Intermittent hypoxia changes the interaction of the kinin-VEGF system and impairs myocardial angiogenesis in the hypertrophic heart.

Intermittent hypoxia (IH) is a feature of obstructive sleep apnea (OSA), a condition highly associated with hypertension-related cardiovascular diseases. Repeated episodes of IH contribute to imbalance of angiogenic growth factors in the hypertrophic heart, which is key in the progression of cardiovascular complications. In particular, the interaction between vascular endothelial growth factor (VEGF) and the kallikrein-kinin system (KKS) is essential for promoting angiogenesis. However, researchers have yet to investigate experimental models of IH that reproduce OSA, myocardial angiogenesis, and expression of KKS components. We examined temporal changes in cardiac angiogenesis in a mouse IH model. Adult male C57BI/6 J mice were implanted with Matrigel plugs and subjected to IH for 1-5 weeks with subsequent weekly histological evaluation of vascularization. Expression of VEGF and KKS components was also evaluated. After 3 weeks, in vivo myocardial angiogenesis and capillary density were decreased, accompanied by a late increase of VEGF and its type 2 receptor. Furthermore, IH increased left ventricular myocardium expression of the B2 bradykinin receptor, while reducing mRNA levels of B1 receptor. These results suggest that in IH, an unexpected response of the VEGF and KKS systems could explain the reduced capillary density and impaired angiogenesis in the hypoxic heart, with potential implications in hypertrophic heart malfunction.

Pattern of sympathetic vasomotor activity induced by GABAergic inhibition in the brain and spinal cord.

BACKGROUND: Knowledge of the central areas involved in the control of sympathetic vasomotor activity has advanced in the last few decades. γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammal nervous system, and a microinjection of bicuculline, an antagonist of GABA type A (GABA-A) receptors, into the paraventricular nucleus of the hypothalamus (PVN) alters the pattern of sympathetic activity to the renal, splanchnic and lumbar territories. However, studies are needed to clarify the role of GABAergic inputs in other central areas involved in the sympathetic vasomotor activity. The present work studied the cardiovascular effects evoked by GABAergic antagonism in the PVN, RVLM and spinal cord. METHODS AND RESULTS: Bicuculline microinjections (400 pMol in 100 nL) into the PVN and rostral ventrolateral medulla (RVLM) as well as intrathecal administration (1.6 nmol in 2 µL) evoked an increase in blood pressure, heart rate, and renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively), inducing a higher coherence between rSNA and sSNA patterns. However, some of these responses were more intense when the GABA-A antagonism was performed in the RVLM than when the GABA-A antagonism was performed in other regions. CONCLUSIONS: Administration of bicuculline into the RVLM, PVN and SC induced a similar pattern of renal and splanchnic sympathetic vasomotor burst discharge, characterized by a low-frequency (0.5 Hz) and high-amplitude pattern, despite different blood pressure responses. Thus, the differential control of sympathetic drive to different targets by each region is dependent, in part, on tonic GABAergic inputs.

Renal denervation reduces sympathetic overactivation, brain oxidative stress, and renal injury in rats with renovascular hypertension independent of its effects on reducing blood pressure.

The underlying mechanisms by which renal denervation (RD) decreases blood pressure (BP) remain incompletely understood. In this study, we investigated the effects of ischemic kidney denervation on different sympathetic outflows, brain and renal expression of angiotensin-II receptors, oxidative stress and renal function markers in the 2-kidney, 1-clip (2K-1C) rat model. Surgical RD was performed in Wistar male rats 4-5 weeks after clip implantation. After 10 days of RD, BP, and the activity of sympathetic nerves projecting to the contralateral kidney (rSNA) and splanchnic region were partially reduced in 2K-1C rats, with no change in systemic renin-angiotensin system (RAS). To distinguish the effects of RD from the reduction in BP, 2K-1C rats were treated with hydralazine by oral gavage (25 mg/kg/day for 1 week). RD, but not hydralazine, normalized oxidative stress in the sympathetic premotor brain regions and improved intrarenal RAS, renal injury, and proteinuria. Furthermore, different mechanisms led to renal injury and oxidative stress in the ischemic and contralateral kidneys of 2K-1C rats. Injury and oxidative stress in the ischemic kidney were driven by the renal nerves. Although RD attenuated rSNA, injury and oxidative stress persisted in the contralateral kidney, probably due to increased BP. Therefore, nerves from the ischemic kidney at least partially contribute to the increase in BP, sympathetic outflows, brain oxidative stress, and renal alterations in rats with renovascular hypertension. Based on these findings, the reduction in oxidative stress in the brain is a central mechanism that contributes to the effects of RD on Goldblatt hypertension.

