SUMMARY1. Na current (INa) was monitored in isolated voltage-clamped frog nodes of Ranvier in order to analyse the pharmacological and kinetic properties of fast and slow phases of inactivation.2. Niflumic acid (0-1-10 mM) and tetrodotoxin (0-3-30 nM) did not alter fast and slow inactivation time courses but preferentially reduced the amplitude of the fast phase of inactivation. The block of both phases of inactivation by niflumic acid and tetrodotoxin was well described if one assumed that more than one molecule of drug reacted with one channel.3. Fast and slow currents, corresponding respectively to fast and slow phases of inactivation, reversed at different potentials, had different threshold voltages of activation and the slopes of their steady-state inactivation curves were different. The recovery from inactivation of the compound INa could be described by the sum of two exponential (plus a delay) corresponding respectively to fast and slow currents.4. When calculated from INa recorded without and with niflumic acid or tetrodotoxin, the slow current activated about three times more slowly than the fast current.5. Large prehyperpolarizations delayed both the activation and the inactivation of the fast current but only the activation of the slow current.6. Lowering the temperature decreased the fast current but increased the slow current.7. We conclude that the inactivatable Na current of the nodal membrane is made up of two components (INa, and INa, ) corresponding to two different and interconvertible forms of the Na channel.

Our transgenic mouse model suggests a role for KvLQT1 channels not only in the mouse cardiac repolarisation but also in the sinus node automaticity and in the propagation of the impulse through the AV node.

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The insulin-like peptide human relaxin-2 was identified as a hormone that, among other biological functions, mediates the hemodynamic changes occurring during pregnancy. Recombinant relaxin-2 (serelaxin) has shown beneficial effects in acute heart failure, but its full therapeutic potential has been hampered by its short halflife and the need for intravenous administration limiting its use to intensive care units. In this study, we report the development of long-acting potent single-chain relaxin peptide mimetics. Modifications in the B-chain of relaxin, such as the introduction of specific mutations and the trimming of the sequence to an optimal size, resulted in potent, structurally simplified peptide agonists of the relaxin receptor Relaxin Family Peptide Receptor 1 (RXFP1) (e.g., 54). Introduction of suitable spacers and fatty acids led to the identification of single-chain lipidated peptide agonists of RXFP1, with subnanomolar activity, high subcutaneous bioavailability, extended half-lives, and in vivo efficacy (e.g., 64).