Data Interpretation Practice Question: Lowacidine Schild Plot

Histamine stimulates the release of hydrochloric acid from parietal cells in the stomach muscosa by binding to histamine $($H$2)$ receptors. The potency of a novel reversible H$2$ receptor antagonist, $$Lowacidine$,$ was investigated using isolated gastric mucosa from the rat.

Dose response curves were prepared in the absence and presence of $$Lowacidine$.$ In cases where $$Lowacidine$$ was used, it was applied $1$h before the histamine. The effects of $$Lowacidine$$ were determined at four concentrations, and the resulting EC$50$ values are shown in the table below:

Lowacidine concentration $($M$)$ Histamine EC$50($M$)$

$02$ x $10-6$

$3\mathrm{.}16$ x $10-77$ x $10-6$

$1$ x $10-61\mathrm{.}46$ x $10-5$

$3\mathrm{.}16$ x $10-63\mathrm{.}37$ x $10-5$

$1$x $10-51\mathrm{.}28$ x $10-4$

$($a$)$ Explain what is meant by the term EC$50.$ In outline, how do you suggest the EC$50$ for histamine would have been determined in this example?

$($b$)$ Explain the meaning of the term $$pA$2$ value$$ for a competitive antagonist.

$($c$)$ Determine the pA$2$ value for $$Lowacidine$$ by plotting a Schild Plot of the effect of $$Lowacidine$$ on histamine induced acid secretion

The pA$2$ values for a further $5$ drugs under test $($A$-$E$)$ on histamine induced acid secretion were determined and are shown on the table below.

Drug pA$2$

A $4\mathrm{.}3$

B $9\mathrm{.}5$

C $3\mathrm{.}1$

D $3\mathrm{.}9$

E $7\mathrm{.}6$

d$.$ Which drug in the table is the most potent antagonist? Justify your answer. What concentration of drug C would produce an EC$50$ of $4$ x $10-6$M$?$ Explain your answer fully.

PTO

In further studies the effect of $$Lowacidine$$ as an antagonist at other histamine receptor subtypes was explored by using histamine$-$induced contraction in guinea$-$pig ileum $($H$1$ receptor$)$ and histamine$-$induced $($H$3$ receptor$)$ pre$-$synaptic inhibition of acetylcholine outflow in an isolated myenteric plexus preparation. The table of pA$2$ values generated is shown below.

Preparation $($receptor$)$

Ileum

$($H$1)$ Gastric mucosa $($H$2)$ Myenteric Plexus $($H$3)$

pA$2$ value

$5\mathrm{.}2$ Your data from above $4\mathrm{.}9$

e$.$ Suggest why the pA$2$ values for Lowacidine are different at each histamine receptor subtype. Explain why the testing of the $$Lowacidine$$ at a number of differing histamine receptor subtypes is necessary.