Significant Cardiovascular Effects Research Articles

Abstract P4-11-01: Cardiovascular Effects of Postmastectomy Irradiation Evident after 15 Years. Results from the South Sweden Breast Cancer Group's Randomised Studies SBII:1 with 25 Years of Follow-Up of Pre-and Postmenopausal Women with Stage II Breast Cancer

Abstract Background: The importance of radiotherapy for local control after mastectomy and breast conservation surgery is well established with a reduction in loco-regional recurrences by two thirds. In early radiotherapy trials the reduction of loco-regional failures did not result in a reduction of mortality due to increased late non-breast cancer mortality. The 2005 overview of radiotherapy by EBCTCG did however show a significantly improved survival with the addition of radiotherapy. Patients and methods: From 1978 to 1985 1100 patients with breast cancer stage II were included in two randomized trials of radiotherapy and adjuvant systemic treatment, SBII:1 pre (Cyclophosphamide per os one year) and SB II:1 post (Tamoxifen 10 mg x 3 one year). The radiotherapy technique and the outcome of these studies have been published previously (Arwidi Å et al. Acta Radiol Oncol 18:273, 1979, Killander F et al. Eur J Cancer 43:2100, 2007, Killander F et al. The Breast 18:309, 2009). An efficient reduction of loco-regional recurrences but no improvement in survival was reported at 25 years of follow-up. Linkage to the following population based Swedish registries was obtained: 1. National Population Registry 2. National Cause of Death Registry, and 3. Swedish Hospital Discharge Registry. Per protocol treatment was administered to 1044 patients, which form the basis for the analyses. We have included both underlying and contributing causes of death due to heart, cerebrovascular and lung disease. Results: After 15 years a significantly increased cardiac mortality was observed in irradiated patients compared to patients given systemic treatment only, and this effect prevailed at 25 years of follow-up. However not until 15 years after radiotherapy significantly higher cardiovascular mortality was observed. When analysing cerebro-vascular mortality the same pattern was seen. Cumulative incidence of non-breast cancer mortality after postmastectomy radiation in pre-and For lung diseases no increase in mortality was discernible. An interesting observation was that in premenopausal patients cardiovascular and cerebrovascular mortality were less pronounced, and that the latency period was longer than for postmenopausal patients. Analyses of all hospital admissions during follow-up showed neither increased overall morbidity nor increased cardiovascular morbidity. Discussion: The significant cardiovascular side effects of radiation observed with the radiotherapy technique used in these studies underlines the importance of careful dose planning and reduction in the volumes of the heart and large vessels, that are exposed to radiation. Extended follow-up is necessary for detection of these late effects. The longer latency and lower cardiovascular mortality in premenopausal patients may reflect lower sensitivity for radiation of normal tissue compared to postmenopausal women. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-01.

Insulin says NO to cardiovascular disease

It is well recognized that insulin resistance found in patients with type 2 diabetes and obesity is a major risk factor for cardiovascular disease. Since its discovery in the 1920s, insulin has been used as an essential therapeutic agent in diabetes for blood glucose management. Recent studies demonstrate that insulin signalling is essential for normal cardiovascular function, and lack of it (i.e. insulin resistance) will result in cardiovascular dysfunction and disease. Moreover, insulin is the key component of glucose-insulin-potassium cocktail and exerts significant cardiovascular protective effect via a phosphatidylinositol3'-kinase-protein kinaseB-endothelial nitric oxide synthase (PI3K-Akt-eNOS)-dependent signalling mechanism in addition to its metabolic modulation, which renders it a potent organ protector in multiple clinical applications. This review focuses on insulin-initiated PI3K-Akt-eNOS survival signalling, with nitric oxide as an 'end effector' delivering cardioprotection in health and disease (especially in ischaemic heart disease), and highlights the impairment of this survival signalling as a key link between insulin resistance and cardiovascular disease.

Propofol as an induction agent for endotracheal intubation can cause significant arterial hypotension in preterm neonates

Propofol is gaining increasing popularity as induction agent for pediatric endotracheal intubation. Recently, propofol has been described for the first time as induction agent for endotracheal intubation in preterm neonates. Propofol seemed to be efficient, safe and ideally suited for the INSURE (Intubation SURfactant Extubation) procedure in preterm neonates. The purpose of this study was to document intubating conditions, vital signs, extubation times and outcome in preterm neonates receiving propofol as induction agent for the INSURE procedure. Preterm neonates with a gestational age of 29-32 weeks and respiratory distress were eligible for INSURE with propofol if their postnatal age was <8 h. Exclusion criteria were any kind of disease not allowing early extubation. There were 13 inborn neonates enrolled for INSURE, mean gestational age was 30 weeks + 3 days, and mean birth weight was 1428 g (range 1170-1780 g). We stopped our observational study ahead of time as a result of significant cardiovascular side effects. Propofol generally offered good intubating conditions, but we encountered severe problems with arterial hypotension. A low propofol bolus of 1 mg kg(-1) caused a distinctive decline in mean arterial blood pressure from 38 mmHg (range 29-42 mmHg) prior premedication to 24 mmHg (22-40 mmHg) 10 min after propofol application. Our experience with propofol as induction agent for endotracheal intubation in preterm neonates reveals distinctive cardiovascular effects, which represent an important risk factor for serious complications of prematurity like intraventricular hemorrhage or periventricular leucomalacia. Propofol should be used with caution in very preterm neonates with respiratory distress during the first hours of life.

Cardiovascular effects following epidural injection of romifidine in isoflurane-anaesthetized dogs

ObjectiveTo investigate the cardiovascular effects of epidural romifidine in isoflurane-anaesthetized dogs. Study designProspective, randomized, blinded experiment. AnimalsA total of six healthy adult female Beagles aged 1.25 ± 0.08 years and weighing 12.46 ± 1.48 (10.25–14.50) kg. MethodsAnaesthesia was induced with propofol (6–9 mg kg−1) and maintained with 1.8–1.9% end-tidal isoflurane in oxygen. End-tidal CO2 was kept between 35 and 45 mmHg (4.7–6.0 kPa) using intermittent positive pressure ventilation. Heart rate (HR), arterial blood pressure and cardiac output (CO) were monitored. Cardiac output was determined using a LiDCO monitor and the derived parameters were calculated. After baseline measurements, either 10 μg kg−1 romifidine or saline (total volume 1 mL 4.5 kg−1) was injected into the lumbosacral epidural space. Data were recorded for 1 hour after epidural injection. A minimum of 1 week elapsed between treatments. ResultsAfter epidural injection, the overall means (± standard deviation, SD) of HR (95 ± 20 bpm), mean arterial blood pressure (MAP) (81 ± 19 mmHg), CO (1.63 ± 0.66 L minute−1), cardiac index (CI) (2.97 ± 1.1 L minute−1 m−2) and stroke volume index (SI) (1.38 ± 0.21 mL beat−1 kg−1) were significantly lower in the romifidine treatment compared with the overall means in the saline treatment [HR (129 ± 24 bpm), MAP (89 ± 17 mmHg), CO (3.35 ± 0.86 L minute−1), CI (6.17 ± 1.4 L minute−1 m−2) and SI (2.21 ± 0.21 mL beat−1 kg−1)]. The overall mean of systemic vascular resistance index (SVRI) (7202 ± 2656 dynes seconds cm−5 m−2) after epidural romifidine injection was significantly higher than the overall mean of SVRI (3315 ± 1167 dynes seconds cm−5 m−2) after epidural saline injection. ConclusionEpidural romifidine in isoflurane-anaesthetized dogs caused significant cardiovascular effects similar to those reportedly produced by systemic romifidine administration. Clinical relevanceSimilar cardiovascular monitoring is required after epidural and systemically administered romifidine. Further studies are required to evaluate the analgesic effects of epidural romifidine.

