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Amphetamines trigger the release of norepinephrine (NE), epinephrine (EPI), and dopamine (DA) in the brain. The adverse effects of methamphetamine (MA) are similar to those of an EPI response, therefore [...]

Author(s): Xiaohan Wang, Richard W. Tsien Author Affiliations: Suspect that modulates the heartbeat is ensnared In the Sherlock Holmes tale The Adventure of the Dancing Men , the detective runs [...], The activity of calcium channels in the heart increases during what is called the fight-or-flight response. An investigation into the 50-year-old mystery of how this occurs has captured a previously overlooked suspect. Protein kinase A targets Rad protein to boost calcium-channel activity.

Several lines of evidence support the view that the premotor sympathetic input to the adrenal gland arises from the rostroventrolateral medulla (RVLM). The aim of this study was to determine whether RVLM neurons play a role in glucose homeostasis. We identified RVLM neurons that control epinephrine secretion by searching for medullospinal neurons that responded to neuroglucoprivation induced by systemic 2-deoxyglucose (2-DG) administration. We tested the effect of disinhibition of the RVLM on arterial blood pressure and plasma glucose concentration. RVLM medullospinal barosensitive neurons (n = 17) were either unaffected or slightly inhibited by 2-DG. In contrast, we found a group (n = 6) of spinally projecting neurons that were excited by 2-DG administration. These neurons were not barosensitive and had spinal conduction velocities in the unmyelinated range ( glucose homeostasis; counterregulation; sympathetic nervous system; adrenal glands doi: 10.1152/ajpendo.00466.2010.

Fatty acid reesterification in adipose tissue is dependent on the generation of glycerol 3-phosphate, and, at least in rodent adipose tissue, this appears to occur primarily through glyceroneogenesis. A key enzyme in this process is pyruvate dehydrogenase kinase 4 (PDK4). PDK4 is induced in white adipose tissue by thiazolidinediones (TZDs) and the inhibition or knockdown of PDK4 inhibits TZD-induced increases in glyceroneogenesis. Since TZDs have many unwanted side effects, we were interested in identifying alternative mechanisms that could regulate PDK4 mRNA expression in white adipose tissue. In this regard we hypothesized that exercise, fasting, and epinephrine would increase PDK4 mRNA levels in rat epididymal adipose tissue. We further postulated that the p38 mitogen-activated protein kinase (MAPK) and 5'-AMP-activated protein kinase (AMPK) signaling pathways would control PDK4 mRNA expression in cultured adipose tissue. Exercise, fasting, and in or ex vivo epinephrine treatment increased PDK4 mRNA levels. These perturbations did not increase the expression of PDK1, -2, or -3. Pyruvate dehydrogenase phosphorylation was increased after an overnight fast and 4 h after the cessation of exercise. In cultured adipose tissue, epinephrine increased p38 and AMPK signaling; however, the direct activation of AMPK by AICAR or metformin led to reductions in PDK4 mRNA levels. The p38 inhibitor SB202190 reduced epinephrine-mediated increases in p38 MAPK activation without altering hormone-sensitive lipase or AMPK phosphorylation or attenuating epinephrine-induced increases in lipolysis. Reductions in p38 MAPK signaling were associated with decreases in PDK4 mRNA expression. The inhibition of peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]) also attenuated the induction of PDK4. Our results are the very first to demonstrate an epinephrine-mediated regulation of PDK4 mRNA levels in white adipose tissue and suggest that p38 MAPK and PPAR[gamma] could be involved in this pathway. p38 mitogen-activated protein kinase; pyruvate dehydrogenase kinase 4 doi: 10.1152/ajpcell.00188.2010.

Formyl peptide receptor-induced chemotaxis of neutrophils depends on the release of ATP and autocrine feedback through purinergic receptors. Here, we show that adrenergic receptor signaling requires similar purinergic feedback mechanisms. Real-time RT-PCR analysis revealed that human embryonic kidney (HEK)-293 cells express several subtypes of adrenergic ([[alpha].sub.1]-, [[alpha].sub.2]-, and [beta]-receptors), adenosine (P1), and nucleotide receptors (P2). Stimulation of [G.sub.q]-coupled [[alpha].sub.1]-receptors caused release of cellular ATP and MAPK activation, which was blocked by inhibiting P2 receptors with suramin. Stimulation of [G.sub.i]-coupled [[alpha].sub.2]-receptors induced weak ATP release, while [G.sub.s]-coupled [beta]-receptors caused accumulation of extracellular ADP and adenosine. [beta]-Receptors triggered intracellular cAMP signaling, which was blocked by scavenging extracellular adenosine with adenosine deaminase or by inhibiting A2a adenosine receptors with SCH58261. These findings suggest that adrenergic receptors require purinergic receptors to elicit downstream signaling responses in HEK-293 cells. We evaluated the physiological relevance of these findings using mouse aorta tissue tings. Stimulation of [[alpha].sub.1]-receptors induced ATP release and tissue contraction, which was reduced by removing extracellular ATP with apyrase or in the absence of [P2Y.sub.2] receptors in aorta rings from [P2Y.sub.2] receptor knockout mice. We conclude that, like formyl peptide receptors, adrenergic receptors require purinergic feedback mechanisms to control complex physiological processes such as smooth muscle contraction and regulation of vascular tone. phenylephrine; isoproterenol; mitogen-activated protein kinase; adenosine 3',5'-cyclic monophosphate; [P2Y.sub.2] knockout mice doi: 10.1152/ajpcell.00122.2010.

In the developing fetus, cerebral artery (CA) contractility demonstrates significant functional differences from that of the adult. This may be a consequence of differential activities of [[alpha].sub.1]-adrenergic receptor ([[alpha].sub.1]-AR) subtypes. Thus we tested the hypothesis that maturational differences in adrenergic-mediated CA contractility are, in part, a consequence of differential expression and/or activities of [[alpha].sub.1]-AR subtypes. In CA from fetal (~140 days) and nonpregnant adult sheep, we used wire myography and imaging, with simultaneous measurement of tension and intracellular [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.i]), radio-immunoassay, and Western immunoblots to examine phenylephrine (Phe)-induced contractile responses. [The [alpha].sub.1A]-AR antagonists (5-MU and WB-4101) completely inhibited Phe-induced contraction in adult but not fetal CA; however, [[[Ca.sup.2+]].sub.i] increase was reduced significantly in both age groups. The [alpha].sub.1D]-AR antagonist (BMY-7378) blocked both Phe-induced contractions and [Ca.sup.2+] responses to a significantly greater extent in adult compared with fetal CA. In both age groups, inhibition of [[alpha].sub.1A]-AR and [[alpha].sub.1B]-AR, but not [[alpha].sub.1D]-AR, significantly reduced inositol 1,4,5-trisphosphate responses to Phe. Western immunoblots demonstrated that the [[alpha].sub.1]-AR subtype expression was only ~20% in fetal CA compared with the adult. Moreover, in fetal CA, the [[alpha].sub.1D]-AR was expressed significantly greater than the other two subtypes. Also, in fetal but not adult CA, Phe induced a significant increase in activated ERK1/2; this increase in phosphorylated ERK was blocked by [[alpha].sub.1B]-AR (CEC) and [[alpha].sub.1D]-AR (BMY-7378) inhibitors, but not by [[alpha].sub.1A]-AR inhibitors (5-MU or WB-4101). In conclusion, in the fetal CA, [[alpha].sub.1B]-AR and [[alpha].sub.1D]-AR subtypes play a key role in contractile response as well as in ERK activation. We speculate that in fetal CA [[alpha].sub.1B]-AR and [[alpha].sub.1D]-AR subtypes may be a critical factor associated with cerebrovascular growth and function. vascular smooth muscle; development; maturation doi: 10.1152/ajpheart.00112.2010.

Right ventricular (RV) failure is a serious common clinical problem that is poorly understood. Therefore, for failing and nonfailing hearts, we examined the distinctive inotropic responses induced in the RV myocardium after the stimulation of a t-adrenergic receptors (ARs). In RV trabeculae from nonfailing mouse hearts, [[alpha].sub.1]-ARs induced a negative inotropic response, consistent with our previous study. In marked contrast, in RV trabeculae from failing hearts, 12 wk after coronary artery ligation, [[alpha].sub.1]-ARs induced a positive inotropic response. Mechanistically, experiments with skinned trabeculae showed that [[alpha].sub.1]-ARs decreased myofilament [Ca.sup.2+] sensitivity in the nonfailing RV myocardium, whereas [[alpha].sub.1]-ARs increased [Ca.sup.2+] sensitivity in heart failure. This suggests that a switch in the [Ca.sup.2+] sensitivity response to [[alpha].sub.1]-AR stimulation explained the switch in the RV [[alpha].sub.1]-AR inotropic response in heart failure. Myosin light chain kinase (MLCK) can increase myofilament [Ca.sup.2+] sensitivity, and the smooth muscle isoform (smMLCK), which is also present in cardiomyocytes, was more abundant in the RV myocardium from failing versus nonfailing hearts. Moreover, the MLCK inhibitor ML-9 prevented the switch of the RV myocardium to a positive [[alpha].sub.1]-AR inotropic response in heart failure. In the left ventricular myocardium, in contrast, [[alpha].sub.1]-AR inotropic responses were not different in failing versus nonfailing hearts, and smMLCK abundance was not increased in heart failure. In relation to human disease, we found that smMLCK mRNA and protein levels were increased in RVs from failing human hearts. We conclude that the RV inotropic response to [[alpha].sub.1]-ARs is switched from negative to positive in heart failure, through a pathway involving increased myofilament [Ca.sup.2+] sensitivity. Since [[alpha].sub.1]-AR agonist catecholamines are elevated in heart failure, increased [[alpha].sub.1]-AR inotropic responses in the RV myocardium may be adaptive in heart failure by helping the failing RV respond to increased pulmonary pressures. right ventricle; myosin light chain kinase; myofilament calcium sensitivy doi:10.1152/ajpheart.00259.2009

Several common genetic variations have been associated with type 2 diabetes, but the exact disease mechanisms are stilt poorly elucidated. Using congenic strains from the diabetic Goto-Kakizaki rat, we identified a 1.4-megabase genomic locus that was Linked to impaired insulin granule docking at the plasma membrane and reduced [beta] cell exocytosis. In this Locus, Adra2a, encoding the alpha2A-adrenergic receptor [aLpha(2A)AR], was significantly overexpressed. Alpha(2A)AR mediates adrenergic suppression of insulin secretion. Pharmacological receptor antagonism, silencing of receptor expression, or blockade of downstream effectors rescued insulin secretion in congenic islets. Furthermore, we identified a single-nucleotide polymorphism in the human ADRA2A gene for which risk allele carriers exhibited overexpression of alpha(2A)AR, reduced insulin secretion, and increased type 2 diabetes risk. Human pancreatic islets from risk allele carriers exhibited reduced granule docking and secreted Less insulin in response to glucose; both effects were counteracted by pharmacological alpha(2A)AR antagonists. 10.1126/science.1176827

Objectives. We estimated associations between job insecurity and change over time in the physical and psychological health of older adult men and women. Methods. We conducted secondary analyses of longitudinal data from men and women (N = 190) born between 1935 and 1952 in the Chicago Health, Aging, and Social Relations Study. We used multivariate regression techniques to test the association of job insecurity with changes in physical health (self-reported global health, resting blood pressure, and urinary catecholamines [epinephrine]) and psychological health (depressive symptoms, hostility, loneliness, and personal stress). We controlled for individual characteristics and baseline measures of the outcomes. Results. Men who experience job insecurity rate themselves in significantly poorer physical health and have higher blood pressure and higher levels of urinary catecholamines compared with men who do not experience job insecurity and women who do. Women who experience job insecurity show higher depressive symptoms and report more hostility, loneliness, and personal stress compared with women who do not experience job insecurity and men who do. Discussion. The correlation between job insecurity and health is different in men and women but may be clinically significant in both populations and is a potentially important threat to older adults' health and well-being. Key Words: Job insecurity--Mental health--Older adults--Physical health. doi: 10.1093/geronb/gbp100

The [beta]-adrenergic receptor (BAR) signaling system is one of the most powerful regulators of cardiac function and a key regulator of [Ca.sup.2+] homeostasis. We investigated the role of [beta]AR stimulation in augmenting cardiac function and its role in the activation of [Ca.sup.2+]/calmodulin-dependent kinase II (CaMKII) using various [beta]AR knockouts (KO) including [[beta].sub.1]ARKO, [[beta].sub.2]ARKO, and [[beta].sub.1]/[[beta].sub.2]AR double-KO (DKO) mice. We employed a murine model of left anterior descending coronary artery ligation to examine the differential contributions of specific (3AR subtypes in the activation of CaMKII in vivo in failing myocardium. Cardiac inotropy, chronotropy, and CaMKII activity following short-term isoproterenol stimulation were significantly attenuated in [[beta].sub.1]ARKO and DKO compared with either the [32ARKO or wild-type (WT) mice, indicating that [[beta].sub.1]ARs are required for catecholamine-induced increases in contractility and CaMKII activity. Eight weeks after myocardial infarction (MI), [[beta].sub.1]ARKO and DKO mice showed a significant attenuation in fractional shortening compared with either the [[beta].sub.1]ARKO or WT mice. CaMKII activity after MI was significantly increased only in the [[beta].sub.1]ARKO and WT hearts and not in the [31ARKO and DKO hearts. The border zone of the infarct in the [32ARKO and WT hearts demonstrated significantly increased apoptosis by TUNEL staining compared with the [[beta].sub.1]ARKO and DKO hearts. Taken together, these data show that cardiac function and CaMKII activity are mediated almost exclusively by the [[beta].sub.1]AR. Moreover, it appears that [31AR signaling is detrimental to cardiac function Following MI, possibly through activation of CaMKII. [Ca.sup.2+]/calmodulin-dependent kinase II; heart failure; apoptosis; knockout mice; pressure-volume relations doi:10.1152/ajpheart.00504.2009

Prenatal hypoxia in mammals causes fetal growth restriction and catecholaminergic overstimulation that, in turn, alter signaling pathways associated with adrenergic receptors. [beta]-Adrenoceptors ([beta]-ARs) are essential for fetal cardiac development and regulation of cardiac contractility. We studied the effects of chronic prenatal hypoxia on cardiac [beta]-AR signaling and the incidence of alterations in the juvenile [beta]-AR system due to the embryonic treatment. We measured functional [beta]-AR density ([B.sub.max] ) through binding with [[sup.3]H]CGP- 12177 and the effect of agonists on [beta]-AR-dependent contractility ([pEC.sub.50]) through concentration-response curves to epinephrine. Eggs from broiler chickens were incubated in normoxia (N, 21% [O.sub.2]) or chronic hypoxia (H, 14% [O.sub.2]). Cardiac tissue from embryos and juveniles was used (15 and 19 day of embryonic development and 14 and 35 days posthatching, E19, E15, P14, and P35, respectively). Relative cardiac enlargement was found in the hypoxic groups at E15, E19, and P14, but not P35. [B.sub.max] significantly decreased in E19H. [B.sub.max] more than doubled posthatching but decreased from P14 to P35. The sensitivity to epinephrine was lower in E19N compared with EI5N, but hypoxia increased the sensitivity to agonist in both E15H and E19H. Despite maintained receptor density, the P35H juvenile displayed a decreased sensitivity to [beta]-AR agonist, something that was not seen in P14H. The postnatal decrease in [beta]-AR sensitivity as an effect of chronic prenatal hypoxia, without a concomitant change in [beta]-AR density, leads us to conclude that the embryonic hypoxic challenge alters the future progression of [beta]-AR signaling and may have important implications for cardiovascular function in the adult. [beta]-adrenergic; embryonic development; hypoxia; receptor density; receptor sensitivity

