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Research Highlights from the Literature

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2004; Volume 14(3) from Clinical Autonomic Research    
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Electrical stimulation of carotid sinus nerves.  A novel treatment for hypertension?        

Chronic hypertension is characterized by resetting of arterial baroreflex, and reduced baroreflex gain with increased sympathetic activity.  It is not clear if baroreflex dysfunction is a primary event in the development of hypertension or simply its consequence, and the role of baroreflexes in long-term control of arterial pressure is unresolved. Regardless, it is possible that chronic activation of the baroreflex could produce sustained hypotension, and this may represent a novel approach to treat drug-resistant hypertension.  In a proof-of-concept study, Lohmeier et al chronically implanted electrodes around both carotid sinuses in dogs.  Electrical activation of the carotid baroreflex produced a prompt and substantial reduction in blood pressure, which was sustained throughout the entire 7 days of baroreflex activation. Heart rate decreased in parallel with blood pressure, as did plasma norepinephrine. Plasma renin activity did not increase despite the sustained fall in blood pressure.  Hemodynamic measures and plasma norepinephrine returned to control levels once baroreflex stimulation was stopped. These data indicate that prolonged baroreflex activation can lead to substantial reductions in blood pressure by suppressing the sympathetic nervous system. Furthermore, sustained sympathoinhibitory effects on renin secretion may contribute to the long-term hypotensive response.

Lohmeier,TE, Irwin,ED, Rossing,MA et al (2004)  Prolonged Activation of the Baroreflex Produces Sustained Hypotension.  Hypertension 43 (part 2):306-311.


Impaired autonomic function contributes to hypertension

Increased sympathoadrenergic activation is thought to contribute to the maintenance of elevated blood pressure levels in hypertension. Increased sympathetic activity could be related to impaired baroreflex restrain (see above), abnormalities in central regulation, or potentiation of sympathetic actions in the periphery.  Zugck et al explored the later possibility by examining sympathetic neurotransmission in isolated perfused hearts from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls.  Electrical field stimulation evoked a higher norepinephrine (NE) overflow from SHR than from WKY hearts. The difference in stimulation-evoked NE overflow was neither due to increased NE stores nor to a higher density of sympathetic nerve endings in SHR hearts. Furthermore, impairment of cardiac NE re-uptake was ruled out, as pharmacological inhibition of NE re-uptake by desipramine similarly increased NE overflow from SHR and WKY hearts. However, inhibition of presynaptic alpha-2 adrenoceptors (alpha-2R) with yohimbine resulted in a significantly larger increase in NE overflow from WKY than from SHR hearts, indicating impairment of presynaptic inhibitory effect of alpha-2R in SHR. Supporting this notion, mRNA concentrations of alpha-2(A), the predominant presynaptic alpha-2R subtype, were reduced in SHR in left stellate ganglia compared with WKY. The authors conclude that the impairment of the alpha-2R mediated presynaptic negative feedback mechanism by a reduced expression of the alpha-2R subtype A may increase cardiac net secretion of NE in SHR and could therefore contribute to their hypertensive phenotype               

Zugck,C, Lossnitzer,D, Backs,J et al (2003)  Increased cardiac norepinephrine release in spontaneously hypertensive rats: role of presynaptic alpha-2A adrenoceptors.  J Hypertens 21:1363-1369.


The beneficial effects of statins may be mediated by improving autonomic function

            Statins are increasingly important in the treatment of cardiovascular diseases.  Their use is likely to expand with the recently lowering of what is considered normal LDL cholesterol levels. Furthermore, some argue that statins should be used in high risk patients even if their cholesterol levels are within normal levels, and the beneficial actions of statins may not be due solely to a reduction in cholesterol levels.  Pliquett et al. previously suggested that the beneficial effects of statins may be related to a reduction in sympathetic tone, based on the finding that simvastatin lowered renal sympathetic nerve activity (RNSA) and improved baroreflex function in conscious normolipemic rabbits with congestive heart failure (CHF, see Autonomic News 13 (4);2003). They now used the same model to assess the effects of statins on indices of cardiac autonomic function.  Simvastatin was given to rabbits with pacing-induced CHF over a 3-wk period. Normal and CHF vehicle-treated rabbits served as controls. CHF was associated with a reduction in heart rate variability, as evidence by a decrease in total power and low and high frequency power of spectral analysis.  Simvastatin improved these indices in a dose related manner.  The authors suggest that statins can be used to treat the autonomic imbalance seen in CHF and recognized as an independent risk factor.  It should be noted, however, that both low and high frequency variabilities were improved without changes in the low-to-high frequency ratio.  It was not determined whether this actually reflected increased cardiac sympathetic function.

Pliquett,RU, Cornish,KG, and Zucker,IH (2003)  Statin therapy restores sympathovagal balance in experimental heart failure.  J Appl Physiol 95:700-704.


