Amir Snapir

Electroencephalogram spindle activity during dexmedetomidine sedation and physiological sleep

Background: Dexmedetomidine, a selective α2‐adrenoceptor agonist, induces a unique, sleep‐like state of sedation. The objective of the present work was to study human electroencephalogram (EEG) sleep spindles during dexmedetomidine sedation and compare them with spindles during normal physiological sleep, to test the hypothesis that dexmedetomidine exerts its effects via normal sleep‐promoting pathways.

An insertion/deletion polymorphism in the α2b-adrenergic receptor gene is a novel genetic risk factor for acute coronary events

OBJECTIVES Our aim was to study whether an insertion/deletion (I/D) polymorphism in the a2Badrenoceptor gene is associated with the risk for cardiovascular diseases. BACKGROUND a2-adrenoceptors mediate contraction of vascular smooth muscle and induce coronary vasoconstriction in humans. The a2-adrenoceptor subtype B mediates vasoconstriction in mice. A variant of the human a2B-adrenoceptor gene that encode saDo fthree residues in an intracellular acidic motif has been shown to confer decreased receptor desensitization. This receptor variant could, therefore, be involved in diseases associated with enhanced vasoconstriction. METHODS This study was part of a prospective population-based study investigating risk factors for cardiovascular diseases in a cohort of middle-aged men from eastern Finland. Nine hundred twelve men aged 46 to 64 years were followed for an average time of 4.5 years. RESULTS In this study population, 192 men (21%) had the D/D genotype; 256 (28%) had the I/I genotype, and 464 (51%) had a heterozygous genotype. In a Cox model adjusting for other coronary risk factors, men with the D/D genotype had 2.2 times (95% confidence interval: 1.1 to 4.4, p 5 0.02) the risk to experience an acute coronary event (n 5 15 for D/D, 10 for I/I and 12 for I/D) compared with men carrying either of the other two genotypes. The a2B-adrenoceptor genotype was not associated with hypertension in this study population. CONCLUSIONS The D/D genotype of the a2B-adrenoceptor is a novel genetic risk factor for acute coronary events, but not for hypertension. (J Am Coll Cardiol 2001;37:1516 ‐22)

Variation in the alpha2B-adrenoceptorgene as a risk factor for prehospitalfatal myocardial infarction and sudden cardiac death

Abstract Objectives Our aim was to corroborate the observed association between the deletion/deletion (DD) genotype of the insertion/deletion polymorphism in the alpha 2B -adrenoceptor (AR) and increased risk for acute myocardial infarction (AMI), and to study whether this genotype also confers an increased risk for sudden cardiac death (SCD). Background Vasospasm has been suggested to play a role in AMI. Alpha 2 -AR mediate coronary vasoconstriction in humans, and studies on mice suggest the involvement of the alpha 2 -AR subtype B in vasoconstriction. A deletion variant of the human alpha 2B -AR has been associated with impaired receptor desensitization in vitro. In a population-based prospective study of 912 middle-aged men, the DD genotype of the alpha 2B -AR conferred an increased risk for AMI. Methods A series of 700 unselected sudden out-of-hospital deaths of middle-aged white men subjected to medico-legal autopsy was analyzed. Results Genotype information was obtained for 683 men (DD = 22%, insertion/deletion = 51%, insertion/insertion = 27%). Carriers of the DD genotype had an increased risk for SCD (n = 278, odds ratio [OR] = 2.0, p = 0.01) and fatal AMI (n = 84, OR = 2.1, p = 0.04) compared with the other two genotypes combined. The risks for SCD and fatal AMI were higher in carriers of the DD genotype who died before the age of 55 years (OR = 4.5 and 5.0, p Conclusions Middle-aged white men carrying the DD genotype of the alpha 2B -AR have a significantly increased risk for SCD and AMI, especially before the age of 55 years.

Effects of Low and High Plasma Concentrations of Dexmedetomidine on Myocardial Perfusion and Cardiac Function in Healthy Male Subjects

Background:Dexmedetomidine, a selective &agr;2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating &agr;2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic &agr;2 adrenoceptors in blood vessels. The goal of this study was to determine the effects of therapeutic and high concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy subjects. Methods:The authors studied 12 healthy young men. Myocardial blood flow (assessed with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data were collected before and during low (measured mean plasma concentration, 0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine. Results:The low concentration of dexmedetomidine reduced myocardial perfusion (mean difference, −27% from baseline [95% confidence interval, −31 to −23%], P < 0.001) in parallel with a reduction in myocardial oxygen demand (estimated by the rate–pressure product (−23% [−28 to −18%], P < 0.001). The high dexmedetomidine plasma concentration did not further attenuate myocardial perfusion (−3% [−12 to +6%] from low dexmedetomidine, P > 0.05; −29% [−39 to −18%] from baseline, P < 0.001) or statistically significantly affect the rate–pressure product (+5% [0 to +10%], P > 0.05). Systolic myocardial function was attenuated by sympatholysis during the low infusion rate and was further attenuated by a combination of the sustained sympatholysis and increased afterload during the high infusion rate. Conclusions:In healthy subjects, plasma concentrations of dexmedetomidine that significantly exceed the recommended therapeutic level do not seriously attenuate myocardial perfusion below the level that is observed with usual therapeutic concentrations and do not induce evident myocardial ischemia.