New Drug Approvals: Silodosin for Benign Prostatic Hyperplasia

To review the pharmacology, pharmacokinetics, clinical trials, and safety of silodosin, a recently approved alpha(1A)-adrenergic receptor (AR) antagonist for benign prostatic hyperplasia (BPH). English-only articles obtained from MEDLINE (1966-October 2009) using the search terms silodosin and KMD-3213 were reviewed. In addition, a search of International Pharmaceutical Abstracts (1970-October 2009) was conducted. Available English-language articles were reviewed, as well as abstracts from available non-English articles. Silodosin reduces urinary symptoms associated with BPH in as little as 1 day after initiation. The largest clinical trial conducted to date demonstrated a decrease in International Prostate Symptom Score of -6.4 +/- 6.63 points compared to -3.5 +/- 5.84 in patients receiving placebo (p < 0.0001). Silodosin also improved urinary flow rates by approximately 2.8 +/- 3.44 mL/sec, which is comparable to other alpha(1)-AR antagonists. The usual dose of silodosin is 8 mg once daily and should be reduced to 4 mg for patients with moderate renal dysfunction. Use is contraindicated in patients with severe renal and hepatic impairment or taking strong CYP3A4 inhibitors. In clinical trials, the most prevalent adverse effects were ejaculatory disturbances, occurring in approximately 28% of patients, although only 2.8% of patients discontinued treatment due to this adverse effect. Preliminary data suggest that, similar to other third-generation alpha(1A)-AR antagonists, silodosin has little potential to cause significant cardiovascular adverse effects such as orthostatic hypotension or syncope. To confirm these findings, long-term studies are still needed, especially in patients taking antihypertensive agents and in those with a history of intolerance to other alpha(1)-AR antagonists. Silodosin was approved by the Food and Drug Administration in 2008. Long-term studies demonstrating improvement in clinically important outcomes of BPH have yet to be published. In addition, pharmacoeconomic analyses would assist in defining its current place in therapy. Until this information is available, silodosin may be best reserved as an alternative to other second- and third-generation alpha(1)-AR antagonists.

Effects of Successive Air and Trimix Dives on Human Cardiovascular Function

The use of trimix (a mixture of oxygen, helium, and nitrogen) has significantly increased among the diver population. However, data indicating how trimix dives at most common depths affect the cardiovascular function are sparse. The purpose of this study was to investigate the cardiovascular effects of trimix dives and compare them with air dives and to determine whether the repetition of dives in successive days affects their extent. Nine professional divers performed four dives in consecutive days where the dive depth was progressively increased to the maximum of 55 m. Divers used air in the first dive, nitrox 25 in the second, and trimix 20/30 in the third and fourth dives. Echocardiography was performed before and after each dive. After each dive, a significantly decreased left ventricular ejection fraction and fractional shortening and an increased end-systolic volume without a change in end-diastolic volume were found, indicating a depressed systolic function of the left side of the heart. Assessment of the ratio between pulmonary artery acceleration time and right ventricular ejection time (used as an indicator of pulmonary artery pressure (PAP)) revealed an increase in PAP after all the dives. No physiologically relevant cumulative effects of the multiple dives or signs of acclimatization were found. The current study shows that the cardiovascular effects of trimix dives do not differ from those of the dives with compressed air. However, it suggests that even a very safe and conservative trimix diving profile exerts significant cardiovascular effects.

Endogenous regulation of cardiovascular function by apelin-APJ

Studies have shown significant cardiovascular effects of exogenous apelin administration, including the potent activation of cardiac contraction. However, the role of the endogenous apelin-APJ pathway is less clear. To study the loss of endogenous apelin-APJ signaling, we generated mice lacking either the ligand (apelin) or the receptor (APJ). Apelin-deficient mice were viable, fertile, and showed normal development. In contrast, APJ-deficient mice were not born in the expected Mendelian ratio, and many showed cardiovascular developmental defects. Under basal conditions, both apelin and APJ null mice that survived to adulthood manifested modest decrements in contractile function. However, with exercise stress both mutant lines demonstrated consistent and striking decreases in exercise capacity. To explain these findings, we explored the role of autocrine signaling in vitro using field stimulation of isolated left ventricular cardiomyocytes lacking either apelin or APJ. Both groups manifested less sarcomeric shortening and impaired velocity of contraction and relaxation with no difference in calcium transient. Taken together, these results demonstrate that endogenous apelin-APJ signaling plays a modest role in maintaining basal cardiac function in adult mice with a more substantive role during conditions of stress. In addition, an autocrine pathway seems to exist in myocardial cells, the ablation of which reduces cellular contraction without change in calcium transient. Finally, differences in the developmental phenotype between apelin and APJ null mice suggest the possibility of undiscovered APJ ligands or ligand-independent effects of APJ.

Comorbidities in heart failure: a key issue

Comorbidities in heart failure: a key issue

The effects of successive air and trimix dives on human cardiovascular function

The use of trimix has significantly increased among diver population. However, the data indicating how the field trimix dives at most common depths affect the cardiovascular function are sparse. The purpose of this study was to investigate the cardiovascular effects of trimix dives and compare them with the air dives, as well as determine whether the repetition of dives in successive days affects their extent. Eight professional divers performed four dives in consecutive days where the dive depth was progressively increased to the maximum of 55 m, and the divers used air in the 1st dive, nitrox 25 for the 2nd, and trimix 20/30 for the 3rd and 4th dive. After each dive, a significantly decreased left ventricular ejection fraction and fractional shortening, as well as increased end‐systolic volume without a change in end‐diastolic volume were found, indicating a depressed systolic function of the left heart. Assessment of the ratio between pulmonary artery acceleration time and right ventricular ejection time revealed an increase in PAP after all the dives. The current study shows that the cardiovascular effects of trimix dives do not differ from those of the dives with compressed air. However, it suggests that even a very safe and conservative trimix diving profile exerts significant cardiovascular effects.This study was supported by the Croatian Ministry of Science, Education and Sports.

Updates on Cytochrome P450-Mediated Cardiovascular Drug Interactions

Cytochrome P (CYP) 450 is a superfamily of hemoproteins that play an important role in the metabolism of steroid hormones, fatty acids, and many medications. Many agents used for management of cardiovascular diseases are substrates, inhibitors, or inducers of CYP450 enzymes.When two agents that are substrates, inhibitors, or inducers of CYP450 are administered together, drug interactions with significant clinical consequences may occur. This review discusses CYP450-mediated cardiovascular drug interactions as well as noncardiovascular drug interactions that produced significant cardiovascular side effects. The principles in predicting drug interactions are also discussed.

Management of neuromuscular block: time for a change?

Management of neuromuscular block: time for a change?

Does Artesunate Prolong the Electrocardiograph QT Interval in Patients with Severe Malaria?

Several antimalarials can cause significant prolongation of the electrocardiograph QT interval, which can be associated with an increased risk of potentially lethal ventricular arrhythmias. High doses of artemether and artemotil have been associated with QT prolongation in dogs, raising the possibility of a class effect with the artemisinin derivatives. Serial electrocardiograms were recorded, and QTc interval was calculated before and after administration of artesunate by intravenous injection in patients with severe falciparum malaria in Bangladesh. Of 21 adult patients with severe malaria enrolled, 8 (38%) died. The mean QTc interval was unaffected by bolus intravenous artesunate (2.4 mg/kg). In two patients, the QTc interval exceeded 0.5 seconds, but in both cases, an alternative explanation was plausible. No effect was observed on the JTc or PR interval, QRS width, blood pressure, or heart rate. Intravenous artesunate does not have significant cardiovascular effects in patients with severe falciparum malaria.

