Targeting calcium channel program (Biocrine)

Precipitation of myocardial ischemia after withdrawal of calcium channel blocking drugs has been observed in some patients, but the mechanism of this phenomenon is not known. Among 15 patients with coronary artery disease who had been treated with nisoldipine, onset of severe unstable angina was observed in 2 and evolution of acute myocardial infarction in 1 patient after abrupt withdrawal of nisoldipine therapy. To determine a mechanism of myocardial ischemia after cessation of nisoldipine therapy, the status of alpha 2 adrenoceptors and platelet sensitivity to epinephrine was examined in 5 patients. After 6 weeks of therapy, there were no changes in the number of alpha 2 adrenoceptors (199 +/- 45 vs 188 +/- 35 fmol/mg protein, mean +/- standard error of the mean) or affinity for antagonist (dissociation constant 5.78 +/- 0.99 vs 4.70 +/- 0.87 nM), but there was a significant (p less than 0.01) increase in the affinity of alpha 2 adrenoceptors for agonist epinephrine. In vitro platelet sensitivity to epinephrine, but not ADP, also increased markedly. It is postulated that an increase in alpha 2-adrenoceptor affinity for agonist may relate to platelet hyperactivity, which may result in severe myocardial ischemia upon withdrawal of calcium blocking drugs in some patients.

Ultradian rhythms of metabolism, body temperature and activity are attenuated or disappear completely during torpor in Djungarian hamsters, for all three ultradian periodicities (URsmall, URmedium and URlarge). URsmall and URmedium disappear during entrance into torpor, whereas URlarge disappear later or continue with a low amplitude. This suggests a tight functional link between torpor and the expression of ultradian rhythms, i.e. torpor is achieved by suppression of metabolic rate as well as silencing of ultradian rhythms. Spontaneous torpor is often initiated after an ultradian burst of activity and metabolic rate, beginning with a period of motionless rest and accompanied by a decrease of metabolic rate and body temperature. To extend previous findings on the potential role of the adrenergic system on torpor induction we analysed the influence of the ß3-adrenergic agonist Mirabegron on torpor in Djungarian hamsters, as compared to the influence of the ß-adrenergic antagonist Propranolol. Hamsters were implanted with 10 day release pellets of Mirabegron (0.06 mg day−1) or Propranolol (0.3 mg day−1). Mirabegron transiently supressed and accelerated ultradian rhythms but had no effect on torpor behaviour. Propranolol did not affect torpor behaviour nor the expression of ultradian rhythms with the dosage applied during this study.