cyclic-gmp and Hypotension

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adrenergic alpha-Antagonists; Arteriosclerosis; Blood Pressure; Carbolines; Contraindications; Coronary Disease; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Interactions; Endothelium, Vascular; Erectile Dysfunction; Heart Rate; Humans; Hypotension; Imidazoles; Isosorbide Dinitrate; Male; Molecular Structure; Myocardial Infarction; Nitric Oxide Donors; Nitroglycerin; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilation; Vasodilator Agents

Refractory hypotension is the main cause of death of patients with septic shock. It has been shown that an excessive release of NO is responsible for the sepsis-induced hypotension and vascular hyporeactivity. Nitric oxide is produced under normal conditions by a constitutive enzyme present, among other cell types, in the endothelial cell, and is necessary for maintenance of normal organ perfusion. Under inflammatory or septic conditions, a new enzyme is expressed in phagocytic cells and vascular smooth muscle cells, giving rise to an uncontrolled NO production that is associated with cytotoxic effects and vasodilatation. Randomized clinical trials have shown that the administration of inhibitors of NO synthesis to patients with septic shock is associated with a greater incidence of shock resolution, without significant adverse effects. The recent discovery of the different biological functions of NO, both under normal and inflammatory conditions, has allowed the development of new concepts about the pathophysiology of septic shock, and has provided the bases to design novel therapeutic strategies for the treatment of septic shock, based on the inhibition of NO synthesis.

Topics: Arginine; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Humans; Hypotension; Leukocytes; Nitric Oxide; Nitric Oxide Synthase; Phagocytes; Randomized Controlled Trials as Topic; Shock, Septic

Ingestion of dietary (inorganic) nitrate elevates circulating and tissue levels of nitrite via bioconversion in the entero-salivary circulation. In addition, nitrite is a potent vasodilator in humans, an effect thought to underlie the blood pressure-lowering effects of dietary nitrate (in the form of beetroot juice) ingestion. Whether inorganic nitrate underlies these effects and whether the effects of either naturally occurring dietary nitrate or inorganic nitrate supplementation are dose dependent remain uncertain. Using a randomized crossover study design, we show that nitrate supplementation (KNO(3) capsules: 4 versus 12 mmol [n=6] or 24 mmol of KNO(3) (1488 mg of nitrate) versus 24 mmol of KCl [n=20]) or vegetable intake (250 mL of beetroot juice [5.5 mmol nitrate] versus 250 mL of water [n=9]) causes dose-dependent elevation in plasma nitrite concentration and elevation of cGMP concentration with a consequent decrease in blood pressure in healthy volunteers. In addition, post hoc analysis demonstrates a sex difference in sensitivity to nitrate supplementation dependent on resting baseline blood pressure and plasma nitrite concentration, whereby blood pressure is decreased in male volunteers, with higher baseline blood pressure and lower plasma nitrite concentration but not in female volunteers. Our findings demonstrate dose-dependent decreases in blood pressure and vasoprotection after inorganic nitrate ingestion in the form of either supplementation or by dietary elevation. In addition, our post hoc analyses intimate sex differences in nitrate processing involving the entero-salivary circulation that are likely to be major contributing factors to the lower blood pressures and the vasoprotective phenotype of premenopausal women.

Topics: Blood Pressure; Brachial Artery; Cardiovascular Diseases; Cross-Over Studies; Cyclic GMP; Double-Blind Method; Female; Heart Rate; Humans; Hyperemia; Hypertension; Hypotension; Life Style; Male; Nitrates; Nitric Oxide; Nitrites; Posture; Potassium Chloride; Potassium Compounds; Prevalence; Random Allocation; Risk Factors; Sex Characteristics; Systole

Infant respiratory distress syndrome (RDS) involves inflammatory processes, causing an increased expression of inducible heme oxygenase with subsequent production of carbon monoxide (CO). We hypothesized that increased production of CO during RDS might be responsible for increased plasma levels of vasodilatory cGMP and, consequently, low blood pressure observed in infants with RDS. Fifty-two infants (no-RDS, n = 21; RDS, n = 31), consecutively admitted to the neonatal intensive care unit (NICU) between January and October 2003 were included. Hemoglobin-bound carbon monoxide (COHb), plasma cGMP, plasma nitric oxide (NOx), and bilirubin were determined at 0-12, 48-72, and at 168 h postnatally, with simultaneous registration of arterial blood pressure. Infants with RDS had higher levels of cGMP and COHb compared with no-RDS infants (RDS vs. no-RDS: cGMP ranging from 76 to 101 vs. 58 to 82 nmol/l; COHb ranging from 1.2 to 1.4 vs. 0.9 to 1.0%). Highest values were reached at 48-72 h [RDS vs. no-RDS mean (SD): cGMP 100 (39) vs. 82 (25) nmol/l (P < 0.001); COHb 1.38 (0.46) vs. 0.91 (0.26)% (P < 0.0001)]. Arterial blood pressure was lower and more blood pressure support was needed in RDS infants at that point of time [RDS vs. no-RDS mean (SD): mean arterial blood pressure 33 (6) vs. 42 (5) mmHg (P < 0.05)]. NOx was not different between groups and did not vary with time. Multiple linear regression analysis showed a significant correlation between cGMP and COHb, suggesting a causal relationship. Mean arterial blood pressure appeared to be primarily correlated to cGMP levels (P < 0.001). We conclude that a CO-mediated increase in cGMP causes systemic vasodilation with a consequent lower blood pressure and increased need for blood pressure support in preterm infants with RDS.

Topics: Biomarkers; Blood Pressure; Carbon Monoxide; Cyclic GMP; Humans; Hypotension; Infant, Newborn; Respiratory Distress Syndrome, Newborn; Statistics as Topic

The objective of this study was to address the feasibility and the biological activity of orally administered human brain natriuretic peptide (hBNP). Proprietary technology has been developed in which short, amphiphilic oligomers are covalently attached to peptides. The conjugated peptides are intended to have an improved pharmacokinetic profile and to enable oral administration. We hypothesized that novel oral conjugated hBNP (CONJ-hBNP) increases plasma hBNP, activates cGMP, and reduces mean arterial pressure (MAP).. This randomized crossover-designed study tested the biological activity of oral CONJ-hBNP compared with oral native hBNP in normal conscious dogs. Measurements of MAP, plasma hBNP, and cGMP were made at baseline (BL) and repeated at 10, 30, 60, 120, 180, and 240 minutes after oral administration. Plasma hBNP was not detectable in dogs at BL. Plasma hBNP was detected after native hBNP and CONJ-HBNP administration. However, plasma hBNP concentration was significantly higher after CONJ-hBNP than after native hBNP administration (P=0.0374 between groups). Plasma cGMP increased after CONJ-hBNP for 60 minutes (from 10.8+/-3 to 36.8+/-26 pmol/mL; P<0.05), whereas it did not change after native hBNP (P=0.001 between groups). MAP decreased at 10 minutes and remained decreased for 60 minutes after CONJ-hBNP (from 113+/-8 to 101+/-12 mm Hg after 10 minutes to 97.5+/-10 mm Hg after 30 minutes to 99+/-13 mm Hg after 60 minutes) while remaining unchanged after native hBNP (P=0.0387 between groups).. This study reports for the first time that novel conjugated oral BNP activates cGMP and significantly reduces MAP, thus implying an efficacious coupling of CONJ-hBNP to the natriuretic receptor-A. These data advance a new concept of orally administered chronic BNP therapy for cardiovascular diseases.

Topics: Administration, Oral; Animals; Blood Pressure; Cross-Over Studies; Cyclic GMP; Dogs; Humans; Hypotension; Male; Models, Animal; Natriuretic Peptide, Brain

To determine the involvement of nitric oxide production in hemodialysis-induced hypotension.. Examination of nitric oxide synthesis, cyclic guanosine 3'5'-monophosphate (cGMP) levels, and endothelin-1 levels in plasma before and after hemodialysis.. Veterans Affairs medical center.. 13 patients with end-stage renal failure who were receiving hemodialysis: Six patients had hypotensive episodes during dialysis and 7 did not.. Patients received heparin at a bolus dose of 2000 U at the initiation of dialysis followed by 1000 U/h during 4-hour hemodialysis sessions.. Nitric oxide production markedly increased during hemodialysis-induced hypotensive episodes; this increase was not seen in patients who did not have a hypotensive episode. In both groups, the plasma cGMP and endothelin-1 levels decreased after hemodialysis. According to multiple regression analysis, standard coefficients of nitric oxide production, plasma cGMP levels, and endothelin-1 levels with mean blood pressure after hemodialysis were -0.743, -0.07, and 0.31, respectively.. Nitric oxide production increased in patients who had a hypotensive episode during hemodialysis but did not increase in those who did not have a hypotensive episode.

