ularitide and Disease-Models--Animal

The short- and long-term morbidity and mortality in acute heart failure is still unacceptably high. There is an unmet need for new therapy options with new drugs with a new mode of action. One of the drugs currently in clinical testing in Phase III is ularitide, which is the chemically synthesized form of the human natriuretic peptide urodilatin. Urodilatin is produced in humans by differential processing of pro-atrial natriuretic peptide in distal renal tubule cells. Physiologically, urodilatin appears to be the natriuretic peptide involved in sodium homeostasis. Ularitide exerts its pharmacological actions such as vasodilation, diuresis, and natriuresis through the natriuretic peptide receptor/particulate guanylate cyclase/cyclic guanosine monophosphate pathway. In animal models of heart failure as well as Phase I and II clinical studies in heart failure patients, ularitide demonstrated beneficial effects such as symptom relief and vasodilation, while still preserving renal function. Subsequently, the pivotal acute decompensated heart failure (ADHF) Phase III study, called TRUE-AHF, was started with the objectives to evaluate the effects of ularitide infusion on the clinical status and cardiovascular mortality of patients with ADHF compared with placebo. This review summarizes preclinical and clinical data supporting the potential use of ularitide in the treatment of ADHF.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Clinical Trials as Topic; Disease Models, Animal; Diuretics; Female; Heart Failure; Humans; Male; Peptide Fragments; Rats, Wistar; Vasodilation

Raised cytokine levels and a hypoperfusion-associated decrease in glomerular filtration rate (GFR) are hallmarks of the genesis of septic acute renal failure (ARF). Therefore, anti-inflammatory as well as renal vasodilating therapeutic strategies may afford renal protection during septic ARF. The present study was designed to determine the effects of administration of urodilatin, pentoxifylline and theophylline to improve renal function in an ex-vivo model of 'septic renal injury'.. Eight series of experiments were performed: no intervention, perfusion with a suspension containing Escherichia coli bacteria (strain 536/21); E. coli + 10 microg/l urodilatin, E. coli + 20 microg/l urodilatin, E. coli + 100 microM theophylline, E. coli + 100 microM pentoxifylline and E. coli + URO 20 microg/l given 90 min after start of perfusion. Renal vascular and glomerular functional parameters as well as TNF-alpha release were analyzed up to 180 min.. Perfusion with E. coli caused an acute deterioration of renal vascular and glomerular function. URO 20 microg/l and PTX decreased renal vascular resistance (RVR) from 83.7 +/- 18.4 to 9.2 +/- 1.1 and 8.6 +/- 2.2 mm Hg/ml/min/g kidney and increased renal perfusion flow rate (PFR) from 8.2 +/- 1.5 to 14.6 +/- 0.8 and 14.1 +/- 2.2 ml/min/g kidney. As a result, GFR improved from 102.1 +/- 15.6 to 442 +/- 48.3 and 525.8 +/- 57 microl/min/g kidney during treatment with URO 20 microg/l and PTX, respectively. Renal TNF-alpha release was significantly reduced by URO 20 microg/l (from 178 +/- 23 to 45.2 +/- 2 and 47 +/- 3 pg/ml) in the E. coli + URO 20 microg/l and by PTX in the E. coli + PTX group if added to the perfusion medium upon start of perfusion. Interestingly, URO 20 microg/l also decreased RVR significantly from 62.2 +/- 6.1 to 35.9 +/- 6.0 mm Hg/ml/min/g kidney, improved PFR from 5.4 +/- 1.0 to 8.7 +/- 1.0 ml/min/g kidney, increased GFR from 160 +/- 43.3 to 280.7 +/- 27.9 microl/min/g kidney, and decreased TNF-alpha release to 122 +/- 18 pg/ml if applied 90 min after induction of septic ARF. In contrast, URO 10 microg/l did not significantly increase urine flow and did not appear to significantly improve renal perfusion. Theophylline showed no beneficial effects at all.. This suggests that urodilatin and pentoxifylline might be useful to protect renal function if given before a septic renal insult. Additionally, treatment with urodilatin is capable of restoring renal function in early Gram-negative sepsis-induced ARF even if given after the septic insult.

