Effect of Isozyme-Selective Inhibitors of Phosphodiesterase on Histamine-Stimulated Cyclic AMP Accumulation in Guinea-Pig Hippocampus

Juurnul ofNetrrochemiAiry Raven Press, Ltd., New York 0 1989 International Society for Neurochemistrq

Effect of Isozyme-Selective Inhibitors of Phosphodiesterase on Histamine-Stimulated Cyclic AMP Accumulation in

Guinea-pig Hippocampus

Clare Stanley, Anthony M. Brown, and Stephen J. Hill

Department of Physiology and Pharmacology, Medical School, Queen 's Medical Centre, Nottingham, England

Abstract: Addition of histamine (0.1 mM) to guinea-pig hippocampal slices causes a 20- to 30-fold increase in the accumulation of cyclic AMP compared with basal levels. This accumulation represents a balance between cyclic AMP production by adenylate cyclase and cyclic AMP breakdown mediated by phosphodiesterase (PDE). However, brain tissues are known to contain several different PDE isozymes. To determine which are involved in this response to histamine, the effect of isozyme-specific PDE inhibitors on cyclic AMP accumulation was examined in the hippocampus. MB 22948 (0.1 mM), an inhibitor of PDEs I and 11, had no significant effect on the response to either 1 pM or 0.1 mM histamine. SKF 94120 (0.1 mM), a PDE 111 inhibitor, was also without effect in the presence of 1 pM histamine, although with 0.1 mM histamine, it caused a weak (1.25-fold compared with

control), but statistically significant, enhancement of cyclic AMP accumulation. However, both rolipram (0.1 mM), a PDE IV inhibitor, and 3-isobutyl-1-methylxanthine (0.1 or 1 mM), an inhibitor of all forms of PDE, significantly increased cyclic AMP accumulation (2.8- to 6.5-fold compared with controls), and the relative size of this effect decreased with increasing histamine concentration. It is concluded that PDE IV is the main PDE isozyme involved in cyclic AMP turnover in guinea-pig hippocampal slices responding to histamine. Key Words: Phosphodiesterase isozymes-Hista- mine - Rolipram - 3 - Isobutyl - 1 - methylxanthine - Hippocampus. Stanley C. et al. Effect of isozyme-selective inhibitors of phosphodiesterase on histamine-stimulated cyclic AMP accumulation in guinea-pig hippocampus. J. Neurochem. 52,67 1-676 (1989).

Histamine is a potent stimulator of cyclic AMP accumulation in guinea-pig brain slices (Daly, 1977; Pa- lacios et al., 1978; Hill et al., 198 l). In slices of guinea- pig hippocampus and cerebral cortex, the response to histamine is mediated by both HI and H2 classes of receptor (Palacios et al., 1978; Hill et al., 1981; Don- aldson et al., 1988). In homogenates of these tissues, however, the effect of histamine on adenylate cyclase activity is mediated exclusively by histamine H2-receptors (Hegstrand et al., 1976; Green et al., 1977). The response to HI-receptor stimulation in brain slices appears to involve a potentiation of the cyclic AMP response to adenosine A2- or histamine H2-receptor stimulation (Palacios et al., 1978; Hill et al., 1981; Hollingsworth and Daly, 1985).

Most tissues, including brain, contain several different phosphodiesterase (PDE) isozymes. Four major isozymes have been described: one with calcium-stimulated activity (PDE I), one having activity with a preference for cyclic GMP (PDE 11), and two preferring

Received February 25, 1988; revised manuscript received June I , 1988; accepted July 21, 1988.

Address correspondence and reprint requests to Dr. S. J. Hill at Department of Physiology and Pharmacology, Medical School,

cyclic AMP, with different Michaelis constants (K,) for the substrate cyclic nucleotide (PDE 111 and PDE IV) (Davis, 1984; Kincaid et al., 1984; Strada et al., 1984; Reeves et al., 1987). In brain homogenates, the calcium-calmodulin dependent isozyme (PDE I) accounts for most (-85%) of the cyclic AMP-metabolising activity (Teshima and Kakiuchi, 1974; Kincaid et al., 1984; Strada et al., 1984). However, we have previously shown that rolipram, a selective inhibitor of PDE IV (Schwabe et al., 1976; Davis, 1984; Nemoz et al., 1985; Reeves et al., 1987), can produce a marked increase in the cyclic AMP accumulation produced by histamine and adenosine, either alone or in combi- nation, in guinea-pig cerebral cortical slices (Donaldson et al., 1988). This suggests that although PDE IV is a minor constituent of brain PDE activity (Kincaid et al., 1984; Nicholson and Wilke, 1987), it may play an important role in regulating the cyclic AMP accumulation produced by neurotransmitter receptor stimulation.

~ ~

Queen's Medical Centre, Clifton Boulevard, Nottingham NG7 2UH, U.K.

Abbreviations used: IBMX, 3-isobutyl-1 -methylxanthine; PDE, phosphodiesterase.

6 71

6 72 C. STANLEY ET AL.

In the present study, we investigated the extent to which the isozymes of PDE are involved in regulating the levels of cyclic AMP produced in response to histamine in slices of guinea-pig hippocampus. This tissue was chosen in preference to cerebral cortex because in the hippocampus a large cyclic AMP response to histamine can be obtained in the absence of endogenous adenosine (Palacios et al., 1978). Endogenous adenosine was eliminated with adenosine deaminase in these experiments, to remove the complication of the adenosine-receptor antagonist properties associated with many PDE inhibitors (Huang et al., 1972; Green and Stanberry, 1977; Smellie et al., 1979). The involvement of the PDE isozymes was evaluated with selective and competitive inhibitors of PDE I and I1 (MB 22948) (Frossard et al., 1981; Weishaar et al., 1986), PDE 111 (SKF 94120) (Gristwood et al., 1986; Reeves et al., 1987), and PDE IV (rolipram) (Reeves et al., 1987). The effects of these isozyme-selective drugs were also compared with that of 3-isobutyl- 1 -methylxanthine (IBMX), which is a nonselective inhibitor of all forms of PDE. Measurements were made at both low and high stimulus levels (which produce low and high accumulations of cyclic AMP, respectively), because it has been reported previously that this affects the size of the relative response to a PDE inhibitor (Donaldson et al., 1988).

MATERIALS AND METHODS

Measurement of [3H]cyclic AMP accumulation Cyclic AMP accumulation was determined using a mod-

ification of the [3H]adenine prelabelling technique described by Shimizu et al. (1969). Hippocampal slices (300 X 300 pm) from three guinea-pigs (Hartley strain, weighing 200-400 g , of either sex) were prepared and labelled with [3H]adenine (0.08 p M , 40 pCi) in 20 ml of Krebs-Henseleit medium as described previously (Donaldson et al., 1988). After labelling, slices were washed three times with 50 ml of Krebs-Henseleit solution at 37°C and finally allowed to settle under gravity. Portions (50 11) of the hippocampal slices were then added to 240 p1 of Krebs medium containing adenosine deaminase ( 1.2 U/ml) and, where appropriate, receptor antagonist or a PDE inhibitor, in flat-bottomed insert vials. Adenosine deaminase was included in all incubations, to remove endogenous adenosine. Tubes were gassed with Oz/COz ( 9 5 3 , capped, and incubated for 15 min at 37°C in a shaking water bath. Agonist was added in 10 p1 of medium after this step and the tubes were gassed again with 02/C02 (955) and incubated further for 10 min.

Incubations were terminated, and cyclic AMP was ex- tracted by addition of 200 pl of ice-cold 1 M HCl. Samples were vortex-mixed and left on ice for at least I5 min before being diluted with 750 pl of distilled water. Slices were pre- cipitated by centrifugation at 1,000 g for 10- 15 min. A 1 -ml sample of the supernatant was taken for analysis of [3H]cyclic AMP content by column chromatography. The recovery of cyclic AMP from the columns was corrected for by “spiking” the samples with 100 pl of [‘4C]cyclic AMP (0.001 pCi). [3H]Cyclic AMP was isolated by sequential Dowex-alumina chromatography as described previously (Donaldson et al.,

1988). The levels of [3H]- and [‘4C]cyclic AMP in the final eluant were determined by liquid scintillation counting. Re- covery of cyclic AMP was routinely -60%.