Does artesunate prolong the electrocardiograph QT interval in patients with severe malaria?

Several antimalarials can cause significant prolongation of the electrocardiograph QT interval, which can be associated with an increased risk of potentially lethal ventricular arrhythmias. High doses of artemether and artemotil have been associated with QT prolongation in dogs, raising the possibility of a class effect with the artemisinin derivatives. Serial electrocardiograms were recorded, and QTc interval was calculated before and after administration of artesunate by intravenous injection in patients with severe falciparum malaria in Bangladesh. Of 21 adult patients with severe malaria enrolled, 8 (38%) died. The mean QTc interval was unaffected by bolus intravenous artesunate (2.4 mg/kg). In two patients, the QTc interval exceeded 0.5 seconds, but in both cases, an alternative explanation was plausible. No effect was observed on the JTc or PR interval, QRS width, blood pressure, or heart rate. Intravenous artesunate does not have significant cardiovascular effects in patients with severe falciparum malaria.

Cambios en la perfusión cerebral inducidos por etomidato en pacientes con epilepsia del lóbulo temporal

Epilepsy is one of the major neurological disorders, affecting roughly 0.5-2% of the world's population and approximately 20-25% of patients are resistant to medication. To analyze the response of cerebral perfusion (assessed by SPECT) and bioelectrical activity (measured in scalp and mesial temporal region) to etomidate. We studied 10 patients presurgically evaluated and studied by video-EEG with foramen ovale electrodes (EFO) and SPECT. Etomidate was administered (0.1 mg/kg), followed by (99)mTc-HmPAO during the study in the video-EEG + EFO. The side-effects consisted of myoclonus (n = 7) and moderate pain (n = 2). There had been no significant respiratory or cardiovascular effects. The bioelectrical activity in the scalp consisted in a brief initial rapid activity, followed by a generalized and hypervoltaged delta pattern for several minutes. In the epileptogenic zone, there was a marked increase of interictal activity. Increased cerebral perfusion was observed in all areas studied, especially in temporal region (mesial and lateral) areas and thalamus. In the tail of the non-epileptic hippocampus, we observed the second largest increase in cerebral perfusion, the only region that is different from contralateral area. Activation by etomidate induces a specific and repetitive response in the bioelectrical activity. In addition, cerebral perfusion changes directly related to the epileptogenic region may serve therefore as a diagnostic tool in the near future.

Endocannabinoids and Liver Disease. V. Endocannabinoids as mediators of vascular and cardiac abnormalities in cirrhosis

Cirrhosis is associated with marked cardiovascular disturbances. These include hyperdynamic circulation characterized by reduced peripheral vascular resistance and mean arterial pressure and increased cardiac output. Despite the baseline increase in cardiac output, ventricular responsiveness to stimuli is blunted. A number of cellular signaling pathways have been shown to contribute to these abnormalities, including central nervous system cardiovascular dysregulation and humoral factors such as nitric oxide. Endogenous and exogenous cannabinoids have significant cardiovascular effects. Recent evidence suggests that increased activity of the endocannabinoid system at multiple levels contributes to development of both cardiac and vascular changes in cirrhosis. This brief review surveys recent in vivo and in vitro findings in an attempt to highlight the areas of agreement and areas of controversy in the field. The endocannabinoid system affects key cardiovascular regulators, including the autonomic nervous system, cardiac muscle, and vascular smooth muscle. The interplay among these modes of action further complicates interpretation of the in vivo findings. The broad range of cardiovascular actions of endocannabinoids provides ample opportunities for pharmacological manipulation. At the same time, it increases the possibility of undesirable side effects, which need to be carefully evaluated in long-term studies.

