Carvedilol prevents severe hypertensive cardiomyopathy and remodeling.
BACKGROUND
Carvedilol (Coreg/Kredex) is an unselective vasodilating beta-blocker with potent antioxidant activity used in the treatment of hypertension, angina, and congestive heart failure. In previous studies, carvedilol has been demonstrated to confer significant cardiac protection in acute ischemic paradigms and reduction of left ventricle hypertrophy in spontaneously hypertensive rats.


OBJECTIVE
To examine the effects of carvedilol on discrete histopathologic changes in the heart induced by severe hypertension in stroke-prone spontaneously hypertensive rats.


METHODS
Three groups of stroke-prone spontaneously hypertensive rats were maintained on 1% NaCl drinking solution and a high-fat (24.5%) diet (salt-fat diet). Two of these groups had their salt-fat diet supplemented by 1200 or 2400 ppm carvedilol. The third group had the same diet but it was not supplemented with drug and this group served as a control. We fed a fourth group of stroke-prone spontaneously hypertensive rats a normal diet and used this group to define cardiac changes induced by salt-fat diet.


METHODS
In total, 33 stroke-prone spontaneously hypertensive rats from these four groups (n = 7-9 in each group) survived for 18 weeks under these treatment regimens and were evaluated in terms of cardiovascular parameters and several quantitative and semiquantitative histopathologic indices that we developed to identify and compare cardiac muscle and vascular pathology/remodeling.


RESULTS
Administration of carvedilol had no effect on systolic blood pressure (range for all salt-fat diet groups 288 +/- 8 to 294 +/- 6 mmHg compared with the value for the normal diet group of 228 +/- 12 mmHg) whereas heart rate was slightly reduced (by 10-18%; P<0.05). Administration of carvedilol produced a significant (P<0.01) dose-related decrease in total cardiac histologic damage (i.e. the sum of several histopathologic indices) induced by the salt-fat diet (i.e. it reduced damage by 54 and 82% at low and high doses, respectively). Specifically, administration of carvedilol produced dose-dependent reductions in histopathologic indices of coronary artery hypertrophy (by up to 88%), hyperplasia (by up to 89%), degeneration of myofiber (by up to 91%), myocardial inflammation (by up to 100%), cardiac fibrosis (by up to 67%), arterial microthrombosis (by up to 95%), and myocardial microinfarction (by up to 100%; all P<0.01). Salt-fat diet induced an increase in total cardiac mass and left ventricle-intraventricular septum cross-sectional area that was completely eliminated by administration of carvedilol (P<0.01).


CONCLUSIONS
These data indicate that carvedilol provides remarkable cardioprotection, by suppressing severe hypertension-induced cardiac remodeling and myopathies at doses that do not reduce systemic blood pressure.
Barone
F C
FC
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. Frank_C_Barone@SBPHRD.Com
Campbell
W G
WG
Nelson
A H
AH
Feuerstein
G Z
GZ
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D002227:Carbazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000077261:Carvedilol; D004032:Diet; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D011412:Propanolamines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D016896:Treatment Outcome
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol