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The explanation states that Ca+2 accumulates in the inner medulla and paipilla of the kidney to inhibit adenyl cyclase. Can someone explain to me how this inhibition occurs?
The explanation states that Ca+2 accumulates in the inner medulla and paipilla of the kidney to inhibit adenyl cyclase. Can someone explain to me how this inhibition occurs?
Lithium causes NDI by the same mechanism.The explanation states that Ca+2 accumulates in the inner medulla and paipilla of the kidney to inhibit adenyl cyclase. Can someone explain to me how this inhibition occurs?
Lithium causes NDI by the same mechanism.
I've actually never heard of that before. Which resource (and where) says that?
I could imagine that increased intracellular charge would shift the equilibrium to the left to disfavor G-alpha-s activation.
However, yet again, with respect to nephrogenic DI, I've still never heard of that.
Both Li and Ca inhibits adenylate cyclase, leading to decreased cAMP, w/o cAMP as 2nd messenger, V2 receptor (Gs) downstream signaling is blocked. This is why. It has nothing to do w/ IP3 mechanism.Inhibition of the phosphatidyl inositol cascade?
That just can't be right...
Where did you read that?
I would think that since lithium is a group ONE metal, if anything, sodium would demonstrate a greater propensity to act via that same pathway, versus calcium or magnesium, which are both group two alkalis.
Both Li and Ca inhibits adenylate cyclase, leading to decreased cAMP, w/o cAMP as 2nd messenger, V2 receptor (Gs) downstream signaling is blocked. This is why. It has nothing to do w/ IP3 mechanism.
Also HCTZ is used for non-Li-induced NDI, amiloride is used for Li-induced NDI, the rationale is that since amiloride blocks ENaC in DT & CD, there is higher Na+ in ductal lumen, and b/c Na & Li compete for reaborption, high Na+ competitive inhibits Li reaborption. HCTZ is not used b/c it increase distal Na delivery resulting in higher than normal Na reabsorption in DT & CD, this facilitates Li reaborption.
To answer the paradoxical question why HCTZ is used for NDI even though it causes hypercalcemia, it is really simple. HCTZ induces production of hyperosmotic urine, remember it acts on the diluting segment, so by preventing polyuira, HCTZ is acting in a way to conserve free water though not directly on the CD.
Nephrogenic diabetes insipidus can also be acquired during treatment with certain drugs, such as demeclocycline... and from electrolyte abnormalities such as hypokalemia and hypercalcemia. All causes of acquired nephrogenic diabetes insipidus have in common the decreased synthesis and function of aquaporin-2 due to impaired vasopressin signaling from V2 receptor binding and activation
Similar to hypokalemia another electrolyte disorder, hypercalcemia, also is associated with the development of NDI. An experimental model of vitamin Dinduced hypercalcemia has been used to study the molecular defects underlying the NDI seen in this disorder.27 Rats treated orally for 7 days with dihydrotachysterol showed a 3-fold increase in urine production, along with a 50% reduction in urine osmolality. Consistent with this, immunoblotting of membrane fractions showed a 50% reduction in AQP2 expression in kidney inner medulla from hypercalcemic rats. Wang et al28 have elucidated the molecular mechanism of this disorder further. They showed that in addition to downregulation of collecting duct AQP2 expression, there was also a significant downregulation of the bumetanide-sensitive Na-K-2Cl cotransporter BSC-1 in membranes from inner the stripe of the outer medulla. This defect in the thick ascending limb may participate in the development of the urinary concentrating defect.
Results We demonstrated that extracellular calcium (Ca2+o) (5 mmol/L) strongly inhibited forskolin-stimulated increase in AQP2 expression in the apical plasma membrane. At least three intracellular pathways activated by extracellular calcium were found to contribute to this effect. Firstly, the increase in cAMP levels in response to forskolin stimulation was drastically reduced in cells pretreated with Ca2+o compared to untreated cells. Second, Ca2+o activated PKC, known to counteract vasopressin response. Third, quantification of F-actin demonstrated that Ca2+o caused a nearly twofold increase in F-actin content compared with basal conditions. All these effects were mimicked by a nonmembrane permeable agonist of the extracellular CaR, Gd3+.
Both Li and Ca inhibits adenylate cyclase, leading to decreased cAMP, w/o cAMP as 2nd messenger, V2 receptor (Gs) downstream signaling is blocked. This is why. It has nothing to do w/ IP3 mechanism.
Also HCTZ is used for non-Li-induced NDI, amiloride is used for Li-induced NDI, the rationale is that since amiloride blocks ENaC in DT & CD, there is higher Na+ in ductal lumen, and b/c Na & Li compete for reaborption, high Na+ competitive inhibits Li reaborption. HCTZ is not used b/c it increase distal Na delivery resulting in higher than normal Na reabsorption in DT & CD, this facilitates Li reaborption.
To answer the paradoxical question why HCTZ is used for NDI even though it causes hypercalcemia, it is really simple. HCTZ induces production of hyperosmotic urine, remember it acts on the diluting segment, so by preventing polyuira, HCTZ is acting in a way to conserve free water though not directly on the CD.
Nephrogenic DI (diabetes insipidus)—Why treat a water-wasting disease with a diuretic? Thiazides increase renal Na excretion → ECF volume contraction → ↓ GFR → ↑ proximal tubular reabsorption of water and Na ∴ less water and Na are lost as urine
Both Li and Ca inhibits adenylate cyclase, leading to decreased cAMP, w/o cAMP as 2nd messenger, V2 receptor (Gs) downstream signaling is blocked. This is why. It has nothing to do w/ IP3 mechanism.
Second, Ca2+o activated PKC, known to counteract vasopressin response.
The explanation states that Ca+2 accumulates in the inner medulla and paipilla of the kidney to inhibit adenyl cyclase. Can someone explain to me how this inhibition occurs?
I think you simply need to know the high yield facts to answer this question. Li,Ca & Na are, for our purposes, cause similar pathology in kidneys when in excessive amounts due to their relationship on the periodic table.