Influence of atenolol and nifedipine on nitric-oxide deficient cardiomyocyte hypertrophy and expression of the cardio-endocrine peptide intermedin and its receptor components.
OBJECTIVE
Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial ischemia, oxidative stress and hypertrophy; expression of adrenomedullin (AM) and intermedin (IMD) and their receptor activity modifying proteins (RAMPs 1-3) is augmented in cardiomyocytes, indicating that the myocardial AM/ IMD system may be activated in response to pressure loading and ischemic insult. The aim was to examine effects on (i) parameters of cardiomyocyte hypertrophy and on (ii) expression of AM and IMD and their receptor components in NO-deficient cardiomyocytes of an intervention chosen specifically for ability to alleviate pressure loading and ischemic injury concurrently.


METHODS
The NO synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 35 mg.kg(-1).day(-1)) was given to rats for 8 weeks, with/ without concurrent administration of beta-adrenoceptor antagonist, atenolol (25 mg.kg(-1).day(-1)) / calcium channel blocker, nifedipine (20mg.kg(-1).day(-1)).


RESULTS
In L-NAME treated rats, atenolol / nifedipine abolished increases in systolic blood pressure and plasma AM and IMD levels and in left ventricular cardiomyocytes: (i) normalized increased cell width and mRNA expression of hypertrophic (sk-alpha-actin) and cardio-endocrine (ANP, BNP, ET) genes; (ii) normalized augmented membrane protein oxidation; (iii) normalized mRNA expression of AM, IMD, RAMP1, RAMP2 and RAMP3.


CONCLUSIONS
normalization of blood pressure and membrane oxidant status together with prevention of hypertrophy and normalization of the augmented expression of AM, IMD and their receptor components in NO-deficient cardiomyocytes by atenolol / nifedipine supports involvement of both pressure loading and ischemic insult in stimulating cardiomyocyte hypertrophy and induction of these counter-regulatory peptides and their receptor components. Attenuation of augmented expression of IMD in this model cannot however be explained simply by prevention of cardiomyocyte hypertrophy.
Bell
David
D
Cardiovascular Research Group, Division of Medicine and Therapeutics, School of Medicine and Dentistry, The Queen's University of Belfast, Belfast, Northern Ireland, UK. d.bell@qub.ac.uk
Zhao
You You
YY
Devine
Adrian B
AB
McDermott
Barbara J
BJ
D053607:Adrenomedullin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001262:Atenolol / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006984:Hypertrophy; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000172:deficiency*; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058262:Receptor Activity-Modifying Protein 1; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D013599:Systole / Q000187:drug effects
C499411:Adm2 protein, rat; D019332:Endothelin-1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009479:Neuropeptides; D010455:Peptides; D011498:Protein Precursors; C545508:Ramp1 protein, rat; C545509:Ramp2 protein, rat; C545510:Ramp3 protein, rat; D058262:Receptor Activity-Modifying Protein 1; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D011956:Receptors, Cell Surface; D020097:Natriuretic Peptide, Brain; D053607:Adrenomedullin; D009569:Nitric Oxide; D001262:Atenolol; D009320:Atrial Natriuretic Factor; D009543:Nifedipine; D019331:NG-Nitroarginine Methyl Ester