Surgical trauma stress has been reported to induce immunosuppression. The mechanisms involved are still unclear. The present study was designed to assess the role of the sympathetic nervous system in regulating splenocyte apoptosis induced by surgical trauma stress. Our results showed that the rats that underwent surgical trauma stress exhibited a significant reduction in splenic cellularity, the loss of splenocytes was likely mediated by apoptosis, for a substantial increase in apoptosis was observed by using DNA gel electrophoresis and TUNEL assay. At the same time, an increase in Fas(CD95/Apo-1) protein expression in splenocytes was also observed. These effects were significantly abolished by either chemical sympathectomy or beta-adrenergic receptor antagonist propranolol. The data clearly revealed that the sympathetic nervous system especially beta-adrenergic receptors was involved in surgical trauma-induced immune alterations via a mechanism of apoptotic cell death.

Apomorphine (Apo), a dopaminergic agonist used for treatment of Parkinson disease, is a potent antioxidant. In addition to its antioxidative effects, the dopaminergic and adrenergic effects of Apo were studied. Isolated perfused rat hearts were exposed to 25 min of no-flow global ischemia (37 degrees C) and 60 min of reperfusion (I/R, control). Drugs were introduced for the first 20 min of reperfusion. The LVDP of the control group recovered to 54.6 +/- 3.3%. Apo-treated hearts had significantly improved recovery (61.6 +/- 5%, p < 0.05). The recovery of the work index LVDP x HR was even bigger: 67.8 +/- 3.7% (Apo treatment) vs 41.7 +/- 4.6% (control, p < 0.001). Haloperidol, a dopaminergic antagonist, did not affect the recovery with Apo. Propranolol, a beta-adrenergic blocker, initially inhibited the effect of Apo. However, the recovery of the combined group (Apo + propranolol) increased and reached significance (LVDP, p < 0.05 vs control group) after cessation of propranolol perfusion. At 60 min of reperfusion this group was superior to Apo-treated hearts (LVDP, p < 0.05). Propranolol (without Apo) did not improve the hemodynamic recovery. The same pattern of recovery applies also to the recovery of the +dP/dt during the reperfusion. L-DOPA was less effective than Apo. I/R caused significant increase in carbonylation of proteins. Apomorphine inhibited the increase in carbonylation. Haloperidol did not affect this beneficial effect of Apo. L-DOPA significantly decreased the carbonylation of proteins. We conclude that the antioxidative effect of Apo is its main mechanism of cardioprotection.

To clarify the role of neural factors in the regulation of apolipoprotein (apo) A-IV expression in the small intestine, we investigated the effect of neural blockers on mRNA levels of apo A-IV in rat small intestine. Either ganglionic blocker (hexamethonium), cholinergic blocker (atropine) or beta-adrenergic blocker (propranolol) was infused intravenously to unrestrained conscious rats for 8 h, and then total RNA was isolated from the small intestine and analyzed using Northern hybridization. Apo A-IV mRNA levels in the ileum were significantly lower in hexamethonium- or atropine-infused rats than in saline- (control) or propranolol-infused rats. Immunoblot analysis showed no difference in plasma apo A-IV concentrations between hexamethonium- and saline-infused groups. The lower mRNA levels of apo A-IV in the ileum of hexamethonium-infused rats were observed even in bile-drained rats, indicating that the lower expression was not due to any changes in bile availability. The ileal apo A-IV mRNA levels were significantly higher in rats infused with lipid emulsion into the ileum than in rats infused with glucose-saline, and the concomitant infusion of intravenous hexamethonium did not affect the higher levels of apo A-IV mRNA. These results suggest that the basal expression of the ileal A-IV gene is at least partially regulated in a site-specific manner by cholinergic neurons.

Computer simulations were performed on models of the beta2-adrenergic receptor dimer, including 5,6-domain swapped dimers which have been proposed as the active, high affinity form (here the dimer interface lies between helices 5 and 6). The calculations suggest that the domain swapped dimer is a high energy structure in both the apo dimer and in the presence of propranolol. In the presence of agonist the energy of the domain swapped dimer is significantly lowered. Analysis of the dimer structure suggests that the agonist-induced conformational change optimizes the helix-helix interactions at the 5-6 interface. An antagonist on the other hand has little effect on these interactions. These observations are consistent with the hypothesis that the agonist functions by shifting the equilibrium in favour of the domain swapped dimer. Indirect support for the domain swapping hypothesis was obtained from the correlated mutations amongst the external residues of the known beta2-adrenergic receptors. These occur mainly at the 5-6 interface at precisely the locations predicted by the simulations; site-directed mutagenesis data in support of a functional role for these lipid-facing correlated residues is presented. The article includes a review of the experimental evidence for G-protein coupled receptor dimerization. Many other aspects of G-protein coupled receptor activation are discussed in terms of this domain swapping hypothesis