Adenosine protects the heart from adrenergic overstimulation. This adeno-protection includes the direct anti-adrenergic action via adenosine [A.sub.1] receptors ([A.sub.1]R) on the adrenergic signaling pathway. An indirect [A.sub.1]R-induced attenuation of adrenergic responsiveness involves the translocation of PKC-[epsilon] to t-tubules and Z-line of cardiomyocytes. We investigated with sarcomere imaging, immunocytochemistry imaging, and coimmunoprecipitation (co-IP) whether [A.sub.1]R activation of PKC-[epsilon] induces the kinase translocation to receptor for activated C kinase 2 (RACK2) in isolated rat and mouse hearts and whether phospholipase C (PLC) is involved. Rat cardiomyocytes were treated with the [A.sub.1]R agonist chlorocyclopentyladenosine (CCPA) and exposed to primary PKC-[epsilon] and RACK2 antibodies with secondaries conjugated to Cy3 and Cy5 (indodicarbocyanine), respectively. Scanning confocal microscopy showed that CCPA caused PKC-[epsilon] to reversibly colocalize with RACK2 within 3 min. Additionally, rat and mouse hearts were perfused and stimulated with CCPA or phenylisopropyladenosine to activate [A.sub.1]R, or with phorbol 12-myristate 13-acetate to activate PKC. RACK2 was immunoprecipitated from heart extracts and resolved with SDS-PAGE. Western blotting showed that CCPA, phenylisopropyladenosine, and phorbol 12-myristate 13-acetate in the rat heart increased the PKC-[epsilon] co-IP with RACK2 by 186, 49, and > 1,000%, respectively. The [A.sub.1]R antagonist 8-cyclopentyl-1,3-dipropylxanthine prevented the CCPA-induced co-IP with RACK2. In mouse hearts, CCPA increased the co-IP of PKC-[epsilon] with RACK2 by 61%. With rat cardiomyocytes, the [beta]-adrenergic agonist isoproterenol increased sarcomere shortening by 177%. CCPA reduced this response by 47%, an action inhibited by the PLC inhibitor U-73122 and 8-cyclopentyl-1,3-dipropylxanthine. In conclusion, [A.sub.1]R stimulation of the heart is associated with PLC-initiated PKC-[epsilon] translocation and association with RACK2. adenosine [A.sub.1] receptor; protein kinase C-[epsilon]; receptor for activated C kinase 2; rodent

Adrenergic stimulation of electrogenic [K.sup.+] secretion in isolated mucosa from guinea pig distal colon required activation of two [beta]-adrenergic receptor subtypes (13-AdrR). Addition of epinephrine (epi) or norepinephrine (norepi) to the bathing solution of mucosae in Ussing chambers increased short-circuit current ([I.sub.sc]) and transepithelial conductance ([G.sub.t]), consistent with this cation secretion. A [beta]-adrenergic classification was supported by propranolol antagonism of this secretory response and the lack of effect by the [alpha]-AdrR antagonists BE2254 ([alpha]l-AdrR) and yohimbine ([alpha]2-AdrR). Subtype-selective antagonists CGP20712A ([beta]1-AdrR), ICI-118551 ([beta]2-AdrR), and SR59320A ([beta]3-AdrR) were relatively ineffective at inhibiting the epi-stimulated [I.sub.sc] response. In combination, CGP20712A and ICI-118551 inhibited the response, which supported a synergistic action by [beta]1-AdrR and [beta]2-AdrR. Expression of mRNA for both [beta]l-AdrR and [beta]2-AdrR was indicated by RT-PCR of RNA from colonic epithelial cells. Protein expression was indicated by immunoblot showing bands at molecular weights consistent with monomers and oligomers. Immunoreactivity (ir) for [beta]1-AdrR and [beta]2-AdrR was prominent in basolateral membranes of columnar epithelial cells in the crypts of Lieberkahn as well as intercrypt surface epithelium. Cells in the pericryptal sheath also had [beta]1-Adr[R.sup.ir] but did not have discernable [beta]2-Adr[R.sup.ir]. The adrenergic sensitivity of [K.sup.+] secretion measured by [I.sub.sc] and [G.sub.t] was relatively low as indicated by [EC.sub.50]s of 41 [+ or -] 7 nM for epi and 50 [+ or -] 14 nM for norepi. Adrenergic activation of electrogenic [K.sup.+] secretion required the involvement of both [beta]1-AdrR and [beta]2-AdrR, occurring with an agonist sensitivity reduced compared with reported values for either receptor subtype. epinephrine; norepinephrine; isoproteranol; CGP20712A; ICI-118551

Adrenergic activation of electrogenic [K.sup.+] secretion in isolated mucosa from guinea pig distal colon was desensitized by peptide-YY (PYY). Addition of PYY or neuropeptide-Y (NPY) to the bathing solution of mucosae in Ussing chambers suppressed the short-circuit current ([I.sub.sc]) corresponding to electrogenic [Cl.sup.-] secretion, whether stimulated by epinephrine (epi), prostaglandin-[E.sub.2] ([PGE.sub.2]), or carbachol (CCh). Neither peptide markedly inhibited the large transient component of synergistic secretion ([PGE.sub.2] + CCh). Sustained [Cl.sup.-] secretory [I.sub.sc] was inhibited ~65% by PYY or NPY, with [IC.sub.50]s of 4.1 [+ or -] 0.9 nM and 9.4 [+ or -] 3.8 nM, respectively. This inhibition was eliminated by BIIE0246, an antagonist of the Y2-neuropeptide receptor (Y2-NpR), but not by Y I-NpR antagonist BVD 10. Adrenergic sensitivity for activation of [K.sup.+] secretion in the presence of Y2-NpR blockade by BIIE0246 was ([IC.sub.50]s) 2.9 [+ or -] 1.2 nM for epi and 13.3 [+ or -] 1.0 nM for norepinephrine, approximately fourfold greater than in the presence of PYY. Expression of mRNA for both Y1-NpR and Y2-NpR was indicated by RT-PCR of RNA from colonic mucosa, and protein expression was indicated by immunoblot. Immunoreactivity (ir) for Y1-NpR and Y2-NpR was distinct in basolateral membranes of columnar epithelial cells in the crypts of Lieberktihn as well as intercrypt surface epithelium. Adrenergic nerves in proximity with crypts were detected by ir for dopamine-[beta]-hydroxylase, and a portion of these nerves also contained [NPY.sup.ir]. BIIE0246 addition increased secretagog-activated [I.sub.sc], consistent with in vitro release of either PYY or NPY. Thus PYY and NPY were able to suppress [Cl.sup.-] secretory capacity and desensitize the adrenergic [K.sup.+] secretory response, providing a direct inhibitory counterbalance against secretory activation. epinephrine; norepinephrine; ATP; adenosine; Y1-neuropeptide receptor; enteric nerves; [beta]-adrenergic receptor; [beta]2-adrenergic receptor

Epinephrine plays a key role in the control of vasomotor tone; however, the participation of the NO/cGMP pathway in response to [beta]-adrenoceptor activation remains controversial. To evaluate the involvement of the endothelium in the vascular response to epinephrine, we assessed NO production, endothelial NO synthase phosphorylation, and tissue accumulation of cGMP in the perfused arterial mesenteric bed of rat. Epinephrine elicited a concentration-dependent increase in NO ([EC.sub.50] of 45.7 pM), which was coupled to cGMP tissue accumulation. Both NO and cGMP production were blocked by either endothelium removal (saponin) or NO synthase inhibition ([N.sup.[omega]]-nitro-L-arginine). Blockade of [[beta].sub.1]- and [[beta].sub.2]-adrenoceptors with 1 [micro]M propranolol or [[beta].sub.3]-adrenoceptor with 10 nM SR 59230A displaced rightward the concentration-NO production curve evoked by epinephrine. Selective stimulation of [[beta].sub.1]-, [[beta].sub.2]-, or [[beta].sub.3]-adrenoceptors also resulted in NO and cGMP production. Propranolol (1 [micro]M) inhibited the rise in NO induced by isoproterenol or the [[beta].sub.2]-adrenoceptor agonists salbutamol, terbutaline, or fenoterol. Likewise, 10 nM SR 59230A reduced the effects of the [[beta].sub.3]-adrenoceptor agonists BRL 37344, CGP 12177, SR 595611A, or pindolol. The NO production induced by epinephrine and BRL 37344 was associated with the activation of the phosphatidylinositol 3-kinase/Akt pathway and phosphorylation of eNOS in serine 1177. In addition, in anaesthetized rats, bolus administration of isoproterenol, salbutamol, or BRL 37344 produced NO-dependent reductions in systolic blood pressure. These findings indicate that [[beta].sub.j]-, [[beta].sub.2]-, and [[beta].sub.3]-adrenoceptors are coupled to the NO/cGMP pathway, highlighting the role of the endothelium in the vasomotor action elicited by epinephrine and related [beta]-adrenoceptor agonists. endothelial nitric oxide synthase; endothelial cells; vasodilation

