Cardiovascular effects of beta 3-adrenoceptor stimulation in perinephritic hypertension.
BACKGROUND
A new beta 3-adrenoceptor (beta3-AR) has been shown to mediate peripheral vasodilation. This study was conducted to evaluate effects of the beta3-AR agonist, SR58611 in normal and hypertensive dogs.


METHODS
In protocol 1, SR58611 was infused in normal dogs after placebo, after beta1/beta2 blockade with nadolol, after beta1/beta2/beta3 blockade with bupranolol and after combined autonomic blockade (CAB). In protocol 2, perinephritic hypertension was produced in dogs, which received SR58611 at 3 and 6 weeks of hypertension. Effects of SR58611 were evaluated at 7 weeks of hypertension after CAB.


RESULTS
In normal dogs, SR58611 produced a dose-dependent decrease in mean aortic pressure (AOP) (from 116 +/- 19 to 100 +/- 19 mmHg, - 14%; P < 0.05) that was accompanied by baroreflex activation (heart rate increased by 70%; P < 0.01). This hypotensive effect resulting from peripheral vasodilation persisted after nadolol or CAB while baroreflex activation was blunted or abolished. A biphasic response of cardiac output, characterized by a rise and a decline (P < 0.05) reflected a reduction in after- and pre-load. After CAB, SR58611 did not modify cardiac contractility. SR58611 stimulated lipolysis as reflected by a 4-fold increase in blood free fatty acids (FFA) (P < 0.0005). Under CAB, the rise of FFA was reduced (P < 0.01). In hypertensive dogs, SR58611 produced a dose-dependent decrease in mean AOP (from 168 +/- 32 to 125 +/- 35 mmHg; - 26%, P < 0.0001), that was greater than in normal dogs (P < 0.05). Reflex-mediated tachycardia also occurred but at higher blood pressure values. Blood FFA rose similarly (P < 0.0001). Under CAB, heart rate remained unchanged but SR58611 still induced a decrease (P < 0.0001) in mean AOP concomitantly with a rise of (dP/dt)/DP40 (P < 0.005), an effect not observed in normal dogs.


CONCLUSIONS
Beta3-AR stimulation exerts hypotensive effects, increases cardiac contractility and stimulates lipolysis in hypertensive dogs.
Donckier
J E
JE
Division of Internal Medicine and Endocrinology, University Hospital of Mont-Godinne, Yvoir, Belgium. Julian.Donckier@mint.ucl.ac.be
Massart
P E
PE
Van Mechelen
H
H
Heyndrickx
G R
GR
Gauthier
C
C
Balligand
J L
JL
D058667:Adrenergic beta-3 Receptor Agonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000502:physiology; D001286:Atropine Derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002046:Bupranolol / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D018738:Hexamethonium / Q000494:pharmacology; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000503:physiopathology; D008066:Lipolysis / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009248:Nadolol / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013997:Time Factors
D058667:Adrenergic beta-3 Receptor Agonists; D000319:Adrenergic beta-Antagonists; D001286:Atropine Derivatives; D011412:Propanolamines; D022702:Receptors, Adrenergic, beta-3; D013764:Tetrahydronaphthalenes; D018738:Hexamethonium; D009248:Nadolol; C006649:methylatropine; D002046:Bupranolol; C076252:amibegron; C033394:CGP 12177