title: Novel therapy approach in primary stroke prevention: simultaneous inhibition of endothelin converting enzyme and neutral endopeptidase in spontaneously hypertensive, stroke-prone rats improves survival.
abstract: OBJECTIVE
  Stroke, frequently a consequence of hypertension, is one of the leading causes of death and neurological disabilities worldwide. In the ischemic brain, levels of endothelin-1, one of the most potent vasoconstrictors, are raised. Anti-inflammatory and neuroprotective effects of endothelin antagonists after stroke have been described in literature. Based on these findings, we investigated the protective effect of the endothelin converting enzyme/neutral endopeptidase blocker, SLV 338, in salt-loaded, stroke-prone, spontaneously hypertensive rats.
  
  
  METHODS
  Male, 8-week-old spontaneously hypertensive stroke-prone rats were put on a high salt diet and treated with either 30 mg/kg or 100 mg/kg SLV 338 or vehicle for 27 weeks. Blood pressure, neurological outcome, body weight, and mortality were investigated throughout treatment. In weeks 1 and 9, animals were housed in metabolic cages for collection of urinary and blood samples and assessment of salt water and food intake. In weeks 22 and 27, additional blood samples were taken. At the end of the study, all brains were analyzed using magnetic resonance imaging.
  
  
  RESULTS
  SLV 338 was well tolerated in all animals. Neurological outcome and infarct size were similar in all groups. Albuminuria was considerably delayed and the incidence of stroke significantly lowered in treated animals. In spontaneously hypertensive stroke-prone rats, treatment with SLV 338 significantly (P = 0·01) improved survival in comparison to the vehicle treated group in a blood pressure-independent manner.
  
  
  CONCLUSIONS
  Our data in spontaneously hypertensive stroke-prone rats demonstrate that combined endothelin converting enzyme/neutral endopeptidase inhibition could offer a new therapeutic approach for primary stroke prevention and improvement of mortality. The mechanism seems to be blood pressure-independent.
authors.affiliation: Center for Cardiovascular Research/ Institut fuer Pharmakologie, Charité-Universitaetsmedizin Berlin, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Wengenmayer
authors.forename: Maxim
authors.initials: M
authors.lastname: Krikov
authors.forename: Susanne
authors.initials: S
authors.lastname: Mueller
authors.forename: Kristin
authors.initials: K
authors.lastname: Lucht
authors.forename: Arno
authors.initials: A
authors.lastname: Villringer
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: Christa
authors.initials: C
authors.lastname: Thoene-Reineke
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D000072396:Endothelin-Converting Enzymes; D006973:Hypertension / Q000201:enzymology* / Q000401:mortality / Q000517:prevention & control*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000201:enzymology* / Q000401:mortality / Q000517:prevention & control*; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes