Daily exercise and gender influence arterial baroreflex regulation of heart rate and nerve activity

C. Y. Chen, S. E. DiCarlo
American Journal of Physiology - Heart and Circulatory Physiology Published 1 November 1996 Vol. 271 no. 5, H1840-H1848

  Before this study, groups had found that exercise training lead to differences in renal sympathetic nerve activity and heart rate, but information was lacking in other nerves. The previous studies had also used either all male or mixed males and female rats, but they hadn't looked specifically at males vs females despite the fact that there were some known differences between the sexes in terms of heart rate during changes in posture.
   Rats were allowed 8-9 weeks of sedentary conditions vs daily spontaneous running (DSR, just like our wheel runners) before being fitted with chronic catheters to allow drug infusion and monitor blood pressure and a chronic electrode to record lumbar sympathetic nerve activity (LSNA). Two days after surgery, the venous catheters were used to infuse PE or nitroglycerin to raise or lower blood pressure, respectively, by 25mmHg. Curves were constructed by comparing the drug-induced changes in blood pressure vs heart rate (HR) and LSNA, compared to resting values.
  DSR increased heart to body weight in both males and females, and caused a resting bradycardia in males but not females. Exercise reduced the maximum HR and its range (maximum minus minimum HR) in females, and the maximum and minimum HR, but not the range.  This corresponded with a DSR-induced reduction in maximum HR gain in females but not males. For LSNA, both males and female had an attenuation in maximum nerve activity and its range, and a corresponding decrease in maximum gain.
  I guess this all means that exercise training lets your body meet physiological demand without doing as much "work" in terms of HR or LSNA, which makes sense. There seems to be a disconnect between nerve activity and heart rate between the sexes though, because there were differences between male and female rats in HR but not LSNA. But trying to get at what those differences might be is an entirely different field with entirely different models. - DJH

The paper I read for this week’s blog directly related to our work using MEMRI and the mapping of brain regions in a rat experimental design of runners versus sedentary animals. MEMRI is commonly used to map the functional and structural organization of the brain. By using manganese as a retrograde tracer, it is able to give a visualization of tracks in the brain. This paper, Eschenko et al, followed closely to the experimental design we are currently studying in the lab. The first experiment utilized 12 rats that received a subcutaneous injection of manganese chloride and were scanned over a period of 16 days. The second experiment utilized 6 rats and were injected with manganese chloride with the intraperitoneal technique. They were tested for a total of one week. Finally, in the third experiment, manganese was enhanced using osmotic pumps. The osmotic pumps were surgically implanted and were used to slowly release manganese over time to eliminate any toxicity that may occur in have adverse effects on the data or even may cause death. The pump was placed into the intraperitoneal space. The most interesting aspect of this paper was the use of the osmotic pump to slowly release manganese into the animal and monitor them over time. This contrasts our experiment in such that we administered an intraperitoneal injection once and scanned the animal over the course of 3 weeks. There results indicated that the osmotic pumps having a slow release of manganese is more manageable by the bodies homeostatic mechanisms and will not produce and toxic effects. Secondly, the method was explored the ability of functional brain mapping in naturally behaving rats.

This is an interesting technique used in the lab and directly relates to our experiment. Depending on the results of our current research, I would be curious to see if we could use an osmotic pump in our rats and compare the results of IP vs Osmotic pump.

Dean

Hindlimb unloading and female gender attenuate baroreflex-mediated sympathoexcitation

Foley CM, Mueller PJ, Hasser EM, Heesch CM.
Am J Physiol Regul Integr Comp Physiol. 2005 Nov;289(5):R1440-7.

In this paper, they looked at the effect of simulated microgravity on renal sympathetic nerve activity (RSNA) and heart rate (HR) and the differences between male and female rats. It was already known that after either circumstance, people were generally less physiologically able to respond to the demands of even simple tasks, like standing up (i.e. they demonstrated orthostatic intolerance) and that women were more likely to have problems than men. This study tried to examine some of the causes of that phenomenon since the effects had been seen, but the causes weren't well demonstrated. They did this by partially suspending rats so that their back legs couldn't touch the ground - in essence, putting the rats through this hindlimb unloading (HU) made them "weightless" for 2 weeks.
Aside from significant reductions in the mass of muscles associated with running, the HU rats had higher resting mean arterial pressure (MAP) and HR compared to controls after they were returned to the ground. They also had a greater maximum HR on the MAP vs HR curve (tested via SNP and PE infusion). When they looked at the baroreflex curves of RSNA, they found that there were reductions in the maximum RSNA during decreases in MAP as a result of both being female and HU, with HU females having the least responsiveness to demand for RSNA. The midpoint of the curves also slightly shifted right (p=0.06), a result of increased in function when there may be no real need for it at higher MAPs.
The takehome message of this paper is a very translational approach to the kind of studies we do - life under different conditions can radically alter the function of the sympathetic nervous system and your ability to respond appropriately to physiological demand for more or less SNA, and these changes may be affect one sex more than the other. -DJH

Role of ventrolateral medulla in generating the 10-Hz rhythm in sympathetic nerve discharge

Susan M. Barman and Gerard L. Gebber
Am J Physiol Regul Integr Comp Physiol 293: R223–R233, 2007.

