Hyperpolarization-activated Cyclic nucleotide-gated Channel and Cardiac Biological Pacemaker:Part Ⅰ

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current ( named Ⅰf, Ⅰh, or Ⅰq). Recent studies have unveiled the molecular identity of HCN (HCN1-4) channels. HCN isoforms are unevenly expressed in the heart, even in the sinoatrial node. Features of HCN currents have been characterized in cardiac and other types of cells or in cell lines transfected with the HCN isoforms. The factors modulating Ih and the physiological significance of HCN channels in the heart have been extensively investigated in recent years. The hypothesis for transplanting and/or creating biological pacemakers to replace diseased sinoatrial and/or atrioventricular nodes has been postulated and tested in animal models. Local overexpression of HCN2 channels in the left atrium or in the left conductive bundle branch of the left ventricle via gene delivery induced significant Ⅰh and escape rhythms during vagal stimulation in canines. In addition, implantation of human mesenchymal stem cells with overexpression of HCN2 channels to the canine left ventricular wall was associated with formation of spontaneous escape rhythms of left-sided origin during vagal-stimulation-induced sinus arrest. This preliminary data suggest that the use of HCN channels may hold great promise in,the development of biological pacemakers.     

STUDIES ON THE TREATMENT OF IDIOPATHIC GYNAECOMASTIA WITH PERCUTANEOUS DIHYDROTESTOSTERONE

We have studied clinical and endocrine parameters in a group (group A) of forth men referred to us because of persistent idiopathic gynaecomastia (of more than 18 months duration), before and during the administration of percutaneous dihydrotestosterone (DHT). The endocrine parameters (testosterone (T), 17 beta-oestradiol (E2), DHT, gonadotrophins (FSH and LH) and prolactin (PRL), were compared to those of control groups of 12 healthy men on DHT therapy (group B) and 10 on placebo (group C). Local administration of DHT was followed by the complete disappearance of gynaecomastia in 10 patients, partial regression in 19 and no change in 11 patients after 4 to 20 weeks of percutaneous DHT (125 mg twice daily). Before treatment the T + DHT/E2 ratio was significantly (P less than 0.001) lower in group A 244 +/- 21 (SEM) than in groups B and C (361 +/- 21) while T, DHT and E2 concentrations were all within the normal range. During DHT treatment plasma hormone levels were measured in 26 patients from group A: DHT levels increases significantly (day 0: 1.63 +/- 0.14 nmol/l; day 15: 12.8 +/- 1.6 nmol/l, P less than 0.001) while T and E2 levels fell significantly (T: day 0: 22.6 +/- 1.2 nmol/l; day 15: 11.0 +/- 1.5 nmol/l, P less than 0.001; E2: day 0: 110.5 +/- 7.12 pmol/l; day 15: 86.79 +/- 9.4 pmol/l, P less than 0.01). The T/E2 ratio decreased from 231 +/- 20 to 164 +/- 27 (P less than 0.05) while the T + DHT/E2 ratio increased significantly (P less than 0.02) to a normal mean value (day 15: 354 +/- 57).(ABSTRACT TRUNCATED AT 250 WORDS)     

THE FIMBRIA-FORNIX/CINGULAR BUNDLE PATHWAYS: A REVIEW OF NEUROCHEMICAL AND BEHAVIOURAL APPROACHES USING LESIONS AND TRANSPLANTATION TECHNIQUES

Extensive lesions of the fimbria-fornix pathways and the cingular bundle deprive the hippocampus of a substantial part of its cholinergic, noradrenergic and serotonergic afferents and, among several other behavioural alterations, induce lasting impairment of spatial learning and memory capabilities. After a brief presentation of the neuroanatomical organization of the hippocampus and the connections relevant to the topic of this article, studies which have contributed to characterize the neurochemical and behavioural aspects of the fimbria-fornix lesion “syndrome” with lesion techniques differing by the extent, the location or the specificity of the damage produced, are reviewed. Furthermore, several compensatory changes that may occur as a reaction to hippocampal denervation (sprouting, changes in receptor sensitivity and modifications of neurotransmitter turnover in spared fibres) are described and discussed in relation with their capacity (or incapacity) to foster recovery from the lesion-induced deficits. According to this background, experiments using intrahippocampal or “parahippocampal” grafts to substitute for missing cholinergic, noradrenergic or serotonergic afferents are considered according to whether the reported findings concern neurochemical and/or behavioural effects. Taken together, these experiments suggest that appropriately chosen fetal neurons (or other cells such as, for instance, genetically-modified fibroblasts) implanted into or close to the denervated hippocampus may substitute, at least partially, for missing hippocampal afferents with a neurochemical specificity that closely depends on the neurochemical identity of the grafted neurons. Thereby, such grafts are able not only to restore some functions as they can be detected locally, namely within the hippocampus, but also to attenuate some of the behavioural (and other types of) disturbances resulting from the lesions. In some respects, also these graft-induced behavioural effects might be considered as occurring with a neurochemically-defined specificity. Nevertheless, if a graft-induced recovery of neurochemical markers in the hippocampus seems to be a prerequisite for also behavioural recovery to be observed, this neurochemical recovery is neither the one and only condition for behavioural effects to be expressed, nor is it the one and only mechanism to account for the latter effects. © 1997 Elsevier Science Ltd. All Rights Reserved.