Fig. 58. Concentration-response curves representing the contraction of the isolated ileum of the guinea pig by histamine, plotted according to Lineweaver and Burk. The pH is varied for the various curves. Note that the curves obtained suggest a competitive relation between histamine and the Η ions. After Rocha e Silva (154).
culated for t h e Η ions (167,168). The concentration of t h e Η ions a t higher p H values ( + 8) m a y be ignored. The p^42 value found is 6.81 ( P9 5 * + 0.11), calcu
lated from 54 experiments performed on 42 organs of 13 animals. The p^42
value is a measure for t h e value of t h e ipKa of t h e anionic site on t h e receptor.
The value obtained is quite comparable t o t h a t found by Rocha e Silva (154), mentioned above.
The pH-dependency of t h e action of a n u m b e r of acetylcholinomimetics, q u a t e r n a r y ammonium bases, on t h e rectus abdominis muscle of t h e frog was also studied. No change in t h e activity occurred with a change in t h e p H over a wide range. The dose-response curves for B u N M e3, for instance, remained
* P95 is the probability interval of the mean value.
382 Ε. J . ARIENS, Α. Μ. SIMONIS, A N D J . Μ. VAN ROSSUM
unchanged over a p H range from 4 t o 8. This means t h a t t h e ~$Ka value of t h e anionic site on t h e receptor is relatively high. This site might, for instance, be constituted of a phosphate group. Because of these relations, t h e rectus abdominis muscle of t h e frog is suitable for studying t h e effect of t h e p H on t h e degree of drug dissociation as an influential component of drug action. For this purpose, an acetylcholinomimetic with a relatively low p l £a value is needed.
Arecoline is mentioned t o have a pKa value of 7.5 (4) and, therefore, seemed log concentration (mg/1)
-6.0 η
6 . 4 6 . 8
-V * \ -V
\ Vx *
- 7 . 2 - \ > I V
\ 1 *
7 . 6
-, Ψτ-, δ
\ : !! •
-8.0
- 8 . 4 - \\\\
I ! ' ""T 1 1 Γ"1
6.4 6.8 7.2 7.6 8.0 8.4
FIG. 5 9 . Experimental curves (isoboles) representing the relation between the pH and the concentration of histamine (dissociated + undissociated) for contractions 5 0 % of the maximum (guinea pig ileum). Note that the curves bend at a pH of about 7, which sug
gests a pKa value for the histamine receptors of about 7. After Rocha e Silva (154).
t o be suitable. However, contrary t o expectations, no clear pH-dependency was found. A check of t h e p Ka value of arecoline showed t h a t it is a b o u t 8.1. This makes it understandable t h a t t h e action of t h e drug is practically not p H -dependent (on a p H range of 4 t o 8). Among t h e m a n y acetylcholinomimetics active on t h e isolated rectus abdominis muscle, no drug could be found with a -pKa value of about 7; all active compounds appeared to have pif a values of a t least 8.5. Also, among t h e acetylcholinolytics with a curarimimetic action no compounds could be found with pKa values sufficiently low t o s t u d y t h e influence of t h e variation in degree of ionization of the cationic groups on t h e activity.
Schild (169a) reported t h a t t h e contraction of t h e ileum of t h e guinea pig
Ι,Π.Β. DIFFERENT RECEPTOR SYSTEMS 383
FIG. 60. A and B. Registrogram of cumulative dose-response curves for histamine. A. Obtained at various values for the pH. Note the shift of the curves to higher concentrations of histamine after lowering of the pH. The lower the pH (the higher the H+ concentration), the larger the shift. These experiments suggest a competitive relation between histamine and the Η ions (compare with Β). B. In the presence of various concentrations of the competitive antagonist neobenodine. Note the shift of the curves to higher concentrations of histamine in the presence of neobenodine. The shift increases with an increase in the neobenodine concentration.
384 Ε. J. ARIENS, Α. Μ. SIMONIS, A N D J. Μ. VAN ROSSUM
caused by acetylcholine is maintained a t p H 9. The contraction induced by t h e relatively weak base, pilocarpine, is t h e n abolished, probably as a result of t h e decrease in t h e q u a n t i t y of ionized base. The conclusion is t h a t t h e cholinergic bases are active only in t h e dissociated form.