Chronic intermittent hypoxia induces changes on the expression and activity of neprilysin (EC 3.4.24.11) in the brain of rats.

Obstructive sleep apnea (OSA) is a frequent sleeping breathing disorder associated with cognitive impairments. Neprilysin (NEP) is responsible for degrading several substrates related to cognition; however, the effect of chronic intermittent hypoxia (CIH) on NEP is still unknown. This study aimed to evaluate the expression and activity of NEP in cognitive-related brain structures of rats submitted to CIH. Western blot, qRT-PCR and enzyme activity assay, demonstrated that a six-week intermittent hypoxia increased NEP expression and activity, selectively in temporal cortex, but not in the hippocampus and frontal cortex. The increase in NEP activity and expression was reverted followed by two weeks recovery in normoxia. These data show that CIH protocol increases the expression and activity of NEP selectively in the temporal cortex. Additional mechanisms must be investigated to elucidate the effects of CIH in cognition.

Aldosterone Contributes to Sympathoexcitation in Renovascular Hypertension.

BACKGROUND: Although angiotensin II (Ang II) is essential to the development of renovascular hypertension, aldosterone plays a role as well. Recent studies have demonstrated a cross-talk between Ang II type 1 and mineralocorticoid receptors in the brain and kidneys. However, the role of aldosterone in the autonomic and renal dysfunction of renovascular hypertension is not well understood. AIM: The current study evaluated whether aldosterone contributes to cardiovascular and renal dysfunction in the 2 kidney-1 clip (2K1C) model. METHODS: Mean arterial pressure (MAP) and baroreceptor reflex for control of the heart rate were evaluated in 2K1C treated or not treated with spironolactone (200mg/kg/day, 7 days). Tonic and reflex control of renal sympathetic nerve activity (rSNA) were assessed in urethane-anaesthetized rats. Plasma renin activity (PRA), kidney renin protein expression, renal injury, and central AT1 receptor protein expression were assessed. RESULTS: Spiro reduced MAP (198±4 vs. 170±9mm Hg; P < 0.05), normalized rSNA (147±9 vs. 96±10 pps; P < 0.05), and increased renal baroreceptor reflex sensitivity in the 2K1C rats. Spiro reduced α-smooth muscle actin expression in the nonclipped kidney in the 2K1C group (5±0.6 vs. 1.1±0.2%; P < 0.05). There was no change in PRA; however, a decrease in renin protein expression in the nonclipped kidney was found in the 2K1C treated group (217±30 vs. 160±19%; P < 0.05). Spiro treatment decreased AT1 receptor in the central nervous system (CNS) only in 2K1C rats (138±10 vs. 84±12%; P < 0.05). CONCLUSION: Aldosterone contributes to autonomic dysfunction and intrarenal injury in 2K1C, these effects are mediated by the CNS.

Effect of postnatal intermittent hypoxia on locomotor activity and neuronal development in rats tested in early adulthood

The present study evaluated the effects of postnatal intermittent hypoxia on locomotor activity and neuronal cell survival in early adulthood rats. During a critical period of brain development on postnatal day (PD) 7-11, male rat pups were exposed to intermittent hypoxia and randomly assigned to three experimental groups: (1) intermittent hypoxia, (2) normoxia, and (3) control (unhandled). One and a half months later on PD56, a behavioral test was conducted, and cell survival was estimated in the hilus, dental gyrus, and CA1 and CA3 subfields of the hippocampus, nucleus accumbens shell and core, dorsal and ventral striatum, and prefrontal cortex. Our results showed that intermittent hypoxia produced hyperactivity that correlated well with psychomotor agitation observed in patients with schizophrenia. Moreover, post-hypoxic rats exhibited a reduction of the number of neurons in the hilar region of the hippocampus and dorsal striatum, structures that have been neuropathologically associated with schizophrenia.These findings suggest that intermittent hypoxia can modify the pattern of locomotor activity and selectively affect neurons in rats tested in early adulthood...

