ularitide and zaprinast

Ularitide (CAS 118812-69-4, urodilatin) is a member of the family of the atrial natriuretic peptides. In the present study, the relaxant effects of ularitide acetate, isoproterenol (isoprenaline) hemisulfate, aminophylline, zaprinast, and different combinations between these drugs were investigated on methacholine chloride-precontracted guinea-pig tracheal smooth muscle. Ularitide acetate was a weaker bronchorelaxant than isoproterenol hemisulfate and aminophylline. Moreover the relaxation induced by ularitide acetate was reversible, while the relaxation induced by isoproterenol hemisulfate, aminophylline, and zaprinast was irreversible. Combinations between in each case two of these substances were overadditive, if the phosphodiesterase-inhibiting component was applicated before the combination partner. Their effects were only additive, if the combination partners were applicated simultaneously. All combinations between ularitide acetate and isoproterenol hemisulfate, aminophylline, or zaprinast respectively relaxed the tracheas irreversibly. These results suggest that ularitide acetate might be a novel partner for classical bronchorelaxants in potent bronchorelaxing combinations in the therapy of asthma bronchiale.

Topics: Aminophylline; Animals; Atrial Natriuretic Factor; Bronchoconstrictor Agents; Bronchodilator Agents; Drug Synergism; Guinea Pigs; In Vitro Techniques; Isoproterenol; Male; Methacholine Chloride; Muscle, Smooth; Peptide Fragments; Phosphodiesterase Inhibitors; Purinones; Trachea

Experimental nephrotic syndrome is characterized by abnormal sodium metabolism, reflected in a blunted natriuretic response both to volume expansion and to infused atrial natriuretic peptide (ANP). The studies presented here examined the relationships among plasma ANP concentration and urinary sodium (VNaV) and cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruil and inner medullary collecting duct (IMCD) cells to ANP and urodilatin (renal natriuretic peptide; RNP) in vitro in rats with Heymann nephritis, an immunologically mediated model of nephrotic syndrome. Nine to 14 days after Ip injection of anti-Fx1A antiserum, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline (2% body weight, given over 5 min). Thirty min after the onset of the infusion, plasma ANP concentration was increased to the same extent in both normal and nephritic rats, compared with their respective hydropenic controls. Despite this increase, UcGMPV was significantly less in nephritic rats after the saline infusion. Accumulation of cGMP by isolated glomeruil and IMCD cells from nephritic rats after incubation with ANP and RNP was also significantly reduced, compared with normal rats. This difference was not related to differences in either density or affinity of renal ANP receptors, but was abolished when accumulation of cGMP was measured in the presence of 10(-3) M isobutylmethylxanthine or Zaprinast, two different inhibitors of cyclic nucleotide phosphodiesterases (PDE). Infusion of Zaprinast into one renal artery in nephritic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. Furthermore, cGMP-PDE activity was increased in IMCD cell homogenates from nephritic compared with normal rats (388 +/- 32 versus 198 +/- 93 pmol/min per mg protein, P < 0.03). These results indicate that blunted volume expansion natriuresis accompanied by cellular resistance to ANP in vitro occurs in an immunologic model of renal injury. The resistance is not related to an alteration in ANP release or binding to its renal receptors, but is suppressed by PDE inhibitors and is associated with increased renal cGMP. PDE activity, thus suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium

Topics: 1-Methyl-3-isobutylxanthine; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Atrial Natriuretic Factor; Cyclic GMP; Diuretics; Glomerular Filtration Rate; Glomerulonephritis; In Vitro Techniques; Kidney Glomerulus; Kidney Tubules, Collecting; Male; Natriuresis; Peptide Fragments; Phosphodiesterase Inhibitors; Purinones; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor