To test the desensitization hypothesis of cardiac beta-adrenergic receptors (beta-AR) in chronic hypoxia, the effect of 1, 3, 7, 15, and 21 days of exposure to hypobaric hypoxia (380 Torr) was evaluated in Wistar rats. Exposure to hypoxia for 1-15 days did not induce any change in right and left ventricular beta-AR density (Bmax) determined with [125I]iodocyanopindolol or in antagonist affinity. After 21 days, Bmax decreased by 24% in the left ventricle. In contrast, no change in beta-AR was shown in the right hypertrophied ventricle. Agonist affinity in the left ventricle was not altered, as shown by the analysis of displacement curves of isoproterenol (normoxia 185 +/- 26 nM, hypoxia 170 +/- 11 nM). Moreover, there was no significant decrease in adenylate cyclase activity (pmol.mg-1.min-1) in the left ventricle. In the right ventricle, a 21-day exposure to hypoxia led to a decrease in basal and maximal activity when stimulated by isoproterenol. A decrease in tissue norepinephrine content was observed after 7 days of hypoxia. In conclusion, these data support the beta-AR downregulation hypothesis as one of the mechanisms of myocardial adaptation to high altitude occurring after 2-3 wk of exposure to hypoxia. The regulation pathways of beta-AR may differ between left nonhypertrophied and right hypertrophied ventricles. No evidence of profound abnormality of signal transduction was shown.

Few models of heart failure (HF) are available for physiological and pharmacological studies. We report here a model of pressure plus volume overload induced in rabbits in which left ventricular (LV) function was studied in the conscious state after instrumentation of the animals with LV pressure catheter and ultrasonic crystals measuring LV diameter. Beta-Adrenoceptors were studied on crude membranes obtained from control (C) and HF rabbits using [3H]CGP 12177. LV weights and end-diastolic diameters were significantly increased in the HF group compared with the C group (by 79 and 38%, respectively). The percentage of diameter systolic shortening was decreased, in the control state, in rabbits with HF (15.3 +/- 1.6%) as compared with C rabbits (29.6 +/- 2.5%) and remained lower in the HF group when end-systolic pressures were matched. Chronotropic response to isoproterenol injection was significantly decreased in rabbits with HF compared with that of C rabbits. Beta-Adrenergic receptor density was decreased in rabbits with HF (39.3 +/- 3.7 fmol/mg) compared with C rabbits (56.7 +/- 4.2 fmol/mg) without affinity changes. This model of chronic HF thus produces a marked hypertrophy with ventricular dilatation and a depression of LV function within 2 mo, factors that are associated with a reduced cardiac responsiveness to catecholamines and a decreased ventricular beta-adrenergic receptor density.

The coupling between myocardial beta-adrenergic receptors, adenylate cyclase activity, and the in vivo cardiac response to catecholamines is controversial in hyperthyroidism. The possibility of species differences in beta-adrenoceptor regulation after thyroxine treatment was studied in dogs and in rats. In dogs instrumented with a left ventricular (LV) pressure micromanometer, hyperthyroidism was induced by L-thyroxine (0.5 mg/kg/day i.v. for 10 days). After hyperthyroidism, heart rate was increased to 167 +/- 10 beats/min (control, 107 +/- 8 beats/min; p less than 0.005) with an increase of peak LV dP/dt from 4,243 +/- 471 to 6,105 +/- 862 mm Hg/sec (p less than 0.01). LV response to injection of increasing doses of isoproterenol and dobutamine was not significantly different before and after induction of the hyperthyroid state, as shown by the unchanged slopes of the LV peak dP/dt versus the log of the dose of isoproterenol and dobutamine. Bmax of beta-receptors measured in crude membranes using 3H-CGP 12177 and in homogenates using 125I-cyanopindolol was not increased in hyperthyroid animals as compared with a control group. Basal adenylate cyclase activity was not different in control and hyperthyroid dogs (32 +/- 3 versus 29 +/- 3 pmol/mg/min), and maximal adenylate cyclase activity response to isoproterenol was similar in control and hyperthyroid dogs. In contrast, in rats subjected to hyperthyroidism (0.5 mg/kg/day i.p. L-thyroxine for 10 days), Bmax of adrenoceptors measured using the same methods was significantly increased as compared with control (+72.5% using 3H-CGP 12177 and +41% using 125I-cyanopindolol, but adenylate cyclase activity was not increased in hyperthyroid rats. We conclude that both adenylate cyclase activity and LV response to catecholamines are not increased by thyroxine-induced hyperthyroidism in dogs and that, in contrast with rats, beta-adrenergic density is not increased in hyperthyroid dogs. This indicates a species difference in myocardial beta-adrenoceptor regulation in response to hyperthyroidism.