The dihydropyridine calcium channel blocker BAY t 7207 attenuates the exercise induced increase in plasma ANF and cyclic GMP in patients with mildly impaired left ventricular function

In man, chronic antihypertensive calcium antagonist treatment improves cardiac function and reduces plasma ANF concentrations. Physical exercise increases cardiac workload and plasma ANF levels. In the present study, we investigated the effects of acute administration of the dihydropyridine calcium antagonist BAY t 7207 (BAY) during bicycle exercise on plasma ANF and plasma cyclic GMP levels, on mean arterial pressure (MAP), heart rate (HR), and on natriuresis and urinary urodilatin excretion.In a randomized, double-blind placebo controlled cross-over trial, 8 patients (age 56.8±2.5 y) with documented coronary artery disease and mildly impaired left ventricular function (EF 50.0±1.3%), received oral BAY (20 mg) or placebo. Forty-five minutes after medication, patients underwent a standardised exercise bicycle test in the supine position (6 min 25 W, 6 min 50 W).Before exercise, MAP was lower after BAY (88.8±4.1 mmHg) than after placebo (95.7±3.5 mmHg; p+0.024), and HR was higher after BAY (76.8±3.5 bpm) than after placebo (69.5±3.6 bpm; p+0.049). Plasma ANF tended to be higher after BAY (31.2±5.6 pg/ml) than after placebo (26.7±5.0 pg/ml), and plasma cGMP was not different (BAY 3.4±0.3, placebo 3.8±0.3 pmol/ml). During exercise, the relative increases in HR (+43%) and MAP (+17%) were identical after BAY and placebo. In contrast, ANF levels during exercise increased by 130±28% after placebo but only by 36±11% after BAY (p+0.011). In parallel, plasma cyclic GMP increased by 61±13% after placebo and by 20±8% after BAY (p+0.013). At the end of exercise, the BAY-induced reduction in plasma cyclic GMP reflected the reduction in diastolic arterial pressure (r+0.717; p+0.045). Compared to placebo, BAY treatment increased the fractional excretion rate of sodium from 0.46±0.11 to 0.90±0.22% (p+0.016), without relation to urinary urodilatin excretion.Thus, the calcium antagonist BAY t 7207 attenuated the exercise-induced increase in plasma ANF and cyclic GMP probably due to its vasodilator effect. The relationship between blood pressure and the ANF system during exercise, which parallels findings during chronic antihypertensive treatment, may open a perspective for early evaluation of long-term therapy with calcium channel blockers.     

URODILATIN (INN: ULARITIDE) AS A NEW DRUG FOR THE THERAPY OF ACUTE RENAL FAILURE FOLLOWING CARDIAC SURGERY

1. Acute renal failure is a severe complication following major cardiac surgery. 2. The effects of urodilatin were evaluated in a randomized, double-blind trial in patients suffering from incipient acute renal failure following cardiac surgery. 3. In the urodilatin group (n= 7) acute renal failure was reverted, whereas in the placebo group (n= 7) six patients had to be haemofiltered or haemodialysed (P < 0.005). 4. Urodilatin induced a rapid onset of diuresis in contrast to placebo-treated patients, who remained oliguric. 5. In the placebo group four of seven patients died while still on haemodialysis (mortality rate 57.1 %) during a postoperative follow-up period of 60 days, while all patients treated with urodilatin survived. 6. On the basis of these results it would appear that urodilatin is an effective drug for the treatment of incipient oliguric acute renal failure following cardiac surgery and for avoiding haemodialysis/haemoflltration.     

Urodilatin: a new approach for the treatment of therapy-resistant acute renal failure after liver transplantation

Abstract A pilot study was performed in patients after liver transplantation (Ltx) to examine the effect of continuous intravenous urodilatin (URO, CDD/ANP-95–126)-infusion as an alternative therapy of acute renal failure (ARF) resistant to conventional therapy. Eight patients who developed ARF after liver transplantation and fulfilled requirements for haemo-dialysis/haemofiltration were treated. After URO infusion was started, renal function improved and all patients developed a strong diuresis and natriuresis within 2–4h. The extracellular expansion due to sodium and water retention in anuric/oliguric ARF lead to an increased central venous pressure (CVP) and elevated blood pressure. During the URO infusion CVP declined and systolic, as well as diastolic, blood pressure were stable. In six patients where haemodialysis/haemofiltration could be avoided, serum creatinine (SC) and blood urea nitrogen (BUN) declined during URO treatment and creatinine clearance (CC) also improved significantly. Fluid and electrolyte disturbances changed promptly and normalized. This was in concordance with renal excretion of electrolytes. Two patients still required haemodialysis/haemofiltration. The six patients who did not require haemodialysis/haemofiltration after URO treatment normalized concerning their renal function and did well in a control period of 12 weeks. The study shows that continuous low dose URO infusion may present a new concept for treatment of postoperative acute renal failure resistant to conventional therapy.     

