atrial-natriuretic-factor and linsidomine
atrial-natriuretic-factor has been researched along with linsidomine* in 15 studies
Other Studies
15 other study(ies) available for atrial-natriuretic-factor and linsidomine
Article | Year |
---|---|
Central nitric oxide blocks vasopressin, oxytocin and atrial natriuretic peptide release and antidiuretic and natriuretic responses induced by central angiotensin II in conscious rats.
The presence of nitric oxide synthase (NOS), the enzyme that catalyses the formation of nitric oxide (NO), in the circumventricular organs and magnocellular neurones suggests an important role of NO in the modulation of vasopressin (AVP) and oxytocin (OT) release. Intracerebroventricular (I.C.V.) injection of angiotensin II (Ang II) stimulates the release of AVP, OT and atrial natriuretic peptide (ANP), with the resultant antidiuretic and natriuretic effects. This study investigated the interaction between nitrergic and angiotensinergic pathways on the release of AVP, OT and ANP and on urinary volume and sodium excretion in water-loaded rats. Unanaesthetized, freely moving, male Wistar rats received two water loads followed by an injection into the lateral ventricle of an inhibitor of NOS (L-NAME), a NO donor [3-morpholinylsydnoneimine chloride (SIN-1) or S-nitroso-N-acetyl penicillamine (SNAP)] or vehicle (isotonic saline) and, 20 min after, they received a second I.C.V. injection of Ang II or vehicle. Injections of L-NAME or Ang II produced an increase in plasma levels of AVP, OT and ANP, a reduction in urinary volume and an increase in sodium excretion. Pretreatment with L-NAME enhanced the Ang II-induced increase in AVP, OT and ANP release, as well as the antidiuresis and natriuresis. Injection of SIN-1 or SNAP did not modify hormonal plasma levels and urinary parameters. In contrast SNAP blocked the AVP, OT and ANP release, as well as antidiuretic and natriuretic responses induced by ANG-II. Thus, the central nitrergic system can act to inhibit AVP, OT and ANP secretion and the antidiuretic and natriuretic effects in response to Ang II. Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Consciousness; Enzyme Inhibitors; Injections, Intraventricular; Male; Molsidomine; Natriuresis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Osmolar Concentration; Oxytocin; Peptide Hormones; Rats; Rats, Wistar; S-Nitroso-N-Acetylpenicillamine; Sodium; Urine; Vasoconstrictor Agents; Vasopressins | 2007 |
Direct comparison of relaxation and cGMP production in human coronary by-pass grafts in response to stimulation with natriuretic peptides and a nitric oxide donor.
In the present study, we investigated the vasodilator properties of A-type, B-type and C-type natriuretic peptides (ANP, BNP and CNP respectively) and the NO (nitric oxide) donor sin-1 (3-morpholino-sydnonimine) in human by-pass grafts. In contrast with previous studies, the same vessel was used to demonstrate a direct link between cGMP production and functional relaxation. Remnants of the IMA (internal mammary artery) and SV (saphenous vein) were obtained from 82 patients undergoing coronary artery by-pass grafting. The responses to cumulative concentrations of ANP, BNP, CNP and sin-1 in vessel rings pre-contracted with a thromboxane A2 agonist (U46619) were measured in an organ bath. Additionally, intracellular cGMP production after single submaximal dose application of these drugs to vessel rings was determined by a RIA. ANP (P=0.001) and sin-1 (P<0.001) caused significant concentration-dependent relaxation of the IMA. In the SV, only sin-1 (P<0.001) induced marked concentration-dependent relaxation. At a single submaximal concentration, significant relaxation as well as intracellular cGMP production were found in response to ANP, BNP and sin-1 in the IMA. In contrast, in the SV, only sin-1 significantly induced cGMP production and relaxation. There was a moderate, but significant, correlation between intracellular cGMP net production and net relaxation in the IMA. In conclusion, ANP, as the most powerful relaxant of all the natriuretic peptides tested on the IMA, may be a possible alternative vasorelaxant to overcome peri-operative vasospasm in this artery. In contrast with sin-1, ANP and BNP were not effective vasorelaxants of the SV. Net relaxation in response to natriuretic peptides correlated with cGMP net concentrations in the IMA. Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Coronary Artery Bypass; Cyclic GMP; Dose-Response Relationship, Drug; Female; Humans; Internal Mammary-Coronary Artery Anastomosis; Male; Mammary Arteries; Middle Aged; Molsidomine; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Nitric Oxide Donors; Saphenous Vein; Tissue Culture Techniques; Vasodilation; Vasodilator Agents | 2006 |
Lack of synergistic effect of molsidomine and sildenafil on development of pulmonary hypertension in chronic hypoxic rats.