The negative correlation between coronary heart disease and plasma levels of HDL has been attributed to the ability of HDL to take up cellular cholesterol. The HDL3-induced removal of cellular cholesterol was reported to be impaired in fibroblasts from patients with familial HDL deficiency (Tangier disease, TD). In addition, we have recently shown that HDL3 stimulates the hydrolysis of phosphatidylcholine (PC) in cholesterol-loaded fibroblasts. To investigate whether this cell signaling pathway is involved in cholesterol efflux mechanisms, we compared the HDL3-induced PC hydrolysis in normal fibroblasts and in fibroblasts from a TD kindred, in whom the HDL3- and apolipoprotein A-I (apo A-I)-induced mobilization of cellular cholesterol was found to be reduced by 50%. The HDL3-induced formation of phosphatidic acid (PA) via PC-specific phospholipase D (PC-PLD) was markedly reduced by 60-80% in these cells, whereas the formation of diacylglycerol (DG) via PC-specific phospholipase C (PC-PLC) was two- to threefold enhanced. Defective regulation of PC-PLC and PC-PLD was similarly observed in response to apo A-I and endothelin, but not in response to the receptor-independent stimulation of PC hydrolysis by PMA. A Tangier-like PA and DG formation pattern could be induced in normal cells after preincubation with pertussis toxin, suggesting the involvement of a G-protein. The impaired mobilization of radiolabeled cellular cholesterol in TD cells could completely be overcome by increasing the PA levels in the presence of the PA phosphohydrolase inhibitor propranolol. Conversely, the inhibition of PA formation in the presence of 0.3% butanol as well as the inhibition of DG formation in the presence of the PC-PLC inhibitor D 609 reduced the mobilization of cellular cholesterol both in normal and in TD cells. Our data indicate that the coordinate formation of PA and DG via PC-PLD and PC-PLC is essential for efficient cholesterol efflux. The molecular defect in this TD kindred appears to affect an upstream effector of protein kinase C responsible for the G-protein-dependent regulation of PC-specific phospholipases.

Native LDL and LDL oxidized under various conditions were compared in terms of their ability to activate platelets. Native LDL did not induce platelet shape change or aggregation, even at high concentrations (2 mg protein/mL). LDL was mildly oxidized with either CuSO4 (mox-LDL) or 3-(N-morpholino)sydnonimine (SIN-1-LDL). Analysis of mox-LDL and SIN-1-LDL showed a small increase of dienes (E234nm from 0.28 +/- 0.04 to 0.55 +/- 0.09, mean +/- SD) and thiobarbituric acid-reactive substance (from 0 to 10.6 +/- 1.5 nmol/mg, mean +/- SEM), no change in apo B electrophoretic mobility, and a minor (12% to 30%) decrease in polyunsaturated fatty acid content. Interestingly, this small oxidative modification of LDL dramatically changed its effect on platelets. Irreversible aggregation and secretion were induced by a threshold concentration of 0.4 mg protein/mL. In contrast, LDL thoroughly oxidized with CuSO4 (ox-LDL) did not aggregate platelets. Although mox-LDL was depleted in antioxidants (alpha- and gamma-tocopherol, alpha- and beta-carotene, and other carotenoids), incubation of mox-LDL with exogenous alpha-tocopherol did not reverse its ability to induce platelet aggregation and secretion. Preincubation of platelets with the cyclooxygenase inhibitor aspirin or the phospholipase A2 inhibitors trifluoperazine, quinacrine, 4-bromophenacyl bromide, and propranolol completely prevented platelet aggregation and secretion caused by mox-LDL or SIN-1-LDL. These results indicate that mildly oxidized LDL activates platelets through a phospholipase A2/cyclooxygenase-dependent pathway. The complete inhibition of mox-LDL-induced platelet aggregation by aspirin could contribute to its beneficial effect in cardiovascular disease.

To study the influence of thyroid hormone on Lp(a) plasma concentration we measured Lp(a), total cholesterol, LDL-C, HDL-C, triglycerides and fT4 levels and determined apo(a) phenotypes in 26 patients with hyperthyroidism in a follow-up study before and after thyreostatic treatment. The pretreatment values of total cholesterol (TC), LDL-C, and Lp(a) were significantly reduced as compared with those of healthy controls. The reduced mean Lp(a) concentrations could not be explained by a difference of apo(a) 'size allele' frequencies between patients and controls. During thyreostatic treatment mean concentrations of TC, LDL-C, and HDL-C increased significantly. The mean Lp(a) value was not changed after 4 weeks of treatment. The individual changes of Lp(a), however, correlated significantly with those of LDL-C levels (R = 0.40, P = 0.04). Eighty-one per cent of the patients showed an increase of Lp(a) or no change of the Lp(a) level and 19% reacted with a decrease upon thyreostatic treatment. The observed lipid and lipoprotein changes were not different in patients with Graves disease or multifocal toxic goiter. The results indicate that Lp(a) plasma levels are decreased in the hyperthyroid state irrespective of the pathogenic mechanism.