Cardiac sympathetic nerve activity is an important short-term controller of cardiac function and arterial pressure. Studies also suggest that long-term increases in cardiac sympathetic nerve activity may contribute to hypertension, coronary artery disease, and cardiac remodeling in heart failure. However, our understanding of the role of cardiac sympathetic nerves in chronic models of cardiovascular disease has been limited by inadequate experimental approaches. The present study was conducted to develop a surgical method to surgically denervate the sympathetic nerves of the rat heart for long-term cardiovascular studies. We characterized the effect of cardiac sympathetic denervation on basal levels of mean arterial pressure (MAP) and heart rate (HR) and the responses to a chronic administration of atenolol, a [[beta].sub.1]-adrenoceptor antagonist. Rats were instrumented with telemetry transmitters for continuous recording of MAP and HR. After a 4-day baseline period, the rats were subjected to bilateral stellate ganglionectomy (SGX; n = 9) or sham surgery (Sham; n = 8). Seven days following SGX or Sham, the rats were administered atenolol for 5 days, followed by a 7-day recovery period. Following a transient decrease, SGX had no effect on basal MAP but decreased HR compared with baseline and Sham rats. Five days of atenolol treatment decreased MAP similarly in SGX and Sham rats. Atenolol resulted in a marked bradycardia in Sham rats but had a neglible effects on HR in SGX rats. The measurement of the content of cardiac catecholamines in all cardiac chambers at the end of the study verified a successful sympathetic denervation. This study confirms that bilateral SGX is a useful method to study the contribution of cardiac sympathetic nerves on the regulation of cardiac function. Moreover, these results suggest that cardiac sympathetic nerves are relatively unimportant in maintaining the basal level of MAP or the depressor response to atenolol in conscious, unrestrained rats. cardiac sympathetic nerve activity; heart rate

The low-pressure volume overload of isolated mitral regurgitation (MR) is associated with increased adrenergic drive, left ventricular (LV) dilatation, and loss of interstitial collagen. We tested the hypothesis that [[beta].sub.1]-adrenergic receptor blockade ([[beta].sub.1]-RB) would attenuate LV remodeling after 4 mo of MR in the dog. [[beta].sub.1]-RB did not attenuate collagen loss or the increase in LV mass in MR dogs. Using MRI and three-dimensional (3-D) analysis, there was a 70% increase in the LV end-diastolic (LVED) volume-to-LV mass ratio, a 23% decrease in LVED midwall circumferential curvature, and a >50% increase in LVED 3-D radius/wall thickness in MR dogs that was not attenuated by [[beta].sub.1]-RB. However, [[beta].sub.1]-RB caused a significant increase in LVED length from the base to apex compared with untreated MR dogs. This was associated with an increase in isolated cardiomyocyte length (171 [+ or -] 5 [micro]m, P < 0.05) compared with normal (156 [+ or -] 3 [micro]m) and MR (165 [+ or -] 4 [micro]m) dogs. Isolated cardiomyocyte fractional shortening was significantly depressed in MR dogs compared with normal dogs (3.73 [+ or -] 0.31 vs. 5.02 [+ or -] 0.26%, P < 0.05) and normalized with [[beta].sub.1]-RB (4.73 [+ or -] 0.48%). In addition, stimulation with the [beta]-adrenergic receptor agonist isoproterenol (25 nM) increased cardiomyocyte fractional shortening by 215% (P < 0.05) in [[beta].sub.1]-RB dogs compared with normal (56%) and MR (50%) dogs. In summary, [[beta].sub.1]-RB improved LV cardiomyocyte function and [beta]-adrenergic receptor responsiveness despite further cell elongation. The failure to attenuate LV remodeling associated with MR could be due to a failure to improve ultrastructural changes in extracellular matrix organization. heart failure; volume overload

Differences in energy metabolism during [[beta].sub.1] and [[beta].sub.2]-adrenergic receptor (AR) stimulation have been shown to translate to differences in the elicited functional responses. It has been suggested that differential access to glycogen during [[beta].sub.1]-compared with [[beta].sub.2]-AR stimulation may influence the peak functional response and modulation of the response during sustained adrenergic stimulation. Interleaved [sup.13]C- and [sup.31]P-NMR spectroscopy was used during [[beta].sub.1]- and [[beta].sub.2]-AR stimulation at matched peak workload (2.5 times baseline) in the isolated perfused rat heart to monitor glycogen levels, phosphorylation potential, and intracellular pH. Simultaneous measurements of left ventricular (LV) function [LV developed pressure (LVDP)], heart rate (HR), and rate-pressure product (RPP = LVDP x HR) were also performed. The heart was perfused under both substrate-free (SF) conditions and with exogenous glucose (G). The greater glycogenolysis was observed during [[beta].sub.1]- than [[beta].sub.2]-AR stimulation with G (54% vs. 38% reduction, P = 0.006) and SF (92% vs. 79% reduction, P = 0.04) perfusions. The greater [[beta].sub.1]-AR-mediated glycogenolysis was correlated with greater ability to sustain the initial contractile response. However, with SF perfusion, the duration of this ability was limited: excessive early glycogen depletion caused an earlier decline in LVDP and phosphorylation potential during [[beta].sub.1] -than [[beta].sub.2]-AR stimulation. Therefore, endogenous glycogen stores are depleted earlier and to a greater extent, despite a slightly weaker overall inotropic response, during [[beta].sub.1]- than [[beta].sub.2]-AR stimulation. These findings are consistent with [[beta].sub.1]-AR-specific PKA-dependent glycogen phosphorylase kinase signaling. receptors; adrenergic; metabolism; magnetic resonance spectroscopy

Ishii H, Niioka T, Watanabe H, Izumi H. Inhibitory effects of excess sympathetic activity on parasympathetic vasodilation in the rat masseter muscle. Am J Physiol Regul Integr Comp Physiol 293: R729-R736, 2007. First published May 30, 2007; doi: 10.1152/ajpregu.00866.2006.--The present study was designed to examine the effect of sympathetic tonic activity on parasympathetic vasodilation evoked by the trigeminal-mediated reflex in the masseter muscle in urethane-anesthetized rats. Sectioning of the superior cervical sympathetic trunk (CST) ipsilaterally increased the basal level of blood flow in the masseter muscle (MBF). Electrical stimulation of the peripheral cut end of the CST for 2 min using 2-ms pulses ipsilaterally decreased in a dependent manner the intensity (0.5-10 V) and frequency (0.1-5 Hz) of the MBF. The CST stimulation for 2 min at superior cervical sympathetic trunk; vasoconstrictor fiber; adrenoceptors; trigeminal-mediated reflex; jaw muscle

Delivering therapeutic levels of lysosomal enzymes across the blood-brain barrier (BBB) has been a pivotal issue in treating CNS storage diseases, including the mucopolysaccharidoses. An inherited deficiency of [beta]-glucuronidase (GUS) causes mucopolysaccharidosis type VII that is characterized by increased systemic and CNS storage of glycosaminoglycans. We previously showed that the neonate uses the mannose 6-phosphate (M6P) receptor to transport phosphorylated GUS (P-GUS) across the BBB and that this transporter is lost with maturation. Induction of expression of this BBB transporter would make enzyme replacement therapy in the adult possible. Here, we tested pharmacological manipulation with epinephrine to restore functional transport of P-GUS across the adult BBB. Epinephrine (40 nmol) coinjected i.v. with [sup.131]I-P-GUS induced the transport across the BBB in 8-week-old mice. The brain influx rate of [sup.131]I-P-GUS (0.29 [micro]l/g per min) returned to the level seen in neonates. Capillary depletion showed that 49% of the [sup.131]I-P-GUS in brain was in brain parenchyma. No increases of influx rate or the vascular space for [sup.125]I-albumin, a vascular marker, was observed with epinephrine (40 nmol), showing that enhanced passage was not caused by disruption of the BBB. Brain uptake of [sup.131]I-P-GUS was significantly inhibited by M6P in a dose-dependent manner, whereas epinephrine failed to increase brain uptake of nonphosphorylated GUS. Thus, the effect of epinephrine on the transport of [sup.131]I-P-GUS was ligand specific. These results indicate that epinephrine restores the M6P receptor-mediated functional transport of [sup.131]I-P-GUS across the BBB in adults to levels seen in the neonate. [beta]-glucuronidase | drug delivery | enzyme replacement therapy | lysosomal storage disease | phosphorylated [beta]-glucuronidase