The present study addressed whether combined treatment with a phosphodiesterase type 5 inhibitor, sildenafil, and a nitric oxide donor, molsidomine, prevents development of pulmonary hypertension in chronic hypoxic rats. Two weeks of hypoxia increased right ventricular systolic pressure, and right ventricular and lung weight. Treatment with either sildenafil (10 mg/kg/day) or molsidomine (15 mg/kg/day) in drinking water reduced right ventricular systolic pressure and weight, while lung weight was unchanged. Combining sildenafil and molsidomine did not have additional effects compared to molsidomine alone. The number of muscularized pulmonary arteries with diameters below 50 microm was increased in vehicle and sildenafil-treated, but not in molsidomine-treated hypoxic rats. Acetylcholine relaxation was blunted in arteries from vehicle and molsidomine-treated, but not in sildenafil-treated rats. In conclusion, both sildenafil and molsidomine blunts pulmonary hypertension and right ventricular hypertrophy in chronic hypoxic rats, but no synergistic effects were observed. Topics: Acetylcholine; Actins; Animals; Atrial Natriuretic Factor; Body Weight; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Guanylate Cyclase; Heart Ventricles; Hypertension, Pulmonary; Hypoxia; Lung; Male; Molsidomine; Muscle, Smooth; Oxadiazoles; Piperazines; Pulmonary Artery; Purines; Quinoxalines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Systole; Vasodilation; Vasodilator Agents | 2005 |
High and low gain switches for regulation of cAMP efflux concentration: distinct roles for particulate GC- and soluble GC-cGMP-PDE3 signaling in rabbit atria.
This study tests the hypothesis that particulate (p) guanylyl cyclase (GC) and soluble (s) GC are involved in the distinct roles for the regulation of cGMP-PDE-cAMP signaling and of mechanical and secretory functions in the heart. Experiments were performed in perfused beating rabbit atria. C-type natriuretic peptide (CNP) and SIN-1, an NO donor, or BAY 41-2272 (BAY), a direct activator for sGC, were used to activate pGC and sGC, respectively. CNP and SIN-1 increased cGMP and cAMP efflux in a concentration-dependent manner. Increase in cAMP was a function of cGMP. The changes in cAMP efflux concentration in terms of cGMP were much more prominent in the atria treated with CNP than in the atria treated with SIN-1. Increase in cAMP efflux concentration was blocked by milrinone but not changed by EHNA. BAY increased cGMP but not cAMP in a concentration-dependent manner. CNP and SIN-1 decreased atrial stroke volume and myocytic ANP release. The decreases in terms of cGMP efflux concentration were much more prominent in the atria treated with CNP than in the atria treated with SIN-1 or BAY. Milrinone accentuated GC agonist-induced decreases in atrial stroke volume and ANP release. In the presence of ODQ, SIN-1 or BAY induced effects were not observed. These data suggest that pGC and sGC activations have distinct roles via cGMP-PDE3-cAMP signaling in the cardiac atrium: high and low gain switches, respectively, for the regulation of cAMP levels and contractile and secretory functions. Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adenine; Animals; Atrial Natriuretic Factor; Biological Transport; Cardiac Pacing, Artificial; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Cyclic Nucleotide Phosphodiesterases, Type 3; Enzyme Inhibitors; Guanylate Cyclase; Heart Atria; Milrinone; Molsidomine; Myocardial Contraction; Myocytes, Cardiac; Natriuretic Peptide, C-Type; Nitric Oxide Donors; Oxadiazoles; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyrazoles; Pyridines; Quinoxalines; Rabbits; Receptors, Cytoplasmic and Nuclear; Second Messenger Systems; Soluble Guanylyl Cyclase; Stroke Volume | 2004 |
Mechanism for muscarinic inhibition of I(Ca(L)) is determined by the path for elevating cyclic AMP in cardiac myocytes.
