Spontaneously Hypertensive Rats Are Highly Vulnerable to AMPA-Induced Brain Lesions

Clotilde Lecrux et al.,
University of Caen, France.
Stroke. 2007
http://stroke.ahajournals.org/content/38/11/3007.full.pdf+html


The fact that chronic arterial hypertension is a major risk factor for cerebral ischemia is well known. However the mechanisms by which arterial hypertension induces brain damage is unknown. In this study the authors were interested in two important steps that could possibly result in understanding the mechanisms. First they compared the evolution of cerebral blood flow during transient ischemia, using a Doppler flowmetry probe between SHRs and WKYs. Secondly they examined the amount of brain damage induced by the administration of NMDA or AMPA (because following ischemia there is overactivation of these ionotropic glutamate receptors) into the striatum using 20 um section stained by thionin. Thirdly since in the SHRs the hypertension develops over a period of time as a control, hypertension was induced in a group of 5 weeks old WKYs rats by renal arterial stenosis and tested over a period of time. Finally they tested whether the increased sensitivity of SHRs to AMPA receptors is linked to the differential expression of its subunits in the striatum using western blot and RT-PCR. The present study provides evidence that SHRs show more specificity to AMPA receptors activation. Even though the levels of AMPA receptors subunits GluR1 and GluR2 were similar between both the strains, the phosphorylated form, pGluR1 is significantly higher in SHRs compared to WKYs. Further SHRs also expressed higher levels of CamKIIalpha protein in the striatum compared to WKYs. In addition, inhibition of this kinase significantly reduced the deleterious effects of AMPA receptors overactivation in the SHRs. This article suggests  that phosphorylation of AMPA receptors, at least in part may explain the propensity of this strain (SHRs) to stroke.

- Madhan

Monosynaptic connection from caudal to rostral ventrolateral medulla in the baroreceptor reflex pathway

S.K. Agarwal and F.R Calaresu

Department of Physiology, University of Western Ontario, London, Ont (Canada)

We already know that CVLM projects to RVLM; this article is one reason why that conclusion has been made. So the authors hypothesized that the CVLM neurons are activated by activation arterial baroreceptors, activation of NTS and there is a monosynaptic between the CVLM and RVLM.  In urethane anesthetized rats they recorded from several neurons within that CVLM. The tested the activity of these neurons by giving a bolus of PE to increase blood pressure and in order to activate the CVLM neurons. By using electrophysiology, they were able to record the activity of the neurons directly. They found that 20 were actually activated. Only 6 were activated by stimulation of the NTS. The same 6 neurons were activated by antidromatic stimulation of the RVLM.   The conclusion that they came to from the experiment were the following 1.) NTS has excitatory inputs to CVLM  2.) CVLM has neurons that are barosensitive and send inhibitory inputs to RVLM 3.) There is a monosynaptic connection between the CVLM and RVLM.

Mandatory Electrocardiographic Screening of Athletes to Reduce Their Risk for Sudden Death. Proven Fact or Wishful Thinking?

A little off-topic, but interesting nonetheless.
Because of their tragic nature, the media-at-large often emphasizes reports of young athletes dying of sudden cardiac arrest (the heart stops) during a practice or a game.  To address this obvious problem, many community groups and even some medical organizations have called for mandatory screening of young athletes for the kinds of electrical heart problems that may lead to a sudden arrest. A few of these programs sprung up in the early and mid-80s in Italy, Israel, and Minnesota USA. Well, the pendulum is beginning to swing the other way, and doctors are questioning the cost/benefit of screening all young athletes. That is the focus of this article.
A recent analysis of Italy's (The world's Ultimate Nannystate) ECG screening program, which ran for 25 years, showed a significant reduction in sudden cardiac death (SCD) during the program period. These authors questioned that result since, by comparison, SCD rates in Italy were high to start out with. A similar program was enacted in Israel in 1986, and the authors retrospectively analyzed the yearly standardized rates of SCD in competitive athletes from 1986-2006 to see if the screening program had an impact.
It did not.
In addition, a similar analysis of the Minnesota program showed the same result. Moreover, the authors concluded that even if one were to take the results of the Italian study as fact, it would cost around $1,500,000 in screenings and additional tests to save one life.Finally, because of the extrememly low incidence of SCD and the less-than-perfect specificity of the ECG, many many more healthy athletes would be excluded from participating because of palse positives than lives would be saved.
I'm not saying that morally one can put a price on human life, but since governments are often amoral they can, and they do.
Draw your own conclusion on how much a random young life is worth to the taxpayer.
-Nick

GABA(A) receptor activation at medullary sympathetic neurons contributes to postexercise hypotension.

Am J Physiol Heart Circ Physiol. 2002 May;282(5):H1615-24.

Kajekar R, Chen CY, Mutoh T, Bonham AC.

Department of Internal Medicine, University of California at Davis, Davis, California 95616, USA.

