Clonidine decreases stress response in patients undergoing carotid endarterectomy under regional anesthesia: a prospective, randomized, double-blinded, placebo-controlled study.

Inadequate analgesia or anxiety may induce an increased stress response in patients undergoing carotid endarterectomy (CEA) under regional anesthesia (RA). Central alpha2 adrenoceptor agonists have significant sedative and analgesic properties, which may attenuate sympathoadrenal activation during CEA and improve the quality of RA. We randomly assigned 80 patients to 2 groups receiving either RA plus placebo (n = 40) or RA plus clonidine 1 microg/kg as the initial loading dose followed by 1 microg.kg(-1).h(-1) (n = 40). RA was performed as combined deep and superficial cervical plexus blockade. Hemodynamic and neurological variables were assessed before, during, and after CEA. Arterial blood samples were collected at defined time points for the determination of plasma concentrations of epinephrine, norepinephrine, cortisol, and creatinine kinase and creatinine kinase-MB. Throughout the study, all patients responded easily to neurological evaluations. Before and during clamping mean arterial blood pressure and heart rate were not different between the groups, but mean arterial blood pressure was lower in the clonidine group (P < 0.01) at skin closure and postoperatively in the intensive care unit. In the placebo group, cortisol, epinephrine, and norepinephrine plasma concentrations were increased significantly (P < 0.05) and more patients required antihypertensive treatment (P < 0.01). Postoperatively the incidence of hypertension (P < 0.001) and development of neurological deficits (P < 0.05) was significantly decreased in the clonidine group. We conclude that 1 microg.kg(-1).h(-1) clonidine suppresses the hyperadrenergic response to CEA without adverse effects on hemodynamics or clinical neurological monitoring.

Thr164Ile polymorphism of the human beta2-adrenoceptor exhibits blunted desensitization of cardiac functional responses in vivo.

In subjects heterozygous for Thr164Ile beta2-adrenoceptor (beta2AR) polymorphism, cardiac responses to beta2AR agonist stimulation are blunted. In this study, we investigated agonist-induced desensitization of Thr164Ile beta2ARs. For this purpose, we assessed in six subjects with heterozygous Thr164Ile beta2ARs and in 10 subjects with homozygous wild-type (WT) beta2ARs the effects of 2-wk oral treatment with 3 x 5 mg/day terbutaline on terbutaline infusion-induced increases in heart rate (HR) and contractility [measured as shortening of HR-corrected duration of electromechanical systole (QS2c)]. Compared with WT beta2AR subjects, Thr164Ile subjects exhibited a blunted terbutaline-induced maximum increase in HR (WT 32 +/- 4 beats/min, Thr164Ile 19 +/- 3 beats/min, P < 0.05) and contractility (WT -54 +/- 2 ms, Thr164Ile -37 +/- 6 ms, P < 0.05). Two-week oral terbutaline treatment desensitized cardiac beta2AR responses to terbutaline infusion (increase in HR: WT 10 +/- 2 beats/min, Thr164Ile 8 +/- 4 beats/min; increase in contractility: WT -22 +/- 5 ms Thr164Ile: -17 +/- 6 ms); however, the extent of desensitization was larger in WT than Thr164Ile beta2AR subjects. Thus, after 2-wk oral terbutaline treatment cardiac, beta2AR responses did not differ anymore between WT and Thr164Ile beta2AR subjects. We conclude that agonist-induced desensitization of cardiac beta2ARs is more pronounced in WT than Thr164Ile subjects. Thus cardiac Thr164Ile subjects appear to be somewhat protected against agonist-induced desensitization.

Effects of atropine on human cardiac beta 1- and/or beta 2-adrenoceptor stimulation.

The aim of this study was to find out whether, in humans, the increase in vagal tone accompanying cardiac beta-adrenoceptor (beta-AR) stimulation might be different dependent on beta1- or beta2-AR stimulation. For this purpose we studied, in six male healthy volunteers (aged 28+/-1 years), the effects of atropine infusion (0.15 microg/kg/min continuously) on increase in heart rate (HR) and contractility (determined as shortening of HR-corrected duration of electromechanical systole-QS2c) evoked by infusion of isoprenaline (3.5-35 ng/kg/min, increasing HR and QS2c via beta1-and beta2-AR), terbutaline (25-150 ng/kg/min, increasing HR and QS2c via beta2-AR), adrenaline (20-160 ng/kg/min, increasing HR via beta2-and QS2c via beta1-AR) and bicycle exercise in supine position (increasing HR and QS2c via beta1-AR). The three beta-AR agonists and exercise increased HR and shortened QS2c in a dose- or work-load-dependent manner, respectively. Atropine enhanced HR-increasing effects of all three beta-AR agonists and exercise; increases were larger for beta2-AR (terbutaline, adrenaline) mediated effects than for beta1-AR (exercise) mediated effects. Moreover, atropine enhanced beta-AR agonists-induced QS2c shortening; however, atropine effects on QS2c were markedly less pronounced than on HR. From the results we conclude that, in humans, beta1-and beta2-AR mediated stimulation evoked HR-increases are composed of two components: increases via direct beta-AR stimulation and simultaneously decreases via increase in vagal tone. In addition, beta-AR mediated increases in contractility are also dampened by simultaneous activation of vagal tone but to a lesser extent possibly because human ventricular myocardium is only sparsely parasympathetically innervated.

The Gln27Glu beta2-adrenoceptor polymorphism slows the onset of desensitization of cardiac functional responses in vivo.

Studies performed have shown that the Arg16Gly allele in beta-adrenoceptors (beta2AR) enhances susceptibility to agonist-induced down-regulation, while the Gln27Glu polymorphism diminishes it. In this study, we tested whether similar phenotypes occur in vivo. We assessed 32 volunteers (mean age 25 +/- 2 years) with different genotypes (group A: wild-type beta2AR, n = 16; group B: homozygous Glu27, n = 10; group C: homozygous Gly16, n = 6) for the effect of 2 weeks treatment with 3 x 5 mg/day oral terbutaline on terbutaline infusion-induced increases in heart rate and contractility (i.e. shortening of heart rate-corrected duration of electromechanical systole, QS2c). At baseline, terbutaline infusion increased heart rate and contractility similarly among subjects in the three groups. Treatment with oral terbutaline for 14 days reduced the ability of intravenous (i.v.) terbutaline to increase heart rate and contractility. The extent of this reduction was similar but the time course of desensitization differed among the three groups. While in groups A and C terbutaline infusion-induced increases in heart rate and contractility were reduced within 24 h after oral ingestion of terbutaline, a significant effect on response to terbutaline infusion was not evident for the first 3 days of terbutaline treatment in group B. The Arg16Gly and the Gln27Glu variants of the beta2AR do not alter the extent of agonist-induced beta2AR desensitization in vivo but Glu27 homozygotes develop desensitization more slowly. This result may have implications for cardiac side-effects in patients who are Glu27 homozygotes and who receive beta2AR agonist therapy.