Does carbachol (CCh) require NO/cGMP for inhibition of L-type calcium current (I(Ca(L))) when either adenylyl cyclase activation or phosphodiesterase suppression is used to raise cAMP?. The effects of the NO donor SIN-1 (3-morpholino-sydnonimine), CCh and atrial natriuretic peptide (ANP) were evaluated when I(Ca(L)) had been stimulated by isoproterenol (ISO) or 3-isobutyl-1-methylxanthine (IBMX) in guinea pig isolated ventricular myocytes (35 degrees C).. Carbachol, SIN-1 or ANP did not affect basal I(Ca(L)); each inhibited IBMX-stimulated I(Ca(L)). Dialyzed (30-100 microM) ODQ (1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one), a soluble guanylyl cyclase (sGC) inactivator, blocked inhibition of IBMX-stimulated I(Ca(L)) by SIN-1 (10 microM) but not by CCh (1-100 microM) or ANP (100 nM). Dialysis with 3 microM LY83583 (6-anilino-5,8-quinolinedione), a particulate (pGC) and sGC inactivator, opposed muscarinic-, ANP- and SIN-1-induced inhibition of IBMX-stimulated I(Ca(L)). Thus CCh can increase cGMP synthesis via pGC. Even with 100 microM [LY83583](pip), CCh inhibited ISO-stimulated I(Ca(L)), an effect referable to suppression of adenylyl cyclase activity. However, 3 microM [LY83583](pip) prevented inhibition of ISO-stimulated I(Ca(L)) by ANP. [LY83583](pip) did not affect inhibition by 8 bromo-cGMP (100 microM) of ISO- or IBMX-stimulated I(Ca(L)). The observations indicate that: (1) myocytes have ODQ-sensitive sGC activated by NO and LY8353-sensitive pGC activated by ANP, (2) CCh does not inhibit I(Ca(L)) via NO, (3) the mechanism for muscarinic inhibition depends upon the cAMP-elevating agent and (4) LY83583 distinguishes between two pathways for muscarinic inhibition.. The nature of the stimulant pathway that increases cAMP determines intracellular transduction of muscarinic inhibition. This hypothesis accords with distinct cyclic nucleotide compartments for the differential expression of muscarinic inhibition of I(Ca(L)). Topics: 1-Methyl-3-isobutylxanthine; Aminoquinolines; Animals; Atrial Natriuretic Factor; Calcium Channels, L-Type; Carbachol; Cyclic AMP; Enzyme Inhibitors; Guinea Pigs; Molsidomine; Muscarinic Agonists; Myocardium; Nitric Oxide Donors; Oxadiazoles; Patch-Clamp Techniques; Second Messenger Systems | 2001 |
Contractility of late pregnant rat myometrium is refractory to activation of soluble but not particulate guanylate cyclase.