Nerve factors important in the development of sympathetic neurons

The neurotrophin nerve growth factor (NGF) plays a crucial role in the development of the sympathetic nervous system. In addition to being required for sympathetic neuron survival in vivo and in vitro, NGF has been shown to mediate axon growth in vitro. Gene deletion approaches to study the role of NGF in sympathetic axon growth in vivo, however, have been unsuccessful because this gene is required for survival. This requirement can be circumvented by a concomitant deletion of Bax, a pro-apoptotic Bcl-2 family member.   Using this approach, Glebova and Ginty generated mice deficient for both NGF and Bax to determine how this would affect peripheral sympathetic target organ innervation. In embryonic and neonatal NGF-/-; Bax-/- mice, sympathetic target innervation was absent in certain organs (such as salivary glands), greatly reduced in others (such as heart), somewhat diminished in a few (such as stomach and kidneys), but not significantly different from control in some (such as trachea). Thus, NGF appears to be required for complete peripheral innervation of both paravertebral and prevertebral sympathetic ganglia targets in vivo independently of its requirement for cell survival. Remarkably, target organs vary widely in their individual NGF requirements for sympathetic innervation.

Yan et al examined the ability of glial cell line-derived neurotrophic factor (GDNF), neurturin, and artemin to induce neurite outgrowth from dorsal root, superior cervical, and lumbar sympathetic ganglia from mice at a variety of development stages, by explanting ganglia onto collagen gels and growing them in the presence of agarose beads impregnated with the different GDNF family ligands. Artemin, GDNF, and neurturin were all capable of influencing neurite outgrowth from dorsal root and sympathetic ganglia, but the responses of each neuron type to the different ligands varied during development. E.g., neurites from dorsal root ganglia responded to artemin at postnatal (P) day 0 and P7, to GDNF at embryonic (E) day 15 and P0, and to neurturin at E15, P0, and P6/7. Neurites from superior cervical sympathetic ganglia and from lumbar sympathetic ganglia responded also to this neurotrophic factor at slightly different development periods.  In general, artemin seems to play a role in inducing neurite outgrowth from sympathetic neurons in the early stages of sympathetic axon pathfinding, whereas GDNF and neurturin are likely to be important at later stages of sympathetic neuron development. Superior cervical and lumbar sympathetic ganglia showed temporal differences in their responsiveness to artemin, GDNF, and neurturin, which probably partly reflects the rostrocaudal development of sympathetic ganglia and the tissues they innervate.

Glebova,NO and Ginty,DD (2004)  Heterogeneous requirement of NGF for sympathetic target innervation in vivo.  J Neurosci 24:743-751.

Yan,H, Newgreen,DF, and Young,HM (2003)  Developmental changes in neurite outgrowth responses of dorsal root and sympathetic ganglia to GDNF, neurturin, and artemin.  Dev Dyn 227:395-401.


Water prevents tilt-induced syncope and augments the pressor effects of ephedra alkaloids

Water ingestion raises blood pressure substantially in patients with perturbed autonomic control and more modestly in older subjects. Lu et al examined if prophylactic water drinking improves orthostatic tolerance to head up tilt in normal healthy adults. They found that 8 of 22 subjects experienced presyncope during the first 30 minutes of tilt, but only 1 experience presyncope the day they drank 16 oz water 5 minutes before tilt.  Water drinking attenuated the heart rate increase associated with tilt while accentuating the increase in total peripheral resistance. The average time study participants tolerated head-up tilt was 26% longer after water (41vs 33 minutes), with a pairwise mean difference of 8 minutes (95% CI, 2.3 to 14.7 minutes). Thus, water enhances tolerance of upright posture in part by increasing peripheral vascular resistance. Water ingestion may constitute a simple and effective prophylaxis against predictable vasovagal reactions in healthy subjects, such as those associated with blood donation (See also Schroeder et al Circulation 2002;106:2806-2811; and Autonomic News, Clin Auton Res 2003;13:4). 

            The use of ephedra alkaloids in over-the-counter preparations has been associated with potentially serious cerebrovascular events.  Because of its potential association with hemorrhagic strokes, phenylpropanolamine (PPA) has been largely substituted by pseudoephedrine, but it is not clear if this is indeed a safer alternative.  It would be important to understand the cardiovascular effects of ephedra alkaloids, but these are normally masked by baroreflex buffering mechanisms.  Jordan et al, therefore, investigated the effects of ephedra alkaloids in patients with autonomic impairment, and explored their potential interaction with water ingestion.  Both PPA and pseudoephedrine, at doses found in nasal decongestants, increased systolic blood pressure (SBP) significantly, and this effect was even greater if given with 500 ml water.  E.g., PPA increased SBP by 822 mm Hg when given with water.  Thus, ephedra alkaloids increase blood pressure significantly in individuals with impaired baroreflex function.  Concomitant ingestion of ephedra alkaloids and water produced a greater increase in blood pressure.  If used cautiously, this interaction can be beneficial in the treatment of orthostatic hypotension.  On the other hand, it could contribute to the cardiovascular complications associated with the use of ephedra alkaloids, considering that baroreflex function varies widely in normal individuals and is impaired in several medical conditions.  Because the mechanism by which ephedra alkaloids may be associated with hemorrhagic strokes is not understood, it seems prudent to reserve pseudoephedrine for patients unresponsive to other therapies.

Lu,CC, Diedrich,A, Tung,CS et al (2003)  Water ingestion as prophylaxis against syncope.  Circulation 108:2660-2665.

Jordan,J, Shannon,JR, Diedrich,A et al (2004)  Water Potentiates the Pressor Effect of Ephedra Alkaloids.  Circulation 109:1823-1825.