Survival benefits of different antiadrenergic interventions in pressure overload left ventricular hypertrophy/failure.
We observed previously that in rats with aortic banding (Bd), development of left ventricular (LV) hypertrophy is opposed by beta-blockade, whereas interventions interfering with alpha-adrenoceptor function also inhibit interstitial fibrosis. To assess whether these differential structural effects do translate into different effects on LV function and on heart failure mortality, Bd or sham Bd 8-week-old rats were randomized to vehicle treatment (Vh), chemical sympathectomy ([Sx] 6-hydroxydopamine, 150 mg/kg IP twice a week), beta-adrenoceptor blockade (propranolol [Pro], 40 mg/kg per day PO), or alpha-adrenoceptor blockade (doxazosin [Dox], 5 mg/kg per day PO). After monitoring survival for 10 weeks, the survivors were anesthetized to undergo echocardiography and intraarterial blood pressure measurement. Bd-Vh rats showed increased LV and lung weights, as well as LV dilation, depressed endocardial and midwall fractional shortening and a restrictive transmitral diastolic flow velocity pattern. Compared with Bd-Vh rats, all of the actively treated Bd rats showed less LV hypertrophy, LV dilation, and lung congestion but no less depression of midwall fractional shortening. In contrast, Sx and Dox but not Pro treatment were also associated with lesser degrees of diastolic dysfunction and, even more importantly, with a striking increase in survival (sham banded rats, 100%; Bd-Vh, 40%; Bd-Pro, 51%; Bd-Sx, 83%; and Bd-Dox, 82%). Although Pro, Sx, and Dox provide similar midterm protection from development of LV hypertrophy and dysfunction and from circulatory congestion, only Sx and Dox favorably affected mortality. These findings indicate that in the aortic banding rat model, alpha-adrenoceptors are importantly involved in the pathogenesis of cardiovascular deterioration and disease progression.
Perlini
Stefano
S
Clinica Medica II, IRCCS San Matteo, Università di Pavia, Pavia, Italy.
Ferrero
Ivana
I
Palladini
Giuseppina
G
Tozzi
Rossana
R
Gatti
Chiara
C
Vezzoli
Monia
M
Cesana
Francesca
F
Janetti
Maria Bianchi
MB
Clari
Francesca
F
Busca
Giuseppe
G
Mancia
Giuseppe
G
Ferrari
Alberto U
AU
D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use*; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery; D001794:Blood Pressure; D017292:Doxazosin / Q000627:therapeutic use; D006333:Heart Failure / Q000188:drug therapy / Q000628:therapy; D006339:Heart Rate; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000628:therapy; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D016627:Oxidopamine; D011433:Propranolol / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013563:Sympathectomy, Chemical
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D016627:Oxidopamine; D011433:Propranolol; D017292:Doxazosin