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In the last few years we have accumulated some evidence that calcium entry blockers could interfere with an endogenous purinergic mechanism, namely, with membrane adenosine receptors.’” This property seemed to be shared by different groups of such drugs, independently from their chemical structure, thus opening new questions on the molecular mechanism of action.24 Among these substances, first flunarizine and then dihydropyridines claimed our attention, and now we want to summarize the findings of our studies, not following the logical development of the adenosine hypothesis in our mind, but assembling our data according to the type of experimental design. In this paper the thread of the argument implies a continuous hypothetical comparison with the adenosine system. Our studies dealt with clinical pharmacological investigations on the circulatory activity of flunarizine either in control subjects or in peripheral obliterative arterial disease (POAD) patients. The design of the study included the plethysmographic investigation of the leg hemodynamics after flunarizine infusion and after treatment with drugs that either block adenosine receptors, such as theophylline, or inhibit adenosine uptake, such as dipyridamole. Finally a cellular model was approached to clarify a possible interference of calcium entry blocker with adenosine a t the membrane receptor level.

Introduction In a previous study we demonstrated that isotonic exercise of the lower limbs in peripheral obliterative arterial disease patients could induce a highly significant decrease in blood filterability in venous blood taken from the femoral vein, besides a significant rise of the lactic acid level with a decrease in venous p02 and an increase in the A-V p02 difference (Guerrini et aI1982). This rheological impairment may be considered as an expression of the hyperviscosity syndrome secondary to vascular disease (Di Perri et al 1983), and as such it might be secondary and dependent to a tissue ischaemia. After isotonic exercise and a recovery period (not more than 30 minutes), the patients were treated with Buflomedil intravenously (100 mg in 2 minutes) and 10 minutes after the end of the infusion they were tested a second time in the same manner. After the second exercise, while the lactic acid level was not significantly different from the corresponding changes after the baseline exercise test, no rheological impairment was observed. These findings suggest, along with the 'in vitro' studies of other authors (Teitel & MussIer 1980, Teitel, Tietz & Vezlen 1981), that the action of the drug may be directed to the red blood cell, preventing the metabolic tissue acidosis from affecting the cell's rheological characteristics (Guerrini et al 1982). The rheological effect of Buflomedil was confirmed by other authors (Coccheri et al 1982, Oormandy & Ernst 1981) while its therapeutic action was demonstrated as well (SunderPlassman, Messmer & Becker 1981, Landgraf, Ehrly & Hildebrandt 1980). On the basis of these findings we set out to evaluate if Buflomedil could induce the same effect if administered per os and we determined to see whether a prolonged treatment could improve the 'performance' of vascular patients.

Objective:To assess the predictivity of predefined variables with respect to long-term mortality in a cohort of patients with chronic critical leg ischaemia (CLI).Design:Prospective observational study.Methods:Census offices were asked to release information on survival or death status of 574 patients with CLI 2 years after their recruitment in the study.Results:Of 522 patients with available information, 165 (31.6%) died within 2 years of hospital admission, mostly from vascular causes as expected. Among the variables considered, male sex, current smoking, arterial hypertension, diabetes mellitus, hypercholesterolaemia, obesity, history of myocardial infarction and low ankle systolic pressure showed no univariate association with mortality. The multivariate analysis also excluded revascularisation procedures and the Fontaine stage as prognostic factors in terms of mortality. Besides age ≥ 70 years (relative risk, RR 1.94; 95% confidence interval (CI) 1.37–2.70), only a history of stroke (RR 1.82; 95% CI 1.19–2.79) and major amputation (RR 1.90; 95% CI 1.30–2.80) were significantly associated with mortality.Conclusions:CLI is a clinical condition of such severity that most of the recognised cardiovascular risk factors cannot further influence the fate of the patients, one-third of whom die within 2 years.

Drugs such as dipyridamole (200 μg/kg/min), an adenosine uptake in hibitor, and theophylline (300 μg/kg/min), an adenosine receptor antagonist, respectively increased and decreased postischemic hypere mia in normal subjects, as well as in POAD patients. Moreover, dipyrida mole pretreatment was able to antag onize the reduction of peak flow in duced by nifedipine, and the potenti ating effect of flunarizine on postis chemic hyperemia was affected sig nificantly by theophylline, thus sug gesting a possible interference of calcium entry blocker drugs with the endogenous adenosine system. In a cellular model (polymorphonuclear leukocytes — PMN) the inhibitory ef fect of calcium entry blockers on stimulated functions (degranulation and free radical production) was highly antagonized by theophylline. Finally, a1H-NMR spectroscopy study showed a binding interaction between adenosine and flunarizine on the cell membrane. An adenosine-re ceptor coupling to the calcium entry blocker channels is suggested.