Effect of postnatal intermittent hypoxia on locomotor activity and neuronal development in rats tested in early adulthood

The present study evaluated the effects of postnatal intermittent hypoxia on locomotor activity and neuronal cell survival in early adulthood rats. During a critical period of brain development on postnatal day (PD) 7-11, male rat pups were exposed to intermittent hypoxia and randomly assigned to three experimental groups: (1) intermittent hypoxia, (2) normoxia, and (3) control (unhandled). One and a half months later on PD56, a behavioral test was conducted, and cell survival was estimated in the hilus, dental gyrus, and CA1 and CA3 subfields of the hippocampus, nucleus accumbens shell and core, dorsal and ventral striatum, and prefrontal cortex. Our results showed that intermittent hypoxia produced hyperactivity that correlated well with psychomotor agitation observed in patients with schizophrenia. Moreover, post-hypoxic rats exhibited a reduction of the number of neurons in the hilar region of the hippocampus and dorsal striatum, structures that have been neuropathologically associated with schizophrenia.These findings suggest that intermittent hypoxia can modify the pattern of locomotor activity and selectively affect neurons in rats tested in early adulthood.(AU)

Interconnectivity of sympathetic and sleep networks is mediated through reduction of gamma aminobutyric acidergic inhibition in the paraventricular nucleus.

Chronic short sleep duration has been linked to sympathoexcitation and increased risk of cardiovascular disease. The central nervous system plays an important role in the regulation of sympathetic activity. Thus, the present study evaluates the pre-autonomic neurones in the paraventricular nucleus of the hypothalamus and rostral ventrolateral medulla after sleep restriction using various protein expression measurements and electrophysiological approaches. Wistar male rats were assigned randomly to two experimental groups: control or sleep restriction for 14 days. Sleep restriction was defined as 20 h of paradoxical sleep deprivation followed by a 4 h sleep permission period using the modified multiple platform method. Micropunches of the paraventricular nucleus of the hypothalamus and rostral ventrolateral medulla were dissected to evaluate the protein expression of angiotensin II receptor, type 1 (AT1), AT2, gamma aminobutyric acidA ) (N-methyl-d-aspartate receptor1) and neuronal nitric oxide synthase neuronal nitric oxide synthase isoform through immunoblotting. Sleep restriction induced a down-regulation of the gamma aminobutyric acidA receptor in the paraventricular nucleus of the hypothalamus. Microinjection of bicuculline, a gamma aminobutyric acid receptor blocker, into the paraventricular nucleus of the hypothalamus increased renal sympathetic activity renal sympathetic nerve activity, mean arterial pressure and heart rate in anaesthetized control rats. However, the amplitude and frequency of renal sympathetic nerve activity was higher in the sleep restriction group. These findings suggest that gamma aminobutyric acidergic inhibition within the paraventricular nucleus of the hypothalamus is involved in sympathoexcitation induced by sleep restriction.

Whole blood hypoxia-related gene expression reveals novel pathways to obstructive sleep apnea in humans.

In this study, our goal was to identify the key genes that are associated with obstructive sleep apnea (OSA). Thirty-five volunteers underwent full in-lab polysomnography and, according to the sleep apnea hypopnea index (AHI), were classified into control, mild-to-moderate OSA and severe OSA groups. Severe OSA patients were assigned to participate in a continuous positive airway pressure (CPAP) protocol for 6 months. Blood was collected and the expression of 84 genes analyzed using the RT(2) Profiler™ PCR array. Mild-to-moderate OSA patients demonstrated down-regulation of 2 genes associated with induction of apoptosis, while a total of 13 genes were identified in severe OSA patients. After controlling for body mass index, PRPF40A and PLOD3 gene expressions were strongly and independently associated with AHI scores. This research protocol highlights a number of molecular targets that might help the development of novel therapeutic strategies.

Acute cocaine treatment increases thimet oligopeptidase in the striatum of rat brain.

Many studies indicate that thimet oligopeptidase (EC3.4.24.15; TOP) can be implicated in the metabolism of bioactive peptides, including dynorphin 1-8, α-neoendorphin, ß-neoendorphin and GnRH. Furthermore, the higher levels of this peptidase are found in neuroendocrine tissue and testis. In the present study, we have evaluated the effect of acute cocaine administration in male rats on TOP specific activity and mRNA levels in prosencephalic brain areas related with the reward circuitry; ventral striatum, hippocampus, and frontal cortex. No significant differences on TOP specific activity were detected in the hippocampus and frontal cortex of cocaine treated animals compared to control vehicle group. However, a significant increase in activity was observed in the ventral striatum of cocaine treated-rats. The increase occurred in both, TOP specific activity and TOP relative mRNA amount determined by real time RT-PCR. As TOP can be implicated in the processing of many neuropeptides, and previous studies have shown that cocaine also alters the gene expression of proenkephalin and prodynorphin in the striatum, the present findings suggest that TOP changes in the brain could play important role in the balance of neuropeptide level correlated with cocaine effects.