The main focus of this study is how inputs of selective and non-selective excitatory amino acid receptor antagonists affect the ventrolateral medulla (VLM) in generating a 10-Hz rhythm in sympathetic nerve discharge. Using urethane-anesthetized, baroreceptor-denervated cats, they would record the changes of frequency in both the right inferior cardiac and  left inferior cardiac nerves. After unilateral injections of bicuculline (GABA-A receptor antagonists) were giving 1 and 5 mm rostral to the obex in the VLM, they found it would completely remove or reduce the 10-Hz rhythm on both sides of the body. Similarly they did unilateral injections kynurenate, (nonselective excitatory amino acid receptor antagonist) but this time did the injections both caudal or rostral in the VLM. Results found that the 10-Hz frequency was reduced but not eliminated. This study shows that GABAerginc transmission is in some way necessary for this 10-Hz rhythm to occur in sympathetic nerve discharge and that both rostral and caudal GABAerginc neurons play a role. - ZAK

Renal And Cardiac Sympathetic Baroreflexes In Hypertensive Rabbits

Geoffrey A Head and Sandra L Burke
Clin Exp Pharmacol Physiol. 2001 Dec;28(12):972-5.

  In this study, rabbits either had a clip fixed around one renal artery to induce hypertension (known as the two kidney one clip or 2k1c technique) or were given a sham surgery. The rabbits’ renal sympathetic nerve activity (RNSA) and heart rate (HR) were compared between groups during infusion of drugs to raise or lower blood pressure (phenylephrine and nitroprusside, respectively).

  At 3 weeks after surgery, there was a strong reduction in the range/maximum nerve activity during decreases in blood pressure (36% lower than sham controls). However the maximum RSNA returned to levels near sham controls by 6 weeks. The resting point and curves for RSNA and HR were both shifted to the right, suggesting an attenuation in sensitivity in both parameters, at 3 and 6 weeks. This brings up questions in my mind about what structures of the baroreflex are being attenuated - because from a baroreceptor-centric point of view, the interpretation is correct... but from a very RVLM-centric point of view, you might try to argue that the baroreflex is actually being facilitated by 2k1c.

  Most interesting is that they say their results conflict with another group's paper showing an INCREASE in maximum RSNA after 2k1c. This was a difference in how the change was quantified. In the other paper, the change was measured as a percent of resting nerve activity, while in this paper it was measured as a percent of the max RSNA activated by a noxious stimulus (smoke). When the authors of this paper adapted the other way of measuring RSNA, they got the same results as the other group. So, how you normalize can make a lot of difference in interpreting your results. - DJH

Lesion of medullary catecholaminergic neurons is associated with cardiovascular dysfunction in rotenone-induced Parkinson's disease rats.

Zhang Z, Du X, Xu H, Xie J, Jiang H.
Eur J Neurosci. 2015 Sep;42(6):2346-55. doi: 10.1111/ejn.13012. Epub 2015 Jul 30.

-Direct link here
In this paper, they examined relationships in the loss of dopaminergic neurons in the substantia nigra with loss of catecholaminergic neurons in the RVLM in rat model cases of rotenone-induced Parkinson's Disease (PD). This is an interesting study because symptoms signifying sympathatic disorders (e.g. instability in heart rate and blood pressure, orthostatic intolerance, etc) are frequently linked with PD and are some of the early warning signs of the disease. They gave rats i.p. injections of rotenone, the insectiside that is known to induce a condition highly similar to PD, and examined groups at different time points. They found that, similar to humans, issues with control of blood pressure (and decreases in plasma epinephrine and norepinephrine) arose before the loss of midbrain dopaminergic neurons or the appearance of motor symptoms. They also noted a decreased influence of low frequencies on heart rate after rotenone, suggesting a decrease in sympathetic never activity. Most interestingly, they noted that there was a loss of TH and DBH positive neurons and a decrease of TH and DBH proteins in the RVLM. These changes occurred early, despite the fact that loss of catecholaminergic neurons occurred later and not at all in the CVLM and NTS, respectively.
So the big questions after reading this paper are what makes C1 neurons so sensitive to rotenone and what else wipes them out? Neuroplasticity is one thing, because it can be reversible... but losing them entirely is another. -DH

Injections of Algesic Solutions into Muscle Activate the Lateral Reticular Formation: A Nociceptive Relay of the Spinoreticulothalamic Tract.

Panneton WM, Gan Q, Ariel M.
PLoS One. 2015 Jul 8;10(7).

I wanted to take a look at this paper mainly because it is fairly similar to some of what we have done in our lab. Instead of stimulating the sciatic nerve, the injected algesic solutions (capsaicin, 6% NaCl, or low pH) into the gastrocnemius muscle, perfused the rats, and then compared the number of Fos+ cells in a number of regions involved in processing and responding to noxious stimuli. The number of Fos+ neurons in these regions was compared to the Fos+ neurons found in saline-injected rats. They analyzed the rostral and cuadal pons, rostral and caudal medulla, and the spinal cord.

Focusing on their results that correspond to our areas of research, they found that algesia caused more Fos+ neurons in both the RVLM and the CVLM, and not much in the RVMM (compare this to facial air puffs causing activation in the RVMM, but not in the RVLM, in last year's paper from the Dampney group), and that some of them were catecholaminergic neurons. Interestingly, even though the algesic solutions were injected unilaterally, Fos+ were not significantly different between sides of the brainstem - this either conflicts with other results (Pillowski group), or adds support to the idea of differential control. -DH