Medizin - Open Access LMU - Teil 07/22 Archiv

In order to assess the effect of food ingestion on splanchnic disposal of human alpha-atrial natriuretic peptide (ANF), hepatic-intestinal removal of ANF was determined before and after a test meal. Hepatic venous and arterial plasma samples were obtained from six subjects, most of whom had only disorders of minor degree. Hepatic blood flow (HBF) increased significantly after meal ingestion (1.10 ± 0.17 [SEM] to 1.51 ± 0.26 L/min, P < .01). Baseline arterial ANF (10.9 ± 3.1 pmol/L) did not change significantly. In contrast, hepatic venous ANF increased after meal intake (5.7 ± 2.0 to 8.4 ± 1.9 pmol/L, P < .05), and accordingly the splanchnic fractional extraction decreased (0.53 ± 0.09 to 0.35 ± 0.08), although this was not statistically significant. Splanchnic clearance of ANF increased from 347 ± 90 mL/min to a maximal value of 615 ± 158 mL/min (P < .05). Splanchnic removal of ANF was 3.0 ± 0.5 pmol/min before and increased to a maximum value (7.1 ± 2.2 pmol/min, P < .05) 35 minutes after ingestion of the meal. Our results showed enhanced splanchnic removal of ANF after food intake. This is due to increased hepatic-intestinal clearance of the peptide consequent on increased splanchnic blood flow, rather than altered fractional extraction of ANF.

1. The vascular actions of atrial natriuretic factor (ANF) have been assessed with other vasoactive agents on the hepatic arterial and portal vascular beds of the anaesthetized dog. 2. Intra-arterial bolus injections of ANF (0.1-50 nmol) caused graded increases in hepatic arterial blood flow representing a vasodilatation of relatively short duration. Vasoconstriction was never observed. 3. The maximum increase in hepatic arterial blood was the same for ANF and isoprenaline (Iso) i.e. approximately 60-70% increase over control flow. 4. On a molar basis, ANF was less potent than Iso although over the higher dose range (10(-9)-10(-7) mol) its vasodilator activity exceeded that of the endogenous vasodilator adrenaline. 5. Intraportal bolus injections (1.0-50 nmol) of ANF did not alter portal inflow resistance since no changes in portal inflow pressure occurred when the portal circuit was perfused at constant inflow volume. 6. This differential action of ANF on the hepatic arterial and portal vascular beds may provide a change in total liver blood flow in favour of the arterial component. 7. ANF, by altering hepatic haemodynamics to favour formation of trans-sinusoidal fluid exchange, may provide a temporary expansion of the extravascular fluid reservoir to buffer any increased venous pressure. However, chronically elevated plasma levels of ANF would encourage the formation of ascitic fluid.

N-terminal (atrial natriuretic factor (ANF) 1-98) and C-terminal (ANF 99-126) fragments of proatrial natriuretic factor (NTA and CTA, respectively) were determined in plasma of healthy subjects adopting different postures and in patients with cirrhosis. Seven healthy subjects were investigated while seated and 30 min after assuming a horizontal position. NTA plasma concentrations increased in subjects in the horizontal position (from 734±250 (SE) fmol/ml to 9021227 fmol/ml; p

The reasons for the resistance to ischaemia of peripheral nerves in diabetics are not well understood. We have now explored whether axonal depolarization underlies this phenomenon, as has previously been proposed. Resistance to ischaemia was determined by the new method of “threshold tracking”. This method revealed an increase in excitability of the peroneal nerve at the popliteal fossa during ischaemia, and a decrease in excitability in the post-ischaemic period. The extent of these alterations in 28 type 1 diabetics without peripheral neuropathy showed a strong correlation with the mean blood glucose concentrations during the last 24 h before examination. To test whether the ischaemic resistance was related to membrane potential, we also measured axonal superexcitability in 11 selected diabetics, since it has been shown that post-spike changes in excitability depend on membrane potential. Changes in excitability of the peroneal nerve were measured in the period between 10 and 30 msec following a conditioning supramaximal compound action potential. Under resting conditions, no differences in the post-spike superexcitability were found between controls and diabetics, despite striking differences in their responses to a 10-min pressure cuff. These observations indicate that membrane depolarization is not involved in the resistance to ischaemia of motor axons in diabetic subjects.