Our purpose was to compare the effects of agents activating particulate or soluble guanylate cyclases on the spontaneous contractile activity of the isolated pregnant rat uterus.. Uterine rings from midpregnant (14-day) and late pregnant (21-day) rats were suspended in organ chambers to record spontaneous contractile activity. Concentration-response curves were obtained for the following natriuretic peptides: atrial, brain, and C-type; concentration-response curves were also obtained for diethylamine nitric oxide, 3-morpholino-sydnominine, and authentic nitric oxide.. All 3 natriuretic peptides inhibited spontaneous uterine contractions equally at midgestation and late gestation. The inhibitory effects of the nitric oxide donors diethylamine nitric oxide, 3-morpholino-sydnominine, and authentic nitric oxide were attenuated in uterine tissues from animals in late stages of pregnancy.. Agents activating either soluble or particulate guanylate cyclase inhibit contractions of uterine rings from midgestation rats, whereas the effects of soluble guanylate cyclase are attenuated at late pregnancy. Thus spontaneous uterine contractions are under the control of both soluble and particulate guanylate cyclases; the former is dependent on gestational age but the latter is not. Topics: Animals; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Enzyme Activation; Female; Guanylate Cyclase; Hydrazines; Molsidomine; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nitric Oxide; Nitric Oxide Donors; Nitrogen Oxides; Pregnancy; Rats; Rats, Sprague-Dawley; Solubility; Uterine Contraction | 2001 |
Investigation of the interaction between nitric oxide and vasoactive intestinal polypeptide in the guinea-pig gastric fundus.
The interaction between nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) was investigated in isolated circular smooth muscle cells and strips of the guinea-pig gastric fundus. VIP induced a concentration-dependent inhibition of carbachol-induced contraction in smooth muscle cells with a maximum at 10(-6) M. The relaxation by 10(-6) M VIP was inhibited for 79.1+/-5.8% (mean+/-s.e. mean) by the NO-synthase (NOS) inhibitor L-N(G)-nitroarginine (L-NOARG; 10(-4) M) in a L-arginine reversible way. Also the inducible NOS (iNOS) selective inhibitor N-(3-(acetaminomethyl)-benzyl)acetamide (1400 W; 10(-6) M) inhibited the VIP-induced relaxation, but its inhibitory effect was not reversed by L-arginine. When cells were incubated with the guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ, 10(-6) M), the protein kinase A-inhibitor (R)-p-cyclic adenosine-3', 5'-monophosphothioate ((R)-p-cAMPS, 10(-6) M) and the glucocorticoid dexamethasone (10(-5) M), the relaxant effect of VIP was decreased by respectively 80.9+/-7.6, 77.0+/-11.6 and 87.1+/-4.5%. In circular smooth muscle strips of the guinea-pig gastric fundus, the VIP (10(-9) - 10(-7) M)-induced relaxations were not significantly influenced by 10(-4) M L-NOARG, 10(-6) M 1400 W, 10(-6) M ODQ and 10(-5) M dexamethasone. These results suggest that iNOS, possibly induced by the procedure to prepare the smooth muscle cells, is involved in the relaxant effect of VIP in isolated smooth muscle cells but not in smooth muscle strips of the guinea-pig gastric fundus. This study illustrates the importance of the experimental method when studying the influence of NOS inhibitors on the relaxation induced by VIP in gastrointestinal smooth muscle preparations. Topics: Adenine; Adrenergic beta-Agonists; Animals; Atrial Natriuretic Factor; Carbachol; Colforsin; Cyclic AMP; Dexamethasone; Electric Stimulation; Enzyme Inhibitors; Gastric Fundus; Guinea Pigs; In Vitro Techniques; Isoproterenol; Molsidomine; Muscle Relaxation; Muscle, Smooth; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitroarginine; Nitroprusside; Pinacidil; Tetrodotoxin; Thionucleotides; Vasoactive Intestinal Peptide | 2000 |
Dual role of cGMP in modulation of macromolecule permeability of aortic endothelial cells.