Spectral analysis of cardiovascular signals has been extensively used to investigate circulatory homeostatic mechanisms. However, the nature of very low-frequency (VLF) fluctuations remains unclear. Because we previously observed enhanced VLF fluctuations in blood pressure (BP) in the sympathectomized rat (a model characterized by markedly increased plasma epinephrine levels), the aims of our study were to assess whether the genesis of VLF fluctuations in BP depends on circulating catecholamines and to determine which adrenergic receptor(s) and which membrane ion channel(s) are involved. We used continuous intra-arterial BP recordings from unanesthetized unrestrained rats to compute the power of VLF fluctuations in BP in the intact condition, during acute ganglionic blockade with hexamethonium, and after restoration of BP levels by infusion (in addition to hexamethonium) of adrenergic agonists (epinephrine, norepinephrine, and clonidine) or nonadrenergic vasoconstrictors (vasopressin). Effects of infusion of specific adrenergic receptor blockers (propranolol, prazosin, and yohimbine) with hexamethonium and catecholamines and infusion of various membrane ion channel blockers on VLF fluctuations in BP were also evaluated. Our results are as follows. 1) Ganglionic blockade drastically reduced BP levels and VLF fluctuations. 2) All vasoconstrictors restored BP levels, but only adrenergic vasoconstrictors generated striking VLF fluctuations in BP. 3) Catecholamine-induced fluctuations were abolished by [[alpha].sub.2]-, but not [[alpha].sub.1]- or [beta]-, adrenergic receptor blockade and by [Ba.sup.2+]-sensitive [K.sup.+] channel or L-type [Ca.sup.2+] channel, but not by other ion channel, blockers. We conclude that, in the conscious, unrestrained ganglion-blocked rat, catecholamine infusion generates VLF fluctuations in BP through stimulation of [[alpha].sub.2]-receptors and activation of [Ba.sup.2+]-sensitive [K.sup.+] channels. These fluctuations may have (patho)physiological relevance under conditions of disrupted circulatory homeostasis. catecholamines; spectral analysis; ganglionic blockade; adrenergic receptors

[beta]-Adrenergic receptors ([beta]-ARs) play a major role in regulating heart rate (HR) and contractility in the intact cardiovascular system. Three subtypes ([[beta].sub.1], [[beta].sub.2], and [[beta].sub.3]) are expressed in heart tissue, and the role of each subtype in regulating cardiac function has previously been determined by using both pharmacological and gene-targeting approaches. However, previous studies have only examined the role of [beta]-ARs in the macrolevel regulation of HR. We employed three knockout (KO) mouse lines, [[beta].sub.1]-KO, [[beta].sub.2]-KO, and [[beta].sub.1]/[[beta].sub.2] double KO (DL-KO), to examine the role that [beta]-AR subtypes play in HR variability (HRV) and in the sympathetic and parasympathetic inputs into HR control. Fast Fourier transformation (FFT) in frequency domain methods of ECG spectral analysis was used to resolve HRV into high- and low-frequency (HF and LF) powers. Resting HR (in beats/min) was decreased in [[beta].sub.1]-KO [488 (SD 27)] and DL-KO [495 (SD 12)] mice compared with wild-type [WT; 638 (SD 30)] or [[beta].sub.2]-KO [656 (SD 51)] (P < 0.0005) mice. Mice lacking [[beta].sub.1]-ARs ([beta]1-KO and DL-KO) had increased HRV (as illustrated by the standard deviation of normal R-R intervals) and increased normalized HF and LF powers compared with mice with intact [[beta].sub.1]-ARs (WT and [[beta].sub.2]-KO). These results demonstrate the differential role of [beta]-AR subtypes in regulating autonomic signaling. chronotropy; sympathetic nervous system; parasympathetic nervous system

This study addressed the hypothesis that the secretion of catecholamines from trout (Oncorhynchus mykiss) chromaffin cells, during hypoxia, is triggered by stimulation of [O.sub.2] chemoreceptors located within the gills. Sodium cyanide was administered into the inspired water (external cyanide) or injected into the gill circulation (internal cyanide) to pharmacologically stimulate external (water sensing) or internal (blood sensing) [O.sub.2] chemoreceptors, respectively. Both of these treatments caused an elevation of circulating catecholamine levels. The response to external, but not internal, cyanide was abolished by removal of the first gill arch. Hypoxia produced an increase in circulating catecholamine levels that was unaffected by removal of the first gill arch or by denervation of the pseudobranch. Cyanide and hypoxia both caused the well-documented cardiorespiratory reflexes normally observed in this species. This study demonstrates, for the first time, that gill [O.sub.2] chemoreceptors can initiate the reflex that leads to catecholamine release from the chromaffin cells and that stimulation of internally oriented [O.sub.2] receptors on all gill arches appears to be the physiologically important mechanism for initiating release. epinephrine; cardiorespiratory reflexes; gills; hypoxia; Oncorhynchus mykiss

Byline: Bruno Levy (1), Arnaud Mansart (2), Pierre-Edouard Bollaert (1), Patricia Franck (3), Jean-Pierre Mallie (2) Keywords: Tissue lactate concentration Tissue adenosine 5 -triphosphate concentration Epinephrine Septic shock Lactate/pyruvate ratio Abstract: Objective. To determine whether epinephrine increases lactate concentration in sepsis through hypoxia or through a particular thermogenic or metabolic pathway. Design. Prospective, controlled experimental study in rats. Setting. Experimental laboratory in a university teaching hospital. Interventions. Three groups of anesthetized, mechanically ventilated male Wistar rats received an intravenous infusion of 15 mg/kg Escherichia coli O127:B8 endotoxin. Rats were treated after 90 min by epinephrine (n=14), norepinephrine (n=14), or hydroxyethyl starch (n=14). Three groups of six rats served as time-matched control groups and received saline, epinephrine, or norepinephrine from 90 to 180degmin. Mean arterial pressure, aortic, renal, mesenteric and femoral blood flow, arterial blood gases, lactate, pyruvate, and nitrate were measured at baseline and 90 and 180 min after endotoxin challenge. At the end of experiments biopsy samples were taken from the liver, heart, muscle, kidney, and small intestine for tissue adenine nucleotide and lactate/pyruvate measurements. Measurements and results. Endotoxin induced a decrease in mean arterial pressure and in aortic, mesenteric, and renal blood flow. Plasmatic and tissue lactate increased with a high lactate/pyruvate (L/P) ratio. ATP decreased in liver, kidney, and heart. The ATP/ADP ratio did not change, and phosphocreatinine decreased in all organs. Epinephrine and norepinephrine increased mean arterial pressure to baseline values. Epinephrine increased aortic blood flow while renal blood low decreased with both drugs. Plasmatic lactate increased with a stable L/P ratio with epinephrine and did not change with norepinephrine compared to endotoxin values. Nevertheless epinephrine and norepinephrine when compared to endotoxin values did not change tissue L/P ratios or ATP concentration in muscle, heart, gut, or liver. In kidney both drugs decreased ATP concentration. Conclusions. Our data demonstrate in a rat model of endotoxemia that epinephrine-induced hyperlactatemia is not related to cellular hypoxia. Author Affiliation: (1) Reanimation Medicale, Hopital Central, 54035, Nancy Cedex, France (2) Laboratoire d'Exploration Fonctionnelle Renale, Faculte de Medecine, 54000, Vandoeuvre-les-Nancy, France (3) Laboratoire de Biochimie, Hopital Central, 54035, Nancy Cedex, France Article History: Received Date: 27/03/2002 Accepted Date: 13/11/2002 Article note: Electronic Publication

