The prevalence of tobacco smoking and coffee drinking place nicotine and caffeine among the most used licit drugs in many societies and their consumption is often characterised by concurrent use. The pharmacological basis for any putative interaction between these drugs remains unclear. Some epidemiological reports support anecdotal evidence, which suggests that smokers consume caffeine to enhance the effects of nicotine. This paper reviews various aspects of the pharmacology of caffeine and nicotine, in humans and experimental animals, important for the understanding of the interactions between these drugs. In particular, recent experiments are reviewed in which chronic exposure to caffeine in the drinking water of rats facilitated acquisition of self-adminstration behavior, enhanced nicotine-induced increases in dopamine levels in the shell of the nucleus accumbens and altered the dopaminergic component of a nicotine discrimination. These studies provide evidence that the rewarding and subjective properties of nicotine can be changed by chronic caffeine exposure and indicate that caffeine exposure may be an important environmental factor in shaping and maintaining tobacco smoking.

Alteration of the Behavioral Effects of Nicotine by Chronic Caffeine Exposure

Papaverine, up to 150 micron, was without effect on resting tension of vas deferens and urinary bladder smooth muscle strips, but caused a dose-dependent inhibition of the phasic component of the 100 mM-K contracture. At 150 micron, papaverine caused an 80 and 60% inhibition of phasic tension in vas deferens and urinary bladder muscle respectively. Papaverine caused a marked dose-dependent reduction in the tonic component of 100 mM-K contractures in both preparations. At 150 micron, papaverine often relaxed preparations below initial starting tension. Addition of 150 micron-papaverine to incubation media caused a fall of 25-30% in 45Ca uptake by both preparations. Papaverine at 150 micron caused a small fall in resting 45Ca efflux from vas deferens and a larger fall in efflux from bladder muscle. However, this papaverine concentration caused a large inhibition of the 45Ca uptake by and 45Ca efflux from both preparations when stimulated by high-K depolarization. Papaverine at 150 micron was without significant effect on Ca binding by either microsomes or mitochondria isolated from both vas deferens and urinary bladder smooth muscle. The main site of papaverine action appears to be on the Ca-influx mechanism responsible for regulating Ca entry during prolonged K depolarization.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1984.sp015151

Inhibition by papaverine of calcium movements and tension in the smooth muscles of rat vas deferens and urinary bladder.

1. 1. Field stimulation responses of rat urinary bladder detrusor smooth muscle were unaffected by atropine, phentolamine, propranolol, caffeine and theophylline. After caffeine or theophylline treatment, previously quiescent detrusor preparations developed pronounced spontaneous contractile activity. 2. 2. Both natural spontaneous contractile activity and field stimulation responses were eliminated in Ca-free EGTA media. After washout, both kinds of activity returned but over quite different time scales. 3. 3. At moderate levels of K+-induced depolarization which inactivate fast Ca-channels, field stimulation responses persisted and additively superimposed upon the K+-induced tension, suggesting that field stimulation-induced depolarization had activated slow voltage-dependent Ca-channels. 4. 4. Amost 61% of detrusor muscle preparations examined showed some spontaneous contractile activity. Such preparations were more sensitive to K+-induced depolarization than quiescent preparations and K+-depolarization greatly accelerated the spontaneous activity of these muscle strips. 5. 5. The slow Ca-channel blockers nifedipine and verapamil eliminated field stimulation responses in the 10−6–10−5M range, but octylonium bromide was far less effective even at 10−4 M. 6. 6. The inorganic Ca-channel blocker Mn2+ inhibited field stimulation responses at 0.5–1.0 mM but La3+ was surprisingly far less effective than Mn2+ in this concentration range, requiring a 1 mM level to achieve a 50% inhibition of response. 7. 7. It is concluded that field stimulation induced a depolarization of rat urinary bladder detrusor muscle which activates slow voltage-dependent Ca-channels. Field stimulation responses and natural spontaneous activity appear to strongly depend upon a sustained Ca influx through these channels for the sustained release of intracellular calcium and the maintenance of contractile force.