The interactions of serotonin 5-HT1A, 5-HT1C/2 and 5-HT3 receptor subtypes with apomorphine-induced locomotor activity (AILA) were investigated in Sprague-Dawley rats. The 5-HT3 antagonists ondansetron and ICS 205-930 had no significant effects on AILA. The 5-HT1A agonist 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) produced an increase in locomotor activity that was independent of DA neurotransmission. The locomotor activity induced by co-administration of apomorphine (APO; 0.25 mg/kg) and 8-OH-DPAT (0.25-1.0 mg/kg) was not significantly higher than those induced by APO alone during the peak period of APO stimulation of locomotor activity, nor were they higher than activity induced by 8-OH-DPAT alone during the same time intervals. The 5-HT1 antagonist (1)-propranolol had a depressant effect on AILA, but only at high doses. Coadministration of (1)-propranolol (5 mg/kg) and 8-OH-DPAT (1.0 mg/kg) elevated spontaneous locomotor activity for the first 10 min of the session when compared to 8-OH-DPAT (1.0 mg/kg) alone. The 5-HT2 antagonist ketanserin along with moderate and high doses of mesulergine depressed AILA, effects which may be mediated by the 5-HT2 antagonist properties of these drugs, by nonspecific sedation or by direct effects of these compounds on DA D2 receptors. In contrast to the high-dose mesulergine depression of AILA, a low dose (0.1 mg/kg) of mesulergine elevated AILA, an effect which was blocked by the 5-HT1C/2 agonist 1-(2,-5-dimethoxy-4-iodophenyl) -2-aminopropane (DOI; 1 mg/kg). Neither of these compounds at the doses tested had significant effects on spontaneous locomotor activity.(ABSTRACT TRUNCATED AT 250 WORDS)

To evaluate the differential effects of beta-blockers on serum lipids and apolipoproteins in normolipidaemic and dyslipidaemic hypertensives, 330 patients with mild to moderate essential hypertension were studied 1 month after placebo therapy and 6 months after monotherapy with propranolol (n = 53), atenolol (n = 66), metoprolol (n = 58), pindolol (n = 53), or celiprolol (n = 100). Serum total cholesterol, triglycerides, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), and apolipoproteins (Apo) A1 and B were measured at baseline and study end. A total of 136 (41.2%) patients were considered normolipidaemic (pretreatment LDL-C < 160 mg.dl-1) and 194 (58.8%) were considered dyslipidaemic (LDL-C > 160 mg.dl-1). Changes in total cholesterol differed between normolipidaemics and dyslipidaemics with propranolol (+13% in normolipidaemics vs -0.5% in dyslipidaemics, P < 0.001), atenolol (+7% vs -2%, P = 0.01), metoprolol (+9% vs -4%, P0.0006), pindolol (+8% vs -9%, P < 0.001), and celiprolol (-1% vs -13%, P = 0.002). HDL-C differed less, with propranolol (-18% vs -13%), atenolol (-6% vs -2%), metoprolol (-2% vs -6%), pindolol (+4% vs +1%), and celiprolol (+9% vs +4%); none of these changes between normolipidaemic and dyslipidaemic patients were statistically significant. LDL-C changes differed the most, with propranolol (+35% vs -1%, P < 0.0001), atenolol (+15% vs -4%, P = 0.001), metoprolol (+12% vs -6%, P = 0.004), pindolol (+12% vs -13%, P < 0.0001), and celiprolol (+3% vs -16%, P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

REM sleep deprivation (REMSD) results in behavioral changes such as the appearance of affective aggression induced by apomorphine (APO) and other dopaminergic agents. REMSD modifies dopamine-mediated behavior as well as the adrenergic receptor sensitivity. This paper evaluates the interaction between these two neurotransmission systems through changes in APO-, DL-DOPA- and fusaric acid (FA)-induced aggressive behavior in REMSD rats pretreated with phentolamine, propranolol, metaraminol, prazosin, clonidine, yohimbine, isoproterenol, butoxamine and maprotiline. Only isoproterenol reduced FA-induced aggressiveness. No specific changes in aggressiveness were noticed with other treatments and not even inhibitors of norepinephrine transmission induced aggressive behavior. It is concluded that norepinephrine had a slight inhibitory action on aggressiveness elicited by dopaminomimetic agents in REMSD rats. Beta-adrenoceptors could be responsible for this effect since only beta-selective drugs reduced aggression. As REMSD reduces beta-adrenoceptor sensitivity, only minor changes in aggressiveness could be observed. It was noted that the three drugs used to induce aggressive behavior elicited different patterns of aggression.