To determine the effects of an increase in lipolysis on the glycogenolytic effect of epinephrine (EPI), the catecholamine was infused portally into 18-h-fasted conscious dogs maintained on a pancreatic clamp in the presence [portal (Po)-EPI+FFA, n = 6] and absence (Po-EPI+SAL, n = 6) of peripheral Intralipid infusion. Control groups with high glucose (70% increase) and free fatty acid (FFA; 200% increase; HG+FFA, n = 6) and high glucose alone (HG+SAL, n = 6) were also included. Hepatic sinusoidal EPI levels were elevated ([DELTA]568 [+ or -] 77 and [DELTA]527 [+ or -] 37 pg/ml, respectively) in Po-EPI+SAL and EPI+FFA but remained basal in HG+FFA and HG+SAL. Arterial plasma FFA increased from 613 [+ or -] 73 to 1,633 [+ or -] 101 and 746 [+ or -] 112 to 1,898 [+ or -] 237 [micro]mol/l in Po-EPI+FFA and HG+FFA but did not change in EPI+SAL or HG+SAL. Net hepatic glycogenolysis increased from 1.5 [+ or -] 0.3 to 3.1 [+ or -] 0.4 mg * [kg.sup.-1] * [min.sup.-1] (P < 0.05) by 30 min in response to portal EPI but did not rise (1.8 [+ or -] 0.2 to 2.1 [+ or -] 0.3 mg * [kg.sup.-1] * [min.sup.-1]) in response to Po-EPI+FFA. Net hepatic glycogenolysis decreased from 1.7 [+ or -] 0.2 to 0.9 [+ or -] 0.2 and 1.6 [+ or -] 0.2 to 0.7 [+ or -] 0.2 mg * [kg.sup.-1] * [min.sup.-1] by 30 min in HG+FFA and HG+SAL. Hepatic gluconeogenic flux to glucose 6-phosphate increased from 0.6 [+ or -] 0.1 to 1.2 [+ or -] 0.1 mg * [kg.sup.-1] * [min.sup.-1] (P < 0.05; by 3 h) and 0.7 [+ or -] 0.1 to 1.6 [+ or -] 0.1 mg * [kg.sup.-1] * [min.sup.-1] (P < 0.05; at 90 min) in HG+FFA and Po-EPI+FFA. The gluconeogenic parameters remained unchanged in the Po-EPI+SAL and HG+SAL groups. In conclusion, increased FFA markedly changed the mechanism by which EPI stimulated hepatic glucose production, suggesting that its overall lipolytic effect may be important in determining its effect on the liver. gluconeogenesis; glycogenolysis

Epidermal growth factor (EGF) interferes with [beta]-adrenergic receptor ([beta]-AR) signaling in adipocytes and hepatocytes, which leads to decreased lipolytic and glycogenolytic responses, respectively. We studied the effect of EGF on the heart. EGF interfered with the cAMP signal generated by [beta]-AR agonists in cardiac myocytes. In perfused hearts, EGF decreased inotropic and chronotropic responses to epinephrine but not to 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate. Sustained epinephrine infusion induced heart contracture, which resulted in altered heart function as demonstrated by decreased inotropy and increased heart rate variability. EGF prevented all these alterations. In the whole animal (anesthetized mice), EGF administration reduced the rise in heart rate induced by a single epinephrine dose and the occurrence of Bezold-Jarisch reflex episodes induced by repeated doses. Sialoadenectomy enhanced the response to epinephrine, and EGF administration restored normal response. All these results suggest that, by interfering with [beta]-AR signaling, EGF protects the heart against the harmful effects of epinephrine. adenosine 3',5'-cyclic monophosphate; heart rate; sialoadenectomy; rats; mice

Individuals with type 1 diabetes demonstrate a hypoglycemia-specific defect in glucagon secretion. To determine whether intraislet hyperinsulinemia plays a role in the genesis of this defect, glucagonsecretory responses to moderate hypoglycemia induced by either insulin or a novel combination of the noninsulin glucose-lowering agents 5-aminoimidazole-4-carboxamide (AICAR) and phlorizin were compared in diabetic BB rats (an animal model of type 1 diabetes) and nondiabetic BB rats. The phlorizin-AICAR combination was able to induce moderate and equivalent hypoglycemia in both diabetic and nondiabetic BB rats in the absence of marked hyperinsulinemia. Diabetic BB rats demonstrated impaired glucagon and epinephrine responses during insulin-induced hypoglycemia compared with nondiabetic rats. In contrast, both glucagon (9- to 10-fold increase) and epinephrine (5- to 6-fold increase) responses were markedly improved during phlorizin-AICAR hypoglycemia. Combining phlorizin, AICAR, and insulin attenuated the glucagon response to hypoglycemia by 70% in the diabetic BB rat. Phlorizin plus AICAR had no effect on counterregulatory hormones under euglycemic conditions. We conclude that [alpha]-cell glucagon secretion in response to hypoglycemia is not defective if intraislet hyperinsulinemia is prevented. This suggests that exogenous insulin plays a pivotal role in the etiology of this defect. type 1 diabetes; counterregulation; epinephrine; insulin; 5-aminoimadazole-4-carboxamide; adenosine 5'-monophosphate-activated protein kinase

Acute renal failure (ARF) contributes substantially to the high morbidity and mortality observed during endotoxemia. We hypothesized that selective blockade of the renal nerves would be protective against ARF during the early (16 h) stage of endotoxemia [5 mg lipopolysaccharide (LPS)/kg ip in mice]. At 16 h after LPS, there was no change in mean arterial pressure, but plasma epinephrine (4,604 [+ or -] 719 vs. 490 [+ or -] 152 pg/ml, P < 0.001), norepinephrine (2,176 [+ or -] 306 vs. 1,224 [+ or -] 218 pg/ml, P < 0.05), and plasma renin activity (40 [+ or -] 5 vs. 27 [+ or -] 2 ng*[ml-.sup.-1]*[h.sup.-1], P < 0.05) were higher in the LPS-treated vs. control mice. The high plasma renin activity level decreased to the control level with renal denervation in endotoxemic mice. After intravenous injection of phentolamine (200 [micro]g/kg), the decrement in mean arterial pressure was significantly greater in LPS-treated vs. control mice (19.4 [+ or -] 3.5 vs. 8.1 [+ or -] 1.5 mmHg, P < 0.01). Sixteen hours after LPS administration, there were significant decreases in glomerular filtration rate (52 [+ or -] 18 vs. 212 [+ or -] 23 [micro]l/min, P < 0.01) and renal blood flow (0.58 [+ or -] 0.08 vs. 0.85 [+ or -] 0.06 ml/min, P < 0.01) in sham-operated mice. The decrement in glomerular filtration rate during endotoxemia was significantly attenuated in mice with denervated kidneys (32 vs. 79%). Moreover, there was no change in renal blood flow during endotoxemia in mice with renal denervation. The present results therefore demonstrate a protective role of renal denervation during normotensive endotoxemia-related ARF in mice, an effect that may be, at least in part, due to a diminished activation of the renin-angiotensin system. glomerular filtration rate; renal blood flow; epinephrine; norepinephrine; sepsis

This study examined the effect of epinephrine on glucose disposal during moderate exercise when glycogenolytic flux was limited by low preexercise skeletal muscle glycogen availability. Six male subjects cycled for 40 min at 59 [+ or -] 1% peak pulmonary [O.sub.2] uptake on two occasions, either without (CON) or with (EPI) epinephrine infusion starting after 20 min of exercise. On the day before each experimental trial, subjects completed fatiguing exercise and then maintained a low carbohydrate diet to lower muscle glycogen. Muscle samples were obtained after 20 and 40 min of exercise, and glucose kinetics were measured using [6,6-[sup.2]H]glucose. Exercise increased plasma epinephrine above resting concentrations in both trials, and plasma epinephrine was higher (P < 0.05) during the final 20 min in EPI compared with CON. Muscle glycogen levels were low after 20 min of exercise (CON, 117 [+ or -] 25; EPI, 122 [+ or -] 20 mmol/kg dry matter), and net muscle glycogen breakdown and muscle glucose 6-phosphate levels during the subsequent 20 min of exercise were unaffected by epinephrine infusion. Plasma glucose increased with epinephrine infusion (i.e., 20-40 min), and this was due to a decrease in glucose disposal ([R.sub.d]) (40 min: CON, 33.8 [+ or -] 3; EPI, 20.9 [+ or -] 4.9 [micro]mol * [kg.sup.-1] * [min.sup.-1], P < 0.05), because the exercise-induced rise in glucose rate of appearance was similar in the trials. These results show that glucose [R.sub.d] during exercise is reduced by elevated plasma epinephrine, even when muscle glycogen availability and utilization are low. This suggests that the effect of epinephrine does not appear to be mediated by increased glucose 6-phosphate, secondary to enhanced muscle glycogenolysis, but may be linked to a direct effect of epinephrine on sarcolemmal glucose transport. glucose transport; exercise

