, following parasympathetic denervation, hypertrophy and urinary diversion, was also investigated. In addition, the binding of various unlabelled antimuscarinic drugs in the guinea pig bladder was compared to that in other tissues in order to study the putative muscarinic receptor subtypes, commonly referred to as M1 and M2. According to this classification the putative M1 receptors prevail in discrete areas of the brain, whereas the M2-receptors predominate in peripheral tissues, such as the exocrine glands and smooth muscles. The receptor density (but not the qualitative properties of the receptors) in the bladder differed between the species. The affinities of various antimuscarinic drugs were virtually identical in the guinea pig and human bladders. In both species, the binding data were found to correlate with functional in vitro data. In the rat bladder, the receptor density was increased after denervation but decreased, below control values, when the denervation was combined with urinary diversion. A decrease was also found after urinary diversion of innervated bladders, whereas the receptor density was unaffected by hypertrophy. These results suggest that the receptors are not involved in the development of supersensitivity and that the receptor levels may be influenced by the functional state of the bladder. Binding studies with classical muscarinic antagonists indicated that the receptors in the guinea pig bladder are indistinguishable from those in the ileum, heart, parotid gland and cerebral cortex. However, four drugs--namely, oxybutynin, dicyclomine, benzhexol and pirenzepine had a much higher affinity for the receptors in the parotid gland and cortex than for those in the other tissues. Moreover, dicyclomine and benzhexol, like pirenzepine, seemed in the cortex to distinguish between two classes of sites exhibiting high and low affinity. The high affinity sites could be selectively labelled with 3H-benzhexol. The ability of oxybutynin, dicyclomine, benzhexol and pirenzepine to discriminate between the receptors in the parotid gland and those in smooth muscle provides further evidence that the M1/M2 concept is inaccurate. The present data indicate that there may be three classes of muscarinic antagonist binding sites.

Exercise tests performed in the clinic give important qualitative and quantitative information. Psychological scaling of main symptoms is most valuable to define a patient's incapacitation and maximal performance. In pharmacological testing this is of utmost importance, particularly in patients with angina pectoris or heart failure. In chronic heart failure there is a poor correlation between the maximal working capacity and the performance of the heart.