Impact of aldosterone receptor blockade on the deleterious cardiac effects of adrenergic activation in hypertensive rats.
Although in hypertension beta-adrenoreceptor activation promotes the transition from cardiac hypertrophy to pump dysfunction, the use of beta-blockers is controversial. As adrenergic activation may mediate adverse effects on the heart through the renin-angiotensin-aldosterone system, we evaluated the effects of the aldosterone receptor blocker, spironolactone (SPIRO), on isoproterenol (ISO)-induced changes in left ventricular cavity size and pump function and the determinants thereof in spontaneously hypertensive rats (SHR). ISO administered for 4.5 months resulted in increases in left ventricular dimensions and a decrease in pump function in SHR but not in normotensive rats, changes that, without affecting blood pressure, were abolished by SPIRO. In SHR, 4-5 days of ISO increased myocardial matrix metalloproteinase-2 activity, which was associated with matrix metalloproteinase-2 but not tissue inhibitor of MMP expression; persisted at 4.5 months; and was prevented by SPIRO. Moreover, after 4.5 months, ISO increased non-cross-linked myocardial collagen concentrations in SHR, which was abolished by SPIRO. Although after 4.5 months, ISO was not associated with increased cardiomyocyte apoptosis, an early (4-5 days) ISO-induced apoptotic effect was noted, which was prevented by SPIRO. Hence, aldosterone receptor blockade may be sufficient to prevent those adverse effects of beta-adrenoreceptor activation responsible for the transition from concentric cardiac hypertrophy to pump dysfunction in hypertension.
Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand, Johannesburg, South Africa.
Demetri G A
DG
Veliotes
Gavin R
GR
Norton
Raul J
RJ
Correia
Hans
H
Strijdom
Danelle
D
Badenhorst
Richard
R
Brooksbank
Angela J
AJ
Woodiwiss
D000318:Adrenergic beta-Agonists / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure / Q000187:drug effects; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007545:Isoproterenol / Q000009:adverse effects* / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D013148:Spironolactone / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D020778:Matrix Metalloproteinase 2; D007545:Isoproterenol