Cocaine administration increases angiotensin I-converting enzyme (ACE) expression and activity in the rat striatum and frontal cortex.

Some central effects of cocaine administration seem to be related to angiotensin II (Ang II) or its metabolites. Nonetheless, it is still an open question whether or not the levels of angiotensin I-converting enzyme (ACE), the main Ang II generating enzyme, are modified by cocaine administration. To evaluate the effect of acute and subchronic cocaine administration on ACE activity and mRNA expression, male rats were randomly assigned to saline or cocaine group. Acute and subchronic cocaine administration induced a significant increase in ACE activity and mRNA expression in the frontal cortex and striatum but not in the hippocampus. These results suggest that some of the Ang II related effects of cocaine upon the central nervous system can be mediated by changes on the expression and activity of ACE in the striatum and frontal cortex.

Sympathetic and angiotensinergic responses mediated by paradoxical sleep loss in rats.

INTRODUCTION: Recent investigations over the past decade have linked the development of hypertension to sleep loss, although the mechanisms underlying this association are still under scrutiny. To determine the relationship between sleep deprivation and cardiovascular dysfunction, we examined the effects of paradoxical sleep deprivation on heart rate, blood pressure, sympathetic nerve activity (SNA) and their consequences in the blood renin-angiotensin system. MATERIALS AND METHODS: Wistar-Hannover male rats were randomly assigned to three experimental groups: 1) control, 2) paradoxical sleep deprivation for 24 h and 3) paradoxical sleep deprivation for 96 h. Blood pressure and heart rate were recorded in awake, freely moving rats. RESULTS: Heart rate was higher in the 96 h paradoxical sleep deprivation group compared with the control group. Renal SNA was increased in all deprived groups. However, no significant statistical differences were observed in blood pressure or splanchnic SNA among groups. Paradoxical sleep deprivation (24 and 96 h) reduced plasma angiotensin II (Ang II) concentrations. CONCLUSIONS: The results suggest that selective sleep deprivation produces an increase in SNA, preferentially in the kidney. Thus, alterations in the sympathetic system in response to sleep loss may be an important pathway through which hypertension develops.

Differential sympathetic activation induced by intermittent hypoxia and sleep loss in rats: Action of angiotensin (1-7).

The present study attempted to evaluate the effects of chronic intermittent hypoxia (CIH) associated with sleep restriction in hemodynamic parameters and the plasma renin-angiotensin system. Wistar-Hannover rats were submitted to isolated CIH exposure (1000-1600 h), sleep restriction (1600-1000 h), defined as 18-h paradoxical sleep deprivation followed by 6-h sleep permission period and CIH associated to sleep restriction for 21 days. The CIH and sleep restriction group showed a preferential increase in renal sympathetic nervous system (rSNA) associated with a reduction in plasma angiotensin (1-7) concentrations. However, CIH-sleep restriction rats did not modify rSNA and showed a higher angiotensin (1-7) concentration when compared to isolated CIH and sleep restriction. These results suggest that CIH and sleep restriction impaired the cardiovascular system, and its association to sleep loss can modify these effects by partially restoring circulating angiotensin (1-7).

Paradoxical sleep deprivation influences sexual behavior in female rats.

INTRODUCTION: Sleep disturbances are a frequent complaint in women and are often attributed to hormonal fluctuations during the menstrual cycle. Rodents have been used as models to examine the effects of sleep deprivation on hormonal and behavioral changes. Among the many comorbidities common to sleep disorders, sexual behavior remains the least well studied. AIM: To determine whether paradoxical sleep deprivation (PSD) can affect sexual receptivity (male acceptance) and proceptivity (male solicitation) behaviors in female rats. METHODS: Female Wistar rats were subjected to PSD or were maintained as controls. After this period, the estrous cycle (proestrus, estrus, and diestrus) was determined, and all females were placed with a sexually experienced male. In order to investigate the role of hormones in sexual behavior, we included additional groups that were artificially induced to be sexually receptive via administration of a combination of estradiol and progesterone. MAIN OUTCOME MEASUREMENTS: Receptivity and proceptivity behaviors, as well as progesterone and corticosterone concentrations were monitored. RESULTS: Selective sleep loss caused a significant increase in proceptivity and receptivity behaviors in females exclusively during the proestrus phase. The rejection response was increased in PSD rats during the estrus and diestrus phases, as compared with PSD-receptive and proestrus females. PSD reduced progesterone levels during the proestrus phase relative to the respective control group during the same phase of the estrous cycle. The PSD-proestrus females that displayed the most robust sexual response exhibited greater concentrations of corticosterone than PSD-diestrus females, with an absence of sexual solicitation behaviors. CONCLUSIONS: PSD produced a distinct response in the hormonal profile that was consistent with the phase of the estrous cycle. These results show that sleep loss can affect sexual motivation and might lead to important clinical implications, including alterations in female physiology and reproductive abnormalities.

Intermittent hypoxia and sleep restriction: motor, cognitive and neurochemical alterations in rats.

The present study evaluated the effects of intermittent hypoxia (IH) and sleep restriction (SR) upon motor and cognitive function in rats. Also evaluated were catecholamine concentrations and tyrosine hydroxylase (TH) protein expression in different regions of the forebrain. Wistar Hannover rats were submitted to IH for 4 days or 21 days (2 min room air to 2 min 10% O(2) for 10:00-16:00 h), followed by SR for 18 h (16:00-10:00 h). Rats were randomly assigned into four experimental groups: (1) control (2) IH (3) SR and (4) IH-SR. In the inhibitory avoidance task, an additional group of rats was submitted to paradoxical sleep deprivation (PSD) for 96 consecutive hours. Results showed that SR induced an increase in motor activity without modifying catecholaminergic turnover in the frontal cortex and striatum. The increase in exploratory activity in SR rats could be the result of impaired habituation. Neither SR periods induced cognitive deficits in the inhibitory avoidance task after 5 or 21 days. However, 96 h of PSD impaired acquisition/retention in rats. Exposure to IH did not affect motor and cognitive function but IH was associated with SR in increased motor activity. After 21 days, IH and IH-SR reduced striatal norepinephrine concentration although neither SR nor IH affected TH protein expression. The results presented here suggest that hypoxia and sleep loss exert distinct deleterious effects upon the central nervous system.

Distinct behavioral and neurochemical alterations induced by intermittent hypoxia or paradoxical sleep deprivation in rats.

The current study investigated the effects of paradoxical sleep deprivation and intermittent hypoxia by examining whether a combination of the two would induce anxiety-like alterations in behavior. The neurochemical effects of these manipulations were investigated by measuring cortical, striatal and hippocampal monoamine concentrations. Wistar Hannover rats were submitted to subchronic (3 days) intermittent hypoxia exposure (alternating cycles of 2 min room air-2 min 10% O2 from 0700-1900 h) and paradoxical sleep deprivation using the single platform method. Rats were randomly assigned to four different protocols: 1) control, 2) intermittent hypoxia during the light period (12 h/day), 3) paradoxical sleep deprivation (24 h/day), and 4) intermittent hypoxia combined with paradoxical sleep deprivation. Rats subjected to intermittent hypoxia showed no modification in the behavioral or neurochemical parameters assessed. Although paradoxical sleep deprivation did not produce alterations in anxiety-like behavior, the rats did increase exploratory activity in the elevated plus-maze. Moreover, a significant increase in striatal epinephrine and hippocampal homovanilic acid (HVA) concentrations was found in the paradoxical sleep deprivation groups, but not in the intermittent hypoxia/paradoxical sleep deprivation group. Of note, both paradoxical sleep deprivation and intermittent hypoxia/paradoxical sleep deprivation groups showed an increase in plasma corticosterone concentration. These results suggest that paradoxical sleep deprivation induces behavioral alterations, and these abnormalities may reflect altered neurotransmission in the brain. When paradoxical sleep deprivation was combined with intermittent oxygen depletion, the behavioral and biochemical parameters were comparable to those of control rats.

Possible participation of D3 and D4 dopaminergic receptors on genital reflexes induced by cocaine in paradoxical sleep deprived male rats.