Statistical analysis of the data was performed by one-way analysis of variance (Barlow, 1983), unless otherwise stated. Each experiment was repeated three or four times. Data are expressed as mean k SEM values, and n in the text refers to the number of separate experiments.

Chemicals Dowex 50W (H+-form; 200-400 mesh), adenosine de-

aminase (type IV), neutral alumina (type WN-3), imidazole, mepyramine maleate, IBMX, and histamine dihydrochloride were obtained from Sigma. [8-3H]Adenine (specific activity = 26 Ci/mmol) was obtained from Amersham, and [8- ‘‘C]cyclic AMP (specific activity = 42.4 mCi/mmol) was from NEN. Gifts of tiotidine (ICI), rolipram (Schering AG), za- prinast (MB 22948; May and Baker), and SKF 94 120 (Smith, Kline and French) are gratefully acknowledged.

RESULTS

Histamine-stimulated cyclic AMP accumulation Incubation of guinea-pig hippocampal slices with 0.1

mM histamine in the presence of adenosine deaminase produced a large stimulation of cyclic AMP accumulation. The increase over basal levels obtained with histamine in this tissue [26.6 (+2.4)-fold, n = 111 was much greater than that obtained in similar experiments using slices of guinea-pig cerebral cortex [7.8 (k0.7)- fold] (Donaldson et al., 1988). The response to histamine (0.1 mA4) was effectively abolished by preincu- bation with the H-receptor antagonist tiotidine (30 pM), which produced inhibition of 96.8 k 0.7% over three experiments. In contrast, the HI-receptor antagonist mepyramine inhibited the response to histamine by only 58 k 6% (n = 3) at a concentration (1 p M ) three orders of magnitude above its dissociation constant (0.6 nM; Hill et al., 1981) for the HI-receptor. These findings support the original contention of Pa- lacios et al. (1978) that the HI-receptor component po- tentiates the direct H2-receptor-mediated cyclic AMP response in guinea-pig hippocampus. The complete attenuation of the response by tiotidine also confirms that adenosine deaminase treatment prevented the cyclic AMP accumulation that is elicited by endogenous adenosine, and augmented by HI-receptor stimulation (Hill et al., 1981).

In the absence of adenosine deaminase, adenosine (0.1 mM) produced a large 50 (*4)-fold increase in cyclic AMP accumulation over basal levels that was approximately double that obtained with histamine (0.1 mM, n = 3; data not shown). In two experiments, simultaneous addition of histamine (0.1 mM) and adenosine (0.1 mA4) produced levels of [3H]cyclic AMP 7.8 (k0.8)- and 6.3 (kO.7)-fold higher, respectively, than that obtained in the presence of 0.1 mM histamine alone. In each case, this response was greater than the sum of the cyclic AMP responses to adenosine and histamine alone, an observation confirming that, as in

PDE ISOZYMES AND CYCLIC AMP ACCUMULATION 6 73

cerebral cortical slices (Hill et al., 1981), histamine can potentiate the response to adenosine in this tissue (Dis- mukes et al., 1976; Daly, 1977).

Effect of isozyme-selective PDE inhibitors The effects of the isozyme-selective inhibitors roli-

pram (PDE IV), SKF 94120 (PDE III), and MB 22948 (PDE I and PDE 11) on the cyclic AMP responses to two different concentrations of histamine are shown in Fig. 1. In a series of four experiments, rolipram (0.1 mM) produced a significant and large increase in the cyclic AMP response to both 1 pM(6.5-fold; p < 0.00 1) and 0.1 mM (2.8-fold; p < 0.001) histamine. In contrast, MB 22948 had no significant effect at either level of stimulation. It was notable, however, that the ethanol vehicle (final concentration = 3% vol/vol) required for MB 22948 produced a small enhancement of the cyclic AMP response to 0.1 mM histamine (Fig. 1). SKF 94 120 produced a weak enhancement of cyclic AMP accumulation that was significant (p < 0.05) only at the higher concentration of histamine.

