Key points
The adrenal hormone aldosterone can stimulate K+ secretion during hyperkalaemia and Na+ reabsorption during hypovolaemia in the kidney.
Angiotensin II is thought to switch the ...physiological mode of action from K+ excretion towards Na+ retention, but how the regulation is achieved when angiotensin II levels are suppressed by high Na+ intake remains unknown.
We report that both dietary K+ depletion and dietary K+ loading provoke renal Na+ retention and increase blood pressure in Na+ replete mice, but these occur through different renal kinase signalling and Na+ transport pathways.
An angiotensin II‐ and aldosterone‐independent activation of the sodium‐chloride cotransporter NCC contributes to the blood pressure increase induced by K+ depletion, whereas the hypertensive response to K+ loading is dependent on neither aldosterone nor Na+ transport via the epithelial sodium channel ENaC.
These findings imply a major impact of K+ homeostasis on renal Na+ handling in the Na+ replete state and suggest a mechanism for the hypertensive effect of the Western diet (high Na+ and low K+) in humans.
A network of kinases, including WNKs, SPAK and Sgk1, is critical for the independent regulation of K+ and Na+ transport in the distal nephron. Angiotensin II is thought to act as a key hormone in orchestrating these kinases to switch from K+ secretion during hyperkalaemia to Na+ reabsorption during intravascular volume depletion, thus keeping disturbances in electrolyte and blood pressure homeostasis at a minimum. It remains unclear, however, how K+ and Na+ transport are regulated during a high Na+ intake, which is associated with suppressed angiotensin II levels and a high distal tubular Na+ load. We therefore investigated the integrated blood pressure, renal, hormonal and gene and protein expression responses to large changes of K+ intake in Na+ replete mice. Both low and high K+ intake increased blood pressure and caused Na+ retention. Low K+ intake was accompanied by an upregulation of the sodium‐chloride cotransporter (NCC) and its activating kinase SPAK, and inhibition of NCC normalized blood pressure. Renal responses were unaffected by angiotensin AT1 receptor antagonism, indicating that low K+ intake activates the distal nephron by an angiotensin‐independent mode of action. High K+ intake was associated with elevated plasma aldosterone concentrations and an upregulation of the epithelial sodium channel (ENaC) and its activating kinase Sgk1. Surprisingly, high K+ intake increased blood pressure even during ENaC or mineralocorticoid receptor antagonism, suggesting the contribution of aldosterone‐independent mechanisms. These findings show that in a Na+ replete state, changes in K+ intake induce specific molecular and functional adaptations in the distal nephron that cause a functional coupling of renal K+ and Na+ handling, resulting in Na+ retention and high blood pressure when K+ intake is either restricted or excessively increased.
Imaging studies help us understand the important role of brainstem and midbrain regions in human trigeminal pain processing without solving the question of how these regions actually interact. In the ...current study, we describe this connectivity and its dynamics during nociception with a novel analytical approach called Partial Similarity (PS). We developed PS specifically to estimate the communication between individual hubs of the network in contrast to the overall communication within that network. Partial Similarity works on trial-to-trial variance of neuronal activity acquired with functional magnetic resonance imaging. It discovers direct communication between two hubs considering the remainder of the network as confounds. A similar method to PS is Representational Similarity, which works with ordinary correlations and does not consider any external influence on the communication between two hubs. Particularly the combination of Representational Similarity and Partial Similarity analysis unravels brainstem dynamics involved in trigeminal pain using the spinal trigeminal nucleus (STN)—the first relay station of peripheral trigeminal input—as a seed region. The combination of both methods can be valuable tools in discovering the network dynamics in fMRI and an important instrument for future insight into the nature of various neurological diseases like primary headaches.
In this study, we evaluated whether combined treatment with ketamine (KET), an N-methyl-D-aspartate receptor antagonist, and morphine (MO) results in positive analgesic effects. Eleven volunteers ...were exposed to a skin burn injury on the leg. The effects of IV KET (9 microg. kg(-1). min(-1); 45 min) and MO (10 microg. kg(-1). min(-1); 10 min) alone and in combination, as well as placebo (saline; 10 min), were studied in a randomized, crossover, double-blinded design. The area of secondary hyperalgesia (SH) for mechanical stimulation was diminished by KET as compared with placebo. Mechanical pain thresholds were increased severalfold with KET and with KET plus MO, both in the primary hyperalgesic (PH; burn injury) and SH area. MO infusion showed no effect on the SH area or pain threshold. Windup-like pain was evaluated by continuous assessment on a visual analog scale during 30 s of repetitive stimulation (40-g load at 3 Hz) and analyzed as a sum of pain scores. The combined treatment (KET plus MO) almost abolished windup-like pain both in the PH and the SH areas, an effect that was not present with monotherapy with KET or MO. This study provides experimental support for a positive analgesic interaction between an N-methyl-D-aspartate receptor antagonist and an opioid on central summation of pain.