The influence of t h e p H on t h e action of acetylcholinomimetics on t h e iso
lated gut of t h e r a t and guinea pig differed from t h a t on t h e rectus abdominis muscle of t h e frog. For t h e isolated gut, a variable degree of p H dependency was found. A relatively small shift in t h e curves occurred a t p H 4, b u t only in a fraction of t h e experiments. The acetylcholinomimetics used are strong q u a t e r n a r y bases. This implies t h a t t h e dependency of t h e action on t h e p H probably can be related t o t h e pH-sensitivity of t h e receptor. This argues for differences between t h e receptors for acetylcholine on t h e rectus abdominis muscle of the frog and on t h e smooth muscle of t h e gut of the r a t . The studies on t h e relationship between structure and activity of acetylcholinomi
metics, in general, also demonstrated t h a t there are differences between nico
tinic and muscarinic receptors (see Table X V I , Section II.A). A s t u d y by Barlow (26a) of t h e effects of t h e p H on t h e activity of nicotine and derivatives on isolated tissues argues t h a t a t t h e neuromuscular junction, t h e univalent nicotinium ion, r a t h e r t h a n t h e un-ionized base, is t h e active form.
Also, binding of curare-like drugs to acid polysaccharides extracted from the electric organ of the electric eel is p H sensitive (96a, 96b).
Kalow (103b) studied the influence of p H changes on the action of curare and dimethyl curare on the rectus abdominis muscle of t h e frog. At p H values for which both phenolic OH groups are in the undissociated form, curare was found t o be more active t h a n a t p H values a t which these groups are dissociated.
Here the p H dependency is due to changes in the drug molecule a n d not to changes in the receptors.
I t should be taken into account t h a t not only changes in p H b u t generally changes in ion composition of t h e medium m a y effect drug action (61, 62,103a, 96d, 142b).
II.B.8.3.6(3) pH, Affinity, and Intrinsic Activity. Various examples of changes in the affinity between drug and receptor under influence of changes in the p H were mentioned. I t is possible t h a t p H dependency for t h e intrinsic activity will also be found in the future. For substrate-enzyme interactions p H dependency is reported for the rate of product formation (k3) as well as for the affinity between substrate and active site on the receptor. An especially interesting experiment in this respect was done b y H a y a s h i (la). The enzyme pepsin and the substrate albumin are brought together a n d spread on a surface such t h a t an intimate mixture is obtained a t an initial p H such t h a t the pepsin is not active. The mixed film is deposited on a glass plate a n d made strongly acid b y means of hydrochloric acid. Then an instantaneous reaction occurs.
Hayashi concluded from his experiments t h a t one molecule of pepsin could act simultaneously with 16 to 18 molecules of albumin and t h a t the necessary
Ι , Ι Ι . Β . D I F F E R E N T RECEPTOR SYSTEMS 385 molecular combinations took place a t t h e time of film formation while the actual hydrolysis occurred only after t h e p H was adjusted. This implies t h a t t h e affinity between enzyme and substrate is less p H dependent in this case t h a n the actual hydrolytic reaction. Experiments on the influence of the p H differences on the enzymic decarboxylation of leucin by leucin-decarboxylase show t h a t the m a x i m u m rate of decarboxylation a t substrate saturation remains constant from p H 5 to 7, this although the Η ions appear to behave as competitive antagonists for the substrate (123b). This implies t h a t the affinity between substrate a n d enzyme is more p H dependent t h a n the actual de
carboxylation.
For further information on t h e relation between t h e biological activity of drugs and t h e p H , t h e reader is referred to Albert's (4) valuable review article a n d t h e papers of Segre et al. (61a, 119c, 121, 173).
C O N C L U D I N G R E M A R K S
I n t h e general introduction we said t h a t w h a t should be expected from a theory is: (1) t h a t it give a simple model of more complicated systems; (2) t h a t it bring a n u m b e r of phenomena under unifying principles; (3) t h a t it induce new experiments and be backed u p by such experiments; and (4) t h a t it leave open t h e possibility of evolution. As far as t h e receptor theory used is concerned, we can now conclude: (1) t h a t t h e model used is not only a simplification b u t even an oversimplification of reality; (2) t h a t it brings m a n y phenomena, particularly dose-effect relations, under a unifying principle; (3) t h a t it leads t o new experiments a n d is often backed u p by t h e m .
Section I I I of P a r t I will demonstrate a further evolution of t h e receptor theory. One of t h e main disadvantages is t h a t t h e use of t h e t e r m " r e c e p t o r "
might give a researcher t h e feeling t h a t he knows w h a t he is dealing with, while t h e contrary is t r u e . The use of t h e t e r m underlines our ignorance.
For those who worry over t h e extensions given t o t h e theory in t h e earlier sections, it m a y be remarked t h a t t h e best theories are those t h a t themselves contribute t o their quick replacement by better ones. We hope t h a t this will be t h e fate of t h e theories presented here, a n d invite t h e reader t o join in t h e efforts t o accomplish this.
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