Rolipram and IBMX A comparison of the effect of rolipram (0.1 mM)

and IBMX (1 mM) (the latter inhibits all forms of PDE) is illustrated in Fig. 2. IBMX produced a pattern of response similar to that obtained with rolipram in the presence of 1 pM or 0.1 mlw histamine. These data, together with the results described above, suggest that PDE IV is the only PDE isozyme that metabolises cyclic AMP at the levels of the nucleotide reached in cells responding to histamine in this brain region. This finding was supported in other studies showing that a com- bination of MB 22948 (0.1 mM) and rolipram (0.1 mlw) did not produce a significant increase in cyclic AMP accumulation over that obtained with rolipram alone, in the presence of either 1 pM or 0.1 mM histamine (data not shown; n = 3).

As in cerebral cortical slices (Donaldson et al., 1988), the percentage increase in cyclic AMP accumulation over controls, obtained with rolipram at 1 pM histamine, was much greater than that obtained at 0.1 miM histamine (Figs. 1 and 2). This effect is seen in more detail in Table 1: The absolute increment in response produced by rolipram increased as the concentration of histamine increased from 1 to 10 pM and then reached a constant value. When the response in the presence of rolipram was expressed relative to that obtained in its absence, however, the effect of the inhibitor decreased markedly as the concentration of histamine, and hence the absolute level of cyclic AMP accumulation, increased (Table 1). Analysis of the data by both paired t test and Wilcoxon signed rank test confirmed that the relative responses in the presence of I pLM histamine were significantly greater than with 0.1 mM histamine (p < 0.00 1 ; n = 1 1). Such a difference in the relative increases at the two histamine concentrations was also observed with both 1 .O (Fig. 2) and 0.1 mM IBMX (p < 0.001; n = 14).

700

600

500

400

*- 300 a0 - C 0 .- I ; 200 E 3 U

m a s 100 < U

U A

.- - - " 0 I

rn L

C R S K F MB E T H

FIG. 1. Effect of rolipram (R; 0.1 mM), SKF 94120 (SKF; 0.1 mu), and MB 22948 (MB; 0.1 mM) on the [3H]cyclic AMP response to 1 p M histamine (a) and 0.1 mM histamine (b). All incubations included adenosine deaminase (1.2 U/ml). Histogram C gives the control response to histamine in the absence of PDE inhibitors. MB 22948 was dissolved in ethanol (final concentration = 3% vol/ vol), and the data obtained with vehicle alone are also shown (ETH). Data are combined mean f SEM values from five determinations in each of four separate experiments. 'To normalise data from individual experiments, results were expressed as a percentage of the control response to 1 ,Unn (a) or 0.1 mM (b) histamine obtained in each experiment. Statistically significant differences from the control response are indicated: "'p c 0.001, +p < 0.05. There was no significant difference between MB 22948 and its control at either concentration of histamine (hatched bars).

DISCUSSION

The data presented in this study confirm previous observations (Rogers et al., 1975; Dismukes et al., 1976; Daly, 1977; Palacios et al., 1978) that histamine is a potent stimulant of cyclic AMP accumulation in slices

J. Neiiruchem., Vol. 52. N o . 3, 1989


6oo r (a' T

500 -

400 -

300 -

200 -

100 -

0-

2 0 0

1°:t C I BMX R

FIG. 2. Comparison of the effect of rolipram (R; 0.1 mM) and IBMX (1 mM) on the cyclic AMP response to 1 pM histamine (a) or 0.1 mM histamine (b) in guinea-pig hippocampal slices. Histogram C gives the basal responses to 1 pM or 0.1 mM histamine. Data are combined mean t SEM values from five determinations in each of three separate experiments. *Data are expressed as a percentage of the control response to 1 &I (a) or 0.1 rnM (b) histamine as described in the legend to Fig. 1. Both roliprarn (see Table 1) and IBMX (1 mu) produced a small increase in the basal accumulation of [3H]cyclic AMP that represented 2.3 and 7.070, respectively, of the increases obtained in the presence of 1 &I histamine. In a typical experiment with IBMX (1 rnM), the PDE inhibitor increased the basal level from 462 * 28 to 1,193 t 72 dprn and the response to 1 pM histamine from 1,908 +- 79 to 10,315 k 207 dDm.

