Interleukin-10 (IL-10) is a powerful suppressor of cellular immune responses, with a postulated role in brain inflammation. First, we have evaluated the role of this cytokine in ischaemic brain damage using IL-10 knockout (IL-10-/-) mice. The middle cerebral artery (MCA) was occluded in either IL-10-/- or wild-type animals of corresponding strain (C57Bl/6) and age. Infarct volume was assessed 24 h later in serial brain sections. Brain infarct produced by MCA occlusion was 30% larger in the IL-10-/- than in wild-type mice (21. 8 +/- 1.2 vs. 16.9 +/- 1.0 mm3, respectively; P < 0.01; Student's t-test). To further characterize these findings, studies were extended to in vitro models. Primary neuronal cortical cultures derived from IL-10-/- animals were more susceptible to both excitotoxicity and combined oxygen-glucose deprivation compared with cell cultures from wild-type mice. Moreover, when added to the culture medium, recombinant murine IL-10 (0.1-100 ng/mL) exerted a concentration-dependent prevention of neuronal damage induced by excitotoxicity in both cortical and cerebellar granule cell cultures taken from either strain. The accordance of in vivo and in vitro data allows us to suggest a potential neuroprotective role of IL-10 against cerebral ischaemia when administered exogenously or made available from endogenous sources.

Selective A2A adenosine receptor agonists are potent vasodilators that reduce blood pressure and induce marked increments in heart rate and plasma renin activity (PRA). To examine the mechanisms and pressor relevance of these cardiac and renin responses, we measured blood pressure and heart rate by telemetry and PRA in separate sets of spontaneously hypertensive rats (SHRs), which were given i.p. 2-hexynyl-5-methylcarboxamidoadenosine (2HE-NECA, 0.01 mg/kg) and 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680, 0.1 mg/kg) alone and after pretreatment with the beta 1-adrenoceptor blocking agent atenolol (100 mg/kg). The effects of 2HE-NECA (0.003 mg/kg) also were examined after pretreatment with the angiotensin-converting enzyme (ACE) inhibitor spirapril (3 mg/kg). Both A2A agonists induced marked reductions in blood pressure, associated with significant increments in heart rate and in PRA. Atenolol reduced blood pressure to the same extent as did the A2A agonists and markedly decreased heart rate and PRA. Pretreatment with atenolol entirely prevented the increase in heart rate and in PRA induced by the two A2A agonists but potentiated only slightly their antihypertensive effect. Spirapril alone reduced blood pressure and increased PRA and when given before 2HE-NECA potentiated its depressor and renin-stimulating effects by 44% and 69%, respectively. These results suggest that the increase in heart rate and in PRA induced by A2A agonists is the result of a reflex increase in sympathetic activity triggered by the decrease in blood pressure rather than of a direct stimulating effect on cardiac and renal A2A-adenosine receptors; the reactive activation of the renin-angiotensin system elicited by these compounds may contribute to blunting their antihypertensive effect.

The newly developed radiotelemetry system offers a number of advantages for the measurement of blood pressure and heart rate in laboratory animals. However, no available statistical methods permit valid use of the many data gathered with this continuous recording of hemodynamic parameters. This study describes elaboration and testing of mathematical functions as applied to the measurement of the effects of drugs on blood pressure and heart rate in spontaneously hypertensive rats. We used parametric functions analogous to those for pharmacokinetic studies. Curve fitting is in fact the only approach that provides reasonable estimates of hemodynamic kinetic constants. Nonlinear functions were assessed by analyzing telemetric hemodynamic effects induced by three adenosine receptor agonists with different selectivity for the A1 or A2a receptor. After acute administration in conscious rats, the A1 agonist 2-chloro-N6-cyclopentyladenosine induced dose-related hypotension (eg, 0.03 mg/kg; peak, -70 mm Hg; time to peak, 0.34 hour) and bradycardia (eg, 0.03 mg/kg; peak, -186 beats per minute [bpm]; time to peak, 0.38 hour). The A2a agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine induced dose-related hypotension (eg, 0.003 mg/kg; peak, -36 mm Hg; time to peak, 0.32 hour) with reflex tachycardia (eg, 0.003 mg/kg; peak, 152 bpm; time to peak, 0.35 hour). The nonselective adenosine agonist 5'-N-ethylcarboxamidoadenosine (0.1 mg/kg) induced hypotension (peak, -75 mm Hg; time to peak, 2.2 hours) and bradycardia followed by tachycardia (first peak, -131 bpm; time to peak, 1.26 hours; second peak, 123 bpm; time to peak, 13.9 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

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