Eduardo Pirotzky

Endothelin and Ca++ agonist Bay K 8644: different vasoconstrictive properties

The mechanism of vasoconstriction induced by endothelin was investigated in rat isolated aorta in comparison with the Ca++ agonist, Bay K 8644. Endothelin (EC50 = 4 nM) induced a slow and sustained contraction in control medium whereas the one elicited by Bay K 8644 (EC50 = 14 nM) necessitating a partly K+ depolarized medium was fast with superimposed rhythmic contraction. By opposition with Bay K 8644, endothelin contraction was not inhibited by the calcium antagonists (1 microM), nifedipine, diltiazem and D 600, and substantially persisted in Ca++ free medium or after depletion of intracellular Ca++ by phenylephrine (1 microM). These data show that endothelin does not act as an activator of potential dependent Ca++ channels but probably through specific receptor(s) as suggested by its mode of vasoconstriction.

Nephrotoxicity of cyclosporine: The role of platelet-activating factor and thromboxane

Cyclosporine (CsA), an immunosuppressive agent, is potentially nephrotoxic. We had previously observed that acute administration of CsA to Munich-Wistar rats induced a decrease in single nephron glomerular filtration rate, due to a decline in glomerular plasma flow, and in the glomerular ultrafiltration coefficient. Moreover, these alterations were prevented when an antagonist of platelet-activating factor (PAF) was administered. In the present study we examined whether the protective effect of the PAF blocker in CsA nephrotoxicity could have been mediated by thromboxane (TxA2). Our data show that the PAF effects were not mediated by TxA2, since administration of dazmegrel, a thromboxane synthetase inhibitor, did not ameliorate the acute renal failure caused by CsA. Thus, PAF appears to be a direct mediator of acute CsA nephrotoxicity, while TxA2 is not significantly involved in this process.

Involvement of Platelet-Activating Factor in Renal Processes

Publisher Summary This chapter focuses on the involvement of platelet-activating factor (PAF) in renal processes. PAF is known to induce aggregation and secretion of platelets, and polymorphonuclear leukocytes. When injected intravenously into guinea pigs and rabbits, it induces thrombocytopenia and neutropenia, hypotension, and shock. Upon injection into skin, PAF elicits increased vascular permeability with plasma exudation that is independent of leukocyte accumulation. These properties implicate PAF as a potential mediator of renal injury. This view is further substantiated by studies demonstrating the immunological and non-immunological release of this mediator from different types of kidney cells. PAF is emerging as a potentially crucial mediator of kidney physiopathology. The chapter also discusses the physiological effects of PAF and role of PAF in renal diseases.

Effect of platelet-activating factor antagonist BN 52063 on the nephrotoxicity of cisplatin.

Cisplatin (DDP) is an effective anticancer agent that has been successfully applied against various solid tumors. However, DDP commonly causes nephrotoxicity. We observed that DDP led to significant alterations in renal microcirculation when administered to Munich-Wistar rats, with a concomitant decrease in single nephron glomerular filtration rate due to reduction in glomerular plasma flow and transcapillary hydraulic pressure difference. BN 52063, a platelet-activating factor antagonist, caused a striking change in acute renal failure induced by DDP leading toward normalization of all parameters of renal function. The results suggest that BN 52063 could be used as a novel drug to control DDP nephrotoxicity.

Lack of effect of atrial natriuretic factor on the tone induced in rat portal vein by platelet-activating factor

The spontaneous myogenic activity of the isolated rat portal vein was inhibited by atrial natriuretic factor or by sodium nitroprusside. These compounds were not effective on the tone induced by PAF-acether or carbachol. 8-Bromo cyclic GMP and dibutyryl cyclic AMP inhibited myogenic activity and reduced the agonist-induced contractions. Only dibutyryl-cyclic AMP significantly inhibited the PAF-acether-induced contractile responses. These results indicate that the tone induced by PAF-acether can be used to discriminate between drugs which selectively increase cyclic nucleotide levels.