Topics: Aged; Cyclic GMP; Endothelins; Female; Heparin; Humans; Hypotension; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Regression Analysis; Renal Dialysis

Nitric oxide (NO)-mediated vasodilatation is a fundamental response of vasculature, however, regulation of NO signaling pathway on resistance vessels in the older adult with hypertension is still unclear. The 16-week-spontaneously hypertensive rats (SHR), the 18-month-SHR (OldSHR), and the age-matched Wistar-Kyoto rats were used to study the changes of mesenteric resistance artery dilatation caused by sodium nitroprusside (SNP). After pre-vasoconstriction by norepinephrine (NE), the response of endothelium-denuded mesenteric artery ring to SNP was observed, and the changes in vascular response after pharmacological interventions of key nodes in the NO/sGC/cGMP/PKG1α signaling pathway were observed as well. RNA sequencing and functional enrichment analyses were used to provide information for conducting validation experiments. Vasodilation of NO in OldSHR was decreased, which significantly correlated with the reduction of PKG-mediated effect. Functional enrichment analysis of RNA sequencing showed that genes encoding important proteins such as sGC and MYPT1 (protein phosphatase 1 regulatory subunit 12A) were downregulated in OldSHR. Molecular biology validation results showed that mRNA expression of both α and β subunits of sGC were reduced, while mRNA and protein expression of PKG1α were reduced in OldSHR. More importantly, the expression of MYPT1 and pS668-MYPT1 was significantly reduced in OldSHR, even under the treatment of SNP. The experiment also revealed an enhanced cAMP system in vasodilation in hypertension, while this function was completely lost in the OldSHR. Therefore, an NO-mediated decrease in vascular smooth muscle relaxation was found in the OldSHR. The dysfunction in cGMP-PKG signaling, in particular, decreased pS668-MYPT1 was mechanistically involved.

Topics: Animals; Cyclic GMP; Hypertension; Hypotension; Mesenteric Arteries; Nitric Oxide; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Vasodilation

We previously demonstrated that nitroxyl causes vasodilation, at least in part, by inducing the formation of an intradisulfide bond between C117 and C195 in the high affinity cyclic guanosine monophosphate-binding site of PKGI (cyclic guanosine monophosphate-dependent protein kinase I). The aim of this study was to determine whether nitroxyl donors lower blood pressure via this novel PKGI activation mechanism in vivo.. To determine this, a C195S PKGI knock-in mouse model was generated that ubiquitously and constitutively expresses a mutant kinase resistant to nitroxyl-induced intradisulfide activation.. Knock-in and wild-type littermates did not differ in appearance, body weight, in PKGI protein expression or blood gas content. Organ weight was similar between genotypes apart from the cecum that was significantly enlarged in knock-in animals. Mean arterial pressure and heart rate monitored in vivo over 24 hours by radio-telemetry revealed neither a significant difference between genotypes at baseline nor during angiotensin II-induced hypertension or sepsis. CXL-1020, a clinically relevant nitroxyl donor, did not lower blood pressure in normotensive animals. In contrast, administering CXL-1020 to hypertensive wild-type mice reduced their blood pressure by 10±4 mm Hg (. Oxidation of C195 in PKGI contributes to the antihypertensive effects observed in response to nitroxyl donors, emphasising the potential importance of nitroxyl donors in pathological scenarios when cyclic guanosine monophosphate levels are reduced and insufficient to activate PKGI.

Topics: Animals; Blood Pressure; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Cyclic GMP-Dependent Protein Kinases; Guanosine; Guanosine Monophosphate; Hypertension; Hypotension; Mice; Nitrogen Oxides; Protein Kinases

The nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway has a significative influence in hemodynamic changes that occur in transplants. Classically, the ischemia-reperfusion syndrome (IRS) is characterized by hypotension and low vascular resistance, when cGMP and nitric oxide (NO) are increased, contributing to oxidative stress, within an inflammatory context. These mechanisms occur in several types of transplants, such as liver, heart, lungs, kidney, which are a therapeutic choice in several clinical conditions when conventional treatments failed. It is well known the significant relation between graft dysfunction or rejection and ischemia-reperfusion injury that is linked to inflammatory response and NO/cGMP pathway activation. This review aims to study the NO/cGMP pathway in solid organ transplants. Finally, we inquire whether physicians do not underestimate the NO/cGMP pathway.

Topics: Cyclic GMP; Hemodynamics; Humans; Hypotension; Liver; Lung; Methylene Blue; Nitric Oxide; Reperfusion; Reperfusion Injury; Signal Transduction; Transplants; Vascular Resistance

Infants on chronic peritoneal dialysis (PD) have an increased risk of developing neurological morbidities; however, the underlying biological mechanisms are poorly understood. In this clinical study, we investigated whether PD-mediated impairment of nitric oxide (NO) bioavailability and signaling, in patients with persistently low systolic blood pressure (SBP), can explain the occurrence of cerebral ischemia.. Repeated blood pressure measurements, serial neuroimaging studies, and investigations of systemic nitrate and nitrite levels, as well as NO signaling, were performed in ten pediatric patients on PD. We consistently observed the loss of both inorganic nitrate (-17 ± 3%, P < 0.05) and nitrite (-34 ± 4%, P < 0.05) during PD, which may result in impairment of the nitrate-nitrite-NO pathway. Indeed, PD was associated with significant reduction of cyclic guanosine monophosphate levels (-59.4 ± 15%, P < 0.05). This reduction in NO signaling was partly prevented by using a commercially available PD solution supplemented with l-arginine. Although PD compromised nitrate-nitrite-NO signaling in all cases, only infants with persistently low SBP developed ischemic cerebral complications.. Our data suggests that PD impairs NO homeostasis and predisposes infants with persistently low SBP to cerebral ischemia. These findings improve current understanding of the pathogenesis of infantile cerebral ischemia induced by PD and may lead to the new treatment strategies to reduce neurological morbidities.

Topics: Arginine; Blood Pressure; Brain; Brain Ischemia; Cerebrovascular Circulation; Cyclic GMP; Female; Homeostasis; Humans; Hypotension; Infant; Infant, Newborn; Male; Nitrates; Nitric Oxide; Nitrites; Peritoneal Dialysis

Bioconversion of glyceryl trinitrate (GTN) into nitric oxide (NO) by aldehyde dehydrogenase-2 (ALDH-2) is a crucial mechanism which drives vasodilatory and antiplatelet effect of organic nitrates in vitro and in vivo. Oxidative stress generated by overproduction of free radical species, mostly superoxide anions and NO-derived peroxynitrite, has been suggested to play a pivotal role in the development of nitrate tolerance, though the mechanism still remains unclear. Here we studied the free radical-dependent impairment of ALDH-2 in platelets as well as vascular tissues undergoing organic nitrate ester tolerance and potential benefit when using the selective peroxynitrite decomposition catalyst Mn(III) tetrakis (4-Benzoic acid) porphyrin (MnTBAP). Washed human platelets were made tolerant to nitrates via incubation with GTN for 4h. This was expressed by attenuation of platelet aggregation induced by thrombin (40U/mL), an effect accompanied by GTN-related induction of cGMP levels in platelets undergoing thrombin-induced aggregation. Both effects were associated to attenuated GTN-induced nitrite formation in platelets supernatants and to prominent nitration of ALDH-2, the GTN to NO metabolizing enzyme, suggesting that GTN tolerance was associated to reduced NO formation via impairment of ALDH-2. These effects were all antagonized by co-incubation of platelets with MnTBAP, which restored GTN-induced responses in tolerant platelets. Comparable effect was found under in in vivo settings. Indeed, MnTBAP (10mg/kg, i.p.) significantly restored the hypotensive effect of bolus injection of GTN in rats made tolerants to organic nitrates via chronic administration of isosorbide-5-mononitrate (IS-5-MN), thus confirming the role of peroxynitrite overproduction in the development of tolerance to vascular responses induced by organic nitrates. In conclusion, oxidative stress subsequent to prolonged use of organic nitrates, which occurs via nitration of ALDH-2, represents a key event in GTN tolerance, an effect counteracted both in vitro and in vivo by novel peroxynitrite decomposition catalyst.

Topics: Aldehyde Dehydrogenase; Animals; Aorta; Blood Platelets; Cyclic GMP; Drug Tolerance; Endothelium, Vascular; Humans; Hypotension; Isosorbide Dinitrate; Male; Metalloporphyrins; Muscle, Smooth, Vascular; Nitrates; Nitric Oxide; Nitrites; Nitroglycerin; Platelet Aggregation; Rats; Thrombin; Tyrosine; Vasodilator Agents

The activation of cyclic guanosine monophosphate (cGMP) production in patients with end-stage liver disease (ESLD) has been associated with hemodynamic instability during orthotopic liver transplantation (OLT). The aim of this prospective, observational study was to investigate the involvement of cGMP in the mediation of profound hypotension during liver graft reperfusion. An additional objective was to determine whether preoperative cGMP levels are associated with intraoperative hemodynamic instability. Forty-four consecutive patients undergoing OLT were included in the study. Blood samples for cGMP analysis were obtained from (1) the radial artery before the surgical incision; (2) the radial artery, portal vein, and flush blood during the anhepatic phase; and (3) the radial artery 20 minutes after liver graft reperfusion. On the basis of a statistical analysis, the patients were divided into 2 groups: group 1 (preoperative cGMP level ≥ 0.05 μmol/L) and group 2 (preoperative cGMP level < 0.05 μmol/L). We demonstrated a significant correlation between the preoperative levels of cGMP and the amount of catecholamine required to maintain hemodynamic stability during reperfusion (r = 0.52, P < 0.001), the length of the hospital stay (r = 0.38, P = 0.01), and the length of the intensive care unit (ICU) stay (r = 0.44, P = 0.004). We also demonstrated a significantly higher intraoperative catecholamine requirement (P < 0.001) and a prolonged postoperative ICU stay (P = 0.02) in group 1 patients versus group 2 patients. In conclusion, this study demonstrates increased baseline cGMP production in patients with ESLD, which is significantly associated with severe hypotension during OLT. We suggest that preoperative levels of cGMP correlate with hemodynamic instability during liver graft reperfusion.

Topics: Adult; Aged; Biomarkers; Catecholamines; Cyclic GMP; End Stage Liver Disease; Female; Hemodynamics; Humans; Hypotension; Intensive Care Units; Length of Stay; Liver Transplantation; Male; Middle Aged; Monitoring, Intraoperative; Prospective Studies; Severity of Illness Index; Time Factors; Up-Regulation; Vasoconstrictor Agents; Young Adult

Outcome of traumatic brain injury (TBI) is impaired by hyperglycemia, hypotension, and glutamate, and improved by insulin. Insulin reduces glutamate concentration, making it uncertain whether its beneficial effect accrues from euglycemia. Glucagon decreases CNS glutamate, lessens neuronal cell injury, and improves neurological scores in mice after TBI. In vitro, glucagon limits NMDA-mediated excitotoxicity by increasing cAMP and protein kinase A (PKA). NMDA receptor activation couples cerebral blood flow (CBF) to metabolism. Dilation induced by NMDA is impaired after fluid percussion brain injury (FPI) due to upregulation of endogenous tPA, which further disturbs cerebral autoregulation during hypotension after fluid percussion injury (FPI). We hypothesized that glucagon prevents impaired NMDA receptor-mediated dilation after FPI by upregulating cAMP, which decreases release of tPA. NMDA-induced pial artery dilation (PAD) was reversed to vasoconstriction after FPI. Glucagon 30 min before or 30 min after FPI blocked NMDA-mediated vasoconstriction and restored the response to vasodilation. PAD during hypotension was blunted after FPI, but protected by glucagon. Glucagon prevented FPI-induced reductions in CSF cAMP, yielding a net increase in cAMP, and blocked FPI-induced elevation of CSF tPA. Co-administration of the PKA antagonist Rp 8Br cAMPs prevented glucagon-mediated preservation of NMDA-mediated dilation after FPI. The pKA agonist Sp 8Br cAMPs prevented impairment of NMDA-induced dilation. These data indicate that glucagon protects against impaired cerebrovasodilation by upregulating cAMP, which decreases release of tPA, suggesting that it may provide neuroprotection when given after TBI, or prior to certain neurosurgical or cardiac interventions in which the incidence of perioperative ischemia is high.

Topics: Analysis of Variance; Animals; Brain Injuries; Cerebral Cortex; Cerebrovascular Circulation; Cyclic GMP; Enzyme-Linked Immunosorbent Assay; Glucagon; Homeostasis; Hypotension; Neurons; Receptors, N-Methyl-D-Aspartate; Swine; Up-Regulation; Vasodilation

Despite increasing use of "targeted therapy," interleukin-2 (IL-2) is unique, because this cytokine can induce long-term remissions in 5% to 7% of patients with metastatic melanoma and renal cancer. Clinical use of IL-2 is limited by severe toxicities, such as hypotension and vascular leak syndrome (VLS). Nitric oxide seems to be involved in the pathogenesis of these toxicities. On the basis of previous studies, we hypothesized that the endothelial nitric oxide synthase (eNOS) is the major source of nitric oxide. Mice with a knockout of the eNOS isoenzyme were treated with IL-2 (800,000 IU twice daily for 5 d). Blood pressure and vascular leak were measured. Inhibitors of superoxide, nitric oxide, and soluble guanylate cyclase were used to probe the mechanism. These experiments showed that IL-2 treatment increased eNOS messenger ribonucleic acid expression and nitric oxide metabolite excretion in eNOS knockout mice. Unlike normal and inducible nitric oxide synthase knockout mice, eNOS knockout mice proved resistant to IL-2-induced hypotension and vascular leak. Although hypotension seems to be mediated by superoxide or peroxynitrite, vascular leak seemed to be mediated by nitric oxide. Inhibition of guanylate cyclase and cyclic guanylate monophosphate formation during IL-2 treatment using methylene blue (MB)-inhibited vascular leak. MB treatment did not interfere with IL-2-induced antitumor mechanisms. Our experiments established that eNOS is a key mediator of IL-2-induced VLS and hypotension. A clinical trial of MB infusion during IL-2 therapy is currently being planned.

Topics: Animals; Blood Pressure; Capillary Leak Syndrome; Carcinoma, Renal Cell; Cyclic GMP; Enzyme Inhibitors; Guanylate Cyclase; Humans; Hypotension; Interleukin-2; Manganese; Melanoma; Methylene Blue; Mice; Mice, Inbred Strains; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type III; omega-N-Methylarginine; Organometallic Compounds; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Soluble Guanylyl Cyclase; Superoxides

In anesthetized normotensive rats, activation of brainstem hemeoxygenase (HO) elicits sympathoinhibition and hypotension. Accordingly, we tested the hypothesis that attenuated basal or induced HO activity in the rostral ventrolateral medulla (RVLM) contributes to hypertension in the spontaneously hypertensive rat (SHR). We measured basal RVLM HO expression and catalytic activity and investigated the effects of intra-RVLM HO activation (hemin) or selective HO isoform 1 (HO-1) inhibition [zinc protoporphyrin IX (ZnPPIX)] on mean arterial pressure (MAP), heart rate, and RVLM neuronal norepinephrine (NE) level (index of sympathetic activity) in conscious SHRs and Wistar Kyoto rats. Basal RVLM HO catalytic activity (bilirubin level) and HO-1 expression were significantly higher in the SHR. These neurochemical findings were corroborated by the significantly greater decreases (hemin) and increases (ZnPPIX) in RVLM NE and MAP in the SHR. By contrast, HO-independent CO release in the RVLM (CO-releasing molecule 3) elicited similar MAP reductions in both rat strains. Furthermore, pretreatment with ZnPPIX or the selective neuronal nitric-oxide synthase (nNOS) inhibitor N-propyl-l-arginine abrogated the neurochemical (RVLM cGMP) and hypotensive responses caused by hemin. In addition to demonstrating, for the first time, higher basal RVLM HO catalytic activity and HO-1 expression in the SHR, the findings suggest: 1) the exaggerated hypotension elicited by intra-RVLM HO activation in the SHR is nNOS-dependent, and 2) in the SHR, the enhanced RVLM HO-nNOS signaling compensates for the reduced expression/activity of the downstream target, soluble guanylyl cyclase. Together, the findings suggest a protective role for the RVLM HO-nNOS pathway against further increases in MAP in the SHR.

Topics: Animals; Blood Pressure; Blotting, Western; Carbon Monoxide; Catheterization; Cyclic GMP; Guanylate Cyclase; Heart Rate; Heme Oxygenase (Decyclizing); Hemin; Hypotension; Injections; Male; Medulla Oblongata; Nitric Oxide; Nitric Oxide Synthase Type I; Norepinephrine; Organometallic Compounds; Protoporphyrins; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Collagen type IV is the major structural component of the basement membrane and COL4A1 mutations cause adult small vessel disease, familial porencephaly and hereditary angiopathy with nephropathy aneurysm and cramps (HANAC) syndrome. Here, we show that animals with a Col4a1 missense mutation (Col4a1(+/Raw)) display focal detachment of the endothelium from the media and age-dependent defects in vascular function including a reduced response to nor-epinephrine. Age-dependent hypersensitivity to acetylcholine is abolished by inhibition of nitric oxide synthase (NOS) activity, indicating that Col4a1 mutations affect vasorelaxation mediated by endothelium-derived nitric oxide (NO). These defects are associated with a reduction in basal NOS activity and the development of heightened NO sensitivity of the smooth muscle. The vascular function defects are physiologically relevant as they maintain in part the hypotension in mutant animals, which is primarily associated with a reduced red blood cell volume due to a reduction in red blood cell number, rather than defects in kidney function. To understand the molecular mechanism underlying these vascular defects, we examined the deposition of collagen type IV in the basement membrane, and found it to be defective. Interestingly, this mutation also leads to activation of the unfolded protein response. In summary, our results indicate that mutations in COL4A1 result in a complex vascular phenotype encompassing defects in maintenance of vascular tone, endothelial cell function and blood pressure regulation.

Topics: Animals; Animals, Newborn; Blood Vessels; Cerebral Hemorrhage; Collagen Type IV; Cyclic GMP; Endothelial Cells; Erythrocyte Volume; Homeostasis; Hypotension; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Muscle, Smooth, Vascular; Mutation; Nitric Oxide; Nitric Oxide Synthase; Unfolded Protein Response; Vasodilation

The aim of the present experiments was to evaluate the differences in arterial pressure between H-Ras lacking mice and control mice and to analyze the mechanisms involved in the genesis of the differences. H-Ras lacking mice and mouse embryonic fibroblasts from these animals were used. Blood pressure was measured using 3 different methods: direct intraarterial measurement in anesthetized animals, tail-cuff sphygmomanometer, and radiotelemetry. H-Ras lacking mice showed lower blood pressure than control animals. Moreover, the aorta protein content of endothelial nitric oxide synthase, soluble guanylyl cyclase, and cyclic guanosine monophosphate-dependent protein kinase was higher in H-Ras knockout mice than in control animals. The activity of these enzymes was increased, because urinary nitrite excretion, sodium nitroprusside-stimulated vascular cyclic guanosine monophosphate synthesis, and phosphorylated vasoactive-stimulated phosphoprotein in aortic tissue increased in these animals. Furthermore, mouse embryonic fibroblasts from H-Ras lacking mice showed higher cyclic guanosine monophosphate-dependent protein kinase promoter activity than control cells. These results strongly support the upregulation of the nitric oxide-cyclic guanosine monophosphate pathway in H-Ras-deficient mice. Moreover, they suggest that H-Ras pathway could be considered as a therapeutic target for hypertension treatment.

Topics: Animals; Aorta; Blood Pressure; Blotting, Northern; Blotting, Western; Cells, Cultured; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Fibroblasts; Guanylate Cyclase; Hypotension; Immunohistochemistry; Mice; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; ras Proteins; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Statistics, Nonparametric; Up-Regulation

In addition to haemodynamic actions, Ucn1 (urocortin 1) has been reported to affect a number of hormonal systems; however, it remains unclear whether Ucn1 modulates circulating hormones under physiological conditions. Accordingly, in the present study, we have examined the effects of Ucn1 on haemodynamics, hormones and renal indices in normal conscious sheep subjected to a nitroprusside-induced hypotensive stimulus designed to alter hormonal levels within the physiological range. Ucn1 administration did not alter the haemodynamic response to nitroprusside-induced hypotension. However, compared with the rise observed on the control day, plasma ANP (atrial natriuretic peptide; P=0.043), BNP (brain natriuretic peptide; P=0.038) and endothelin-1 (P=0.011) levels were reduced following Ucn1 administration. Associated with this significant reduction in natriuretic peptides, the increase in urinary sodium output associated with rising pressures post-nitroprusside was abolished following Ucn1 administration (P=0.048). Ucn1 had no significant effect on the response of hormones of the renin-angiotensin-aldosterone system or the hypothalamo-pituitary-adrenal axis. In conclusion, Ucn1, administered at physiologically relevant levels during nitroprusside-induced hypotension, attenuates the secretion/release of endothelin-1 and the cardiac natriuretic peptides ANP and BNP. Suppression of ANP and BNP probably led to an attenuated natriuretic response to recovery from acute hypotension. The threshold for the action of Ucn1 on the natriuretic peptides and endothelin-1 appears to be below that of other actions of Ucn1.

Topics: Aldosterone; Angiotensin II; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Corticotropin-Releasing Hormone; Cyclic GMP; Heart Rate; Hypotension; Natriuretic Peptide, Brain; Nitroprusside; Sheep; Urocortins

Activated protein C (APC) is an important modulator of vascular function that has antithrombotic and anti-inflammatory properties. Studies in humans have shown modulation of endotoxin-induced hypotension by recombinant human APC, drotrecogin alfa (activated), however, the mechanism for this effect is unclear. We have found that APC suppresses the induction of the potent vasoactive peptide adrenomedullin (ADM) and could downregulate lipopolysaccharide (LPS)-induced ADM messenger RNA (mRNA) and nitrite levels in cell culture. This effect was dependent on signaling through protease-activated receptor 1. Addition of 1400W, an irreversible inducible nitric oxide synthase (iNOS) inhibitor, inhibited LPS-induced ADM mRNA, suggesting that ADM induction is NO mediated. Furthermore, in a rat model of endotoxemia, APC (100 microg/kg, i.v.) prevented LPS (10 mg/kg, i.v.)-induced hypotension, and suppressed ADM mRNA and protein expression. APC also inhibited iNOS mRNA and protein levels along with reduction in NO by-products (NOx). We also observed a significant reduction in iNOS-positive leukocytes adhering to vascular endothelium after APC treatment. Moreover, we found that APC inhibited the expression of interferon-gamma (IFN-gamma), a potent activator of iNOS. In a human study of LPS-induced hypotension, APC reduced the upregulation of plasma ADM levels, coincident with protection against the hypotensive response. Overall, we demonstrate that APC blocks the induction of ADM, likely mediated by IFN-gamma and iNOS, and suggests a mechanism that may account for ameliorating LPS-induced hypotension. Furthermore, our data provide a new understanding for the role of APC in modulating vascular response to insult.

Topics: Adrenomedullin; Animals; Blotting, Western; Cell Line; Cell Movement; Cyclic AMP; Cyclic GMP; Endothelial Cells; Gene Expression; Humans; Hypotension; Interferon-gamma; Leukocytes; Lipopolysaccharides; Lung; Male; Nitric Oxide Synthase Type II; Nitrites; Nitrogen Oxides; Protein C; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Sildenafil citrate (Viagra) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5, which might enhance the vasorelaxant and natriuretic actions of atrial natriuretic peptide (ANP) in patients with heart failure. The objective of this study was to examine the combined effect of Viagra on hemodynamic changes during infusion of exogenous ANP.. Healthy male beagles were used to assess systemic blood pressure, pulmonary artery pressure (PAP), and plasma levels of cGMP. After hemodynamic variables were measured, 0.1 microg.kg(-1).min(-1) of ANP was given during this study. One hour after initiating infusion of ANP, 2 mg/kg of sildenafil citrate or vehicle was given orally via a nasogastric tube. Hemodynamic changes were measured before and 1 h after these administrations. Mean systemic and PAP decreased during infusion of ANP, and further decreased after sildenafil citrate administration, however, mean systemic blood pressure decreased within 10 mmHg. Plasma levels of cGMP also increased after sildenafil citrate administration.. In normal dogs, sildenafil citrate enhances the vasodilator effect of ANP by increasing the cGMP level, however, the concomitant use of sildenafil citrate with ANP will not induce severe hypotension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dogs; Drug Synergism; Heart Rate; Hypotension; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

1. Regional haemodynamic responses to a continuous, 4-day infusion of the selective phosphodiesterase type 5 inhibitor, UK-357,903 (0.133 or 1.33 mg x kg(-1) h(-1)) were measured in conscious spontaneously hypertensive rats, and compared with those of enalapril (1 mg x kg(-1) h(-1)). 2. Both doses of UK-357,903 caused modest reductions in mean blood pressure that were not dose-dependent and only significantly different from the vehicle effects on Day 1 of the study (mean -11.8 and -15.3 mmHg for low and high doses, respectively). UK-357,903 had mesenteric and hindquarters vasodilator effects, which were, again, similar for both dose levels and only significantly different from vehicle on Day 1. Neither dose of UK-357,903 affected renal vascular conductance or heart rate. 3. Although the haemodynamic effects of UK-357,903 were not clearly dose-related and some appeared to wane with time, geometric mean plasma levels of UK-357,903 increased in proportion to dose, and were sustained throughout the infusion period. Furthermore, plasma cyclic guanosine monophosphate, a biomarker of phosphodiesterase 5 inhibition, was persistently elevated, and increased with increasing dose. 4. Enalapril caused a fall in mean blood pressure on day 1 (-14.1 mmHg) that was associated with dilatation in renal, mesenteric and hindquarters vascular beds. The haemodynamic effects of enalapril were sustained or increased over the 4-day infusion, although plasma free drug levels were stable. 5. In conclusion, we have shown regional and temporal changes in the haemodynamic effects of UK-357,903, which may be due to activation of compensatory mechanisms, but there were no signs of functional compensation to the cardiovascular effects of enalapril.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Angiotensin I; Animals; Cardiovascular Physiological Phenomena; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Hemodynamics; Hypotension; Infusions, Intravenous; Male; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pyrimidinones; Radioimmunoassay; Rats; Rats, Inbred SHR; Renin; Sulfones; Time Factors

A low blood pressure is common in preterm infants with respiratory distress syndrome (RDS). A diminished vascular resistance appears to be an important cause. The endogenous production of nitric oxide (NO), a mediator of vascular smooth muscle relaxation, has been shown to be higher in infants with RDS than in those without. Infants with persistent pulmonary hypertension showed decreased endogenous NO levels as compared with controls. Severe RDS in preterm infants may be accompanied by persistent pulmonary hypertension. To elucidate the role of NO in RDS and low blood pressure, we determined the endogenous NO production in infants with and without RDS by measuring urinary nitrite and nitrate excretions and plasma cGMP levels. In consecutively admitted preterm infants (gestational age <32 weeks), urine samples for measurement of NO(2) and NO(3) and plasma samples for the determination of the cGMP concentrations were serially collected during the 1st week of life. Arterial blood pressure, therapy to support blood pressure, and additional relevant clinical data were registered simultaneously. 27 infants with and 39 without RDS were included. The urinary NO(x) levels increased in all patients and were not different between both groups. The plasma cGMP concentrations were higher in the RDS group on days 2, 3, 4, and 7 (p < 0.05). The severity of RDS was positively correlated with plasma cGMP (r = 0.50, p = 0.0001). Although the arterial blood pressure did not differ between the groups, more blood pressure support was needed in the RDS infants during the first 4 days (p < 0.05). A positive correlation was found between blood pressure support and plasma cGMP (r = 0.34, p < 0.0001). The endogenous NO production was not different in infants with and without RDS. Increased plasma cGMP levels in the RDS infants were associated with the severity of RDS and the intensity of antihypotensive treatment. The origin of cGMP in infants with RDS requires further research.

Topics: Blood Pressure; Cyclic GMP; Gestational Age; Humans; Hypotension; Infant, Newborn; Infant, Premature; Nitrates; Nitric Oxide; Nitrites; Respiration, Artificial; Respiratory Distress Syndrome, Newborn

We investigated whether sildenafil citrate (Viagra) may reduce the dose of nitrovasodilators to induce deliberate hypotension. Ten mongrel dogs were acutely instrumented with a femoral artery catheter and a pulmonary artery catheter. Sodium nitroprusside (SNP; 1-16 microg. kg(-1). min(-1)) or nitroglycerin (NTG; 2-32 microg. kg(-1). min(-1)) was IV given to induce hypotension. The study consisted of two occasions, in a random order, in each animal: one with sildenafil pretreatment (1 mg/kg IV followed by 0.3 mg. kg(-1). h(-1)) and the other without to serve as a control. Hemodynamic variables were continuously monitored. Plasma cyclic guanosine monophosphate (cGMP) concentrations were measured by radioimmunoassay. Both SNP and NTG produced dose-dependent decreases in mean arterial blood pressure without affecting the heart rate in the presence as well as in the absence of sildenafil. Systemic vascular resistance index and mean pulmonary arterial pressure were also decreased. The magnitude of mean arterial blood pressure and systemic vascular resistance index reductions caused by SNP was augmented by sildenafil, whereas that caused by NTG was not affected. Neither SNP nor NTG alone altered the plasma cGMP concentrations. Sildenafil increased the plasma cGMP concentration, which was further increased by SNP but not affected by NTG. These results indicate that sildenafil may reduce the dose of SNP in producing deliberate hypotension in the dog. The potentiation of SNP-induced hypotension by sildenafil may be related to an augmented accumulation of cGMP.. Sildenafil may reduce the dose of sodium nitroprusside required to induce deliberate hypotension and hence the potential for cyanide toxicity.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cyclic GMP; Dogs; Drug Synergism; Female; Hypotension; Male; Nitroglycerin; Nitroprusside; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Nitric oxide (NO) plays a central role in the pathogenesis of septic shock. However, the role of the NO produced by endothelial NO synthase (eNOS) in septic shock is still unclear. We examined the effect of chronic eNOS overexpression and the role of eNOS-derived NO in lipopolysaccharide (LPS)-induced septic shock using eNOS transgenic (Tg) mice.. LPS was intraperitoneally injected into Tg and control mice. No differences existed in the peak plasma nitrate and nitrate levels induced by LPS between the 2 genotypes. In LPS-treated control mice, blood pressure progressively declined and reached 60% of basal levels (from 97+/-3 to 59+/-3 mm Hg) 24 hours after LPS injection. In contrast, the blood pressure of LPS-treated Tg mice fell only 15% from basal levels (from 84+/-4 to 71+/-4 mm Hg) after the first 6 hours and, thereafter, it remained at this level. LPS-induced increases in the expression of the mRNA of both vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 in the lungs were significantly lower in Tg mice than in control mice. LPS-induced pulmonary leukocyte infiltration and increases in lung water content were also significantly attenuated in Tg mice. Histological examination revealed that lung injury after LPS injection was milder in Tg mice. Furthermore, Tg mice exhibited enhanced survival from LPS-induced septic shock compared with control mice.. Chronic eNOS overexpression in the endothelium of mice resulted in resistance to LPS-induced hypotension, lung injury, and death. These effects are associated with the reduced vascular reactivity to NO and the reduced anti-inflammatory effects of NO.

Topics: Animals; Aorta; Blood Pressure; Cyclic GMP; Edema; Female; Granulocytes; Hypotension; Immunity, Innate; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple Organ Failure; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitrites; Organ Size; Peroxidase; Shock, Septic; Vasodilation

The antihypertensive mechanism of alpha2-adrenoceptor agonists, such as clonidine and rilmenidine, is not completely elucidated, although it is probably due to reduction of sympathetic tone mediated by stimulation of central alpha2-adrenoceptors. Because activation of alpha2-adrenoceptors on endothelial cells induces release of endothelium-derived relaxing factor (EDRF), we determined whether nitric oxide (NO) release is involved in the antihypertensive action of clonidine and rilmenidine. In chloralose-anesthetised Wistar rats, systolic and diastolic arterial blood pressures were recorded on a polygraph. Intravenous injection of clonidine or rilmenidine (control group) caused a rapid increase of arterial blood pressure. followed by a long-lasting hypotensive effect. The hypotensive effects, estimated as the area enclosed by the decrease in diastolic pressure during the 20 min after clonidine and rilmenidine injections, were 574+/-60 and 410+/-59 mm Hg/min, respectively. The delta decrease in diastolic arterial blood pressure observed 20 min after intravenous injections of clonidine and rilmenidine was 48+/-5 and 34+/-3 mm Hg, respectively. Clonidine and rilmenidine injected 5-10 min after intravenous pretreatment with L-NAME (2 and 1 mg/kg) or methylene blue (10 mg/kg) induced hypotensive effects that were significantly smaller than that observed for the control group. These results suggest that the antihypertensive effects of clonidine and rilmenidine also may be modulated by the NO-cyclic guanosine monophosphate (cGMP) pathway at the level of the central nervous system and/or at the vascular peripheral circulation.

Topics: Anesthesia; Animals; Antihypertensive Agents; Blood Pressure; Clonidine; Cyclic GMP; Drug Interactions; Enzyme Inhibitors; Hypotension; Male; Methylene Blue; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxazoles; Rats; Rats, Wistar; Rilmenidine

Hypotension induced pial artery dilation is prostaglandin-dependent in the newborn pig. Prostaglandins, in turn, elicit vasodilation through cGMP and cAMP dependent mechanisms and K+ channel activation contributes to cyclic nucleotide induced vasodilation. The present study was designed to characterize the role of ATP sensitive (KATP) and calcium sensitive (Kca) channel activation in hypotension induced pial artery dilation in newborn pigs equipped with a closed cranial window. Glibenclamide and iberiotoxin, KATP and Kca channel antagonists, attenuated hypotension induced dilation (36+/-1 vs. 14+/-2% before and after iberiotoxin). Combined administration of these K+ channel antagonists eliminated the vascular response. Hypotension induced dilation was associated with elevated cerebrospinal fluid (CSF) cAMP but not cGMP concentration (1023+/-29 vs. 1566+/-39 fmol/ml for cAMP). L-NNA, a nitric oxide (NO) synthase inhibitor, and Rp 8-Br cGMPs, a protein kinase G inhibitor, had no effect but Rp 8-Br cAMPs, a protein kinase A inhibitor, attenuated hypotensive dilation (35+/-1 vs. 16+/-2% before and after Rp 8-Br cAMPs). Dilation by the cAMP analogue 8-Bromo cAMP (10(-8), 10(-6) M) was attenuated by glibenclamide and iberiotoxin (8+/-1 and 17+/-1 vs. 4+/-1 and 9+/-1% before and after glibenclamide). These data show that both KATP and Kca channel activation contribute to hypotension induced dilation. These data suggest that dilation during hypotension results from the sequential release of prostaglandins and cAMP, which, in turn, activates both the KATP and Kca channel.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adenosine Triphosphate; Animals; Animals, Newborn; Arteries; Calcium; Cyclic AMP; Cyclic GMP; Female; Glyburide; Hypotension; Ion Channel Gating; Male; Nitric Oxide; Peptides; Pia Mater; Potassium Channels; Swine; Vasodilation

This study was to investigate possible mechanisms associated with vascular hyporeactivity to vasoconstrictor agents in rats with endotoxaemia. Wistar-Kyoto rats were anaesthetised and injected with endotoxin [E. coli lipopolysaccharide (LPS); 10 mg/kg, i.v.] for 4 h. Pressor responses to noradrenaline (NA; 1 microg/kg, i.v.) were determined prior to and at every hour after LPS injection. After the in vivo experiment, rat thoracic aortas were excised and prepared as rings 3-4 mm in width. The endothelium was mechanically removed to evaluate K(+)-channel activity and the effects of nitric oxide (NO) on the vascular smooth muscle. Our results demonstrated that: (1) injection of LPS caused a significant fall in blood pressure and a severe vascular hyporeactivity to NA in the anaesthetised rat, (2) the relaxation induced by the K(+)channel opener cromakalim was greater in rings obtained from endotoxaemic rats and this enhanced relaxation was partially inhibited by pretreatment of these rings with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of the NO/cGMP pathway, (3) endotoxaemia for 4 h was also associated with a profound vascular hyporeactivity to NA ex vivo and this vascular hyporesponsiveness was partially inhibited by ODQ, tetraethylammonium (TEA, a non-selective inhibitor of K(+)-channels) and charybdotoxin [CTX, a selective inhibitor of large conductance calcium-activated K(+)- channels (BK(Ca))], but not by apamin, and (4) the combination of TEA or CTX with ODQ completely restored that vascular responsiveness to normal. These results suggest that activation of BK(Ca) and overproduction of NO in the vascular smooth muscle simultaneously contribute to vascular hyporeactivity to vasoconstrictor agents in endotoxaemia.

Topics: Animals; Apamin; Charybdotoxin; Cyclic GMP; Endotoxins; Hemodynamics; Hypotension; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Nitric Oxide; Potassium Channels; Rats; Rats, Inbred WKY; Tetraethylammonium Compounds

To investigate the possible involvement of endogenous nitric oxide (NO) in acute hypotension during maintenance hemodialysis, we measured the plasma concentration of the nitrate anion NO3-, a stable metabolite of NO, in 19 patients undergoing hemodialysis. We analyzed heart rate variability to estimate the relationship between autonomic nervous activity and NO production, low-frequency/high-frequency components (L/H) as a parameter of cardiac sympathetic activity, and high-frequency power as a parameter of cardiac vagal activity. Six patients developed severe hypotension (a change in mean blood pressure during dialysis > or = 20 mm Hg), four patients developed mild hypotension (a change in mean blood pressure < or = 19 mm Hg and > or = 1 mm Hg), and nine patients did not develop hypotension. The plasma levels of NO3- before dialysis were markedly elevated in the severely hypotensive group compared with the patients who showed no hypotension (566+/-122 micromol/L v 133+/-38 micromol/L; P < 0.01), and this difference disappeared midhemodialysis and after hemodialysis. The plasma concentration of NO3- before dialysis was significantly associated with both the change in mean blood pressure during dialysis (r= -0.735; P = 0.003) and the mean blood pressure after dialysis (r = -0.675; P = 0.0015). The L/H ratio was inhibited before or after dialysis in the severely hypotensive group compared with the nonhypotensive group, and hypotension during dialysis was correlated with the inhibited L/H ratio before (r = 0.784; P = 0.001) or after (r = 0.822; P = 0.001) dialysis. Plasma NO3- concentrations were correlated with the L/H ratio before (r = -0.553; P = .014) or after (r = -0.546; P = 0.015) dialysis. These results suggest that inhibited sympathetic activity is one of the causes of acute hypotension during dialysis, and the enhanced production of NO is involved in this inhibition of the sympathetic activity in patients having a hypotensive episode during dialysis. The plasma concentration of NO3- before dialysis may be a predictor of the risk of hypotension during dialysis in patients with end-stage renal disease.

Topics: Acute Disease; Anions; Blood Pressure; Cyclic GMP; Endothelin-1; Female; Heart Rate; Humans; Hypotension; Kidney Failure, Chronic; Male; Middle Aged; Nitrates; Nitric Oxide; Renal Dialysis; Sympathetic Nervous System

Topics: Cyclic GMP; Drug Interactions; Erectile Dysfunction; Female; Humans; Hypotension; Male; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Cyclic GMP; Drug Interactions; Erectile Dysfunction; Humans; Hypotension; Male; Nitrates; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones

Nitric oxide (NO), constitutively produced by endothelial nitric oxide synthase (eNOS), plays a major role in the regulation of blood pressure and vascular tone. We generated transgenic mice overexpressing bovine eNOS in the vascular wall using murine preproendothelin-1 promoter. In transgenic lineages with three to eight transgene copies, bovine eNOS-specific mRNA, protein expression in the particulate fractions, and calcium-dependent NOS activity were confirmed by RNase protection assay, immunoblotting, and L-arginine/citrulline conversion. Immunohistochemical studies revealed that eNOS protein was predominantly localized in the endothelial cells of aorta, heart, and lung. Blood pressure was significantly lower in eNOS-overexpressing mice than in control littermates. In the transgenic aorta, basal NO release (estimated by Nomega-nitro-L-arginine-induced facilitation of the contraction by prostaglandin F2alpha) and basal cGMP levels (measured by enzyme immunoassay) were significantly increased. In contrast, relaxations of transgenic aorta in response to acetylcholine and sodium nitroprusside were significantly attenuated, and the reduced vascular reactivity was associated with reduced response of cGMP elevation to these agents as compared with control aortas. Thus, our novel mouse model of chronic eNOS overexpression demonstrates that, in addition to the essential role of eNOS in blood pressure regulation, tonic NO release by eNOS in the endothelium induces the reduced vascular reactivity to NO-mediated vasodilators, providing several insights into the pathogenesis of nitrate tolerance.

Topics: Animals; Aorta; Blood Pressure; Cattle; Cyclic GMP; Disease Models, Animal; Gene Expression Regulation; Hypotension; Immunohistochemistry; Lung; Mice; Mice, Transgenic; Muscle Contraction; Muscle Relaxation; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Phenotype; Promoter Regions, Genetic; RNA, Messenger; Vasodilation

Topics: Animals; Cyclic AMP; Cyclic GMP; Heparin; Hypotension; Models, Cardiovascular; Myocardial Contraction; Nitric Oxide; Protamines; Rabbits

Protamine reversal of heparin anticoagulation often causes systemic hypotension, and in vitro studies suggest that this may be mediated by release of nitric oxide from the endothelium. The present investigations were designed to evaluate the direct myocardial effects of protamine and to determine in vivo whether nitric oxide inhibition can prevent hypotension during protamine infusion.. Protamine sulfate (50 microg/ml) was added to perfusate of eight isolated rabbit heart preparations; in six other preparations, a similar concentration of prolamine was added to heparinized (5 U/ml) Krebs perfusate. Left ventricular developed pressure, maximum rate of pressure rise, and heart rate declined significantly (p < 0.01) in hearts exposed to protamine only (65.0% +/- 6.6%, 55.5% +/- 6.0%, and 87.6% +/- 2.5% of baseline, respectively), whereas protamine added to heparinized perfusate caused little change in developed pressure, maximum rate of pressure rise, and heart rate (85.3% +/- 5.4%, 84.9% +/- 5.5%, and 98.8% +/- 1.6%). To study systemic effects of protamine, we measured hemodynamic parameters in 12 heparinized dogs (150 U/kg). During protamine infusion (1.5 mg/kg intravenously over 30 seconds), mean blood pressure decreased by 46% +/- 7% from baseline (P < 0.05), cardiac output decreased by 38% +/- 4% (p < 0.05), and systemic vascular resistance decreased bv by 14& +/- 9%. After hemodynamic stabilization, Ng-monomethyl-L-arginine (2 mg/kg), a competitive inhibitor of nitric oxide synthesis, was administered to six dogs, and methylene blue (2 mg/kg), an inhibitor of cyclic guanosine monophosphate synthesis, was administered to the remaining six dogs. After treatment with Ng-monomethyl-L-arginine and methylene blue, the second infusion of protamine sulfate caused no significant change in blood pressure or cardiac output. In an additional six dogs, Ng-monomethyl-L-arginine pretreatment (5 mg/kg) blocked the effects of the first dose of protamine. The effect of Ng-monomethyl-L-arginine could be reversed by the addition of (6 mg/kg) L-arginine but not D-arginine.. Protamine-heparin complex does not cause direct myocardial depression but does lead to severe hypotension in vivo. The finding that hypotension can be blocked by inhibitors of the nitric oxide pathway confirms previous in vitro studies indicating that the effects of protamine are mediated, in part, by the vascular endothelium. Further, these studies suggest a novel approach to prevention of hemodynamic complications caused by heparin reversal after cardiopulmonary bypass.

Topics: Animals; Arginine; Blood Pressure; Cardiac Output; Cyclic GMP; Dogs; Endothelium, Vascular; Enzyme Inhibitors; Female; Hemodynamics; Heparin; Hypotension; In Vitro Techniques; Male; Methylene Blue; Models, Cardiovascular; Myocardial Contraction; Nitric Oxide; omega-N-Methylarginine; Protamines; Rabbits

Amifostine, a chemo- and radioprotective agent developed as adjunctive therapy for malignancies, induces hypotension after approximately 20% of patient administrations. This study examines the molecular mechanisms underlying hypotension induced by amifostine. Amifostine and its metabolite, WR-1065, induced dose-dependent hypotension in anesthetized rats that was not blocked by N(G)-methyl L arginine (L-NAME), an NO synthase inhibitor. WR-1065 but not amifostine induced concentration-dependent relaxation of isolated rat aortic rings in an endothelium-independent fashion. Relaxation was not associated with increases in cGMP or cAMP and could not be blocked by L-NAME or indomethacin. Similarly, neither amifostine or WR-1065 activated adenylyl, particulate guanylyl, or soluble guanylyl cyclases. WR-1065 relaxed rat aortic rings precontracted with norepinepherine, suggesting alpha-adrenergic blocking activity. However, neither amifostine nor WR-1065 altered the ability of prazosin or phentolamine to bind to alpha-adrenergic receptors. Further, WR-1065 had no effect on receptor-mediated increases in intracellular calcium in BAL 17 murine B lymphocytes in vitro. Thus, hypotension after administration of amifostine is mediated by WR-1065 and appears to result from direct relaxation of vascular smooth muscle. Smooth muscle relaxation induced by WR-1065 is not related to production of nitric oxide, prostaglandins, or cyclic nucleotides; alpha-adrenergic receptor antagonism; or interference with receptor-dependent increases in intracellular calcium. Administration of ephedrine, an efficacious adrenergic agonist, attenuated hypotension induced by amifostine in anesthetized rats and may be useful in alleviating hypotension associated with amifostine administration in patients.

Topics: Adrenergic Agents; Amifostine; Animals; Aorta, Thoracic; Arginine; Blood Pressure; Calcium; Cyclic AMP; Cyclic GMP; Ephedrine; Hypotension; In Vitro Techniques; Ligands; Male; Mercaptoethylamines; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Radiation-Protective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha

The effects of myoglobin on renal microcirculation were studied in anesthetized rats subjected to hemorrhagic hypotension. Capillary flow distribution was determined by allowing two dyes to circulate for 3 and 1 min, respectively, freezing the left kidney and quantifying the dye distribution in histological sections by analyzing the distances of regularly spaced test points to the next dye-labeled capillary. Control experiments showed 88% of distances to be < 12 microns in the cortex [medullary outer stripe (OS): 77%, inner stripe (IS): 93%] and no distance to be > 60 microns. Myoglobin induced disturbances in intrarenal perfusion with a significantly higher potency of (Fe2+)- as compared to (Fe3+)-myoglobin. With the reduced species, the fraction of distances > 60 microns increased to 54% in the cortex (OS: 69%; IS: 67%). L-NAME, an inhibitor of nitric oxide synthesis, induced similar defects of perfusion. The cGMP analogue 8-Br-cGMP was able to nearly completely prevent these effects. The results support the view that myoglobin when released during hemorrhagic hypotension impairs renal microcirculation supposedly by scavenging the endogenous relaxing factor nitric oxide.

Topics: Anesthesia, Intravenous; Animals; Cyclic GMP; Enzyme Inhibitors; Hemorrhage; Hypotension; Iron; Kidney; Male; Microcirculation; Myoglobin; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Renal Circulation

The effects of a continuous i.v. infusion of urodilatin at a dose of 30 ng kg-1 min-1 were studied in a patient with congestive heart failure. After 30 min, urodilatin had induced a marked stimulation of plasma cyclic GMP concentrations. In parallel haematocrit increased. No significant diuresis and no change of invasive haemodynamics was observed. After 2 h the patient developed a profuse perspiration. Eighty minutes later he suffered from dizziness due to hypotension (blood pressure 80/40 mmHg) and a sudden bradycardia (50 bpm). Urodilatin was discontinued and symptoms were relieved by bed tilt and rapid infusion of isotonic saline solution. Mechanisms contributing to these adverse effects may be fluid extravasation to the third space and sympathoinhibitory effects known to occur with natriuretic peptide infusion.

Topics: Atrial Natriuretic Factor; Blood Pressure; Bradycardia; Cardiac Output; Cyclic GMP; Heart Failure; Heart Rate; Hematocrit; Humans; Hypotension; Infusions, Intravenous; Male; Middle Aged; Peptide Fragments

Cyclic GMP (cGMP) dependent vasodilating agents (natriuretic peptides, nitric oxide) inhibit secretion of endothelin-1 (ET-1) in cultured endothelial cells. However, in circulatory conditions associated with acute hypotension, a marked increase in plasma ET-1 has repeatedly been observed. Therefore, after administration of cGMP-dependent agents in hypotensive dose, the net effect of these opposing influences on ET-1 release may shed light on the mechanisms determining circulating levels of this peptide. We have studied the effect of a hypotensive dose of atrial natriuretic peptide (n = 16), 8-Br-cGMP (n = 5), and papaverin (n = 7) on plasma ET-1 in anesthetized dogs. All agents produced marked increases in the peptide level at the end of infusion (178, 280, and 240% of the last preinfusion level, respectively) and a mean arterial blood pressure (MAP) decrease of 19, 18, and 42 mmHg (1 mmHg = 133.3 Pa), respectively. In all three protocols, plasma ET-1 continued to rise when the hypotensive agent was discontinued and remained elevated for 2-3 h postinfusion, even though MAP was normalized. There was a close positive correlation between the maximal increment in plasma ET-1 and the maximal decrease in MAP (r = 0.67, p < 0.001). These results show that acute hypotension due to directly acting vasodilators is a potent stimulus for systemic release of ET-1, even when due to agents known to inhibit ET-1 production in cultured endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Cyclic GMP; Dogs; Endothelins; Female; Glomerular Filtration Rate; Hypotension; Male; Papaverine

Hypotension in septic shock is a reflection of unregulated nitric oxide (NO) production and vascular smooth muscle guanylyl cyclase activation. We examined the effect of methylene blue on lipopolysaccharide (LPS)-induced shock in anesthetized rabbits. Shock was induced with 150 micrograms/kg LPS after measurement of mean arterial pressure, platelet cGMP, and total plasma NO (nitrogen monoxide+S-nitrosothiol) content. Measurements were repeated before and after the intravenous administration of 1, 5, and 10 mg/kg methylene blue in response to a 55% reduction in mean arterial pressure. At baseline, mean +/- SEM arterial pressure was 88 +/- 3 mm Hg, which fell to 51 +/- 3 mm Hg after LPS (P < .05). Methylene blue at doses of 1, 5, and 10 mg/kg produced a prompt dose-dependent increase in mean arterial pressure to 69 +/- 2, 77 +/- 3, and 81 +/- 2 mm Hg, respectively (P < .05 versus mean arterial pressure after LPS) in association with normalization of plasma total NO content (P < .05); however, methylene blue did not significantly affect intraplatelet cGMP levels. Thus, methylene blue restores normal arterial pressure in rabbits with septic shock. This effect is associated with persistent elevation of intraplatelet cGMP levels and normalization of total plasma NO content. These data are consistent with methylene blue-mediated inhibition of NO synthase and/or degradation of NO in this model and suggest a novel therapeutic approach to the treatment of septic shock.

Topics: Animals; Blood Pressure; Cyclic GMP; Hypotension; Lipopolysaccharides; Methylene Blue; Nitric Oxide; Rabbits; Shock, Septic; Sulfhydryl Compounds

To determine if N omega-nitro-L-arginine (NNA), an inhibitor of the synthesis and/or release of endothelium-derived relaxing factor (EDRF), alters the response to zaprinast, a selective inhibitor of cyclic GMP (cGMP) phosphodiesterase, zaprinast (3-30 mg/kg) or vehicle (1 ml/kg) was given to conscious, spontaneously hypertensive rats (SHR) in a cumulative i.v. dose-response manner 30 min after pretreatment with NNA (1 or 3 mg/kg) or saline (1 ml/kg). Mean arterial pressure (MAP) was measured 5 min after each dose of zaprinast. Five minutes after the last dose of zaprinast (30 mg/kg), the rats were anesthetized with pentobarbital (25 mg i.v.). A segment of the abdominal aorta was freeze-clamped in situ and removed for the determination of cGMP levels. NNA (3 mg/kg) decreased basal aortic cGMP levels by 54% and increased MAP by 37 +/- 2 mm Hg. Zaprinast (30 mg/kg) increased aortic cGMP by 187% and decreased MAP by 49 +/- 4 mm Hg. NNA (3 mg/kg) reduced the accumulation of cGMP in aortic tissue (from 4.1 +/- 0.4 to 1.3 +/- 0.1 fmol/microgram protein) and attenuated the depressor response (from -49 +/- 4 to -31 +/- 4 mm Hg) produced by zaprinast. These data are consistent with the hypothesis that NNA inhibits the tonic release of EDRF and that the depressor effects of zaprinast are due, at least in part, to the potentiation of the vasodilator effects of EDRF in vivo. Moreover, since the changes in MAP produced by NNA and zaprinast were significantly correlated with cGMP levels in aortic tissue, the concentration of cGMP in vascular tissue may be a determinant of blood pressure in SHR.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Analysis of Variance; Animals; Aorta, Abdominal; Arginine; Blood Pressure; Cyclic GMP; Hypotension; Male; Muscle, Smooth, Vascular; Nitroarginine; Purinones; Radioimmunoassay; Rats; Rats, Inbred SHR

The pharmacological activities of synthetic mammalian brain natriuretic peptides (BNP) from the human, pig and rat were examined in rats. These peptides all elicited diuresis and hypotension, relaxed isolated rat aorta, augmented cyclic GMP concentration in cultured rat vascular smooth muscle cells, and bound to the cells with a high affinity. Pig and rat BNPs were as active as atrial natriuretic peptides from the human and the rat (alpha-hANP and alpha-rANP) for the diuretic and hypotensive effects as well as for cyclic GMP augmentation, while human BNP was about 10 times less potent. Rat BNP was not as active as the other peptides in competing with the binding of [125I]alpha-hANP to rat vascular smooth muscle cells. Thus, the BNPs did not have identical pharmacological profiles although the potencies of the peptides for cyclic GMP augmentation correlated well to those for vasorelaxation.

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Binding, Competitive; Brain; Cells, Cultured; Cyclic GMP; Diuretics; Humans; Hypotension; Male; Molecular Sequence Data; Muscle Relaxation; Muscle, Smooth, Vascular; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Rats; Rats, Inbred Strains; Recombinant Proteins; Swine

The intravenous injection of an ED50 natriuretic dose (1 microgram) of synthetic ANF decreases blood pressure by 61 +/- 6 mmHg in 2-K, 1-C, and of 45 +/- 6 mmHg in 1-K, 1-C hypertensive rats, which was positively correlated with its initial level only in the 2-K, 1-C group. The hypotensive response lasted longer in the latter (greater than 40 min) than in normotensive sham-operated rats. No difference in duration was seen between 1-K, 1-C hypertensive and its uninephrectomized normotensive controls. The diuretic response to ANF was higher in 2-K, 1-C rats. No hematocrit changes were observed in any group. ANF induced a rise in urinary kallikrein in all groups but the 1-K, 1-C. Urinary kallikrein excretion was positively correlated with natriuresis in normotensive but not in hypertensive groups. ANF induced an increase in urinary cGMP excretion in all groups but the 1-K, 1-C, and an increase in plasma cGMP in the normotensive sham-operated animals. Our results suggest that the fall in blood pressure induced by synthetic ANF could be due to vasodilatation, a drop in cardiac output cannot, however, be eliminated. Whether the hypotensive effect of ANF is mediated by cGMP remains to be demonstrated.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Disease Models, Animal; Female; Hypertension, Renovascular; Hypotension; Kallikreins; Nephrectomy; Rats; Rats, Inbred Strains; Time Factors

In order to study the influence of hypoxia on cyclic nucleotides in the brain, we reduced arterial Po(2) for 15-30 min in lightly anaesthetised and artificially ventilated rats to obtain values ranging from about 45 to about 10 mm Hg. In an additional group (arterial Po(2) 18-22 mm Hg), the tissue hypoxia was aggravated by moderate arterial hypotension (mean arterial blood pressure about 80 mm Hg). In all animals, electrocortical activity was recorded. Cyclic GMP concentrations in cerebral cortex were unchanged in all groups but one. In that group, in which tissue hypoxia was severe enough to induce a suppression-burst EEG pattern and a measurable reduction in the adenylate energy charge, cyclic GMP concentrations were slightly increased (p less than 0.05). Cyclic AMP concentrations remained unaltered at all degrees of hypoxia studied. It is concluded that changes in cyclic nucleotides in brain tissue occur first at such severe degrees of hypoxia of the duration studied that function and metabolism are profoundly altered.

Topics: Animals; Brain; Cyclic AMP; Cyclic GMP; Electroencephalography; Hypotension; Hypoxia; Male; Oxygen; Partial Pressure; Rats