http://repub.eur.nl/res/aut/9530/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/13783/ 2005-07-01T00:00:00Z 1. Mineralocorticoid receptor (MR) antagonism with spironolactone reduces mortality in heart failure on top of ACE inhibition. To investigate the underlying mechanism, we compared the actions of both aldosterone and spironolactone to those of angiotensin (Ang) II in the rat heart. 2. Hearts of male Wistar rats were perfused according to Langendorff. Ang II and aldosterone increased left ventricular pressure (LVP) by maximally 11+/-4 and 9+/-2%, and decreased coronary flow (CF) by maximally 36+/-7 and 20+/-4%, respectively. Spironolactone did not significantly affect LVP or CF. 3. In hearts that were exposed to a 45-min coronary artery occlusion and 3 h of reperfusion, a 15-min exposure to spironolactone prior to occlusion reduced infarct size (% of risk area) from 68+/-2 to 45+/-3%, similar to the reduction (34+/-2%) observed following 'preconditioning' (15 min occlusion followed by 10 min reperfusion) prior to the 45-min occlusion. Aldosterone exposure did not affect infarct size (71+/-5%). 4. In cardiomyocytes, aldosterone decreased [(3)H]thymidine incorporation maximally by 73+/-3%, whereas in cardiac fibroblasts it decreased [(3)H]proline incorporation by 33+/-7%. Spironolactone inhibited both effects. Ang II increased DNA and collagen synthesis, and these effects were reversed by aldosterone. 5. In conclusion, aldosterone induces positive inotropic and vasoconstrictor effects in a nongenomic manner, and these effects are comparable to those of Ang II. Aldosterone reduces DNA and collagen synthesis via MR activation, and counteracts the Ang II-induced increases in these parameters. MR blockade reduces infarct size and increases LVP recovery following coronary artery occlusion. The MR-related phenomena may underlie, at least in part, the beneficial actions of spironolactone in heart failure. http://repub.eur.nl/res/pub/7457/ 2004-06-11T00:00:00Z It is clearly evident from the literature that headache has troubled mankind from the dawn of civilization (Rapoport & Edmeads, 2000). A variety of methods have been used throughout the ages in an attempt to alleviate or cure this pain; these may have been the most appropriate at that time, and were probably seen as “cutting edge”. Today they seem at best amusing, and at worst cruel and barbaric. The earliest concepts in migraine were those of the supernatural, with migraine believed to be due to malevolent beings within the head; treatment based on this idea included incantations and application to the head of substances intended to drive out the demons and spirits (Edmeads, 1991). These were also driven out physically, as in the Neolithic period (8500-7000 BC). The people living in this time used the method of trepanation, a kind of neurosurgery, which involved removing circular chunks of skull so that the spirits causing the headache could escape. Over 50% of the trepanned skulls have shown evidence of healing, indicating a high survival rate for this operation. Although the scientific rationale behind trepanation is not understood, it is surprising that this procedure was performed as a treatment for migraine as late as the mid 17th century (Edmeads, 1991; Rapoport & Edmeads, 2000). http://repub.eur.nl/res/pub/13200/ 2003-09-01T00:00:00Z 1. Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive trigeminal sensory nerves, seems to be involved in the pathogenesis of migraine. Hence, CGRP receptor antagonists may serve as a novel treatment for migraine. This study was therefore designed to investigate the effects of BIBN4096BS (100, 300 and 1000 microg kg-1, i.v.), a potent and selective CGRP receptor antagonist, on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Both vagosympathetic trunks were cut and phenylephrine was infused into the carotid artery (i.c.) to support carotid vascular tone. 2. Infusions of capsaicin (0.3, 1, 3 and 10 microg kg-1 min-1, i.c.) did not alter the heart rate, but dose-dependently increased the mean arterial blood pressure. This moderate hypertensive effect was not modified by BIBN4096BS. 3. Capsaicin infusion (10 microg kg-1 min-1, i.c.) increased total carotid, arteriovenous anastomotic and tissue blood flows and conductances as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. These responses to capsaicin were dose-dependently blocked by BIBN4096BS. 4. Capsaicin infusion (10 microg kg-1 min-1, i.c.) more than doubled the jugular venous plasma concentration of CGRP. This effect was not blocked, but rather increased, by BIBN4096BS. 5. The above results show that BIBN4096BS behaves as a potent antagonist of capsaicin-induced carotid haemodynamic changes that are mediated via the release of CGRP. Therefore, this compound may prove effective in the treatment of migraine.