A Placebo-Controlled Trial of Prucalopride for Severe Chronic Constipation

In this 12-week trial, we aimed to determine the efficacy of prucalopride, a selective, high-affinity 5-hydroxytryptamine4 receptor agonist, in patients with severe chronic constipation. In our multicenter, randomized, placebo-controlled, parallel-group, phase 3 trial, patients with severe chronic constipation (< or =2 spontaneous, complete bowel movements per week) received placebo or 2 or 4 mg of prucalopride, once daily, for 12 weeks. The primary efficacy end point was the proportion of patients having three or more spontaneous, complete bowel movements per week, averaged over 12 weeks. Secondary efficacy end points were derived from daily diaries and validated questionnaires completed by patients. Adverse events, clinical laboratory values, and cardiovascular effects were monitored. Efficacy was analyzed in 620 patients. The proportion of patients with three or more spontaneous, complete bowel movements per week was 30.9% of those receiving 2 mg of prucalopride and 28.4% of those receiving 4 mg of prucalopride, as compared with 12.0% in the placebo group (P<0.001 for both comparisons). Over 12 weeks, 47.3% of patients receiving 2 mg of prucalopride and 46.6% of those receiving 4 mg of prucalopride had an increase in the number of spontaneous, complete bowel movements of one or more per week, on average, as compared with 25.8% in the placebo group (P<0.001 for both comparisons). All other secondary efficacy end points, including patients' satisfaction with their bowel function and treatment and their perception of the severity of their constipation symptoms, were significantly improved with the use of 2 or 4 mg of prucalopride as compared with placebo, at week 12. The most frequent treatment-related adverse events were headache and abdominal pain. There were no significant cardiovascular effects of treatment. Over 12 weeks, prucalopride significantly improved bowel function and reduced the severity of symptoms in patients with severe chronic constipation. Larger and longer trials are required to further assess the risks and benefits of the use of prucalopride for chronic constipation. (ClinicalTrials.gov number, NCT00483886 [ClinicalTrials.gov].).

GC-MS analysis and cardiovascular activity of the essential oil of Ocotea duckei

The essential oils obtained by steam distillation from the roots, stems, leaves and fruits of Ocotea duckei had their composition analyzed by GC-MS. The pharmacological activity of these oils was also evaluated showing significant cardiovascular effects. Forty-nine substances were identified, consisting of a complex mixture of monoterpenes (45%) and sesquiterpenes (55%). The fruits yielded (1.9%) more essential oil than the stems (1.0%), roots (0.8%) and leaves (0.7%). The main component in the oil of the leaves was trans-caryophyllene (60.54%), in the stem bark beta-eudesmol (27.51%) and in the fruits, dl-limonene (30.12%). The predominant essential oil component in the roots was elemol (24.31%). In non-anaesthetized normotensive rats, the essential oils from different parts of Ocotea duckei (leaves, fruits, stem and roots) induced significant (p < 0.05) hypotension followed by bradycardia.

Androgendeprivation in der Therapie des Prostatakarzinoms

Androgen deprivation (ADT) by medical or surgical castration represents the standard therapeutic approach for managing prostate cancer (PCA) with systemic or locoregional metastases. Although ADT has been successfully used for more than 60 years, there are still major controversies with regard to the initiation (early versus delayed), type (complete versus monotherapy), and duration (continuous versus intermittent) of treatment. It is the purpose of this review to critically present the results of the various ADT options. Bilateral orchiectomy and subcutaneous application of luteinising hormone-releasing hormone (LHRH) analogues represent the guideline-recommended standard treatment for metastatic PCA, whereas estrogens are no longer recommended because of significant cardiovascular side effects despite comparable therapeutic efficacy. Antiandrogen monotherapy with bicalutamide is comparable to LHRH analogues in men with minimal tumour burden. However, survival rates are inferior in patients with extensive metastatic disease, in whom medical or surgical castration should be favoured. Complete ADT results in a median survival benefit of about 5% in men with low metastatic tumour burden, and it cannot be recommended for routine use. Early ADT is associated with a significant advantage in terms of symptom-free survival and prevention of metastasis-associated complications, but it does not result in a prolonged progression-free and overall survival when compared with delayed ADT. Despite encouraging results, intermittent ADT remains an experimental therapeutic approach that should be considered on an individual basis in carefully selected patients. Adjuvant ADT is still discussed controversially for men after radical prostatectomy, whereas it has become the standard approach in patients who undergo external beam radiation for locally advanced PCA.