Severe hypotension and bradycardia after continuous intravenous infusion of urodilatin (ANP 95–126) in a patient with congestive heart failure

Abstract. The effects of a continuous i.v. infusion of urodilatin at a dose of 30 ng kg^-1 min^-1 were studied in a patient with congestive heart failure. After 30 min, urodilatin had induced a marked stimulation of plasma cyclic GMP concentrations. In parallel haematocrit increased. No significant diuresis and no change of invasive haemodynamics was observed. After 2 h the patient developed a profuse perspiration. Eighty minutes later he suffered from dizziness due to hypotension (blood pressure 80/40 mmHg) and a sudden bradycardia (50bpm). Urodilatin was discontinued and symtoms were relieved by bed tilt and rapid infusion of isotonic saline solution. Mechanisms contributing to these adverse effects may be fluid extravasation to the third space and sympathoinhibitory effects known to occur with natriuretic peptide infusion.     

Haemodynamic and renal effects of urodilatin in healthy volunteers

Urodilatin (ANF(95-126)), an analogue of the atrial natriuretic factor (ANF(99-126)), has recently been isolated from human urine. To study haemodynamic and renal effects of synthetic urodilatin, 18 healthy male volunteers (age 26.1 +/- 0.8 years; X +/- SEM) received i.v. bolus injections of urodilatin at doses of 1, 2 or 4 micrograms kg-1 body weight (bw) (n = 6 per dosage group). Urodilatin dose-dependently increased heart rate and cardiac index. A dose-dependent increase in plasma cyclic GMP levels was also observed. Urinary cyclic GMP excretion, urine flow and natriuresis increased 7-fold, 5-fold and 4-fold, respectively. Renal effects were not different between dosage groups. Compared with ANF(99-126), after urodilatin the reduction in mean pulmonary arterial pressure (PAP) was more pronounced (2 micrograms kg-1, n = 6; ANF -1.8 +/- 0.5, URO: -5.5 +/- 1.1 mmHg, P less than 0.05). Furthermore, after urodilatin the reduction of PAP lasted continuously from 2 up to 90 min after injection, while ANF(99-126) produced only a transient decrease of PAP. Similarly the reduction of pulmonary capillary wedge pressure (PCWP) by urodilatin from 9.3 +/- 1.2 to 3.8 +/- 0.9 mmHg (P less than 0.05) was also sustained up to 90 min post administration. These data in healthy volunteers suggest that, due to prolonged reduction of PAP and PCWP with increases of cardiac index and reduction of systemic vascular resistance, urodilatin might exhibit beneficial effects in cardiovascular disease.     

尿钠素在DM2-N中的变化及意义

目的:探讨尿钠素(URO)对2型糖尿病(DM2)早期肾小管损伤筛选的价值.方法:采用放免法检测正常对照组(41例)、DM2无肾病组(33例)、DM2早期糖尿病肾病(DN)组(37例)和DM2合并肾病组(26例)尿液中的URO,分析各组间URO水平的变化并与尿微量白蛋白与尿肌酐比值(mA/UCr)进行相关分析.URO诊断...     

The kidney in heart failure: Vasodilator-natriuretic systems

Summary: Congestive heart failure (CHF) is a complex clinical syndrome in which the kidney has a central pathophysiological role. an imbalance between vasoconstrictor-antinatriuretic and vasodilator-natriuretic forces is a key feature of the pathophysiology of CHF. This review summarizes current understanding of disturbances in vasodilator-natriuretic systems in CHF. the key vasodilator systems involved are: the natriuretic peptide family atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), urodilatin, dopamine (DA), endothelium-derived relaxing factors and prosraglandins. Renal responses to ANP are blunted in CHF, under the influence of haemodynamic, neuro-humoral, receptor and post-receptor events. BNP, secreted in response to left ventricular load, may circulate in high concentrations in CHF, with similar effects to ANP. Urodilatin is a newly discovered peptide of renal origin whose physiological role is under investigation. Neural endopeptidase inhibitors have shown some promise in the treatment of human CHF, particularly when combined with ACE inhibition or angiotensin II receptor blockade. the renal DA system is influenced by sodium intake and DA metabolism is altered in CHF. the place of orally active DA prodrugs and DA agonist in the management of patients with CHF is still undecided. In CHF, basal release of nitric oxide may be preserved or even enhanced. However, stimulated release of nitric oxide may be reduced. Renal effects of nitric oxide or arginine in CHF have yet to be defined. Renal prostaglandins play an important role in offsetting renal and systemic vasoconstriction and fluid retention in CHF. the recent availability of specific receptor antagonist should lead to clearer definition of the relative roles of renal angiotensin II inhibition and bradykinin potentiation in the benefical responses to angiotensin converting enzyme (ACE-1) in CHF. Prostaglandin-E1 (PG-E₁) and prostaglandin-E₂ (PG-E₂) infusion may have some benefit for the treatment of severe CHF. Adrenomedullin, a vasodilator-natriuretic peptide closely related to the calcitonin gene-related peptide family, is present in high concentrations in the kidney. Plasma concentrations of adrenomedullin are increased after acute cardiac injury and in CHF. Its roles in renal physiology and in the pathophysiology of CHF are under investigation. Overall, there is considerable potential to exploit these vasodilator-natriuretic systems in management strategies for CHF.     