Topics: Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Disease Models, Animal; Escherichia coli Infections; Humans; Kidney; Male; Pentoxifylline; Peptide Fragments; Perfusion; Rats; Rats, Sprague-Dawley

In a model of acute pulmonary hypertension in intact rabbits, we investigated the vasodilatory potency of intravascularly administered urodilatin, a renal natriuretic peptide type A known to stimulate particulate guanylate cyclase. Urodilatin infusion was performed in the absence and presence of the phosphodiesterase (PDE) type 5 inhibitor dipyridamole. Stable pulmonary hypertension was evoked by continuous infusion of the thromboxane mimetic U46619, resulting in approximate doubling of the pulmonary artery pressure (PAP). When infused as sole agents, both urodilatin and dipyridamole dose-dependently attenuated the pulmonary hypertension, with doses for a 20% decrease in PAP being 30 ng/kg min for urodilatin and 10 microg/kg min for dipyridamole. A corresponding decrease in systemic arterial pressure (SAP) was noted to occur in response to both agents. Sequential intravenous administration of a subthreshold dose of dipyridamole (1 microg/kg min), which per se did not affect pulmonary and systemic hemodynamics, and a standard dose of urodilatin (30 ng/kg min) resulted in a significant amplification of both the PAP and the SAP decrease in response to the natriuretic peptide. At the same time, manifold enhanced plasmatic cyclic guanosine monophosphate (cGMP) levels were detected. Aerosolized dipyridamole also dose-dependently attenuated pulmonary hypertension, with only 1 microg/kg min being sufficient for a 20% decrease in PAP, with no SAP decline. Preceding administration of subthreshold aerosolized dipyridamole (50 ng/kg min) did, however, cause only a minor amplification of the pulmonary vasodilatory response to a subsequently infused standard dose of urodilatin. In conclusion, this is the first study to show that urodilatin does possess vasodilatory potency in the pulmonary circulation, and enhanced plasma levels of cGMP and synergy with the PDE5 inhibitor dipyridamole both strongly suggest that this effect proceeds via guanylate cyclase activation. The effect of infused urodilatin is, however, not selective for the pulmonary vasculature, as the systemic vascular resistance declines in a corresponding fashion.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dipyridamole; Disease Models, Animal; Drug Synergism; Guanylate Cyclase; Hypertension, Pulmonary; Infusions, Intravenous; Peptide Fragments; Phosphodiesterase Inhibitors; Pulmonary Artery; Pulmonary Circulation; Rabbits

In humans as well as in experimental models the hallmark of ischemic acute renal failure (ARF) is a profound diminution in glomerular filtration rate (GFR) and renal blood flow. Both calcium antagonists and a-ANP have been reported to exert beneficial effects in ischemic ARF. No data, however, exist about combined administration of the natriuretic peptide urodilatin and calcium channel blockers. We therefore investigated the effects of urodilatin (URO, 40 micrograms/kg/h, i.v.) and diltiazem (DIL, 300 micrograms/kg/h, i.v.) in the rat given immediately after clamping of both renal arteries for 40 min. Compared to controls (0.07 +/- 0.01) depressed GFR (ml/min/100 g) was clearly elevated with URO (0.16 +/- 0.03), DIL (0.13 +/- 0.03) and URO + DIL (0.14 +/- 0.02) after the ischemic lesion. After cessation of drug delivery the beneficial effects were blunted in the URO group, in contrast to the DIL and URO + DIL group, where GFR was significantly elevated compared to controls even 3 h after starting reperfusion. Besides that also urine flow, sodium excretion and blood pressure were examined. In conclusion both URO and DIL exert beneficial effects in ischemic ARF in the rat while infused. In contrast to URO DIL showed prolonged beneficial effects even after cessation of drug delivery. An additional effect of both drugs could not be observed.

Topics: Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Diltiazem; Disease Models, Animal; Diuretics; Drug Synergism; Female; Glomerular Filtration Rate; Kidney; Natriuresis; Peptide Fragments; Rats; Rats, Sprague-Dawley; Urodynamics