Cardiovascular Effects of Lignans Isolated from Saururus chinensis

Saururus chinensis has been widely used as a traditional medicine for the treatment of beriberi, hypertension, pneumonia, edema, jaundice and gonorrhea. However, there is only limited information on the cardiovascular effects of S. chinensis extract or its single compounds. The present study was performed to investigate the effects of active lignans isolated from the extract of S. chinensis on vascular responses and heart functions. The vasorelaxant activity-guided fractionation of roots extract of S. chinensis led to the isolation of eight lignans as active principles. These lignans produced concentration-dependent relaxations of the endothelium-intact aortic preparations of rat aorta. Particularly, saucerneol ( 1), saucerneol D ( 2) and machilin D ( 8) exhibited distinctive vasorelaxant activity (EC (50) values: 2.2, 12.7 and 17.8 microM, respectively), which were significantly inhibited by removal of functional endothelium or pretreatment with N(G)-nitro-L-arginine methyl ester. Saucerneol ( 1) and saucerneol D ( 2) caused a significant decrease in left ventricular pressure, +dP/dt (max) and heart rate in isolated hearts. These results suggest that several lignans including saucerneol ( 1), saucerneol D ( 2) and machilin D ( 8), isolated from the ethanol extract of the roots of S. chinensis, have significant cardiovascular effects such as vasorelaxant and negative inotropic actions.

Defective Phosphatidylinositol 3-Kinase Signaling in Central Control of Cardiovascular Effects in the Nucleus Tractus Solitarii of Spontaneously Hypertensive Rats

Recently we have shown functional involvement of the phosphatidylinositol 3-kinase (PI3K)-Akt-nitric oxide synthase (NOS) signaling pathway in central control of cardiovascular effects in the nucleus tractus solitarii (NTS) of normotensive Wistar-Kyoto (WKY) rats. In this study we determined whether PI3K/Akt signaling was defective in spontaneously hypertensive rats (SHR). WKY rats and SHR were anesthetized with urethane. Mean blood pressure (MBP) and heart rate (HR) were monitored intra-arterially. Unilateral microinjection (60 nL) of insulin (100 IU/mL) into the NTS produced prominent depressor and bradycardic effects in 8- and 16-week-old normotensive WKY and 8-week-old SHR. However, no significant cardiovascular effects were found in 16-week-old SHR after insulin injection. Furthermore, pretreatment with PI3K inhibitor LY294002 and NOS inhibitor L-NAME into the NTS attenuated the cardiovascular response evoked by insulin in WKY and 8-week-old SHR but not in 16-week-old SHR. Unilateral microinjection of 1 mmol/L of PI(3,4,5)P(3) (phosphatidylinositol 3,4,5-triphosphate), a phospholipids second messenger produced by PI3K, into the NTS produced prominent depressor and bradycardic effects in 8- or 16-week-old WKY rats as well as 8-week-old SHR but not in 16-week-old SHR. Western blot analysis showed no significant increase in Akt phosphorylation in 8-week-old pre-hypertensive SHR after insulin injection. Similar results were also found in hypertensive 16-week-old SHR. Our results indicate that the Akt-independent signaling pathway is involved in NOS activation to regulate cardiovascular effects in the NTS of 8-week-old pre-hypertensive SHR. Both Akt-dependent and Akt-independent signaling pathways are defective in hypertensive 16-week-old SHR.