Glucose absorption via the sodium glucose-linked transporter (SGLT)-I, decreases the glucose concentration in the ruminant forestomach and may ameliorate or prevent ruminal lactic acidosis. Because acidotic ruminants show increased sympathetic activity, the possibility of adrenergic modulation of SGLT-1 was investigated. Glucose uptake into ovine ruminal epithelia was measured in Ussing chambers after the addition of 200 [micro]mol/L [sup.14]4C-labeled glucose to the mucosal solution. Glucose uptake decreased (P < 0.05) by >50% in comparison with control after mucosal addition of the SGLT-1 inhibitor, phlorizin (100/[micro]mol/L). Serosal preincubation with 100 [micro]mol/L epinephrine increased (P < 0.05) the phlorizin-sensitive glucose uptake in the absence and presence of indomethacin (10 [micro]mol/L). The effect of epinephrine was simulated by [beta]-(100 [micro]mol/L isoproterenol) and [beta][sup.2]-receptor agonists (10 [micro]mol/L terbutaline), as well as by direct stimulation of adenylyl cyclase (10 [micro]mol/L forskolin). The serosal addition of methoxamine, clonidine, dobutamine or,BRL 37344 had no effect. Inhibition of protein kinase A with 2 [micro]mol/L H 89 completely abolished the stimulation of glucose uptake by epinephrine. We conclude that ruminal SGLT-1 can be stimulated via [beta][sub.2]-dependent generation of cyclic adenosine monophosphate. KEY WORDS: * glucose absorption * cAMP * epinephrine * rumen * sheep

This study was conducted to test the hypothesis of the activation of glucose-6-phosphatase (G-6-Pase) in situations where the liver is supposed to sustain high glucose supply, such as during the counterregulatory response to hypoglycemia. Hypoglycemia was induced by insulin infusion in anesthetized rats. Despite hyperinsulinemia, endogenous glucose production (EGP), assessed by [[3-.sup.3]H]glucose tracer dilution, was paradoxically not suppressed in hypoglycemic rats. G-6-Pase activity, assayed in a freeze-clamped liver lobe, was increased by 30% in hypoglycemia (P < 0.01 vs. saline-infused controls). Infusion of epinephrine (1 [micro]g*[kg.sup.-1]*[min.sup.-1]) in normal rats induced a dramatic 80% increase in EGP and a 60% increase in G-6-Pase activity. In contrast, infusion of dexamethasone had no effect on these parameters. Similar insulin-induced hypoglycemia experiments performed in adrenalectomized rats did not induce any stimulation of G-6-Pase. Infusion of epinephrine in adrenalectomized rats restored a stimulation of G-6-Pase similar to that triggered by hypoglycemia in normal rats. These results strongly suggest that specific activatory mechanisms of G-6-Pase take place and contribute to EGP in situations where the latter is supposed to be sustained. dexamethasone; endogenous glucose production

We tested the hypothesis that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia. Twelve healthy young adults were studied on two separate occasions, once after infusions of a pharmacological dose of [alpha]-(1-24)-ACTH (100 [micro]g/h) from 0930 to 1200 and 1330 to 1600, which raised plasma cortisol levels to ~45 [micro]g/dl on day 1, and once after saline infusions on day 1. Hyperinsulinemic (2.0 mU * [kg.sup.-1] * [min.sup.-1]) stepped hypoglycemic clamps (90, 75, 65, 55, and 45 mg/dl glucose steps) were performed on the morning of day 2 on both occasions. These markedly elevated antecedent endogenous cortisol levels reduced the adrenomedullary (P = 0.004, final plasma epinephrine levels of 489 [+ or -] 64 vs. 816 [+ or -] 113 pg/ml), sympathetic neural (P = 0.0022, final plasma norepinephrine levels of 244 [+ or -] 15 vs. 342 [+ or -] 22 pg/ml), parasympathetic neural (P = 0.0434, final plasma pancreatic polypeptide levels of 312 [+ or -] 37 vs. 424 [+ or -] 56 pg/ml), and neurogenic (autonomic) symptom (P = 0.0097, final symptom score of 7.1 [+ or -] 1.5 vs. 10.6 [+ or -] 1.6) responses to subsequent hypoglycemia. Growth hormone, but not glucagon or cortisol, responses were also reduced. The findings that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia are potentially relevant to cortisol mediation of hypoglycemia-associated autonomic failure, and thus a vicious cycle of recurrent iatrogenic hypoglycemia, in people with diabetes mellitus. epinephrine; norepinephrine; glucagon; diabetes; hypoglycemia-associated autonomic failure

Cell-attached recordings revealed [K.sup.+] channel activity in basolateral membranes of guinea pig distal colonic crypts. Inwardly rectified currents were apparent with a pipette solution containing 140 mM [K.sup.+]. Single-channel conductance ([Gamma]) was 9 pS at the resting membrane potential. Another inward rectifier with [gamma] of 19 pS was observed occasionally. At a holding potential of -80 mV, [Gamma] was 21 and 41 pS, respectively. Identity as [K.sup.+] channels was confirmed after patch excision by changing the bath ion composition. From reversal potentials, relative permeability of [Na.sup.+] over [K.sup.+] ([P.sub.Na]/[P.sub.K]) was 0.02 [+ or -] 0.02, with [P.sub.Rb]/[P.sub.K] = 1.1 and [P.sub.Cl]/[P.sub.K] < 0.03. Spontaneous open probability ([P.sub.o]) of the 9-pS inward rectifier ([sup.gp][K.sub.ir]) was voltage independent in cell-attached patches. Both a low ([P.sub.o] = 0.09 [+ or -] 0.01) and a moderate ([P.sub.o] = 0.41 [+ or -] 0.01) activity mode were observed. Excision moved [sup.gp][K.sub.ir] to the medium activity mode; [P.sub.o] of [sup.gp][K.sub.ir] was independent of bath [Ca.sup.2+] activity and bath acidification. Addition of [Cl.sup.-] and [K.sup.+] secretagogues altered [P.sub.o] of [sup.gp][K.sub.ir]. Forskolin or carbachol (10 [micro]M) activated the small-conductance [sup.gp][K.sub.ir] in quiescent patches and increased [P.sub.o] in low-activity patches. [K.sup.+] secretagogues, either epinephrine (5 [micro]M) or prostaglandin [E.sub.2] (100 nM), decreased [P.sub.o] of [sup.gp][K.sub.ir] in active patches. This [sup.gp][K.sub.ir] may be involved in electrogenic secretion of [Cl.sup.-] and [K.sup.+] across the colonic epithelium, which requires a large basolateral membrane [K.sup.+] conductance during maximal [Cl.sup.-] secretion and, presumably, a lower [K.sup.+] conductance during primary electrogenic [K.sup.+] secretion. chloride secretion; potassium secretion; prostaglandin [E.sub.2]; epinephrine

Glucagon binding to hepatocytes has been known for a long time to not only stimulate intracellular cAMP accumulation but also, intriguingly, induce a significant release of liver-borne cAMP in the blood. Recent experiments have shown that the well-documented but ill-understood natriuretic and phosphaturic actions of glucagon are actually mediated by this extracellular cAMP, which inhibits the reabsorption of sodium and phosphate in the renal proximal tubule. The existence of this 'pancreato-hepatorenal cascade' indicates that proximal tubular reabsorption is permanently influenced by extracellular cAMP, the concentration of which is most probably largely dependent on the insulin-to-glucagon ratio. The possibility that renal cAMP receptors may be involved in this process is supported by the fact that cAMP has been shown to bind to brush-border membrane vesicles. In other cell types (i.e., adipocytes, erythrocytes, glial cells, cardiomyocytes), cAMP eggress and/or cAMP binding have also been shown to occur, suggesting additional paracrine effects of this nucleotide. Although not yet identified in mammals, cAMP receptors (cARs) are already well characterized in lower eukaryotes. The amoeba Dictyostelium discoideum expresses four different cARs during its development into a multicellular organism, cARs belong to the superfamily of seven transmembrane domain G protein-coupled receptors and exhibit a modest homology with the secretin receptor family (which includes PTH receptors). However, the existence of specific cAMP receptors in mammals remains to be demonstrated. Disturbances in the pancreato-hepatorenal cascade provide an adequate pathophysiological understanding of several unexplained observations, including the association of hyperinsulinemia and hypertension, the hepatorenal syndrome, and the hyperfiltration of diabetes mellitus. The observations reviewed in this paper show that cAMP should no longer be regarded only as an intracellular second messenger but also as a first messenger responsible for coordinated hepatorenal functions, and possibly for paracrine regulations in several other tissues. Dictyostelium discoideum; liver; adipose tissue; glucagon; epinephrine; parathyroid hormone; insulin; hypertension; hepatorenal syndrome; diabetes mellitus; sodium; phosphate

