Background/Aims:
The colonic H
+
, K
+
ATPase (HKA2) is a heterodimeric membrane protein that exchanges luminal K
+
for intracellular H
+
and is involved in maintaining potassium homeostasis. Under homeostatic conditions, the colonic HKA2 remains inactive, since most of the potassium is absorbed by the small intestine. In diarrheal states, potassium is secreted and compensatory potassium absorption becomes necessary. This study proposes a novel mechanism whereby the addition of penicillin G sodium salt (penG) to colonic crypts stimulates potassium uptake in the presence of intracellular nitric oxide (NO), under sodium-free (0-Na
+
) conditions.
Methods:
Sprague Dawley rat colonic crypts were isolated and pHi changes were monitored through the ammonium prepulse technique. Increased proton extrusion in 0-Na
+
conditions reflected heightened H
+
, K
+
ATPase activity. Colonic crypts were exposed to penG, L-arginine (a NO precursor), and N-nitro l-arginine methyl ester (L-NAME, a NO synthase inhibitor).
Results:
Isolated administration of penG significantly increased H
+
, K
+
ATPase activity from baseline, p 0.0067. Co-administration of arginine and penG in 0-Na
+
conditions further upregulated H
+
, K
+
ATPase activity, p <0.0001. Crypt perfusion with L-NAME and penG demonstrated a significant reduction in H
+
, K
+
ATPase activity, p 0.0058.
Conclusion:
Overall, acute exposure of colonic crypts to penG activates the H
+
, K
+
ATPase in the presence of NO. This study provides new insights into colonic potassium homeostasis.
Prostate cancer is a major health issue with an incidence of 1,100,000 worldwide. Eventually, 20–40% of curatively treated patients will face a biochemical recurrence. Lately, the treatment options in metastasized hormone sensitive prostate cancer (mHSPC) were rapidly evolving after years of stagnation. Encouraging results in clinical trials of combination treatment of androgen deprivation therapy with either chemotherapy or second-generation hormonal treatment indicate a paradigm shift in this clinical scenario. In the light of this, the current review is focusing on the concept and initial results of the Phase III (ARCHES) trial investigating enzalutamide plus androgen deprivation therapy in mHSPC. Moreover, a comprehensive appraisal of the expanding landscape of systemic therapies for mHSPC is provided.
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