The effect of guanosine 3',5'-cyclic monophosphate (cGMP) on cytosolic Ca2+ dynamics and associated alterations in macromolecule permeability was investigated in cultured monolayers of aortic endothelial cells. Addition of the membrane-permeable cGMP analogue 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 5 x 10(-4)M) or activators of the soluble (3-morpholinosydnonimine, 10(-5) M) or the particulate guanylyl cyclase (atrial natriuretic peptide, 10(-7) M) to unstimulated monolayers led to a decrease in permeability (8-BreGMP: 62 +/- 8% of control) without affecting low basal cytosolic Ca2+ concentration ([Ca2+]i, 87 +/- 8 nM). In contrast, under conditions of elevated [Ca2+]i (503 +/- 95 nM) and increased permeability (155 +/- 7% of control) induced by 10(-6) M ionomycin, 8-BrcGMP, 3-morpholinosydnonimine, or atrial natriuretic peptide provoked a further increase in permeability (8-BrcGMP: 255 +/- 27%). These agents failed to increase permeability when added before or after the ionomycin-triggered transitory rise in [Ca2+]i. The increase in permeability in response to 8-BrcGMP was due to a secondary further rise in [Ca2+]i (758 +/- 87 nM), which was abolished in the absence of extracellular Ca2+, indicating influx of exogenous Ca2+ as the cause. Changes in [Ca2+]i and permeability were inhibited, in the presence of the Rp diastereomer of 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphothioate (2 x 10(-5) M), an inhibitor of the cGMP-dependent protein kinase. These findings show that, depending on [Ca2+]i, cGMP can play opposite roles in endothelial permeability in one and the same cell preparation. Topics: Animals; Aorta; Atrial Natriuretic Factor; Calcium; Capillary Permeability; Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Enzyme Activation; Extracellular Space; Guanylate Cyclase; Macromolecular Substances; Molsidomine; Serum Albumin; Stimulation, Chemical; Swine | 1997 |
Oxygen modulation of guanylate cyclase-mediated retinal pericyte relaxations with 3-morpholino-sydnonimine and atrial natriuretic peptide.
This study explores at which level of the guanylate cyclase pathway oxygen modulates retinal pericyte relaxation induced by nitric oxide (NO).. Bovine retinal microvascular pericytes were grown on silicone. On silicone, pericyte contractile tone induces wrinkles. Drug-induced relaxation was quantified as a reduced number of wrinkles after exposure to 3-morpholino-sydnonimine (SIN-1) or atrial natriuretic peptide (ANP) in the absence or in the presence of either 0.3 microM methylene blue (MB), a guanylate cyclase inhibitor, or 10 microM hemoglobin, a NO scavenger; and under 100% oxygen (hyperoxia), ambient air (normoxia), or 100% nitrogen (hypoxia).. Pericytes were relaxed with SIN-1 and ANP in a concentration-dependent manner (EC50: 0.1 microM and 0.01 microM, respectively). Relaxations induced by SIN-1 or ANP were inhibited (P < 0.001) by MB, whereas hemoglobin inhibited only SIN-1 relaxations (P < 0.001). Relaxations induced by SIN-1, but not by ANP were increased (P < 0.001) under hypoxia and decreased (P = 0.002) under hyperoxia.. SIN-1 and ANP relax pericytes through the activation of guanylate cyclase (inhibited by MB), but only SIN-1 through an extracellular release of NO (inhibited by hemoglobin). That oxygen only modulates pericyte relaxations induced by SIN-1 (NO-mediated) but not those induced by ANP suggests that an interaction between oxygen and NO might participate in the capillary network's blood-flow modulation according to local tissue oxygen tension. Topics: Animals; Atrial Natriuretic Factor; Cattle; Cells, Cultured; Guanylate Cyclase; Hemoglobins; Methylene Blue; Molsidomine; Nitric Oxide; Oxygen; Retinal Vessels; Vasodilator Agents | 1997 |
Heterogeneity in the vasorelaxing effect of nicorandil on dog epicardial coronary arteries: comparison with other NO donors.
The relaxation responses to nicorandil, nitroglycerin (NTG), and cromakalim were compared in isolated dog large (>1.5 mm inside diameter) and small (<0.3 mm inside diameter) epicardial coronary arteries. Nicorandil and NTG produced more potent relaxing effects in large coronary arteries. In contrast, cromakalim produced greater relaxation in small arteries. No significant differences were observed in the nitric oxide (NO)-induced response after treatment with superoxide dismutase. The responses to 8-bromo-cyclic guanosine monophosphate (cGMP), SIN-1, and atrial natriuretic peptide did not differ in arteries of different sizes. Treatment with L-cysteine had no significant effect on the relaxation responses to NTG in both large and small coronary arteries. Oxyhemoglobin and glibenclamide inhibited relaxation induced by nicorandil in large and small coronary arteries. Oxyhemoglobin had a greater suppressive effect on the response to nicorandil in large coronary arteries than in small coronary arteries. Methylene blue inhibited the response to nicorandil in large coronary arteries. These findings suggest that nicorandil behaves predominantly as a nitrate in large epicardial coronary arteries rather than small epicardial arteries and that this difference between large and small coronary arteries with regard to the nitrate action of nicorandil may be the result of a pathway in which nicorandil is converted to NO. Topics: Animals; Atrial Natriuretic Factor; Benzopyrans; Coronary Vessels; Cromakalim; Cyclic GMP; Dogs; Female; Glyburide; In Vitro Techniques; Male; Methylene Blue; Molsidomine; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Niacinamide; Nicorandil; Nitric Oxide; Nitroglycerin; Nitroprusside; Oxyhemoglobins; Pyrroles; Vasodilator Agents | 1997 |
Interaction between cGMP-dependent dilators and autoregulation in rat preglomerular vasculature.
The influence of guanosine 3',5'-cyclic monophosphate (cGMP)-dependent dilators on autoregulatory responses (AR) of arcuate arteries (ArcA) and afferent arterioles at early sites and at juxtaglomerular sites (JAA) was assessed by videomicroscopy using in vitro blood-perfused juxtamedullary nephron preparations. AR were quantified as fractional changes in luminal diameter induced by doubling blood perfusion pressure (60-120 mmHg). Baseline AR ranged from 17 +/- 2% to 21 +/- 2% in ArcA and from 24 +/- 2% to 34 +/- 4% in JAA. Direct perivascular applications of increasing concentrations of 8-bromo-cGMP (8-BrcGMP, 10 microM to 1 mM), of the NO donors sodium nitroprusside (10 microM to 1 mM) and 3-morpholino-sydnonimine chlorhydrate (SIN1; 10 microM to 1 mM), and of rat atrial natriuretic factor (ANF, 0.1 nM to 10 nM) dose- and pressure-dependently dilated all vessels at 60 mmHg. Concomitantly, AR values were dose-dependently reduced or reversed to pressure-induced dilations. During application of 8-BrcGMP and NO donors, the segmental gradient of sensitivity of AR was ArcA > JAA; the opposite gradient was found with ANF (i.e., JAA > ArcA). The present results demonstrate that compounds known to utilize the cGMP-signaling pathway act as modulators of AR along the juxtamedullary preglomerular vasculature. Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Dose-Response Relationship, Drug; Homeostasis; Kidney Glomerulus; Male; Molsidomine; Nitroprusside; Rats; Rats, Sprague-Dawley; Renal Circulation; Vasodilator Agents | 1995 |
Nitric oxide-induced microvascular permeability alterations: a regulatory role for cGMP.
This study evaluated the physiological effects of compounds that alter guanosine 3',5'-cyclic monophosphate (cGMP) on the increase in vascular protein clearance induced by nitric oxide (NO) synthesis inhibition in the feline small intestine. A lymphatic vessel draining the small bowel was cannulated; vascular protein clearance and intestinal blood flow were measured. N omega-nitro-L-arginine methyl ester (L-NAME), the NO inhibitor, was infused (0.5 mumol/min) into the superior mesenteric artery. Vascular protein clearance increased approximately 4.6-fold, whereas blood flow decreased to 50% of control. Elevation of cGMP by 1) cytosolic guanylate cyclase activation with a NO donor (SIN 1) or 2) a cGMP analogue, 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP) completely prevented the rise in microvascular permeability associated with L-NAME. Moreover, these compounds reduced (almost 90%) baseline vascular protein clearance, whereas inhibition of cytosolic guanylate cyclase with methylene blue significantly increased this parameter. Atrial natriuretic factor (ANF) has been reported to increase tissue cGMP levels and microvascular permeability. In this study, ANF did indeed increase intestinal microvascular permeability however this occurred independent of changes in intestinal cGMP levels. These data support a role for cGMP associated with NO-induced microvascular permeability alterations and raise the possibility that ANF has a cGMP-independent effect on microvascular permeability within the intestine. Topics: Animals; Arginine; Atrial Natriuretic Factor; Capillary Permeability; Cats; Cyclic GMP; Intestines; Methylene Blue; Molsidomine; NG-Nitroarginine Methyl Ester; Nitric Oxide; Regional Blood Flow | 1993 |
Vascular relaxation and cyclic guanosine monophosphate in a rat model of high output heart failure.