A single bout of mild or moderate exercise in a hypertensive individual leads to post exercise hypotension (PEH). Two important features of PEH are a reduction in sympathetic nerve activity (SNA) and an intact baroreflex system. In this study the authors investigated the possible mechanisms underlying PEH. The experiments were performed in male spontaneously hypertensive rats (SHR) seperated in two groups, PEH group were subjected to single bout of exercise on a motor driven treadmill at 15m/min, 10 degree for 40 min or to a sham exercise group (sham-PEH) placed in treadmill with no exercise for 40 min. This study provides some interesting findings, during PEH the spontaneous firing activity of the cardiovascular sympathetic neurons in the RVLM are significantly decreased along with a reduced lumbar SNA. The reduced neuronal activity were mediated at least in part by a GABAa receptor mechanism, which was tested by injection of muscimol and bicuculine on RVLM. Muscimol and bicuculine produced a current-related decrease and increase in unit activity respectively supporting the above findings. Finally they also found that during PEH the baroreceptor control of RVLM activity is reduced. These findings suggest the possibility that increased signaling of GABA at RVLM neurons may contribute to PEH by decreasing sympathetic outflow.

- Madhan

http://ajpheart.physiology.org/content/282/5/H1615.full.pdf+html

Depressor neurons in rabbit caudal medulla act via GABA receptors in rostral medulla

W.W. Blessing

Department of Medicine, Centre for Neuroscience, flinders University of South Australia, Bedford Park, 5042 South Australia, Australia

This article is an older article by Blessing. This laboratory investigated whether cardiovascular responses can be affected by CVLM and if RVLM is necessary for the transmission of the signal. They used microinjection technique, in order to investigate their question. Using male rabbits, they recorded from the renal nerve along with the arterial pressure and heart rate. They used horseradish peroxidase for histological identification of the areas that they injected into. Microinjections of bicuculline (bic), a GABA_A  receptor antagonist at different doses into the RVLM was done. Then after every bic microinjection they waited 5 minutes and then glutamate was injected in the CVLM.  For another group of rabbits they used a mixed agonist antagonist (Muscimol and bic) that was microinjected into the RVLM and then they either microinjected strychnine (glycine blocker) or Phenotolamine (α-adrenergic receptor blocker) and then injected glutamate in the CVLM and recorded the responses. What they found by doing the following experiments was that GABA is playing a role in modulating RVLM effects on sympathetic output by acting on GABA receptors in the RVLM. Also they found that CVLM does release GABA that acts on the GABA receptors in the RVLM to decrease sympathetic output. Finally they demonstrated that CVLM has an effect on cardiovascular responses by acting on GABA receptors in the RVLM and not by acting on glycine and α-adrenergic receptors.

Differential drives from rostral ventrolateral medullary neurons to three identified sympathetic outflows.

McAllen RM, May CN.


This article dates back to more than a decade ago. Microinjection of glutamate in the RVLM of cats have shown to drive the sympathetic outflow differentially based on the area stimulated. Muscle vasoconstrictor activity were driven when the injections were lateral whereas skin vasocontrictor responses were driven when the injections are medial with in the RVLM. In this study the authors were interested in investigating whether seperate RVLM neurons controlling different vasomotor outflows holds true for tissues other than skin and kidney. In addition they further studied the relative strenghts of such specific drives and the location of their cells of origin. Several microinjections of sodium glutamate were given in a grid like pattern covering the RVLM. All the recording were made in cats anesthetized using chloralose. Muscle vasoconstrictor (MVC), visceral vasoconstrictor (VVC), and renal sympathetic nerves (RSN) were recorded. Findings from this study suggest that each of these sympathetic outflow are driven by a seperate population of neurons with in the RVLM.

American Journal of Physiology, 1994
http://ajpregu.physiology.org/content/267/4/R935.full.pdf+html

-Madhan

Dendritic morphology of neurons in medial prefrontal cortex, hippocampus, and nucleus accumbens in adult SH rats.

The brain is very susceptible to hypertension-induced damage. In addition to the well-known increased risk of stroke in hypertensive patients, hypertension alone (rat model) can induce changes in neuron structure in a cognitive brain center. The aim of this study was to characterize the differences in neuron morphology in three cognitive centers, the medial Prefrontal Cortex (mPFC), Hippocampus (Hcx), and Nucleus Accumbens (NAcc). They utilized Golgi-Cox staining to analyze 1260 (!!) neurons in 21 spontaneously hypertensive rats (SHR) and 21 Wistar-Kyoto rats (WKY). They also measured blood pressure via a tail cuff in both groups to confirm the presence of hypertension. Finally, they assesed activity in a novel environment (i.e. curiosity). Dendritic spines, a morphologic structure, usually indicate the presence of a synapse. In general, spine density decreased in both groups over time while overall dendritic length remained the same. Spine density decreased more in SHR versus WHY. The activity level (or curiosity) of SHRs was greater than WKYs. The authors hypothesize that alterations in dopaminergic regulation in these centers is related to the behavioral differences documented between the two strains. They go on to suggest that alterations in these and other structures during hypertension are an important component of the hypertensive syndrome.

-Nick