Urodilatin (Ularitide, INN): a potent bronchodilator in asthmatic subjects

Abstract. Atrial natriuretic peptide (CDD/ANP-99–126) has been identified as a bronchodilator in various species including humans. We investigated the effect of urodilatin (CDD/ANP-95–126) in 18 clinically stable asthmatics showing an increase of the FEV₁ by ≥15% after salbutamol inhalation. Prior to the study inhaled β₂-agonists were withheld for 8 h. After baseline measurements of lung function parameters (FEV₁, VC, PEF, MEF₇₅, MEF₅₀, MEF₂₅), blood pressure, and heart rate in intravenous infusion of 20, 40 or 60 ng kg^-1 min^-1 urodilatin was administered for 40min in the morning. All measurements were repeated every 10 min during the infusion, for 30 min thereafter, and after the inhalation of l.25 mg salbutamol. Forty and 60 ng kg^-1min^-1 urodilatin showed a significant effect on the central (FEV_l, PEF, MEF₇₅) and peripheral airways (MEF₅₀, MEF₂₅) after 10 min infusion ( P <0.05). A broncho-dilation not significantly different from l.25 mg salbutamol was induced by 40 ng kg^-1 min^-1 in the central airways only, while 60 ng kg^-1 min^-1 led to a similar effect at all levels of the bronchial tree. Lung function parameters returned to baseline within 30 min after cessation of the urodilatin infusion. Heart rate showed a tendency to increase after 40min infusion ( P <0.05), but blood pressure did not change significantly. In conclusion, the maximal bronchodilating effect of intravenous urodilatin in clinically stable asthmatics was comparable to l.25 mg salbutamol.     

Natriuresis in conscious dogs caused by increased carotid [Na+] during angiotensin II and aldosterone blockade

The renal response to a selective increase in the Na⁺ concentration of the blood perfusing the central nervous system was investigated in conscious dogs treated with the converting enzyme inhibitor enalaprilat and the aldosterone antagonist canrenoate. In split-infusion experiments the plasma [Na⁺] of carotid blood was increased (approx. 6 mM) by bilateral infusion of hypertonic NaCl. Concomitantly distilled water was infused into the v. cava making the sum of the infusions isotonic. In control experiments isotonic saline was infused at identical rates into all three catheters. Na⁺ excretion increased markedly in both series, 103 ± 14 to 678± 84 μmol min^-1 during split-infusion and 90 ± 14 to 496 ± 74 μmol min^-1 during the isotonic volume expansion. Peak rate of excretion, peak fractional sodium excretion, and cumulative sodium excretion were all significantly higher (P < 0.05) during split-infusion than during control experiments. Plasma vasopressin increased only during split-infusion (0.68 ± 0.11 to 2.4 ± 0.8 pg ml^-1) while the increases in plasma atrial natriuretic peptide were similar in the two series. Urinary excretion of urodilatin (ANP95-126) increased significantly more during split-infusion (46 ±11 to 152 ±28 fmol min^-1) than during the isotonic volume expansion (45 ± 14 to 84 ± 16 fmol min^-1) (P < 0.05). It is concluded that the natriuretic mechanisms activated by a selective increase in the Na⁺ concentration of carotid blood and associated with increased excretion of urodilatin cannot be eliminated by blockade of the renin-angiotensin-aldosterone system.     

Synthesis of phospho-urodilatin by combination of global phosphorylation with the segment coupling approach

The chemical synthesis of biologically active phosphorylated urodilatin (CDD/ANP-95-126) was achieved by using a strategy of coupling protected peptide segments in solution. Three protected peptide segments corresponding to urodilatin (1-14) with side chain-unprotected Ser¹⁰, (15-24) and (25-32) were prepared manually using Fmoc chemistry on an aminopropyl polystyrene resin with the super acid-labile HMPB linker. For the coupling of segments, the carboxy group of the C-terminal segment (25-32) was converted into the tert-butyl ester by treatment with TBTA. The protected peptide segments were coupled in the presence of EDC/HOOBt or TBTU/HOBt to yield fully protected urodilatin with a free hydroxy function at Ser¹⁰. Introduction of the phosphate was performed with Et₂NP(OtBu)₂ and tetrazole followed by oxidation of the phosphite. Alternatively, a prephosphorylated protected segment (1-14) was used in the segment condensation. Our investigations indicate that both pathways, phosphorylation of protected urodilatin in solution and use of a prephosphorylated building block, are suitable methods to obtain a large phosphopeptide of high purity without formation of H-phosphonates or other by-products. © Munksgaard 1996.