Investigating aging effects on the sympathetic nervous system and ascertaining underlying central nervous system (CNS) mechanisms mediating sympathetic stimulation is clinically pertinent because of the possible interconnection of cardiovascular disease development with age-dependent sympathetic nervous changes. Because of previous evidence linking human CNS neuronal noradrenergic function and sympathetic activity, we investigated the influence of aging on brain norepinephrine turnover in 22 healthy men aged 20-30 yr and 16 healthy men aged 60-75 yr by measuring the internal jugular venous overflow of norepinephrine and its lipophilic metabolites. Sympathoneural and adrenal medullary function was also studied, using plasma catecholamine isotope dilution methodology and regional central venous sampling. In the older men there was increased norepinephrine turnover in suprabulbar subcortical brain regions, 317 [+ or -] 50 ng/min compared with 107 [+ or -] 18 ng/min in younger men. A differentiated sympathetic nervous activation was also present in older men. Overall, levels of both cardiac and hepatomesenteric norepinephrine spillover were directly correlated with subcortical norepinephrine turnover. These findings suggest that in sympathetic nervous activation accompanying aging, as has previously been demonstrated with the sympathetic nervous stimulation in human hypertension and heart failure, there is an underlying sympathoexcitatory influence of noradrenergic projections to suprabulbar subcortical regions. epinephrine; heart; kidneys; adrenal medulla

Gender difference in the glucagon response to glucopenic stress in mice. Am J Physiol Regulatory Integrative Comp Physiol 282: R281-R288, 2002.--A gender difference in the glucagon response to insulin-induced hypoglycemia was previously demonstrated in humans. Whether this reflects a gender difference in autonomic activation or in pancreatic [alpha]-cell regulation is not known. We investigated the glucagon, epinephrine, and norepinephrine responses to neuroglycopenic stress induced by 2-deoxy-D-glucose (2-DG) or insulin in female and male mice. 2-DG increased plasma glucagon levels by 559 [+ or -] 68% in females versus 281 [+ or -] 46% in males (P < 0.01). Plasma levels of epinephrine or norepinephrine after 2-DG administration did not differ between genders. During insulin-induced hypoglycemia, the glucagon response was similarly higher in females (P < 0.001), whereas the plasma catecholamine response was higher in males (P < 0.05). In vivo, the glucagon response to carbachol or clonidine was higher in females (P < 0.05). In isolated islets, the glucagon response to carbachol (100 [micro]M; P = 0.003) but not to clonidine (1 [micro]M) was larger in females. We conclude that in addition to a larger [alpha]-cell mass (previously described in female mice), an increased sensitivity of the glucagon-producing [alpha]-cell to cholinergic activation contributes to the larger glucagon response to glucopenic stress in female mice. hypoglycemia; autonomic nervous system; epinephrine; norepinephrine; males; females

Cao, Wei-Hua, and Shaun F. Morrison. Differential chemoreceptor reflex responses of adrenal preganglionic neurons. Am J Physiol Regulatory Integrative Comp Physiol 281: R1825-R1832, 2001.--Adrenal sympathetic preganglionic neurons (ADR SPNs) regulating the chromaffin cell release of epinephrine (Epi ADR SPNs) and those controlling norepinephrine (NE ADR SPNs) secretion have been distinguished on the basis of their responses to stimulation in the rostral ventrolateral medulla, to glucopenia produced by 2-deoxyglucose, and to activation of the baroreceptor reflex. In this study, we examined the effects of arterial chemoreceptor reflex activation, produced by inhalation of 100% [N.sub.2] or intravenous injection of sodium cyanide, on these two groups of ADR SPNs, identified antidromically in urethane-anesthetized, artificially ventilated rats. The mean spontaneous discharge rates of 38 NE ADR SPNs and 51 Epi ADR SPNs were 4.4 [+ or -] 0.4 and 5.6 [+ or -] 0.4 spikes/s at mean arterial pressures of 98 [+ or -] 3 and 97 [+ or -] 3 mmHg, respectively. Ventilation with 100% [N.sub.2] for 10 s markedly excited all NE ADR SPNs (+222 [+ or -] 23% control, n = 36). In contrast, the majority (40/48; 83%) of Epi ADR SPNs were unaffected or slightly inhibited by ventilation with 100% [N.sub.2] (population response: +6 [+ or -] 10% control, n = 48). Similar results were obtained after injection of sodium cyanide. These observations suggest that the network controlling the spontaneous discharge of NE ADR SPNs is more sensitive to brief arterial chemoreceptor reflex activation than is that regulating the activity of Epi ADR SPNs. The differential responsiveness to activation of the arterial chemoreceptor reflex of the populations of ADR SPNs regulating epinephrine and norepinephrine secretion suggests that their primary excitatory inputs arise from separate populations of sympathetic premotor neurons and that a fall in arterial oxygen tension is not a major stimulus for reflex-mediated adrenal epinephrine secretion. hypoxia; sympathoexcitation; epinephrine; adrenal chromaffin cells Received 26 April 2001, accepted in final form 10 July 2001

Cryer, Philip E. Hypoglycemia-associated autonomic failure in diabetes. Am J Physiol Endocrinol Metab 281: E1115-E1121, 2001.--Hypoglycemia is the limiting factor in the glycemic management of diabetes. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response to falling glucose levels in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic and the resulting neurogenic symptom responses) and thus a vicious cycle of recurrent hypoglycemia. Perhaps the most compelling support for HAAF is the finding that as little as 2-3 wk of scrupulous avoidance of hypoglycemia reverses hypoglycemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected individuals. Insight into this pathophysiology has led to a broader view of the clinical risk factors for hypoglycemia to include indexes of compromised glucose counterregulation and provided a framework for the study of the mechanisms of iatrogenic hypoglycemia and, ultimately, its elimination from the lives of people with diabetes. glucagon; epinephrine; sympathetic nervous system

This article discusses the relationship between stress, blood pressure, and mood. An analysis of heart rate, job satisfaction, adrenaline, and cortisone is presented.

Byline: John A. Myburgh (1), Richard N. Upton (1), Cliff Grant (1), Allison Martinez (1) Keywords: Catecholamines Propofol Cardiac output First pass dilution Infusions Clearance Pharmacokinetics Abstract: Objective: To determine the effects of exogenous ramped infusions of epinephrine, norepinephrine and dopamine on arterial and effluent brain blood concentrations of propofol under steady state intravenous anesthesia. Design: Prospective, randomized animal study. Setting: University research laboratory. Subjects: Five adult female merino sheep. Interventions: Induction (5 mg/kg) and continuous infusion of propofol (15 mg/min) with controlled mechanical ventilation to maintain PaCO.sub.2 40 mmHg. After 1 h of continuous anesthesia, each animal randomly received ramped infusions of epinephrine, norepinephrine (10, 20, 40 Aug/min) and dopamine (10, 20, 40 Aug*kg*min) in 3x5 min intervals followed by a 30-min washout period. Measurements: Arterial and sagittal sinus whole blood for determination of propofol concentrations using high-pressure liquid chromatography. Cardiac output using a thermodilution method. Level of consciousness using an observational scale. Main results: All three drugs significantly and transiently increased cardiac output in a dose-dependent fashion to a maximum of 146--169% of baseline. Baseline arterial and sagittal sinus propofol concentrations were not statistically different prior to catecholamine infusions. All three drugs significantly reduced mean arterial propofol concentrations (95% CI, p Author Affiliation: (1) Department of Anaesthesia and Intensive Care, University of Adelaide, Royal Adelaide Hospital, Adelaide, Australia (2) Address for correspondence: Department of Intensive Care, The St George Hospital, Gray Street, Kogarah 2217, Sydney, Australia Article History: Received Date: 15/05/2000 Accepted Date: 03/11/2000 Article note: Electronic Publication

The relationship between lipolysis and adipose tissue blood flow (ATBF) in response to adrenaline and the effect of endurance exercise training on these responses were studied. Findings showed that the lipolytic and ATBF responses to adrenaline are coordinated when plasma adrenaline concentration is less than or equal to 1.6 nM. However, at higher adrenaline concentrations, lipolysis continues to increase while ATBF remains constant.

The rise in hepatic glucose production (HGP) during intense exercise is accompanied by a simultaneous increase in epinephrine, which indicates that adrenalin may be essential in regulating HGP. To further study this, six trained men were studied twice. Findings revealed that adrenalin may increase HGP during exercise in trained men. However, adrenalin during intense exercise cannot fully account for the increase in HGP.