Dopaminergic agonist apomorphine (Apo, 1-100 mumol.L-1) had a concentration-dependent positive inotropic effect on guinea pig left atria. This effect was not changed obviously when the influences of sympathetic and parasympathetic nerves were eliminated by reserpine and atropine, respectively. Apo had little inotropic action on guinea pig papillary muscles. The time course of positive inotropic effect of Apo was different from that of isoprenaline and phenylephrine. Apo influenced the isometric contraction curves in a different way from isoprenaline. Dopaminergic antagonist haloperidol antagonized the positive inotropic effect of Apo. This effect was also competitively antagonized by dopamine DA1 antagonist SCH 23390. While dopamine DA2 antagonist domperidone, beta-adrenergic antagonist propranolol and alpha-adrenergic antagonist phentolamine did not obviously influence the effect of Apo. We concluded that the positive inotropic effect of Apo was mediated by postsynaptic dopamine DA1 receptors in guinea pig left atria.

The authors studied the effect of anaprilin monotherapy (dose: 160-200 mg/daily for 10 months) on the level of atherogenic apolipoproteins (apo A, apo B) and fractions of plasma cholesterol in 34 patients with ischemic heart disease, stable exertion angina pectoris (class 2-3). It was established that changes in the plasma lipid and apoprotein spectrum result in an increase of apo B, decrease of apo 1, increase of apo B/apo A1, decrease of high-density lipoprotein cholesterol (HDLCS) and a different dynamics of HDLCS/apo A1. The established changes in the lipid metabolism are of atherogenic character.

In conscious renal artery-ligated rats, a high renin hypertensive rat model, DuP 753, a p.o. active nonpeptide angiotensin II (AII) receptor antagonist, decreased blood pressure at 0.1 to 3 mg/kg given i.v. or at 0.3 to 10 mg/kg given p.o. with an i.v. ED30 of given i.v. or at 0.3 to 10 mg/kg given p.o. with an i.v. ED30 of 0.78 mg/kg and a p.o. ED30 of 0.59 mg/kg. The antihypertensive efficacy of DuP 753 was similar to that of captopril. Unlike the peptide AII antagonist saralasin, DuP 753 did not cause a transient increase in blood pressure, suggesting absence of agonistic activity. At 3 mg/kg p.o., DuP 753 lowered blood pressure for at least 24 hr and did not change heart rate, suggesting a long duration of antihypertensive effect. At 3 mg/kg i.v., DuP 753 inhibited the pressor response to AII but not to norepinephrine or vasopressin. Pretreatment of renal artery-ligated rats with captopril, saralasin or propranolol, but not with prazosin, hydralazine or indomethacin, abolished or reduced the antihypertensive effect of DuP 753. In the deoxycorticosterone acetate hypertensive rat, a low renin model, DuP 753 did not lower blood pressure. These results suggest that DuP 753 is a p.o. active, antihypertensive agent in renal artery-ligated rats with a similar antihypertensive efficacy as captopril. The antihypertensive effect of DuP 753 is most likely related to the blockade of the vasoconstrictor effect of AII. Unlike saralasin, DuP 753 does not have agonistic activity.

The effects of bunazosin and propranolol administration on hypertension and serum levels of lipids, lipoproteins and apolipoproteins were studied in a controlled, randomized multicenter study. After a 4-week washout period, 48 patients with mild to moderate essential hypertension were randomly assigned to either the bunazosin or the propranolol group. Twenty-four were treated with bunazosin (1 to 3 mg t.i.d.) and 24 with propranolol (10 to 40 mg t.i.d.) for 12 weeks. Systolic and diastolic blood pressures decreased significantly in both groups. After 12 weeks of bunazosin treatment, significantly lowered apolipoprotein (apo) B and apo B/apo A-I ratio (p less than 0.05, in both cases) were observed, in contrast to no changes in the propranolol group. Although the changes were not significant, bunazosin tended to decrease the ratio of total cholesterol minus HDL cholesterol to HDL cholesterol. There were no significant changes in total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apo A-I, apo A-II, apo C-II, apo C-III and apo E for either bunazosin or propranolol. The difference between the two drugs was significant for the apo B/apo A-I ratio (p less than 0.05). Bunazosin monotherapy was shown to be as effective in reducing blood pressure as propranolol. In addition, its favorable effects on lipoprotein metabolism seem to offer an additional advantage in mitigating coronary risk.