15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Renal-Insufficiency

Kidney failure is associated with changes in renal vascular responses to angiotensin (Ang) II. We characterized expression of Ang II receptors and the renal vasoconstrictor and vasodilator responses to Ang II in kidneys from sham-operated and kidney failure rats. In the isolated perfused kidney of sham-operated rats, Ang II (1, 2, 4, and 8 ng) increased perfusion pressure by 27+/-6, 41+/-10, 54+/-11, and 74+/-12 mm Hg, respectively. These responses were amplified by 62+/-10% (P<0.05) in kidney failure rats. Losartan (1 micromol/L), an angiotensin type 1 (AT(1)) receptor blocker, abolished renal vasoconstriction induced by Ang II, unmasking a renal vasodilatation that was greater in kidney failure rats. CGP-42112 (1 micromol/L) or PD 123,319 (1 micromol/L), angiotensin type 2 (AT(2)) receptor ligands, blunted Ang II-induced renal vasodilatation. In the renal tissue of kidney failure rats, there was a marked increase in expression of AT(1) and AT(2) mRNA receptor. Ang II-induced vasodilatation was blunted by eicosatetraynoic acid (1 micromol/L), the all-purpose inhibitor of arachidonic acid metabolism; clotrimazole (1 micromol/L), an inhibitor of epoxygenase-dependent arachidonic acid metabolism; or Nomega-nitro-L-arginine methyl ester (L-NAME; 1 micromol/L), an inhibitor of NO synthesis. On stimulation with Ang II, 20-HETE was the predominant product released into the renal effluent of sham-operated rats, whereas epoxy-eicosatrienoic acids were the predominant products released into the effluent of kidney failure rats. These data suggest that during development of kidney failure, there is induction of the AT(2) receptors, which may account for increased Ang II-dependent vasodilatation through the predominant release of epoxyeicosatrienoic acids.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 5,8,11,14-Eicosatetraynoic Acid; Angiotensin II; Animals; Antihypertensive Agents; Arachidonic Acid; Clotrimazole; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Gene Expression Regulation; Imidazoles; In Vitro Techniques; Indomethacin; Kidney; Losartan; Male; NG-Nitroarginine Methyl Ester; Oligopeptides; Pyridines; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renal Insufficiency; RNA, Messenger; Vasodilation

Respiratory or renal failure is associated with changes in blood pH. Changes in pH may have profound effects on vascular tone and reactivity. Site of action of acidosis in the pulmonary vasculature and the role of nitric oxide production remain unclear.. We utilized isolated rat lung preparation perfused with autologous blood (Hct = 20%, flow rate = 33 ml/min), and investigated the effect of acidosis and alkalosis (induced by ventilation with high and low inspired CO2) on vascular resistance and the role of nitric oxide during resting and elevated tone conditions. Changes in resistance were described in terms of small and large arteries and veins, using the vascular occlusion technique.. Acidosis (Pco2 = 66.7 +/- 0.7 mmHg, pH = 7.17 +/- 0.01, Po2 = 255 +/- 3 mmHg) caused vasoconstriction under resting and increased vascular tone conditions (U46619-induced). The changes in resistance occurred primarily in the small arteries. In contrast, alkalosis (Pco2 = 20.1 +/- 0.3 mmHg, pH = 7.61 +/- 0.01, Po2 = 244 +/- 3 mmHg) caused vasodilation only at elevated tone conditions. Nitro-L-arginine (LNA), an inhibitor of nitric oxide synthase, increased vascular resistance slightly but did not modulate the responses to pH, suggesting that such responses are not nitric oxide dependent. During KCl-induced contraction, the effects of pH were abolished.. We conclude that in rat lung, acidosis causes an increase in pulmonary vascular resistance at normal and elevated tone conditions. Furthermore, the response is limited primarily to the small arteries, and is not mediated by nitric oxide. Alkalosis tends to cause the opposite effects. The effects of acidosis and alkalosis were abolished when vascular tone was elevated with a low dose of KCl, suggesting that vascular response to pH may involve changes in membrane potential.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acidosis; Alkalosis; Analysis of Variance; Animals; Enzyme Inhibitors; Hydrogen-Ion Concentration; Hypercapnia; Hypocapnia; Lung; Male; Microcirculation; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Potassium Chloride; Pulmonary Artery; Pulmonary Veins; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Respiratory Insufficiency; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents