Activation Of Vasoconstriction Research Articles

Phospholipase C-β3 is dispensable for vascular constriction but indispensable for vascular hyperplasia

Angiotensin II (AngII) induces the contraction and proliferation of vascular smooth muscle cells (VSMCs). AngII activates phospholipase C-β (PLC-β), thereby inducing Ca2+ mobilization as well as the production of reactive oxygen species (ROS). Since contraction is a unique property of contractile VSMCs, signaling cascades related to the proliferation of VSMCs may differ. However, the specific molecular mechanism that controls the contraction or proliferation of VSMCs remains unclear. AngII-induced ROS production, migration, and proliferation were suppressed by inhibiting PLC-β3, inositol trisphosphate (IP3) receptor, and NOX or by silencing PLC-β3 or NOX1 but not by NOX4. However, pharmacological inhibition or silencing of PLC-β3 or NOX did not affect AngII-induced VSMC contraction. Furthermore, the AngII-dependent constriction of mesenteric arteries isolated from PLC-β3∆SMC, NOX1−/−, NOX4−/− and normal control mice was similar. AngII-induced VSMC contraction and mesenteric artery constriction were blocked by inhibiting the L-type calcium channel Rho-associated kinase 2 (ROCK2) or myosin light chain kinase (MLCK). The activation of ROCK2 and MLCK was significantly induced in PLC-β3∆SMC mice, whereas the depletion of Ca2+ in the extracellular medium suppressed the AngII-induced activation of ROCK2, MLCK, and vasoconstriction. AngII-induced hypertension was significantly induced in NOX1−/− and PLC-β3∆SMC mice, whereas LCCA ligation-induced neointima formation was significantly suppressed in NOX1−/− and PLC-β3∆SMC mice. These results suggest that PLC-β3 is essential for vascular hyperplasia through NOX1-mediated ROS production but is nonessential for vascular constriction or blood pressure regulation.

Post-injury Inhibition of Endothelin-1 Dependent Renal Vasoregulation Mitigates Rhabdomyolysis-Induced Acute Kidney Injury.

In patients with rhabdomyolysis, the overwhelming release of myoglobin into the circulation is the primary cause of kidney injury. Myoglobin causes direct kidney injury as well as severe renal vasoconstriction. An increase in renal vascular resistance (RVR) results in renal blood flow (RBF) and glomerular filtration rate (GFR) reduction, tubular injury, and acute kidney injury (AKI). The mechanisms that underlie rhabdomyolysis-induced AKI are not fully understood but may involve the local production of vasoactive mediators in the kidney. Studies have shown that myoglobin stimulates endothelin-1 (ET-1) production in glomerular mesangial cells. Circulating ET-1 is also increased in rats subjected to glycerol-induced rhabdomyolysis. However, the upstream mechanisms of ET-1 production and downstream effectors of ET-1 actions in rhabdomyolysis-induced AKI remain unclear. Vasoactive ET-1 is generated by ET converting enzyme 1 (ECE-1)-induced proteolytic processing of inactive big ET to biologically active peptides. The downstream ion channel effectors of ET-1-induced vasoregulation include the transient receptor potential cation channel, subfamily C member 3 (TRPC3). This study demonstrates that glycerol-induced rhabdomyolysis in Wistar rats promotes ECE-1-dependent ET-1 production, RVR increase, GFR decrease, and AKI. Rhabdomyolysis-induced increases in RVR and AKI in the rats were attenuated by post-injury pharmacological inhibition of ECE-1, ET receptors, and TRPC3 channels. CRISPR/Cas9-mediated knockout of TRPC3 channels attenuated ET-1-induced renal vascular reactivity and rhabdomyolysis-induced AKI. These findings suggest that ECE-1-driven ET-1 production and downstream activation of TRPC3-dependent renal vasoconstriction contribute to rhabdomyolysis-induced AKI. Hence, post-injury inhibition of ET-1-mediated renal vasoregulation may provide therapeutic targets for rhabdomyolysis-induced AKI.

A Foundation for the Neural Control of Viral Fever

Fever, an acute‐phase neurally‐regulated increase in body temperature, is thought to be an adaptive response to optimize host defenses against invading pathogens. However, fever can be an unpleasant symptom of infection and excessive fever (>41oC) can cause irreversible protein denaturation and result in tissue damage, seizure, coma and death. Common therapeutic approaches to fever include the use of non‐steroidal anti‐inflammatory drugs and cyclooxygenase inhibitors, however these approaches are ineffective for reducing prostaglandin‐independent fevers, can interfere with adaptive and innate immune defenses and are contraindicated for use in some viral infections, including SARS‐CoV2. Although research over the past couple of decades has defined the fundamental central nervous system (CNS) pathways necessary for the lipopolysaccharide model of bacterial fever, the CNS circuits mediating viral fevers are almost completely unknown. Double‐stranded RNA is an intermediary in viral replication and serves as a pathogen‐associated molecular pattern that elicits the acute phase responses to viral infection. Systemic administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic double stranded RNA, mimics the acute phase responses to viral infection. Neurons in the rostral raphe pallidus area (rRPa) and the dorsomedial hypothalamus play important roles in the control of the sympathetic outflow to thermoeffectors, therefore we hypothesized that neurons in these areas would be essential for fever elicited by a model of viral fever, intravenous (iv) poly I:C. Female and male Sprague Dawley rats anesthetized with urethane and α‐chloralose (for BAT sympathetic nerve recording, n=3) or isoflurane (for cutaneous vasoconstriction experiments, n=3) received iv poly I:C (1mg/kg for experiments with sympathetic nerve recording, or 500μg/kg for experiments for cutaneous vasoconstriction). Systemically administered poly I:C increased BAT SNA (+601 ± 161% baseline), BAT temperature (TBAT; +3.1 ± 0.8°C), and expired CO2 (+0.9 ± 0.2%). Poly I:C also elicited CVC, as observed by reductions in paw or tail skin temperature (TPAW/TTail) (‐2.6 ± 1.2°C). A nanoinjection of the ionotropic glutamate receptor antagonists, AP5 and CNQX in the rRPa reversed poly I:C‐evoked increases in BAT SNA (‐596 ± 128% baseline), TBAT (‐1.3 ± 0.2°C), and expired CO2 (‐0.5 ± 0.1%). Nanoinjection of AP5 and CNQX into the DMH reversed the polyI:C‐evoked reduction in TPAW/TTail (+2.8 ± 1.1°C). These data suggest that the activity of neurons in the rRPa and the DMH are necessary for poly I:C‐induced activation of BAT thermogenesis and cutaneous vasoconstriction. These data define critical components of the neural circuits for poly I:C‐induced fever, highlight differences between the neural circuitry mediating bacterial fever and viral fever, and provide a foundation for elucidating additional brain mechanisms responsible for viral fever.

CONTRAST-INDUCED NEPHROPATHY: PREVALENCE, DIAGNOSIS, PREVENTION AND TREATMENT

Resume. Medical imaging has become an important diagnostic and therapeutic tool in clinical medicine in the era of great technological advances. One of the most frequent and important adverse drug reactions during angiographic studies is contrast-induced nephropathy. Study of epidemiology, risk factors for the development of contrast-induced nephropathy, possible ways of prevention and treatment to reduce the frequency and severity of this complication, improve the quality of patient therapy and reduce the cost of treating complications. Materials and methods. The search for information in the database PubMed, Scopus, Web of Science, e-library, etc. was carried out using the following words and phrases: percutaneous coronary intervention, coronary angiography, contrast-induced nephropathy. Results. The incidence of contrast-induced nephropathy during coronary angiography varies from 2 to 25 %, however, in high-risk groups it can reach 50 %. To prevent the development of contrast-induced nephropathy, there are a number of pharmacological and non-pharmacological approaches. Its prevention is most relevant in high-risk patients. Conclusions. Minimizing the volume of the radiopaque agent, preventing and correcting hypovolemia, preventing the activation of vasoconstriction are the most effective measures to prevent contrast-induced nephropathy.

Chronic ablation of TRPV1-sensitive skeletal muscle afferents attenuates the muscle metaboreflex.

Exercise intolerance is a hallmark symptom of cardiovascular disease and likely occurs via enhanced activation of muscle metaboreflex-induced vasoconstriction of the heart and active skeletal muscle which, thereby limits cardiac output and peripheral blood flow. Muscle metaboreflex vasoconstrictor responses occur via activation of metabolite-sensitive afferent fibers located in ischemic active skeletal muscle, some of which express transient receptor potential vanilloid 1 (TRPV1) cation channels. Local cardiac and intrathecal administration of an ultrapotent noncompetitive, dominant negative agonist resiniferatoxin (RTX) can ablate these TRPV1-sensitive afferents. This technique has been used to attenuate cardiac sympathetic afferents and nociceptive pain. We investigated whether intrathecal administration (L4-L6) of RTX (2 µg/kg) could chronically attenuate subsequent muscle metaboreflex responses elicited by reductions in hindlimb blood flow during mild exercise (3.2 km/h) in chronically instrumented conscious canines. RTX significantly attenuated metaboreflex-induced increases in mean arterial pressure (27 ± 5.0 mmHg vs. 6 ± 8.2 mmHg), cardiac output (1.40 ± 0.2 L/min vs. 0.28 ± 0.1 L/min), and stroke work (2.27 ± 0.2 L·mmHg vs. 1.01 ± 0.2 L·mmHg). Effects were maintained until 78 ± 14 days post-RTX at which point the efficacy of RTX injection was tested by intra-arterial administration of capsaicin (20 µg/kg). A significant reduction in the mean arterial pressure response (+45.7 ± 6.5 mmHg pre-RTX vs. +19.7 ± 3.1 mmHg post-RTX) was observed. We conclude that intrathecal administration of RTX can chronically attenuate the muscle metaboreflex and could potentially alleviate enhanced sympatho-activation observed in cardiovascular disease states.

Abstract 16876: Saturated Arterial Vasoconstriction in the Fontan Circulation

Background: Cardiac afterload in the Fontan circulation is enhanced due to sequentially connected pulmonary circulation to the systemic circulation. As the augmentation of afterload, which includes both of venous and arterial components, markedly compromise stroke volume in the Fontan patients, identification of primary culprit is vitally important to determine therapeutic targets in preserving circulation and end-organ function. We tested our hypothesis that the augmentation of cardiac afterload in the Fontan circulation is attributed by the compensative arterial constriction in addition to the venous congestion. Methods: Transient inferior vena-caval occlusion (IVCO) was applied to induced venous congestion in 23 Fontan and 87 postoperative biventricular circulation patients(BVC), and augmentation of arterial elastance (Ea) was measured with constructing ventricular pressure-volume relationship. Results: As compared with BVC patients, lower cardiac output in the Fontan patient was attributed by the augmented afterload with similar contractile function. While increase of CVP was augmented in the Fontan pts as compared to those with BVC (p=0.0016), increase of Ea was similar in both groups, suggesting suppressed response of increasing Ea in the Fontan pts. This was further supported by the negative relationship between CVP increase and Ea augmentation (p=0.048). Consistent with this, increase of Ea by induced venous congestion was negatively correlated with mean circulatory filling pressure (p=0.025) as well as systemic vascular resistance (p=0.047). Importantly, augmentation of Ea was independent of renin-angiotensin-aldosterone system (RAAS). Conclusions: Augmentation of afterload by induced venous congestion was rather saturated in the Fontan circulation, suggesting chronic activation of excessive compensatory vasoconstriction at baseline, which involves entire vascular system. As this response was independent of RAAS activity, in addition to RAAS blockade, structural and functional interventions to suppress cardiovascular remodeling should be implemented for the further reduction of cardiac afterload.

Abstract P344: Increased Expression and Function of Endothelin Receptors in Aorta of (mRen2)27 Hypertensive Rats

Endothelin-1 (ET-1) contributes to various cardiovascular diseases including hypertension. ET-1 is produced in the endothelium and acts via ET A receptors, located in smooth muscle cells, and via ET B receptors, located in both endothelium and smooth muscle cells. Activation of ET A produces vasoconstriction, whereas endothelial ET B activation mediates vasodilation, with previous studies showing that ET-1-mediated vasoconstriction is enhanced in hypertension. We hypothesized that increased ETA-mediated function is present in vasculature of the (mRen2)27 hypertensive rat. Western blotting of total protein extracts from thoracic aorta was used to determine expression of ET A and ET B from Sprague-Dawley (SD n=4) and (mRen2)27 hypertensive (n=5) rats. Specificity of western blot signals for ET A and ET B was assessed by using pre-absorption of primary antibody with the corresponding antigenic peptide and intensity of signals was measured by densitometry (NIH-J Image). Contractile responses to ET-1 (10 -11 -10 -7 M) in intact and denuded aorta were determined by wire myography (Multi Myograph, DMT-USA) in the presence of the ET A blocker BQ123 (10 -6 M) or the ET B blocker BQ788 (10 -6 M). Contraction to ET-1 was expressed as maximal response (ET MAX as %K MAX ) and sensitivity (pD 2 =-Log [EC 50 ]). In aortae from (mRen2)27 rats ET A and ET B receptor expression (48 and 31 kDa bands) was greater relative to aortae of SD rats (p<0.05). ET-1 contraction showed increased sensitivity in (mRen2)27 vs SD aortae (pD 2 , 8.17±0.15 vs 7.76±0.12, p<0.05) with similar ET MAX (157±16 vs 145±6 %K MAX , p>0.05). In intact arteries, blockade of ET B increased ET-1 sensitivity (pD 2 8.4±0.3, p<0.05) in SD without effect on intact arteries from (mRen2)27 rats. In denuded arteries, ETB blockade increased ET MAX only in aortae from (mRen2)27 (205±12 vs 152±5, p<0.05). Thus, increased ET A expression mediates greater ET-1-dependent contraction in vasculature of (mRen2)27 rats. In (mRen2)27 rats, loss of endothelial ET B receptor function in intact arteries may contribute to enhanced constrictor responses to ET-1, whereas increased ET B receptors in smooth muscle cells provide a counterbalancing vasodilation to offset maximal contractile effects of ET-1 in this model of hypertension.

Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction.

MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results.

Complication of Cirrhosis Portal Hypertension: A Review

Portal hypertension is responsible for most of the complications that mark the transition from compensated to decompensated cirrhosis, namely variceal hemorrhage, ascites and hepatic encephalopathy. Gastroesophageal varices result almost solely from portal hypertension, although the hyperdynamic circulation contributes to variceal growth and rupture. Ascites results from sinusoidal hypertension (portal hypertension) and sodium retention, which is, in turn, secondary to vasodilatation and activation of neurohumoral systems. The hepatorenal syndrome results from extreme vasodilatation with extreme decrease in effective blood volume and maximal activation of vaso constrictive systems, renal vasoconstriction and renal failure, which is probably an indirect effect of the changes in splanchnic circulation. Spontaneous bacterial peritonitis, a frequent precipitant of the hepatorenal syndrome, most probably results from deficient immunity, resulting in pathological gut bacterial translocation. Hepatic encephalopathy results from portosystemic shunting and hepatic insufficiency leading to accumulation of neurotoxins, mainly ammonia, in the brain. As for any illness, prediction of death in cirrhosis is essential in its management; and the development of portal hypertension and its complications have important prognostic value.

Autoimmune Basis for Postural Tachycardia Syndrome

BackgroundPatients with postural tachycardia syndrome (POTS) have exaggerated orthostatic tachycardia often following a viral illness, suggesting autoimmunity may play a pathophysiological role in POTS. We tested the hypothesis that they harbor functional autoantibodies to adrenergic receptors (AR).Methods and ResultsFourteen POTS patients (7 each from 2 institutions) and 10 healthy subjects were examined for α1AR autoantibody‐mediated contractility using a perfused rat cremaster arteriole assay. A receptor‐transfected cell‐based assay was used to detect the presence of β1AR and β2AR autoantibodies. Data were normalized and expressed as a percentage of baseline. The sera of all 14 POTS patients demonstrated significant arteriolar contractile activity (69±3% compared to 91±1% of baseline for healthy controls, P<0.001) when coexisting β2AR dilative activity was blocked; and this was suppressed by α1AR blockade with prazosin. POTS sera acted as a partial α1AR antagonist significantly shifting phenylephrine contractility curves to the right. All POTS sera increased β1AR activation (130±3% of baseline, P<0.01) and a subset had increased β2AR activity versus healthy subjects. POTS sera shifted isoproterenol cAMP response curves to the left, consistent with enhanced β1AR and β2AR agonist activity. Autoantibody‐positive POTS sera demonstrated specific binding to β1AR, β2AR, and α1AR in transfected cells.ConclusionsPOTS patients have elevated α1AR autoantibodies exerting a partial peripheral antagonist effect resulting in a compensatory sympathoneural activation of α1AR for vasoconstriction and concurrent βAR‐mediated tachycardia. Coexisting β1AR and β2AR agonistic autoantibodies facilitate this tachycardia. These findings may explain the increased standing plasma norepinephrine and excessive tachycardia observed in many POTS patients.

Obesity and risk of vascular disease: importance of endothelium-dependent vasoconstriction.

Obesity has become a serious global health issue affecting both adults and children. Recent devolopments in world demographics and declining health status of the world's population indicate that the prevalence of obesity will continue to increase in the next decades. As a disease, obesity has deleterious effects on metabolic homeostasis, and affects numerous organ systems including heart, kidney and the vascular system. Thus, obesity is now regarded as an independent risk factor for atherosclerosis-related diseases such as coronary artery disease, myocardial infarction and stroke. In the arterial system, endothelial cells are both the source and target of factors contributing to atherosclerosis. Endothelial vasoactive factors regulate vascular homeostasis under physiological conditions and maintain basal vascular tone. Obesity results in an imbalance between endothelium-derived vasoactive factors favouring vasoconstriction, cell growth and inflammatory activation. Abnormal regulation of these factors due to endothelial cell dysfunction is both a consequence and a cause of vascular disease processes. Finally, because of the similarities of the vascular pathomechanisms activated, obesity can be considered to cause accelerated, 'premature' vascular aging. Here, we will review some of the pathomechanisms involved in obesity-related activation of endothelium-dependent vasoconstriction, the clinical relevance of obesity-associated vascular risk, and therapeutic interventions using 'endothelial therapy' aiming at maintaining or restoring vascular endothelial health. This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.

Lung Cell Hypoxia: Role of Mitochondrial Reactive Oxygen Species Signaling in Triggering Responses

Lung cells experience hypoxia during development, during travel to high altitude, and in acute and chronic lung diseases. The functional responses evoked by hypoxia are diverse and generally act to protect the cells from hypoxic injury, although some lung cell responses are counterproductive because they degrade normal function of the organ. The cellular O(2) sensor responsible for many of these responses involves the mitochondrial electron transport chain. Under hypoxic conditions, increased release of reactive oxygen species from the inner mitochondrial membrane to the intermembrane space leads to the activation of transcription factors, including hypoxia-inducible factor, activation of hypoxic pulmonary vasoconstriction, activation of AMP-dependent protein kinase, and internalization of the membrane Na,K-ATPase from the basolateral membrane of alveolar epithelial cells. Although the specific targets of reactive oxygen species signals are not fully understood, this signaling pathway is critical for development and for normal lung responses in the newborn and the mature lung.

Abstract 4927: Thrombin Activation of Proteinase-Activated Receptor 1 (PAR1) Induces Ca 2+ -Independent Vasoconstriction by Activating the Production of Reactive Oxygen Species in the Pulmonary Artery

Thrombotic pulmonary arteriopathy is associated with ~50% of primary pulmonary artery hypertension (PAH). Thrombin and its receptor PAR 1 are thus suggested to play a critical role in the pathogenesis and pathophysiology of PAH. However, the role of thrombin in the regulation of pulmonary artery contraction still remains largely unknown. This study thus aimed to elucidate the contractile mechanism of thrombin in the isolated porcine pulmonary artery. In the presence of extracellular Ca 2+ ([Ca 2+ ] o ), thrombin induced a sustained contraction with a small sustained elevation of [Ca 2+ ] i and an increase in myosin light chain (MLC) phosphorylation. The contractile effect of thrombin was abolished by either a protease inhibitor or a PAR 1 antagonist, while it was mimicked by an agonist peptide for PAR 1 , but not PAR 4 . In the absence of [Ca 2+ ] o , thrombin induced a sustained contraction to an extent similar to that seen in the presence of [Ca 2+ ] o , but no significant increase in [Ca 2+ ] i or MLC phosphorylation was observed. A similar Ca 2+ -independent contraction was induced by H 2 O 2 . Pretreatment with N -acetyl cysteine substantially inhibited the Ca 2+ -independent contraction induced by thrombin and H 2 O 2 . The fluorescence imaging of reactive oxygen species (ROS) revealed the thrombin- induced production of ROS in the absence of [Ca 2+ ] o . When a scavenger enzyme glutathione peroxidase was suppressed, the ROS production by thrombin was observed both in the presence and absence of [Ca 2+ ] o , thus suggesting that thrombin is capable of producing ROS regardless of the presence or absence of [Ca 2+ ] o , while this effect was veiled by the scavenger activity in the presence of [Ca 2+ ] o . Rho kinase inhibitor inhibited not only the thrombin-induced contraction in the presence of [Ca 2+ ] o , but also the Ca 2+ -independent contraction induced by thrombin and H 2 O 2 and the thrombin-induced ROS production, thus suggesting multiple roles of Rho kinase. This study thus provides the first evidence that the thrombin activation of PAR 1 induces pulmonary vasoconstriction via Ca 2+ -dependent as well as Ca 2+ -independent and ROS-mediated contractile mechanisms. PAR 1 is thus suggested to be useful as a novel therapeutic target for the treatment of PAH, especially when associated with thrombus.

Exposure to ultrafine carbon particles at levels below detectable pulmonary inflammation affects cardiovascular performance in spontaneously hypertensive rats

BackgroundExposure to particulate matter is a risk factor for cardiopulmonary disease but the underlying molecular mechanisms remain poorly understood. In the present study we sought to investigate the cardiopulmonary responses on spontaneously hypertensive rats (SHRs) following inhalation of UfCPs (24 h, 172 μg·m-3), to assess whether compromised animals (SHR) exhibit a different response pattern compared to the previously studied healthy rats (WKY).MethodsCardiophysiological response in SHRs was analyzed using radiotelemetry. Blood pressure (BP) and its biomarkers plasma renin-angiotensin system were also assessed. Lung and cardiac mRNA expressions for markers of oxidative stress (hemeoxygenase-1), blood coagulation (tissue factor, plasminogen activator inhibitor-1), and endothelial function (endothelin-1, and endothelin receptors A and B) were analyzed following UfCPs exposure in SHRs. UfCPs-mediated inflammatory responses were assessed from broncho-alveolar-lavage fluid (BALF).ResultsIncreased BP and heart rate (HR) by about 5% with a lag of 1–3 days were detected in UfCPs exposed SHRs. Inflammatory markers of BALF, lung (pulmonary) and blood (systemic) were not affected. However, mRNA expression of hemeoxygenase-1, endothelin-1, endothelin receptors A and B, tissue factor, and plasminogen activator inhibitor showed a significant induction (~2.5-fold; p < 0.05) with endothelin 1 being the maximally induced factor (6-fold; p < 0.05) on the third recovery day in the lungs of UfCPs exposed SHRs; while all of these factors – except hemeoxygenase-1 – were not affected in cardiac tissues. Strikingly, the UfCPs-mediated altered BP is paralleled by the induction of renin-angiotensin system in plasma.ConclusionOur finding shows that UfCPs exposure at levels which does not induce detectable pulmonary neutrophilic inflammation, triggers distinct effects in the lung and also at the systemic level in compromised SHRs. These effects are characterized by increased activity of plasma renin-angiotensin system and circulating white blood cells together with moderate increases in the BP, HR and decreases in heart rate variability. This systemic effect is associated with pulmonary, but not cardiac, mRNA induction of biomarkers reflective of oxidative stress; activation of vasoconstriction, stimulation of blood coagulation factors, and inhibition of fibrinolysis. Thus, UfCPs may cause cardiovascular and pulmonary impairment, in the absence of detectable pulmonary inflammation, in individuals suffering from preexisting cardiovascular diseases.

Reversal of Physiological Deficits Caused by Diminished Levels of Peptidylglycine α-Amidating Monooxygenase by Dietary Copper

Amidated peptides are critically involved in many physiological functions. Genetic deletion of peptidylglycine alpha-amidating monooxygenase (PAM), the only enzyme that can synthesize these peptides, is embryonically lethal. The goal of the present study was the identification of physiological functions impaired by haploinsufficiency of PAM. Regulation of the hypothalamic-pituitary-thyroid axis and body temperature, functions requiring contributions from multiple amidated peptides, were selected for evaluation. Based on serum T(4) and pituitary TSH-beta mRNA levels, mice heterozygous for PAM (PAM(+/-)) were euthyroid at baseline. Feedback within the hypothalamic-pituitary-thyroid axis was impaired in PAM(+/-) mice made hypothyroid using a low iodine/propylthiouracil diet. Despite their normal endocrine response to cold, PAM(+/-) mice were unable to maintain body temperature as well as wild-type littermates when kept in a 4 C environment. When provided with additional dietary copper, PAM(+/-) mice maintained body temperature as well as wild-type mice. Pharmacological activation of vasoconstriction or shivering also allowed PAM(+/-) mice to maintain body temperature. Cold-induced vasoconstriction was deficient in PAM(+/-) mice. This deficit was eliminated in PAM(+/-) mice receiving a diet with supplemental copper. These results suggest that dietary deficiency of copper, coupled with genetic deficits in PAM, could result in physiological deficits in humans.

Protection Against Blast-Induced Mortality in Rats by Hemin

A critical immediate determinant of survival after exposure to blast overpressure (BOP) is cardiovascular and respiratory impairment related to disruption of the alveolar septa and pulmonary capillaries and resulting in acute pulmonary hemorrhage. Hemoglobin (Hb) released from red cells can contribute to lethality by activation of oxidative stress reactions and severe vasoconstriction associated with hypoperfusion in the pulmonary microcirculation. Heme oxygenase-1 (HO-1) is activated by hemin, a product of Hb degradation and may confer protection against hemoglobin-mediated oxidative cell and tissue damage. Rats were injected intraperitoneally with hemin (50 mg/kg) or phosphate buffered saline (PBS). Twenty hours later, animals were placed in a shock tube and exposed to blast overpressure with mean intensity of approximately 160 kPa. Nonblasted sham-injected animals served as controls. HO-1 mRNA and HO-1 protein in lungs was induced by injection of hemin. Exposure to blast resulted in confluent lung hemorrhage and mortality ( approximately 65%). Hemin injection significantly improved the survival rate of animals compared with PBS injected animals (p = 0.01). The protection by hemin against blast may involve antioxidative and vasodilatory effects of HO-1, although, the precise mechanisms of the protection are unknown.

Nitric Oxide–Mediated Zinc Release

See related article, pages 1575–1583 Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism in the lung that redistributes pulmonary blood flow from areas of low oxygen tension to areas of high oxygen availability. This mechanism thus optimizes pulmonary gas exchange.1–3 Impairment of HPV can result in severe hypoxemia. However, under conditions of global alveolar hypoxia, it becomes grossly ineffective and acute pulmonary hypertension occurs because of the overall contraction of the resistance vessels of the lung. Moreover, permanent activation of hypoxic vasoconstriction may contribute to the structural remodeling process of the pulmonary vasculature in chronic hypoxia.3 Despite the recognition of the importance of hypoxic vasoconstriction for pulmonary gas exchange by von Euler and Liljestrand in 1946, the underlying oxygen sensing and signal transduction processes have yet to be fully elucidated.4 Presently, mitochondria and NAD(P)H oxidases are proposed as possible oxygen sensors. However, there is great controversy as to the role of reactive oxygen species, ie, whether they are up- or downregulated in hypoxia, mediating HPV. The original redox hypothesis assumes a decrease in reactive oxygen species (ROS), shifting the cellular redox state toward a more reduced state and resulting in the inhibition of Kv channels in pulmonary arterial smooth muscle cells.2 In contrast, there is also substantial evidence that an increase in ROS production during hypoxia triggers intracellular calcium release and thus the hypoxic vasoconstrictor response.1,3 It is clearly evident that HPV is ultimately induced by an increase in intracellular calcium, and it is generally accepted that L-type calcium channels and Kv channels are essential components of the underlying signal transduction process.2 The AMP-activated protein kinase/cADP-ribose pathway and cytochrome P450 enzymes have also been suggested to contribute to the regulation of HPV, and recently, TRPC6 has been identified as an essential …

Aldosterone

During the past decade, there has been heightened interest in aldosterone as a cardiovascular risk factor, fueled by studies documenting its effects on tissues other than epithelial cells. Of particular interest is the role of aldosterone in exacerbating vascular injury. It is likely that the mechanisms mediating the vascular effects of aldosterone differ from its effects on epithelial cells, eg, the renal collecting tubule. For more than a quarter of a century, it also had been assumed that the primary mechanism of aldosterone was mediated by activation of the mineralocorticoid receptor (MR), which in turn increased transcription of MR-responsive genes. Recently, it has been documented that aldosterone can produce rapid cellular responses—MR-mediated increases in phosphorylation of transduction factors, eg, extracellular signal regulated kinase 1 and 2 (ERK1/2), protein kinase C (PKC), and endothelial nitric oxide synthase (eNOS), and changes in intracellular calcium and hydrogen ions—in addition to its traditional genomic responses. Sometimes these rapid effects are called “nongenomic.” However, it is likely that even the “rapid” actions of aldosterone can lead to genomic effects. Thus, we will use the terms “rapid” and “genomic” to contrast 2 major mechanisms of action of aldosterone. These rapid effects may be beneficial or detrimental depending on the environment in which aldosterone is acting. For example, phosphorylation of eNOS in endothelial cells leading to increased NO production and vasodilation would likely be beneficial in an environment where there is decreased perfusion to a vital organ. Activation of vasoconstriction through increases in cytosolic calcium or phosphorylation of ERK1/2 and PKC would be beneficial in hypotension secondary to injury. …

The dorsomedial hypothalamus: a new player in thermoregulation

Neurons in the dorsomedial hypothalamus (DMH) play key roles in physiological responses to exteroceptive ("emotional") stress in rats, including tachycardia. Tachycardia evoked from the DMH or seen in experimental stress in rats is blocked by microinjection of the GABA(A) receptor agonist muscimol into the rostral raphe pallidus (rRP), an important thermoregulatory site in the brain stem, where disinhibition elicits sympathetically mediated activation of brown adipose tissue (BAT) and cutaneous vasoconstriction in the tail. Disinhibition of neurons in the DMH also elevates core temperature in conscious rats and sympathetic activity to least significant difference interscapular BAT (IBAT) and IBAT temperature in anesthetized preparations. The latter effects are blocked by microinjection of muscimol into the rRP, while microinjection of muscimol into either the rRP or DMH suppresses increases in sympathetic nerve activity to IBAT, IBAT temperature, and core body temperature elicited either by microinjection of PGE(2) into the preoptic area (an experimental model for fever), or central administration of fentanyl. Neurons concentrated in the dorsal region of the DMH project directly to the rRP, a location corresponding to that of neurons trans-synaptically labeled from IBAT. Thus these neurons control nonshivering thermogenesis in rats, and their activation signals its recruitment in diverse experimental paradigms. Evidence also points to a role for neurons in the DMH in thermoregulatory cutaneous vasoconstriction, shivering, and endocrine adjustments. These directions provide intriguing avenues for future exploration that may expand our understanding of the DMH as an important hypothalamic site for the integration of autonomic, endocrine, and behavioral responses to diverse challenges.

The Theoretical Basis for Using Apnoeic Oxygenation via the Non-ventilated Lung during One-lung Ventilation to Delay the Onset of Arterial Hypoxaemia

At the time one-lung ventilation is initiated, nitrogen from the atmosphere may enter the non-ventilated lung via a double-lumen tube connector that has been left open to air, even momentarily. Ongoing oxygen uptake from the non-ventilated lung raises the partial pressure of nitrogen. This should lead to activation of hypoxic pulmonary vasoconstriction and a reduction in intra-pulmonary shunting. However, in spite of this, some patients still become hypoxaemic. In such cases, it may be advantageous to have excluded nitrogen from the non-ventilated lung by connecting it to an oxygen source at ambient pressure. Ongoing apnoeic oxygenation, while the airways are patent, and as the lung collapses, should delay the onset of arterial desaturation. In this paper we review the theoretical basis for apnoeic oxygenation during one-lung ventilation, and in particular on oxygen uptake by the non-ventilated lung prior to and during its subsequent collapse.