zaprinast and Ischemia

Disruption of endothelial barrier properties with development of noncardiogenic pulmonary edema is a major threat in lung ischemia-reperfusion (I/R) injury that occurs under conditions of lung transplantation. Inhaled nitric oxide (NO) reduced vascular leakage in lung I/R models, but the efficacy of this agent may be limited. We coadministered NO and zaprinast, a cGMP-specific phosphodiesterase inhibitor, to further augment the NO-cGMP axis. Isolated, buffer-perfused rabbit lungs were exposed to 4.5 h of warm ischemia. Reperfusion provoked a transient elevation in pulmonary arterial pressure and a negligible rise in microvascular pressure followed by a massive increase in the capillary filtration coefficient and severe lung edema formation. Inhalation of 10 parts/million of NO or intravascular application of 100 microM zaprinast on reperfusion both reduced pressor response and moderately attenuated vascular leakage. Combined administration of both agents induced no additional vasodilation at constant microvascular pressures, but additively protected against capillary leakage paralleled by a severalfold increase in perfusate cGMP levels. In conclusion, combining low-dose NO inhalation and phosphodiesterase inhibition may be suitable for the maintenance of graft function in lung transplantation by amplifying the beneficial effect of the NO-cGMP axis and avoiding toxic effects of high NO doses.

Topics: Animals; Blood Pressure; Capillary Permeability; Compliance; Cyclic GMP; Female; In Vitro Techniques; Ischemia; Male; Nitric Oxide; Organ Size; Phosphodiesterase Inhibitors; Pulmonary Artery; Pulmonary Circulation; Purinones; Rabbits; Reperfusion Injury

Atrial natriuretic factor (ANF) has been demonstrated to be effective in the treatment of acute renal failure (ARF) in both rat and humans. The biological effects of ANF are presumed to be mediated by the generation of intracellular 3',5'-cyclic guanosine monophosphate (cGMP). Therefore, the current investigation examined whether zaprinast (M&B 22948), a guanosine 3',5'-cyclic monophosphate (cGMP)-specific phosphodiesterase inhibitor, would be effective in the treatment of established acute renal failure in the rat. Acute renal failure was induced by 60 minutes of bilateral renal artery clamping. Twenty-four hours after the ischemic insult, rats received either vehicle (5% Dextrose), zaprinast (0.03 or 0.3 mg/kg/min) or ANF24 (0.2 micrograms/kg/min) intravenously for four hours. Renal function, as measured by daily serum creatinine (days 1 to 7) and day 2 inulin clearances, was dramatically improved by zaprinast but not ANF treatment. Forty-eight hours post-renal ischemia, glomerular filtration rate (GFR) was 0.14 +/- 0.04 (ml/min/100 g body wt) in the vehicle and 0.94 +/- 0.29 in the zaprinast treated animals. To evaluate the mechanism by which zaprinast accelerated renal recovery, we measured regional blood flow in the postischemic rat kidneys during drug treatment with a laser doppler flowmeter. Both high and low dose zaprinast significantly increased cortical (17%) and outer medullary blood flow (40% and 60%), an effect not seen with ANF. In summary, zaprinast is effective in the treatment of established ischemic ARF. The mechanism by which zaprinast accelerates renal recovery is due to its unique ability to stimulate regional renal blood flow and increase intracellular cGMP in the setting of tissue ischemia.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Creatinine; Cyclic AMP; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Inulin; Ischemia; Male; Purinones; Rats; Rats, Sprague-Dawley; Renal Circulation

Platelets have been implicated in the pathophysiology of ischemia-reperfusion injury. In this study, antiplatelet effects of cyclic GMP (cGMP)- and cyclic AMP (cAMP)-mediated agents were evaluated in renal ischemia in pentobarbital-anesthetized rats. Renal ischemia was induced by unilateral occlusion of the left renal artery (40 min) followed by reperfusion (30 min) with the contralateral kidney serving as control. 111Indium-labeled platelets, drugs or vehicle were administered 30 min before induction of renal ischemia. Occlusion of the left renal artery for 20, 40 or 60 min resulted in a 100, 300 and 600% increase (over contralateral right kidney) in the platelet-associated 111indium activity in the ischemic kidney. In all subsequent studies the kidney was occluded for 40 min to test the antiplatelet activity of individual agents. 8-Br-cGMP (0.1 and 0.3 mg/kg/min i.v.), zaprinast (0.1 mg/kg/min i.v.) and sodium nitroprusside (0.003 and 0.01 mg/kg/min i.v.) significantly attenuated platelet accumulation in renal ischemia, whereas 8-Br-cAMP (0.3 mg/kg/min i.v.) or milrinone (0.1 mg/kg i.v. bolus, plus 0.01 mg/kg/min) did not. Minoxidil (0.01 and 0.03 mg/kg/min i.v.), a vasodilator which produced equihypotensive effects as the cGMP-mediated agents, and milrinone failed to prevent platelet accumulation. These results demonstrate that modulation of the platelet function by cGMP agents can be dissociated from their blood pressure lowering effects. cGMP is known to inhibit both platelet adhesion and aggregation, whereas cAMP is only active against aggregation. The present findings provide further evidence that cGMP-mediated drugs may afford effective antiplatelet action in an in vivo model of ischemia-reperfusion injury.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Animals; Blood Platelets; Cyclic AMP; Cyclic GMP; Ischemia; Kidney; Male; Nitroprusside; Platelet Aggregation Inhibitors; Purinones; Rats; Reperfusion