title: Cardiac-specific effects of parathyroid hormone-related peptide: modification by aging and hypertension.
abstract: OBJECTIVE
  Parathyroid hormone-related peptide (PTHrP) improves heart function of post-ischemic and stunned myocardium and is released from the heart under ischemic conditions. Hypertrophic hearts from spontaneously hypertensive rats (SHR) develop a reduced ischemic tolerance, show reduced expression of PTHrP and develop paradoxical effects in regard to PTHrP. We hypothesized that PTHrP is causally involved in reduced ischemic tolerance of hypertrophied hearts. This hypothesis was tested by addition of a cardiac-specific PTHrP agonist or antagonist during ischemia and investigation of the functional recovery during the early phase of reperfusion.
  
  
  METHODS
  Hearts from male normotensive adult (6 months) or old (12 months) Wistar and SHR rats were perfused at a constant flow for 20 min and then exposed for 30 or 15 min to global zero-flow ischemia followed by 30 min reperfusion. PTHrP agonist (PTHrP1-36) or antagonist (5Ile,23Trp,36Tyr-PTHrP1-36) (each 100 nmol/l) were added briefly before the onset of ischemia to ensure that they were present at the beginning of reperfusion. Heart function was determined by insertion of a balloon catheter into the left ventricle. Left ventricular developed pressure (LVDP), dP/dtmax, dP/dtmin, left ventricular end-diastolic pressure (LVeDP), heart rate (HR) and coronary resistance (CR) were recorded.
  
  
  RESULTS
  Reduced post-ischemic recovery in old SHR was confirmed. Hearts from all four groups responded normally to exogenous PTHrP with a positive chronotropic effect under non-ischemic conditions. In hearts from adult normotensive rats, a beneficial effect of released endogenous PTHrP was confirmed. However, addition of the cardiac-specific PTHrP antagonist during ischemia significantly improved post-ischemic recovery in hearts from old normotensive rats and SHR. This beneficial effect of the antagonist was accompanied by a significant reduction in post-ischemic LVeDP and was more pronounced in adult SHR. This effect was also observed when the hearts were paced (4 Hz). Upon short-term ischemia (15 min), in the absence of ischemia-induced rigor contraction, the antagonist improved LVDP recovery in hearts from old normotensive rats.
  
  
  CONCLUSIONS
  In summary, a protective effect of released endogenous PTHrP was confirmed for hearts from adult normotensive rats. This effect is converted into an opposite effect in hearts from SHR and old normotensive rats. Therefore, released endogenous PTHrP can contribute to reduced ischemic tolerance in hypertrophied hearts and during aging.
authors.affiliation: Physiologisches Institut, Justus-Liebig-Universität Giessen, Aulweg 129, D-35392 Giessen, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Ross
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Schlüter
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002404:Catheterization; D006339:Heart Rate; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D014655:Vascular Resistance
chemical_list: D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; C079957:parathyroid hormone-related peptide (1-36)