of guinea-pig hippocampus. Both histamine HI- and Hz-receptors participate in this response (Rogers et al., 1975; Dismukes et al., 1976; Palacios et al., 1978), although it is clear from studies with selective antagonists in both guinea-pig hippocampus and cerebral cortex that the H,-mediated cyclic AMP response is dependent on the activation of histamine H2- or adenosine AZ- receptors (Palacios et al., 1978; Hill et al., 1981; Hill, 1987). Thus, although 60% of the response to histamine in the present study was sensitive to HI-receptor antagonism, both H ] - and H2-receptor-mediated responses were effectively abolished by the selective H2-antagonist tiotidine in the presence of adenosine deaminase. The most likely explanation for this phe- nomenon is that stimulation of HI-receptors poten- tiates the cyclic AMP response to Hz-receptor stimulation (Palacios et al., 1978; Hill, 1987). This hypothesis is supported by evidence that histamine HI-receptor stimulation has no direct effect on adenylate cyclase

activity in isolated hippocampal membranes (Hegs- trand et al., 1976; Green et al., 1977).

Studies with the selective PDE IV inhibitor rolipram showed that this agent could produce a significant and marked 6.5- and 2.8-fold enhancement of the cyclic AMP response to 1 pM and 0.1 mM histamine, respectively, in slices of guinea-pig hippocampus. A similar effect in slices of guinea-pig cerebral cortex has been observed previously (Donaldson et al., 1988). In contrast, MB 22948, which is a selective inhibitor of PDE I and I1 (Weishaar et al., 1986), was without significant effect on the response to either concentration of histamine. The concentration of MB 22948 used (0.1 mM) was chosen to produce a selective inhibition of PDE I and I1 of -10 p M ) (England et al., 1986; Weishaar et al., 1986) without any significant effect on the cyclic AMP-specific isozymes of PDE (IC50 = 350-700 p M ) (Weishaar et al., 1986). One explanation for the lack of effect of MB 22948 in the present study might be that it does not gain access to the PDE enzymes in the cells. However, this seems unlikely, because a rapid and potent relaxation of rat lung strips, together with an increase in cyclic nucleotide levels, has been obtained with MB 22948 at concentrations of 0.1-10 pM(Frossard et al., 1981).

The selective PDE I11 inhibitor SKF 94 120 produced only a weak effect in slices of guinea-pig hippocampus, yielding a significant increase in cyclic AMP accumulation of only 25% at the higher concentration of histamine used (0.1 mM). As with MB 22948, this lack of effect does not appear to be due to the use of an inappropriate concentration of inhibitor (0.1 mM) or problems of tissue penetration, because SKF 94 120 has a low K, for inhibition of PDE 111 (2.4 pM; Reeves et al., 1987) and is a potent and rapidly acting inotropic agent in cardiac muscle at micromolar concentrations (Gristwood et al., 1986).

These data, together with the similarity in the pattern of the responses obtained with rolipram (a PDE IV- specific inhibitor) and IBMX (a nonselective inhibitor of PDE), suggest that PDE IV is the predominant iso-

TABLE 1. Efect of rolipram (0.1 mM) on accumulation of r3Hlcvclic AMP at different concentrations of histamine

Accumulation of [3H]cyclic AMP (dpm)

Histamine Ratio (PM) Control Rolipram (rolipram/control)

0 510 f 55 775 t 46" 1.5 1 1,322 t 59' 8,331 +- 943" 6.3

100 21,268 t_ 903' 48,737 t 828" 2.3 10 11,612 t 619' 38,415 t 3,71 I" 3.3

Data are mean k SEM values from five determinations in a single experiment. Similar results were obtained in two further experiments.

