prostaglandin-h2 and Kidney-Diseases

PGH2 and TxA2 exert their actions via tissue specific, receptor isoforms. PGH2/TxA2-dependent platelet aggregation and contraction of vascular and bronchial smooth muscle and of glomerular mesangial cells occur via receptors linked to activation of phospholipase C. Although PGH2/TxA2 appear to be of little importance in the maintenance of renal function under physiological circumstances, increased renal TxA2 biosynthesis has been documented in a variety of animal models of renal disease and in some clinical disorders (Table 2). The effects of this eicosanoid on renal tissues in vitro and of pharmacological manipulation of TxA2 synthesis and action in vivo suggest that such interventions will provide new drugs for the treatment of human kidney disease.

Topics: Animals; Humans; Kidney; Kidney Diseases; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Thromboxane A2

Several [(1H-imidazol-1-yl)methyl]- and [(3-pyridinyl)methyl] pyrroles were prepared and evaluated in vitro as thromboxane synthetase inhibitors in human platelet aggregation studies. A number of structures, e.g. 10b,f,g,i (respective IC50 values: 1 microM, 50 nM, 42 nM, 44 nM) showed superior in vitro inhibition of TXA2 synthetase when compared to the standard dazoxiben (1). However, it was found that in vitro potency did not translate into nor correlate with in vivo activity when these compounds were evaluated in mice in a collagen-epinephrine-induced pulmonary thromboembolism model. (E)-1-Methyl-2-[(1H-imidazol-1-yl)methyl]-5-(2-carboxyprop-1-enyl) pyrrole (10b) was found to offer protection against collagen-epinephrine-induced mortality in mice, thereby demonstrating that oral administration is an effective route for absorption of this drug. Additional evidence for the oral effectiveness of 10b in lowering serum TXB2 levels was obtained by performing ex vivo radioimmunoassay experiments with rats. A 13-week study of 10b in rats with reduced renal mass was conducted in order to evaluate the role of TXA2 production in hypertension and renal dysfunction. Although serum and urinary TXB2 levels in rats were found to be lowered during this study by 10b, the levels of urinary protein excretion remained comparable to that of the control group.

Topics: Animals; Aorta; Biological Availability; Blood Platelets; Chemical Phenomena; Chemistry; Humans; Imidazoles; Inflammation; Kidney Diseases; Male; Mice; Microsomes; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pyridines; Pyrroles; Rats; Structure-Activity Relationship; Swine; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase