S(-)-nornicotine increases dopamine release in a calcium-dependent manner from superfused rat striatal slices.

The present study demonstrates that S(-)-nornicotine evoked a concentration-dependent increase in dopamine (DA) release from superfused rat striatal slices. The increase in DA release was indicated by an S(-)-nornicotine-induced overflow of endogenous 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatal superfusate and by an S(-)-nornicotine-induced increase in tritium overflow from striatal slices preloaded with [3H]DA. Low concentrations (0.01-1.0 microM) of S(-)-nornicotine, which did not evoke endogenous DOPAC overflow, also were unable to modulate electrically evoked DOPAC overflow. The increase in DOPAC overflow induced by S(-)-nornicotine was compared with that produced by S(-)-nicotine. Comparing equimolar concentrations (0.1-100 microM) of S(-)-nornicotine and S(-)-nicotine, superfusion with S(-)-nornicotine resulted in a significantly greater DOPAC overflow. In contrast to the effect of S(-)-nicotine, S(-)-nornicotine evoked a sustained increase in DOPAC overflow for the entire period of S(-)-nornicotine exposure. Furthermore, DOPAC overflow evoked by S(-)-nornicotine in control Krebs buffer was inhibited by superfusion with a low-calcium buffer. Moreover, in the low-calcium buffer, DOPAC overflow induced by 30 and 100 microM S(-)-nornicotine was not different from that with no S(-)-nicotine, tobacco products and a known metabolite of S(-)-nicotine, increases DA release in a calcium-dependent manner in superfused rat striatal slices. It is interesting that unlike S(-)-nicotine, there does not appear to be desensitization to this effect of S(-)-nornicotine.

Acute and chronic effects of losartan (DuP 753) on blood pressure and vascular reactivity in normotensive rats.

The effects of in vivo treatment with the nonpeptide subtype 1 angiotensin II receptor antagonist, losartan, on blood pressure and vascular reactivity in normotensive male Sprague-Dawley rats were studied. Initial acute experiments demonstrated that blood pressure was significantly decreased six hours following a single injection of losartan (10 mg/kg, sc), but returned to control levels by 24 hours post-injection. Pressor responses to angiotensin II (0.1 ug/kg, iv) in these rats were significantly attenuated 2 and 24 hours following losartan injection. For chronic studies, rats were injected once daily for 21 days with either the same dose of losartan or saline vehicle. Blood pressure and pressor responses to angiotensin II were assessed at the end of the 21 day treatment period. A significant decrease in blood pressure was observed in chronic losartan treated rats 6 hours after the last injection on day 21; however, as in the acute studies, blood pressure had returned to control values by 24 hours post-injection. Although blood pressure had returned to normal, pressor responses to angiotensin II were significantly attenuated in chronic losartan treated rats 24 hours after the last injection. Following the in vivo studies, aortae and tail arteries were removed for experiments on vascular reactivity. Acute and chronic losartan treatment had no effect on KCl and norepinephrine reactivity. Endothelial-dependent and independent relaxation responses were also unaltered. A significant decrease in the maximal contractile response to angiotensin II was observed in aorta from acute and chronic losartan treated rats. Electrical stimulation-induced responses were unaltered in tail arteries from rats acutely treated with losartan but were potentiated in rats chronically treated with losartan. Exogenously applied angiotensin II, in concentrations which did not elicit contractile responses, potentiated electrical stimulation-induced responses of tail arteries from control rats but did not influence responses in arteries from acute and chronic losartan treated rats. These results demonstrate that losartan has significant blood pressure lowering effects in normotensive rats. Interestingly, although blood pressure returns to normal by 24 hours post-injection, pressor responses to angiotensin II remain attenuated in acute and chronic losartan treated rats. Finally, losartan treatment results in specific alterations in vascular reactivity associated with the actions of angiotensin II.

Phencyclidine-induced desensitization of striatal dopamine release.