An abnormal ratio between Na+ and K+ conductances seems to be the cause for the depolarization and paralysis of skeletal muscle in primary hypokalemic periodic paralysis. Recently we have shown that the k+ channel opener cromakalim hyperpolarizes mammalian skeletal muscle fibers. Now we have studied the effects of this drug on the twitch force of muscle biopsies from normal and diseased human skeletal muscle. Cromakalim had little effect on the twitch force of normal muscle whereas it strongly improved the contraction force of fibers from patients suffering from hypokalemic periodic paralysis. Recordings of intracellular K+ and Cl- activities in human muscle and isolated rat soleus muscle support the view that cromakalim enhances the membrane K+ conductance (gK+). These data indicate that K+ channel openers may have a beneficial effect in primary hypokalemic periodic paralysis.

We have identified a 19 kd protein of the mitochondrial outer membrane (MOM19). Monospecific IgG and Fab fragments directed against MOM19 inhibit import of precursor proteins destined for the various mitochondrial subcompartments, including porin, cytochrome c1, Fe/S protein, F0 ATPase subunit 9, and F1 ATPase subunit β. Inhibition occurs at the level of high affinity binding of precursors to mitochondria. Consistent with previous functional studies that suggested the existence of distinct import sites for ADP/ATP carrier and cytochrome c, we find that import of those precursors is not inhibited. We conclude that MOM19 is identical to, or closely associated with, a specific mitochondrial import receptor.

Of 521 patients with erectile dysfunction in whom a multidisciplinary approach was used, 145 (27.8%) showed venous leakage as (concomitant) etiology of the impotence in dynamic cavernosography. The rate of the maintenance flow corresponded well with the response to a standardized intracavernosal injection of vasoactive drugs (p < 0.05) in patients with venous leakage. The maintenance flow increased with the age in secondary impotent men. It was not statistically different in patients with or without concomitant arterial insufficiency (p = 0.19). Fifty-one of 145 patients (32.2%) presented a pathologic cavernosal drainage via a single venous system; 94/145 (64.8%) showed a combined venous leakage. The type of leakage corresponded neither to the maintenance flow nor to the response to intracavernosal injections. Our findings show that standardized intracavernosal testing and Doppler have a high predictive value for the status of the venous occlusive system. Exact evaluation of the type of leakage can be made by bidimensional cavernosography only.

Mitochondrial heat-shock protein hsp60 functions in the folding of proteins imported into mitochondria. Folding occurs at the surface of hsp60 in an ATP-mediated reaction, followed by release of the bound polypeptides. We propose that hsp60 catalyses protein folding.

The biogenesis of cytochrome c1 involves a number of steps including: synthesis as a precursor with a bipartite signal sequence, transfer across the outer and inner mitochondrial membranes, removal of the first part of the presequence in the matrix, reexport to the outer surface of the inner membrane, covalent addition of heme, and removal of the remainder of the presequence. In this report we have focused on the steps of heme addition, catalyzed by cytochrome c1 heme lyase, and of proteolytic processing during cytochrome c1 import into mitochondria. Following translocation from the matrix side to the intermembrane-space side of the inner membrane, apocytochrome c1 forms a complex with cytochrome c1 heme lyase, and then holocytochrome c1 formation occurs. Holocytochrome c1 formation can also be observed in detergent-solubilized preparations of mitochondria, but only after apocytochrome c1 has first interacted with cytochrome c1 heme lyase to produce this complex. Heme linkage takes place on the intermembrane- space side of the inner mitochondrial membrane and is dependent on NADH plus a cytosolic cofactor that can be replaced by flavin nucleotides. NADH and FMN appear to be necessary for reduction of heme prior to its linkage to apocytochrome c1. The second proteolytic processing of cytochrome c1 does not take place unless the covalent linkage of heme to apocytochrome c1 precedes it. On the other hand, the cytochrome c1 heme lyase reaction itself does not require that processing of the cytochrome c1 precursor to intermediate size cytochrome c1 takes place first. In conclusion, cytochrome c1 heme lyase catalyzes an essential step in the import pathway of cytochrome c1, but it is not involved in the transmembrane movement of the precursor polypeptide. This is in contrast to the case for cytochrome c in which heme addition is coupled to its transport directly across the outer membrane into the intermembrane space.