Christian Drummer

Soluble Guanylyl Cyclase and Platelet Functiona

Soluble guanylyl cyclase is abundantly present in platelets. This heterodimeric heme-protein is activated by nitric oxide (NO) and is involved in the inhibitory action of NO on platelet function. NO interferes with early steps of platelet activation involving calcium mobilization and inhibits both adhesion and aggregation. NO is formed endogenously from endothelium and a variety of other cell types. The nitrovasodilators, commonly used for the treatment of angina pectoris, also act through the release of NO. The release of NO from these drugs is enzyme coupled, and only a little NO is released from these drugs spontaneously. Platelets do not contain the enzyme system(s) that releases NO from organic nitrates. These drugs can therefore only weakly activate platelet-soluble guanylyl cyclase and inhibit platelet activation in vitro. However, NO is released from these drugs in the vessels and can reach the platelets close to the vessel wall in vivo. Therefore, many effects of these drugs in the primary or secondary prevention of myocardial infarction might come from their antiplatelet action rather than from their ability to dilate vessels. Knowledge of the mechanisms by which soluble guanylyl cyclase is activated has contributed considerably to our understanding of the mechanisms of regulation of platelet function and has presented us with new therapeutic possibilities.

Effects of nitric oxide-containing compounds on increases in cytosolic ionized Ca2+ and on aggregation of human platelets.

The present study was undertaken to determine the modulatory effects of nitric oxide (NO)-releasing compounds on increases in cytosolic ionized calcium ([Ca2+]i) and on aggregation of gel-filtered human platelets induced via diverse agonists. We used various sydnonimines and organic nitrates as donors of NO. Gel-filtered and fura-2-loaded platelets were stimulated with ADP (4-8 microM), collagen (2-10 micrograms/ml) or thrombin (0.02-0.05 IU/ml), respectively. Half-maximal inhibiting effects of sydnonimines on agonist-evoked increases in [Ca2+]i were observed between 30 and 1000 nM, while half-maximal inhibiting effects of the compounds on aggregation were between 3 and 500 nM. The compound C 87-3754, which is the bioactive metabolite of pirsidomine, was a much stronger inhibitor of increases in [Ca2+]i than of platelet aggregation. This was due to an enhanced NO release from this compound exposed to ultraviolet light during Ca2+ measurement. The organic nitrates isosorbide 5-mono-nitrate and nicorandil inhibited both aggregation and increase of cytosolic ionized calcium in stimulated platelets at half-maximal concentrations of approximately 200 microM. The present results suggest that some of the effects of NO on platelets are independent of cytosolic ionized calcium. The results also suggest that some of the inhibitory effects of NO-releasing compounds correspond rather to the presence of the A forms (NO-containing intermediates) than to the presence of free NO.

Long-term elevations of dietary sodium produce parallel increases in the renal excretion of urodilatin and sodium

The effects of dietary sodium intake on the renal excretion of urodilatin and of sodium were examined in six healthy male subjects. The 24-day study period was divided into three phases of 8 days each. Subjects Ingested 2.8 mequiv sodium (kg body weight)−1 day−1 during the first phase, 5.6 mequiv (kg body weight)−1 day−1 during the second phase, and 8.4 mequiv (kg body weight)−1 day−1 during the third phase. The excretion of both sodium (P<0.002) and urodilatin (P<0.006) increased in response to the increasing dietary sodium, while urine flow did not change. Urinary urodilatin excretion correlated closely with renal sodium excretion (P<0.001). Serum aldosterone levels (P<0.01) as well as serum renin levels (P<0.05) significantly decreased with increasing sodium intake. Plasma [Arg]vasopressin levels increased significantly (P<0.05). Plasma atrial natriuretic factor and cGMP levels as well as urinary cGMP excretion rates were unaltered by the changes in sodium intake. We conclude from these results that the renal natriuretic peptide, urodilatin, but not the main cardiac member of the natriuretic peptide family may be involved in the regulation of day-to-day sodium balance.

Body Fluid Metabolism at Actual and Simulated Microgravity

Recent observations from space missions indicate that weightlessness does not induce an increase in diuresis and natriuresis in astronauts. Rather, both oral fluid and sodium intake as well as renal fluid and sodium output appear reduced compared with the preflight condition. In addition, influences of reduced energy intake may be more important for total body fluid content inflight than generally assumed. Decreases in plasma volume and observations of upper body edema formation inflight indicate, in addition, an increased extravasation as a result of the headward fluid shift in weightlessness. Current simulations models of microgravity for body fluid metabolism are valid for simulations of the central fluid shift occurring in microgravity. Since weightlessness appears to decrease central venous pressure and does not induce an increased renal fluid and sodium excretion, while simulations models have opposite effects, additional models to simulate adaptation of body fluid metabolism to weightlessness might be necessary.

Low Urinary Albumin Excretion in Astronauts during Space Missions

Background: Physiological changes occur in man during space missions also at the renal level. Proteinuria was hypothesized for space missions but research data are missing. Methods: Urinary albumin, as an index of proteinuria, and other variables were analyzed in 4 astronauts during space missions onboard the MIR station and on the ground (control). Mission duration before first urine collection in the four astronauts was 4, 26, 26, and 106 days, respectively. On the ground, data were collected 2 months before mission in two astronauts, 6 months after in the other astronauts. A total of twenty-two 24-hour urine collections were obtained in space (n per astronaut = 1–14) and on the ground (n per astronaut = 2–12). Urinary albumin was measured by radioimmunoassay. For each astronaut, mean of data in space and on the ground was defined as individual average. Results: The individual averages of 24 h urinary albumin were lower in space than on the ground in all astronauts; the difference was significant (mean ± SD, space and on the ground = 3.41 ± 0.56 and 4.70 ± 1.20 mg/24 h, p = 0.017). Dietary protein intake and 24-hour urinary urea were not significantly different between space and on the ground. Conclusions: Urinary albumin excretion is low during space mission compared to data on the ground before or after mission. Low urinary albumin excretion could be another effect of exposure to weightlessness (microgravity).

Vasopressin, hypercalciuria and aquaporin--the key elements for impaired renal water handling in astronauts?

Accessible online at: www.karger.com/journals/nef There is growing interest in integrating various adaptations occurring in renal function during space flight in order to develop a new rationale for future research in the field. Experience derived from research programs in some of the 400 astronauts, who have been in space, indicates that significant changes in renal sodium and water handling take place under Ì-gravity conditions. We have recently reviewed in detail these components of fluid balance and kidney function in space [1–7]. An additional burden on our present understanding is added by the weightlessness-dependent bone loss, which causes hypercalciuria. Therefore, in this review we are in consecutive sections describing ‘Body Fluid Regulation in Space’, ‘Calcium and Bone Metabolism in Space’, ‘Involvement of Renal Aquaporins’, and the ‘Pathophysiology of Clinical Hypercalciuria’ with the aim to provide a rationale for the impairment in water handling as a consequence of the increase in luminal calcium concentration in the collecting duct. On this basis, we generate a new hypothesis on how the kidney function and body fluid regulation are modified during Ì-gravity. Body Fluid Regulation in Space