" p < 0.00 I compared with data obtained in the absence of rolipram. ' p < 0.001 compared with data obtained in the absence of histamine (analysis of variance of log-transformed data).

J . Nritnithein , l i i l . 52, hb. 3. I989

PDE ISOZYMES AND CYCLIC AMP ACCUMULATION 6 75

zyme responsible for cyclic AMP metabolism in cells responding to histamine in guinea-pig hippocampal slices. This is remarkable when one considers that the soluble calcium-calmodulin-dependent PDE isozyme PDE I accounts for >85% of all PDE activity in the brain (Schultz and Schmidt, 1986). This suggests that some compartmentation of PDE enzymes must occur in brain tissues and that PDE I, 11, and 111 may be important in metabolising cyclic AMP accumulated in other cellular compartments (or cells) or in responses initiated by other neurotransmitters. There is evidence for such functional compartmentation of PDE in pe- ripheral tissue. In guinea-pig cardiac muscle, inhibition of PDE IV produces a much larger increase in cyclic AMP accumulation than inhibition of PDE 111, yet only the latter is associated with an inotropic effect (Gristwood and Owen, 1986; Murray et al., 1987).

A feature of the data obtained with rolipram in hippocampal slices is that the percentage increase in cyclic AMP accumulation produced by rolipram at higher histamine concentrations is much lower than that obtained in the presence of 1 pM histamine. A similar observation has been made under similar steady-state conditions, i.e., 10 min of agonist stimulation, in guinea-pig cerebral cortex (Donaldson et al., 1988). This behaviour would not be expected if PDE IV were the only enzyme involved in cyclic AMP breakdown and if rolipram acted as a simple competitive inhibitor (Donaldson et al., 1988). We suggested previously that in guinea-pig cerebral cortex, this effect might be due to other (rolipram-insensitive) PDE isozymes, i.e., PDE I, 11, or 111, being recruited as the levels of cyclic AMP increased (Donaldson et al., 1988). However, this can- not explain the present findings in guinea-pig hippocampus, because inhibitors of these other isozymes had no effect on cyclic AMP accumulation at low or high stimulus levels. The smaller effect of IBMX or rolipram at higher histamine concentrations also appears not to be due to a depletion of [3H]adenine and [3H]ATP, because much higher levels of [3H]cyclic AMP could be produced in hippocampal slices following simultaneous addition of histamine (0.1 mM) and adenosine (0.1 mM). Indeed, such a limitation on the production of [3H]cyclic AMP would be unexpected, because rolipram has no effect on cyclic AMP synthesis (Donald- son et al., 1988) and the demand for substrate, i.e., ATP, should, therefore, remain unchanged.

One possible explanation for the smaller effect of rolipram at higher histamine concentrations is that the V,,, of the PDE activity is increased at these higher concentrations. This might be a consequence of the higher histamine concentration itself. However, a similar effect is also seen with adenosine (Donaldson et al., 1988) and noradrenaline (Schwabe et al., 1976) as agonists, an observation suggesting that it is the higher level of cyclic AMP, rather than the higher agonist concentration, that is responsible. One possibility is that PDE is activated by cyclic AMP at a site separate from its catalytic site (see Nemoz et al., 1985), and that

the PDE inhibitors compete with cyclic AMP at only one of these sites. However, other authors have found no evidence for such a complex interaction between cyclic AMP and PDE IV (Reeves et al., 1987). An al- ternative possibility is that cyclic AMP might act via protein kinase A and subsequent phosphorylation of the PDE enzyme.

In summary, this study has shown that PDE IV is the primary PDE isozyme involved in cyclic AMP turnover in cells responding to histamine in guinea- pig hippocampus. This finding may also apply to cells responding to other neurotransmitters and may explain why inhibitors of PDE IV have behavioural (antidepressant) effects (Wachtel, 1983; Schultz and Schmidt, 1986; Wachtel and Schneider, 1986).

Acknowledgment: We thank the Wellcome Trust for fi- nancial support.

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Effect of Isozyme-Selective Inhibitors of Phosphodiesterase on Histamine-Stimulated Cyclic AMP Accumulation in Guinea-Pig Hippocampus