Effects of common polymorphisms in the α1A-, α2B-, β1- and β2-adrenoreceptors on haemodynamic responses to adrenaline

Common naturally occurring polymorphisms have been identified in the coding regions of the alpha(1A)-, alpha(2B)-, beta(1)- and beta(2)-adrenoceptor (AR) genes [alpha(1A)-AR R492C, alpha(2B)-AR insertion/deletion (I/D), beta(1)-AR R389G, beta(2)-AR G16R and beta(2)-AR Q27E] and are associated with modified in vivo and in vitro functionality. We tested their possible effects on the haemodynamic responses to intravenous adrenaline (20, 40, 80 and 160 ng/kg of body weight per min; 5 min for each infusion rate) before and after beta-blockade (propranolol) in 16 young healthy men. We monitored changes in heart rate, blood pressure (BP), ECG, coronary flow velocity and plasma adrenaline and noradrenaline. The Cys/Cys (CC) genotype of the alpha(1A)-AR R492C polymorphism was associated with a longer ECG PR interval before and during the adrenaline infusions. The deletion/deletion (D/D) genotype of the alpha(2B)-AR I/D polymorphism was associated with blunted coronary blood flow increases during the adrenaline infusion before beta-blockade. The beta(1)-AR R389G polymorphism was not associated with modified responses to infused adrenaline. Subjects carrying the Gly/Gly (GG) genotype of the beta(2)-AR G16R polymorphism demonstrated increases in diastolic BP upon adrenaline infusion, whereas diastolic BP was decreased in the other genotype groups. These results suggest that, upon acute adrenaline infusion, the alpha(2B)-AR D/D genotype confers increased vasoconstriction and that the beta(2)-AR GG genotype confers reduced vasodilatation.

G-protein beta3 subunit C825T polymorphism: no association with risk for hypertension and obesity.

OBJECTIVE Several recent studies have indicated that a C825T polymorphism in the gene encoding the G-protein beta3 subunit is a significant risk factor for hypertension and obesity. In this study, we tested whether this polymorphism is associated with hypertension and obesity in white men. DESIGN Population-based prospective cohort study. METHODS We followed a cohort of 903 men, aged 42-61 years at baseline, for an average time of 4.2 years. Genotyping was performed by polymerase chain reaction. RESULTS The genotype distribution was in Hardy-Weinberg equilibrium: 514 (57%) had the CC genotype, 49 (5%) had the TT genotype and 340 (38%) were heterozygous (T:C = 0.24:0.76). There was no statistically significant difference between the genotype groups in respect to baseline and end of follow-up risk for hypertension or obesity, systolic or diastolic blood pressure, or body mass index. CONCLUSION We conclude that the C825T polymorphism of the G-protein beta3 subunit gene does not notably contribute to the development of hypertension or obesity, and is not a significant determinant for blood pressure and body mass index in white men.

Effects of nitric oxide synthase inhibition on dexmedetomidine-induced vasoconstriction in healthy human volunteers

BACKGROUND This study aimed to assess the contribution of endothelial nitric oxide synthesis to the net responses of human peripheral blood vessels in vivo to the selective alpha(2)-adrenoceptor agonist dexmedetomidine. METHODS Two groups of healthy young men were studied. In the first experiment, after brachial plexus block, the responses of digital arteries to systemically administered dexmedetomidine (target plasma concentration 1.2 ng ml(-1)) were studied using a photoplethysmograph (n=10) during i.a. infusions of saline and the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA) (8 micromol min(-1)). In a separate experiment, after pre-treatment with acetylsalicylic acid, responses to increasing doses of dexmedetomidine (0.01-164 ng min(-1)) in the presence and absence of L-NMMA were compared in dorsal hand veins (DHV) (n=10) using linear variable differential transformers. RESULTS L-NMMA significantly augmented dexmedetomidine-induced vasoconstriction of digital arteries as assessed by an increase in light transmission through a finger and by a decrease in finger temperature. The mean (95% confidence interval) extent of the additional effect of L-NMMA over the constrictor effect of dexmedetomidine alone was 19% (14-24) (P<0.0001). In DHV, L-NMMA had variable effects on the dexmedetomidine-constriction dose-response curve. In three subjects, the curve was shifted significantly to the left (with a >10-fold difference in ED(50)), but ED(50) was only marginally affected by L-NMMA in the other subjects (difference in ED(50) <five-fold). CONCLUSIONS The endothelial NOS enzyme has a significant role in opposing the vasoconstrictor action of dexmedetomidine at drug concentrations within the therapeutic range.

