Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis.

1. We have recently demonstrated that chronic infusion of Angiotensin II into apoE-/- mice promotes the development of abdominal aortic aneurysms. To determine the involvement of specific Angiotensin II receptors in this response, we co-infused Angiotensin II (1000 ng kg(-1) min(-1) for 28 days) with losartan (30 mg kg(-1) day(-1)) or PD123319 (3 mg kg(-1) day(-1)) to antagonize AT1 and AT2 receptors, respectively. 2. Infusion of Angiotensin II promoted the development of abdominal aortic aneurysms in 70% of mature female apoE-/- mice. The formation of aortic aneurysms was totally inhibited by co-infusion of Angiotensin II with losartan (30 mg kg(-1) day(-1); P=0.003). In contrast, the co-infusion of Angiotensin II with PD123319 resulted in a marked increase in the incidence and severity of aortic aneurysms. 3. To determine whether AT2 antagonism also promoted Angiotensin II-induced atherosclerosis, Angiotensin II was infused into young female apoE-/- mice that had little spontaneous atherosclerosis. In these mice, co-infusion of PD123319 led to a dramatic increase in the extent of atherosclerosis. This increase was associated with no change in plasma lipid concentrations and only transient and modest increases in blood pressure during co-infusion with PD123319. 4. While antagonism of AT1 receptors totally prevented the formation of aneurysms, antagonism of AT2 receptors promoted a large increase in the severity of Angiotensin II-induced vascular pathology.

Restorative effects of GDNF on striatal dopamine release in rats treated with neurotoxic doses of methamphetamine.

Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in striatal dopamine (DA) release and content. Glial cell line-derived neurotrophic factor (GDNF) has pronounced effects on dopaminergic systems in vivo, including neuroprotective effects against METH. The present experiments were designed to examine the ability of GDNF to reverse, or accelerate recovery from, METH-induced alterations in striatal DA release. Male Fischer-344 rats were administered METH (5 mg/kg, s.c.) or saline 4 times in one day at 2-hour intervals. Seven days later the animals were anesthetized and given a single injection of 10 microg GDNF, or vehicle, into the right striatum. Three weeks later microdialysis experiments were carried out in both the right and left striata to examine basal and evoked levels of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). In animals treated with METH followed by vehicle 7 days later, there were significant reductions in potassium- and amphetamine-evoked overflow of DA, and in basal levels of DOPAC and HVA, compared to control animals. In rats treated with METH followed 7 days later with GDNF, there were significant increases in potassium- and amphetamine-evoked overflow of DA on the right, GDNF-treated, side of the brain compared to the left side. Basal levels of DOPAC and HVA were also elevated on the GDNF-treated side of the brain. These results suggest that GDNF can accelerate recovery of dopaminergic release processes in the striatum of rats treated with neurotoxic doses of METH.

Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice.

Increased plasma concentrations of angiotension II (Ang II) have been implicated in atherogenesis. To examine this relationship directly, we infused Ang II or vehicle for 1 month via osmotic minipumps into mature apoE(-/-) mice. These doses of Ang II did not alter arterial blood pressure, body weight, serum cholesterol concentrations, or distribution of lipoprotein cholesterol. However, Ang II infusions promoted an increased severity of aortic atherosclerotic lesions. These Ang II-induced lesions were predominantly lipid-laden macrophages and lymphocytes; moreover, Ang II promoted a marked increase in the number of macrophages present in the adventitial tissue underlying lesions. Unexpectedly, pronounced abdominal aortic aneurysms were present in apoE(-/-) mice infused with Ang II. Sequential sectioning of aneurysmal abdominal aorta revealed two major characteristics: an intact artery that is surrounded by a large remodeled adventitia, and a medial break with pronounced dilation and more modestly remodeled adventitial tissue. Although no atherosclerotic lesions were visible at the medial break point, the presence of hyperlipidemia was required because infusions of Ang II into apoE(+/+) mice failed to generate aneurysms. These results demonstrate that increased plasma concentrations of Ang II have profound and rapid effects on vascular pathology when combined with hyperlipidemia, in the absence of hemodynamic influences.

Recovery of presynaptic dopaminergic functioning in rats treated with neurotoxic doses of methamphetamine.

