The Regulation Of The Catecholamine-β-adrenoreceptor-cAMP System In Hypertension And Heart Failure

Objective: The purposes of this study were to comprehensively investigate the changes and significance of catecholamines-β- adrenoreceptor (β-AR) -cAMP system in patients with essential hypertension (EH) and congestive heart failure (CHF). Method: A total of 134 patients with EH underwent echocardiography. The normal morphology (n=26), concentric remodeling (n=41), concentric hypertrophy (n=28), and eccentric hypertrophy (n=39) were defined by the relative wall thickness at diastole (RWT) <0.44 and ≥0.44, respectively and left ventricular mass index (LVMI) <150g/m~2 and ≥150 g/m2, respectively. Forty healthy males were studied as normal controls. Plasma levels of norepinephrine (NE) and epinephrine (E) were measured by the high performance liquid chromatography. The density of lymphocytes B-AR (Bmax) and the content of intralymphocyte cAMP in peripheral blood were measured by ~3H-dihydroalpneolol as ligand and protein binding assay, respectively. And then, Br and B2-AR responsiveness in 134 EH patients with different LV geometric patterns were examined by treadmill exercise and Salbutamol test, respectively. A total of 601 identified EH patients with a baseline and follow-up (last examination 60+/-26 months apart) plasma levels of NE and E, the lymphocytes Bmax, and the content of intralymphocyte cAMP in peripheral blood were measured for an additional 24+/-12 months. One hundred and seven patients with CHF (New York Heart Association (NYHA) functional Class III-IV) entered, and their plasma levels of NE and E, the lymphocytes Bmax, and the content of intralymphocyte cAMP in peripheral blood were examined by the high performance liquid chromatography, 3H-dihydroalpneolol as ligand, and protein binding assay, respectively. And then, a baseline and follow-up (last examination 51+/-16 months apart) plasma levels of NE and E, lymphocytes Bmax, and intralymphocyte cAMP content in peripheral blood were measured for an additional 14+/-8 months in 83 CHF patients. Major cardiogenic death events were registered. Results: (1) Plasma levels ofNE and E in normal ventricular geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy groups were higher than those in control group;Bmax and the content of intralymphocyte cAMP in peripheral blood in normal ventricular geometry, concentric remodeling, and concentric hypertrophy groups were higher than those in control group, however, these in eccentric hypertrophy group were lower than those in control group. Among the 4 groups, plasma levels of NE and E were increasing in turn in normal morphology, concentric remodeling, concentric hypertrophy and eccentric hypertrophy groups;the density of lymphocytes B-AR and the content of intralymphocyte cAMP of peripheral blood in normal morphology, concentric remodeling, and concentric hypertrophy groups were increasing in turn, but in eccentric hypertrophy group was decreased in patients with EH. In addition, when some LV remodeling phenomena, ventricular hypertrophy and dilatation, haven't appeared in clinical, the density of lymphocytes B-AR and the content of intralymphocyte cAMP in peripheral blood have significantly increased such as normal morphology group (RWT and LVMI are normal);and when heart failure haven't appeared in clinical, the density of lymphocytes B-AR and the content of intralymphocyte cAMP in peripheral blood have significantly decreased, such as eccentric hypertrophy group (EF￡60%). (2) .Patients with EH in the group of concentric remodeling, concentric hypertrophy and eccentric hypertrophy, heart rate (HR) in response to the treadmill test (peak exercise-resting rate) was higher significantly (P<0.05, P<0.01, P<0.01, respectively) than that in the control group. In the group of concentric remodeling and concentric hypertrophy, the chronotropic doses of salbutamol required to increase the heart rate by 30 beats/min [chronotropic dose 30 (CD30)] were lower significantly (P<0.05, P<0.01, respectively) than that in the control group, however, in the group of eccentric hypertrophy CD30 was higher significantly (P<0.01) than that in the control group. (3) When stratifying the study population by NE, or E (median 4 nmol/L), Bmax (median 600fmol/107cell), and cAMP (median 5.0 pmol/mg.pro) above and below the median values in both parameters categories from baseline to follow-up, those above the median hadcomposite cardiovascular events end point (all P<0.001) and high cardiovascular death (p=0.0015, p=0.0027, p=0.0076, and p=0.0051, separately, by log-rank test). After the last follow-up, in Cox analyses adjusting for other standard factors as well as treatment effect, plasma levels of NE (hazard ratio [HR] 1.22, 95% confidence interval [Cl] 1.17-1.28, p=0.0008), or E (HR 1.53, 95% Cl 1.18 to 2.00, p=0.002), lymphocytes Bmax (HR 1.12, 95% Cl 1.06 to 1.17, p=0.007), and intralymphocyte cAMP levels (HR 1.15, 95% Cl 1.09 to 1.21, p=0.005) separately predicted cardiovascular mortality. Plasma levels of NE, or E, separately predicted the fatal/nonfatal myocardial infarction (NE, HR 1.25, 95% Cl 1.19-1.31, p=0.0001;E, HR 1.55, 95% Cl 1.16-2.06, p=0.003) and the fatal/nonfatal stroke (NE.HR 1.28, 95% Cl 1.21-1.36, p=0.002;E, HR 1.27, 95% Cl 1.19-1.36, p=0.004);Bmax, and cAMP levels predicted the fatal/nonfatal myocardial infarction (Bmax, HR 1.85.CI 1.53-2.22, P=0.002;cAMP, HR 1.76.CI 1.39-2.21, P=0.003), whereas, were not significant predictor of fatal/nonfatal stroke. (4) In patients with CHF, plasma level of NE and E were significantly increased compared with control group (P<0.001, P<0.01, respectively), and the Bmax and the content of cAMP in peripheral lymphocyte were significantly lower than in control group (all p<0.01). The levels of plasma E and NE increased according to the NYHA classification III to IV, both the pmax and content of cAMP deceased according to the NYHA classification III to IV. After the last follow-up, in Cox analyses adjusting for other standard factors as well as treatment effect, persistence NE >4.0nmol/L (HR: 2.91;95% Cl 1.08 to 7.33;p=0.015) . or E >3.5nmol/L (HR: 2.64;95% Cl 1.02 to 6.41;p=0.019), and the intralymphocyte cAMP>3.5 pmol/mg.pro (HR: 2.79;95% Cl 1.04 to 6.83;p=0.017) from baseline to follow-up were significant adverse prognostic predictors, but not lymphocytes Bmax. The cardiovascular mortality was significantly increased in patients with NE above 4.0nmol/L, or E above 3.5nmol/L, and intralymphocyte cAMP content above 3.5 pmol/mg.pro (p=0.0014, p=0.0017, p=0.0019, separately, by log-rank test). In cardiogenic deaths group plasma level of NE, or E, and intralymphocyte cAMP were significantly increased compared with survivalgroup. In sudden death group, plasma levels of NE and E were significantly increased compared with worsening heart failure group and survival group (all P<0.01). In worsening heart failure group intralymphocyte cAMP was significantly increased compared with sudden death group and survival group (all p<0.01). Bmax in peripheral lymphocyte had no significant difference (p>0.05) among the sudden death, worsening heart failure, and survival groups. Conclusion : (1) The catecholamine-P-adrenergic system was related to left ventricular remodeling of hypertension. In this process, the catecholamine was increasing continually. The density of (J-AR and the levels of cAMP in peripheral lymphocytes were increased at first and then decreased was shown. And, these changes of intracellular biochemical messages transduction system are earlier than the changes of the pathologic structural change of LV and of myocardial function. (2) In EH patients with difference LV geometric, pV AR responsiveness increase, whereas pV AR responsiveness increase at concentric remodeling and concentric hypertrophy, and decrease at eccentric hypertrophy. (3) Plasma levels of NE and E were significant predictor of cardiovascular mortality, fatal/nonfatal myocardial infarction, and fatal/nonfatal stroke. The lymphocytes Bmax and intralymphocyte cAMP levels in peripheral blood were significant predictor of cardiovascular mortality and fatal/nonfatal myocardial infarction, but not stroke. (4). The level of plasma NE and E increased, and both the 3 max and content of cAMP deceased in CHF patients. The persistent increase in circulating catecholamines and intralymphocyte cAMP content may increase long-term mortality in CHF patients, and high plasma catecholamine levels may be associated with sudden death, high intralymphocyte cAMP content may be associated with worsening heart failure in CHF patients.