Estimation of cardiac output in a pharmacological trial using a simple method based on arterial blood pressure signal waveform: a comparison with pulmonary thermodilution and echocardiographic methods.

ObjectiveCardiac output (CO) has traditionally been measured using invasive techniques, which involve an element of risk. Thus, a reliable less-invasive method for determining CO would be very valuable for research use. We tested whether simple analysis of the arterial pulse waveform, not requiring large-vessel catheterisation or expensive equipment, could provide an estimate of CO that is accurate enough for pharmacological studies.MethodsWe measured CO in 11 healthy male subjects who received low and high doses of dexmedetomidine (α2-adrenoceptor agonist), using pulse contour analysis, echocardiography and pulmonary thermodilution techniques.ResultsAt baseline, these methods gave the following mean (SD) values of CO: 6.18 (1.59), 5.22 (1.35) and 7.03 (1.54) l/min, respectively. High-dose dexmedetomidine reduced CO to 4.50 (0.68), 3.65 (0.65) and 4.80 (0.89) l/min, corresponding to −25 (14) %, −28 (12) % and −30 (14) % reductions from baseline, respectively. The pulse contour method described these dexmedetomidine-induced changes in CO very similarly to the thermodilution and echocardiographic methods. The limits of agreement [bias (2SD)] were 0.55 (2.55) and −0.10 (2.04) l/min, respectively.ConclusionThe minimally invasive pulse contour analysis technique might be suitable for pharmacological studies for the detection of major drug-induced reductions in CO.

Alpha-2B adrenoceptor polymorphism and peripheral vasoconstriction

Objectives Alpha-2B adrenoceptors (AR) mediate vasoconstriction in the mice. A human alpha-2B AR deletion (D) variant has been associated with loss of short-term agonist-promoted receptor desensitization, which may lead to increased vasoconstriction upon alpha-2 AR activation. This study tested the hypothesis that alpha-2 AR activation will induce enhanced vasoconstriction in carriers of the alpha-2B AR DD genotype, compared to carriers of the II or the DI genotypes. Methods We administered 1 μg/kg dexmedetomidine (an alpha-2 agonist) intravenously to 80 surgical patients in whom sympatholytic effects of the drug were attenuated by general anesthesia. Measurements were made of finger blood volume (an indicator of vasoconstriction) by photoplethysmographic determination of light transmission through a finger (LTF) and of hemodynamic variables. Results Dexmedetomidine increased LTF (vasoconstriction), induced an initial increase in systolic blood pressure and decreased heart rate in all genotype groups (P<0.0001 for all). Three min after the start of dexmedetomidine infusion, the increase in LTF was more pronounced (P=0.014) in the DD group compared to the DI and II groups. There were no significant differences in LTF values between the groups at the end of or 5 min after dexmedetomidine infusion. There were no differences in systolic blood pressure or heart rate values between the groups during or after the dexmedetomidine infusion. Conclusions The results of this study confirm that the alpha-2 agonist dexmedetomidine induced marked peripheral vasoconstriction. Subjects with the alpha 2B DD genotype had an enhanced vasoconstrictive response at the beginning of dexmedetomidine infusion. However, this enhanced vasoconstrictive response was not sustained throughout or after the 15-min dexmedetomidine infusion.

Effect of α2B-Adrenoceptor Polymorphism on Peripheral Vasoconstriction in Healthy Volunteers

Background:Alpha-2B adrenoceptor is the vasoconstrictive subtype in the mouse. Human &agr;2B-AR deletion (D) allele has been associated with loss of short-term agonist-promoted receptor desensitization, which may lead to increased vasoconstriction on &agr;2 activation. The goal of this study was to test the hypothesis that &agr;2B-adrenoceptor activation induces enhanced vasoconstriction in carriers of the DD genotype, compared with carriers of the insertion/insertion (II) genotype. Methods:The authors administered increasing doses of dexmedetomidine (targeting plasma concentrations of 0.15, 0.3, 0.6, and 1.2 ng/ml) to 16 healthy young volunteers (8 carrying the &agr;2B DD genotype, 8 carrying the II genotype) in whom sympatholytic effects of the drug were attenuated by general anesthesia. Measurements were made of finger blood volume (an indicator of vasoconstriction) by photoplethysmographic determination of light transmitted through a finger, finger blood flow by venous occlusion plethysmography, and hemodynamic variables. Results:All concentration of dexmedetomidine increased light transmitted through the finger (vasoconstriction) and systolic blood pressure and decreased heart rate in both groups (P < 0.001 for all). Dexmedetomidine reduced finger arterial inflow only in the DD group (P < 0.001). Dexmedetomidine had no effect on finger venous outflow or venous capacitance. There were no significant differences between the II and DD groups in any of the variables. Conclusions:The results of this study confirm the &agr;2 agonist induced vasomotor and hemodynamic effects in peripheral vasculature. However, the results do not support the hypothesis that &agr;2B-adrenoceptor polymorphism has an effect on peripheral vasoconstriction in humans.