This is the first experimental study in humans to find synergistic analgesic effects with coadministration of the N-methyl-D-aspartate receptor antagonist ketamine and morphine on pain involving central sensitization phenomena.
Musculoskeletal pain is a major clinical problem. By using various experimental models in humans, the understanding of the basic mechanisms behind muscle pain can increase, thereby giving hope for ...new and optimized treatment. Opioids are increasingly often used to treat muscle pain. There are, however, a limited number of previous studies on opioids and muscle pain, most of them using a relative low, single dose. Therefore, we wanted to further study the effect of two rather high doses of alfentanil (25 and 75
ng/ml) and morphine (0.14 and 0.28
mg/kg) in human volunteers. The study consisted of two parallel studies with morphine and alfentanil, respectively, and was conducted as randomized, double-blinded, placebo-controlled, 3-way cross-over. We used intramuscular infusion of hypertonic saline and intramuscular electrical stimulation to induce experimental pain. Visual analog scale (VAS)-score, intramuscular electrical pain thresholds and pain area (local and referred) were measured.
Both alfentanil and morphine at their highest doses induced a 6 to 7-fold increase in pain thresholds to single and repetitive (5 stimulations, 2
Hz) electrical stimulation. Alfentanil and morphine also reduced VAS score about 4 to 5-fold during suprathreshold electric stimulation and during infusion of hypertonic saline. None of the drugs decreased referred pain. There were no apparent differences between the drugs, in terms of effect or adverse reactions.
In conclusion, this is the first study to compare two high doses of alfentanil and morphine on experimental muscle pain in humans. Both alfentanil and morphine reduced experimental muscle pain. There were no indications of any true pharmacodynamic differences between the two drugs.
This study examines the dose dependent analgesic effects of two doses of morphine and a single dose of alfentanil on experimentally induced cutaneous pain. In 16 healthy volunteers pain was induced ...by a skin burn injury and by continuous electrical skin stimulation. Mechanical pain thresholds (PT, von Frey filament), area of secondary hyperalgesia (SH) and ‘wind-up like pain’ upon repetitive stimulation (40-g load, 3
Hz, 30
s) were assessed. Analgesic effects on these pain parameters were tested at steady-state IV infusions of morphine, 50% (plasma concentration 15
ng/ml) and 100% (plasma concentration 30
ng/ml) of maximal tolerable dose to be given to healthy volunteers, and with an effective dose of alfentanil (plasma concentration 70
ng/ml). All effects were compared to active placebo, midazolam infusion (20
μg/kg for 10
min). Alfentanil significantly diminished the SH area in the burn injury model as well as in the electrical pain model. Additionally, alfentanil increased PT several fold in both models. The high dose of morphine showed a similar analgesic response pattern as alfentanil even though the effects were only statistically significant in the electrical pain model. The low dose of morphine as well as placebo did not affect these pain parameters. ‘Wind-up like pain’ was not influenced by any of the given drugs. In conclusion, the present study clearly indicates dose dependent effects of morphine on experimentally induced cutaneous pain. The high dose of morphine (30
ng/ml) was approximately equianalgesic to the administered alfentanil dose (70
ng/ml).
Purpose
To investigate if the
T
2
* of Achilles tendons can discriminate between chronic Achilles tendinosis and healthy controls; to correlate with clinical score; to evaluate its short‐term ...repeatability; and to estimate minimal detectable change.
Materials and Methods
Twenty patients, with chronic mid‐portion Achilles tendinosis, and 10 controls without history of Achilles tendon symptoms, were examined with a 3T MR scanner with a 3D flash ultrashort time to echo sequence with five different echo times. The sequence was run twice to test repeatability. The tendon border was delineated on axial slices at three different levels in the calculated
T
2
* maps. The clinical severity of Achilles tendinosis was measured by a VISA‐A questionnaire.
Results
There was a significant difference in mean
T
2
* between symptomatic and control tendons (
P
< 0.001). In patients with unilateral symptoms no significant difference in
T
2
* was found between symptomatic and contralateral asymptomatic tendons (
P
= 0.19). There was no significant correlation between clinical severity and
T
2
* (
r
= –0.28,
P
= 0.22). The short‐term repeatability of
T
2
* showed a coefficient of variation of 18%, a least significant change of 50%, and the intraclass correlation coefficient had an average consistency of 0.99.