Field stimulation responses of rat urinary bladder detrusor smooth-muscle. Dependence upon slow calcium channel activity determined by K+ depolarization and calcium antagonists.

SUMMARY
Recent studies of the control of stomatal aperture by abscisic acid (ABA) have suggested that its cellular action depends on the availability of calcium ions, which appear to function as secondary messengers. Stimulus-response coupling may, therefore, be similar to that found in many animal tissues.

We report here preliminary evidence that ABA has a profound effect on some mammalian tissues and on a cyanobacterium. Studies on smooth muscles from the vas deferens and bladder of rat showed that 10−6 M ABA enhanced field stimulation responses by about 25 %. This effect was inhibited by the calcium-channel blocker, nifedipine. In K+-depolarized bladder smooth muscle in which the fast calcium channels were voltage-inactivated, 10−6 M ABA augmented contracture tension, and enhanced the slow tonic phase of the response which is known to be dependent on the activity of slow calcium channels. Comparative studies using ABA and the synthetic calcium agonist BAY K 8644 suggested that there are close parallels in the mode of action of the two compounds. Heal smooth muscle was remarkably sensitive to ABA, showing enhancement of K+ contracture tension by up to 400% at only 10−9 to 10−8 M ABA.

In cultures of Nostoc 6720, low concentrations of ABA (about 10 −7 M) caused a substantial increase in the heterocyst/vegetative cell ratio. Addition of ABA further enhanced the increase in heterocyst content caused by increases in the concentration of Ca2+ in the medium. These observations provide further support for the proposal that ABA functions as a calcium agonist, a concept consistent with similarities between the action of ABA and the calcium ionophore A23187. In cultures of Nostoc 6720, high (> 10−5 M) concentrations of ABA had an inhibitory effect, and some evidence of a similar dose-response relationship was found in mammalian tissues.

Preliminary studies using 45Ca2+ suggested that ABA stimulates the influx of calcium into both vasa deferentia and Nostoc 6720. It is concluded that ABA may function as a calcium agonist when applied to a wide range of prokaryotic and eukaryotic cells. A recent observation that it is present in the brain of some mammals suggests that this ‘plant hormone’ may be of much wider biological significance than hitherto recognized. The similar responses of plant, animal and cyanobacterial cells to ABA might indicate the presence of cellular mechanisms which have been genetically conserved through many stages of evolution.

https://nph.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-8137.1986.tb00643.x

Is abscisic acid a universally active calcium agonist

Comparative study of the effects of cyclic nucleotide phosphodiesterase inhibitors on bone resorption and cyclic AMP formation in vitro.

Caffeine and theophylline (0.1-5.0 mM) relaxed rat ileal muscle and reduced spontaneous rhythmicity. They inhibited the K-induced tonic contractures of rat vas deferens and bladder muscle strips but were without significant effect on the phasic responses to K. Theobromine (1.0-2.5 mM) induced contractures in ileal muscle and enhanced both the phasic and tonic components of K-induced contractures in vas deferens and bladder muscle strips. Theophylline and caffeine inhibited by varying degrees the 45Ca efflux from ileal, vas deferens and bladder muscle strips during the slow intracellular phase, but theobromine significantly stimulated 45Ca slow compartment efflux in all three types of muscle. Caffeine and theophylline both depressed, to varying degrees, the 45Ca influx into all three muscles while theobromine stimulated 45Ca influx in all cases. Caffeine and theophylline were either without much effect or slightly stimulated calcium binding by microsomes and mitochondria isolated from ileum, vas deferens and bladder, while theobromine significantly inhibited calcium binding by both sub-cellular fractions in all three muscles. The inhibitory action of caffeine and theophylline on these muscles appears to be due to inhibition of calcium influx coupled with some stimulation of intracellular binding. Theobromine's excitatory action appears to be related to stimulation of calcium influx and inhibition of cellular calcium binding.

E. Bayton

Papers

Influence of some common methylxanthines on contractile responses and calcium mobilization of ileal, vas deferens and bladder smooth muscle