Previous studies have demonstrated that paradoxical sleep deprivation (PSD) potentiates cocaine-induced genital reflexes in male rats and both D1 and D2 receptors may play a role in those effects, and to examine the possibility that such might involve other dopaminergic receptors, we investigated the effects of D3 and D4 receptor subtype antagonists on cocaine-induced reflexes in sleep-deprived rats. Separate groups of PSD rats received saline, D3 (U9919A; 0.75, 1.5 and 3 mg/kg) or D4 (L745870; 0.75, 1.5 and 3 mg/kg) antagonists prior to acute cocaine challenge. Results demonstrated that U9919A induced significant reduction in the number of animals that displayed erection and the frequency of erection at two smaller doses, while no significant difference was reported for the D4 receptor antagonist. Although our studies indicate that there is a relevant participation of D3 receptors in male sexual function, D4 receptors seem not to exert an essential role in this model.

Influence of chronic cocaine treatment and sleep deprivation on sexual behavior and neurogenesis of the male rat.

The present study investigated the influence of chronic cocaine treatment on genital reflexes associated with paradoxical sleep deprivation (PSD), and possible alterations in hippocampus neurogenesis of the male rat. At 21 days of age, the rats were distributed into two groups and injected with saline or cocaine (7 mg/kg, three times a week for 12 weeks). At age 90 days, they were submitted to a four-day period of PSD (PSD groups) or maintained in home-cages (control groups), challenged with saline or cocaine administration, and placed in observation cages to assess genital reflexes. Two additional groups were used to quantify neurogenesis. PSD rats treated chronically with cocaine and challenged with saline did not differ from their respective control groups. The association of PSD with cocaine potentiated penile erection (PE) when compared to PSD-saline (saline challenged) rats, and these effects were similar to those observed in long-term cocaine treated rats. The bromodeoxyuridine (BrdU) assay indicated a reduction in BrdU-positive cells in the adult hippocampus after chronic cocaine treatment. These findings show that long-term cocaine treatment from brain development through adulthood had a marked effect on sexual responses and neuronal proliferation.

Effects of different substance misuse in genital reflexes of paradoxical sleep deprived male rats.

As psychostimulants are widely abused, their neurochemical and behavioral effects have been extensively studied for many years. Our previous data demonstrate that paradoxical sleep deprivation (PSD) enhances drug-induced penile erection and ejaculation. PSD in association to drugs of abuse like cocaine potentiated genital reflexes in male rats. In this sense, the present study investigated if three substances abused by young people--such as Delta(9)-tetrahydrocannabinol (Delta(9)THC), alcohol and caffeine--had any significant effect on the genital reflexes in PSD rats. The results indicated that PSD induced erection in 50% of the rats and 20% ejaculated. In addition, there was no significant alteration in the number of animals exhibiting genital reflexes neither on the frequency of these behaviors when challenged with Delta(9)-THC or alcohol or caffeine after 96 h of PSD. These findings show that Delta(9)THC, alcohol and caffeine when administrated isolated did not produce alterations in genital reflexes in the PSD male rats.

Involvement of nitric oxide in cocaine-induced erections and ejaculations after paradoxical sleep deprivation.

OBJECTIVES: As nitric oxide (NO) is involved in penile erectile (PE) function and also influences the sleep-wake cycle, we speculated that NO could play a role in PE and ejaculation of paradonical sleep deprivation (PSD) rats. METHODS: Animals were pretreated with N(G)-nitro-L-arginine methyl ester (L-NAME, ip) and L-arginine (ip and icv) prior to saline or cocaine injection. RESULTS: Cocaine-induced PE in 90% of PSD rats, 60% of which ejaculated. L-NAME reduced the frequency of erection, but had no effect in the proportion of PSD-cocaine-injected rats displaying this response. L-NAME had no effect in saline groups. L-Arginine in PSD-saline rats reduced the proportion of animals displaying PE at the highest dose and reduced the frequency of PE at all doses in both saline and cocaine groups. The icv administration of L-arginine reduced PE only in PSD-cocaine rats. Results indicate that common to both drugs, whether it was NO synthase (NOS) inhibitor or NO precursor, was their capacity to strongly reduce PE frequency in cocaine-treated rats. Moreover, L-arginine (ip) played a relevant inhibitory role in the erection displayed by PSD rats. CONCLUSIONS: Our findings suggest that the stimulating effects of PSD associated or not with cocaine on erection can be modified by alterations in the NO system.