The biophysical and pharmacological characteristics of skeletal muscle ATP-sensitive K+ channels are modified in K+-depleted rat, an animal model of hypokalemic periodic paralysis.

We evaluated the involvement of the sarcolemmal ATP-sensitive K+ channel in the depolarization of skeletal muscle fibers occurring in an animal model of human hypokalemic periodic paralysis, the K+-depleted rat. After 23-36 days of treatment with a K+-free diet, an hypokalemia was observed in the rats. No difference in the fasting insulinemia and glycemia was found between normokalemic and hypokalemic rats. The fibers of the hypokalemic rats were depolarized. In these fibers, the current of sarcolemmal ATP-sensitive K+ channels measured by the patch-clamp technique was abnormally reduced. Cromakalim, a K+ channel opener, enhanced the current and repolarized the fibers. At channel level, two open conductance states blocked by ATP and stimulated by cromakalim were found in the hypokalemic rats. The two states could be distinguished on the basis of their slope conductance and open probability and were never detected on muscle fibers of normokalemic rats. It is known that insulin in humans affected by hypokalemic periodic paralysis leads to fiber depolarization and provokes paralysis. We therefore examined the effects of insulin at macroscopic and single-channel level on hypokalemic rats. In normokalemic animals, insulin applied in vitro to the muscles induced a glybenclamide-sensitive hyperpolarization of the fibers and also stimulated the sarcolemmal ATP-sensitive K+ channels. In contrast, in hypokalemic rats, insulin caused a pronounced fiber depolarization and reduced the residual currents. Our data indicated that in hypokalemic rats, an abnormally low activity of ATP-sensitive K+ channel is responsible for the fiber depolarization that is aggravated by insulin.

Synthesis and pharmacological evaluation of perhydropyrrolo [3,4-c]pyridine derivatives.

Several N,N'-bis-alkyl-perhydropyrrolo[3,4-c]pyridines 4 and the corresponding bis-quaternary derivatives 5 have been prepared through standard methods starting from the bicyclic dilactam 2. Compounds 4 and 5 were evaluated for their inhibitory properties against acetylcholine (ACh), 1,1-dimethylphenyl piperazinium iodide (DMPP), 5-hydroxytryptamine (5-HT) and histamine (H1), and the guinea pig isolated ileum. Pharmacological data indicated that the strongest anticholinergic activity was shown by the dibenzyl amine 4 g, which among the tested molecules presented also a rather potent effect at the ganglia level, resulting about three times more potent than hexamethonium as ganglionic blocking agent. The preliminary SAR coming from the analysis of the pharmacological results are presented and discussed.

[Intensive treatment of septic shock]. / Aspetti inerenti al trattamento intensivo dello shock settico.

In order to identify a septic shock syndrome, the Limulus test (positive results in 10 cases out of 12) is preferable to hemoculture (positive in 9 cases out of 22), as a valid tool for a precocious diagnosis and to support both the clinical diagnosis and the precocious case finding of the septic conditions. According to the Authors, as far as intensive treatment is concerned, the simultaneous finding of the central venous pressure (CVP) and the lung capillary (LC) allows an accurate evaluation of the rate of cardiac impairment and the alterations to the distribution of blood volume in connection with treatment. The Authors have also reported the data related to the clinical course of illness and mortality rate (68%) in 21 cases of septic shock, as well as the hemodynamic parameters with the pertinent correlations (CVP-PAP-Pcp and Da-v) in 12 patients affected by septic shock from the very beginning and throughout the whole period of treatment.