Increased release of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) from slices of striatum of DBA/2J mouse in response to administration of phencyclidine (PCP) in vitro has been observed to be transient, despite continued exposure to PCP. To determine whether this transient response was a result of depletion of releasable pools, toxicity or an adaptive response (desensitization), the recovery of the response to PCP was evaluated. Slices in the control condition were exposed to PCP (300 microM) during test-exposure only. Slices in the PCP pre-exposure condition, were exposed first to PCP (30 microM; pre-exposure) and subsequently to PCP (300 microM; test-exposure). During a washout period (0, 30, 60 or 120 min) between exposures to PCP, the slices were superfused in the absence of PCP. Pre-exposure to PCP diminished the subsequent response to test-exposure to PCP (49 and 37% of control for DA and DOPAC, respectively) after 0 min washout. Overflow of DA evoked by PCP returned towards control values but remained decreased (66% of control) after up to 120 min washout. However, overflow of DOPAC did not return to control values after 60 min washout. Thus, the diminished dopaminergic response, resulting from continued exposure to PCP was not due to depletion of the releasable pool or cytotoxicity but rather to a dynamic adaptive response of the dopaminergic neuron to PCP.

DuP 753, a nonpeptide angiotensin II-1 receptor antagonist, alters dopaminergic function in rat striatum.

The purpose of this study was to determine if the nonpeptide angiotensin II-1 receptor antagonist DuP 753 after, acute or chronic administration in vivo or after in vitro exposure, altered indices of dopaminergic function in rat striatum. In vivo studies examined the effect of acute and chronic 21-day administration of DuP 753 (10 mg/kg, s.c.) on levels of dopamine (DA) and its metabolite, dihydroxyphenylacetic acid (DOPAC). To determine if chronic treatment with DuP 753 was able to inhibit the pressor response to angiotensin II, a single i.v. dose of angiotensin II (0.1 microgram/kg) was administered 18 hours after the last dose of DuP 753. Acute DuP 753 resulted in significantly decreased (14%) levels of DA. Chronic DuP 753 resulted in increased (1.64 fold) levels of DOPAC, although DA levels were not altered. The single i.v. administration of angiotensin II resulted in increased (88%) DOPAC levels regardless of chronic DuP 753. The in vitro effect of DuP 753 (0.1 nM-1.0 microM) on basal and field stimulation-evoked release of DA and DOPAC was determined in superfused striatal slices from drug naive rats. DA was not detected in these experiments. DuP 753 did not alter basal outflow of DOPAC. At low concentrations (1.0-10 nM), DuP 753 decreased (53%) stimulation-evoked DOPAC overflow; however, at concentrations greater than 10 nM, the inhibitory effect was diminished. Nomifensine (10 microM; a DA uptake inhibitor) was included in the superfusion buffer in order to measure the effect of DuP 753 on the concentration of DA in superfusate. DuP 753 had no effect on basal DA and DOPAC outflow.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of [3H]dopamine uptake into rat striatal slices by quaternary N-methylated nicotine metabolites.

The effects of quaternary N-methylated nicotine derivatives were examined on in vitro uptake of [3H]dopamine ([3H]DA) in rat striatal slices. Striatal slices were incubated with a 10 microM concentration of the following compounds: N-methylnicotinium, N-methylnornicotinium, N-methylcotininium, N,N'-dimethylnicotinium and N'-methylnicotinium salts. The results clearly indicated that significant (60%) inhibition of [3H]DA uptake occurred with those compounds possessing a N-methylpyridinium group; whereas, compounds that were methylated at the N'-pyrrolidinium position were less effective or exhibited no inhibition of [3H]DA uptake. The results suggest that high concentrations of quaternary N-methylated nicotine metabolites which are structurally related to the neurotoxin MPP+, and which may be formed in the CNS, may protect against Parkinson's Disease and explain the inverse relationship between smoking and Parkinsonism reported in epidemiologic studies.