Conclusion
T
2
* may help to differentiate between chronic Achilles tendinosis and healthy controls but was not associated with the clinical score. However, and notably, the reproducibility of the method was low and the number of patients was small. J. Magn. Reson. Imaging 2016;43:1417–1422.
Background: Muscle pain is a major clinical problem but the underlying mechanisms and its pharmacological modulation need further investigation. This study on 15 volunteers evaluates if two ...experimental muscle pain models are sensitive to µ‐receptor agonists and to an N‐methyl‐D‐aspartate (NMDA)‐receptor antagonist.
Methods: In the left tibialis anterior, intramuscular electrical (IMES) pain thresholds were determined for single (SPTmuscle) and five (RPTmuscle) repeated stimuli. Also pain to suprathreshold stimulation at 150% of RPTmuscle, 10 s, was assessed on a visual analog scale (VAS) as AUCimes (area under the VAS curve). In the right TA muscle, pain intensity on infusion of 0.5 ml of hypertonic saline, 5% (AUCsaline) and pain distribution indicated as local and referred were evaluated. Pain variables were assessed before, during and after intravenous infusions of morphine (10 µg kg−1 min−1, 10 min), alfentanil (target‐controlled infusion, plasma concentration; 60 ng ml−1, 60 min) and ketamine (10 µg kg−1 min−1, 60 min). All data were normalized to baseline pain values (before drug infusions were initiated) and compared with placebo (midazolam, 2 µg kg−1 min−1, 10 min).
Results: SPTmuscle increased (log mean values ± SD, mA) with morphine (0.11 ± 0.17, P < 0.05), alfentanil (0.28 ± 0.24, P < 0.001) and ketamine (0.19 ± 0.18, P < 0.01) as compared with placebo (−0.03 ± 0.12). Alfentanil and ketamine also increased RPTmuscle (0.25 ± 0.21, P < 0.01 and 0.21 ± 0.19, P < 0.05, respectively) as compared with placebo (0.00 ± 0.17). Pain to IMES (AUCimes) was reduced (median values 25th−75th percentiles, cm × s) by alfentanil and ketamine (−19.7 −14.6 – −29.6 and−12.8 −8.3 – −27.8, P < 0.05, respectively) vs. placebo (−0.8 1.6 – −12.3). Similar drug effects were seen when pain to infusion of hypertonic saline (AUCsaline) was assessed (alfentanil:−388 −99 – −677 and ketamine:−326 −227 – −573, P < 0.05 compared with placebo: 150 449–−240). Ketamine also reduced the size of the local pain area (−58.4 −21.2 – −176.1, < 0.05) as compared with placebo (−0.4 70.6 – −13.4). The frequency of referred pain was also lower when ketamine was given (3/13, P < 0.05) vs. placebo (9/14).
Conclusion: The study demonstrates that experimental muscle pain induced in humans by electrical stimulation and infusion of hypertonic saline is sensitive to pharmacological modulation similar to preclinical animal tests and clinical trials. The data suggest that these models can be valuable tools in analgesic drug development.
Purpose
To investigate if the T2* of Achilles tendons can discriminate between chronic Achilles tendinosis and healthy controls; to correlate with clinical score; to evaluate its short‐term ...repeatability; and to estimate minimal detectable change.
Materials and Methods
Twenty patients, with chronic mid‐portion Achilles tendinosis, and 10 controls without history of Achilles tendon symptoms, were examined with a 3T MR scanner with a 3D flash ultrashort time to echo sequence with five different echo times. The sequence was run twice to test repeatability. The tendon border was delineated on axial slices at three different levels in the calculated T2* maps. The clinical severity of Achilles tendinosis was measured by a VISA‐A questionnaire.
Results
There was a significant difference in mean T2* between symptomatic and control tendons (P < 0.001). In patients with unilateral symptoms no significant difference in T2* was found between symptomatic and contralateral asymptomatic tendons (P = 0.19). There was no significant correlation between clinical severity and T2* (r = –0.28, P = 0.22). The short‐term repeatability of T2* showed a coefficient of variation of 18%, a least significant change of 50%, and the intraclass correlation coefficient had an average consistency of 0.99.
Conclusion
T2* may help to differentiate between chronic Achilles tendinosis and healthy controls but was not associated with the clinical score. However, and notably, the reproducibility of the method was low and the number of patients was small. J. Magn. Reson. Imaging 2016;43:1417–1422.
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