Repeated administration of methamphetamine (METH) to animals can result in long-lasting decreases in striatal dopamine (DA) content. In addition, the evoked overflow of striatal DA is reduced in rats 1 week after neurotoxic doses of METH. However, whether these functional changes in DA release are permanent or tend to recover over time has not been established. In the present study we used in vivo electrochemistry and microdialysis to examine evoked overflow of DA in the striatum of METH-treated rats at several time points after treatment to determine if DA overflow would spontaneously recover. Male Fischer-344 rats were administered METH (5 mg/kg, s.c. ) or saline four times in one day at 2 hr intervals. In vivo electrochemistry experiments in anesthetized rats, and in vivo microdialysis studies in awake rats, were carried out 1 week, 1 month, 6 months, and 12 months after treatment. At 1 week after treatment there were significant decreases in potassium- and amphetamine-evoked overflow of DA, and in clearance of DA, in the striatum of the METH-treated animals. Basal extracellular levels of DA and its metabolites were also decreased. Evoked overflow had partially recovered by 1 month. By 6 months evoked overflow of DA appeared to be normal in the METH-treated rats. However, whole tissue levels of striatal DA were still significantly decreased. All parameters were back to control values by 12 months. These results suggest that presynaptic dopaminergic functioning can recover to normal levels in the striatum of METH-treated rats by 12 months after treatment.

Augmented methamphetamine-induced overflow of striatal dopamine 1 day after GDNF administration.

Glial cell line-derived neurotrophic factor (GDNF) can attenuate the dopamine (DA)-depleting effects of neurotoxic doses of methamphetamine (METH) when given 1 day prior to the METH. The neurotoxic effects of METH may be due, in part, to sustained increases in extracellular levels of DA. It is therefore possible that GDNF may be altering the effects of METH by influencing extracellular levels of DA during the METH treatment. The purpose of the present study was to determine if GDNF has effects on extracellular levels of DA in the striatum by 24-h post-administration. GDNF (10 microgram in 2 microliter vehicle) or vehicle was injected into the right striatum or substantia nigra of anesthetized male rats. The next day the animals were anesthetized again and dialysis probes were positioned in both the right and left striata and perfused with artificial cerebrospinal fluid. Following the collection of baseline samples the rats were administered METH (5 mg/kg, s.c.). The METH injections dramatically increased extracellular DA levels on both sides of the brain. However, levels on the GDNF injected side were significantly greater than levels on the contralateral side. Basal levels of DA were not significantly different between the two sides, but levels of DA metabolites were elevated on the GDNF side. Post-mortem tissue levels of DA metabolites, but not DA, were also elevated in the striatum and substantia nigra. These results indicate that GDNF has significant effects on DA neuron functioning within 24 h of administration and that GDNF can augment DA overflow while inhibiting the neurotoxic effects of METH.

GDNF protection against 6-OHDA-induced reductions in potassium-evoked overflow of striatal dopamine.

Glial cell line-derived neurotrophic factor (GDNF), when administered before 6-hydroxydopamine (6-OHDA), has been shown to prevent the reduction in nigral dopamine (DA) levels and tyrosine hydroxylase-positive neurons normally observed after 6-OHDA lesions. The present study examined the ability of GDNF to prevent 6-OHDA-induced reductions in striatal DA release and reductions in striatal and nigral DA levels. GDNF (10 micrograms), or vehicle, was injected into the right nigra of anesthetized male Fischer-344 rats and was followed 6 hr later by intranigral 6-OHDA or saline. Three to four weeks later the animals were anesthetized with urethane and prepared for in vivo electrochemistry. Potassium-evoked overflow of DA was dramatically decreased in the right striatum of the vehicle + 6-OHDA-treated animals. GDNF appeared to prevent the reduction in evoked overflow of DA in the right striatum of the 6-OHDA-treated animals. However, in comparison with that in animals that received GDNF + saline, the overflow of DA was significantly reduced in the GDNF + 6-OHDA animals. Similarly, although nigral levels of DA were above normal in the GDNF + 6-OHDA-treated animals, they were below DA levels found in GDNF + saline-treated rats. Striatal DA levels were partially protected by GDNF. In animals examined 10-12 weeks after the GDNF and 6-OHDA treatments, the apparent protective ability of GDNF on the evoked overflow of DA in the striatum was diminished. Thus, although intranigral GDNF can prevent 6-OHDA-induced reductions in nigral DA levels, long-term protection of the evoked overflow of DA in the striatum is minimal.

Effects of neurotoxic doses of methamphetamine on potassium and amphetamine evoked overflow of dopamine in the striatum of awake rats.

The effects of neurotoxic doses of methamphetamine on basal and evoked overflow of dopamine in the striatum were examined in awake rats using microdialysis. Male Fischer-344 rats were administered methamphetamine (5 mg/kg s.c.) or saline four times in 1 day at 2-h intervals. Microdialysis experiments were carried out 1 week later. Basal levels of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were reduced in the striatum of the methamphetamine-treated animals. Local application of excess potassium (100 mM) and amphetamine (100 microM), and intraperitoneal injection of amphetamine (1.5 mg/ kg), led to increased levels of extracellular dopamine in the striatum of both methamphetamine- and saline-treated rats. However, the increase was significantly less in the methamphetamine-treated animals. Tissue levels of dopamine and metabolites were reduced in the striata of rats treated with methamphetamine. These results indicate that treatment with neurotoxic doses of methamphetamine can lead to functional changes in dopamine release in the striatum of Fischer-344 rats.