Low output heart failure induces abnormalities of endothelium dependent vasodilation, but the mechanisms responsible for this remain unclear. As blood flow can alter endothelial cell function, in particular nitric oxide (NO) release, the activity of endothelium derived relaxing factor (EDRF) was investigated in a rat model of high output heart failure.. The thoracic aorta upstream of an aorto-caval fistula in rats was submitted to hormonal changes (similar to those in heart failure) and to high blood flow (opposite to that found in low output heart failure). Functional and biochemical arterial properties were studied in aorto-caval fistula rats and in sham operated rats three months after operation. The vascular responses were studied by exposing aortic segments from fistula and sham operated rats to increasing concentrations of agonists. Aortic cyclic guanosine monophosphate (cGMP) concentration was assessed as an index of NO synthase activity. The effect of NO synthase blockade on functional and biochemical arterial properties was also studied.. Plasma atrial natriuretic factor (ANF) was increased in fistula rats compared to sham operated rats. The concentrations of acetylcholine or the calcium ionophore A23187 required to produce 10% and 50% maximum relaxation (EC10 and EC50) were similar in the two groups. Relaxation in response to low concentrations of Sin-1 (an NO donor) was shifted rightwards in fistula rats and EC10 was greater than in the controls. The aortic cGMP concentration was higher in aorto-caval fistula rats than in sham operated rats (p = 0.008). The differences between aorto-caval fistula rats and sham operated rats were probably the result of increased basal EDRF-NO release in the former, since NO synthase blockade abolished the differences in both aortic cGMP and the dose-response curve to Sin-1.. The arterial wall upstream of a chronic aorto-caval fistula has increased cGMP content and hyposensitivity to Sin-1, which may be due to enhanced basal EDRF-NO release. These changes, strikingly different from those found in the low output heart failure, suggest that haemodynamic rather than neuroendocrine factors play a determinant role in the altered vasodilator response in heart failure. Topics: Acetylcholine; Animals; Atrial Natriuretic Factor; Calcimycin; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Failure; Male; Molsidomine; Nitric Oxide; Rats; Rats, Wistar; Vasodilation | 1993 |
Role of the L-arginine-NO pathway and of cyclic GMP in electrical field-induced noradrenaline release and vasoconstriction in the rat tail artery.
1. The possible roles of the L-arginine-NO pathway and of guanosine 3':5'-cyclic monophosphate (cyclic GMP) in regulating the prejunctional release of noradrenaline and neurogenic vasoconstriction were investigated in the perfused rat tail artery. 2. In the presence of N omega-nitro-L-arginine methyl ester (L-NAME; 30 microM), an inhibitor of NO formation, the vasoconstrictor responses to perivascular nerve stimulation (24 pulses at 0.4 Hz, 0.3 ms, 200 mA) and to exogenous noradrenaline (1 microM) were significantly enhanced, whereas the stimulation-evoked tritium overflow from [3H]-noradrenaline preloaded arteries was not modified. The vasoconstriction enhancing effect of L-NAME was prevented by L-arginine (1 mM) but not D-arginine (1 mM) and was abolished by removal of the endothelium. 3. The NO donor, 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1; 0.1-30 microM), and the cyclic GMP phosphodiesterase inhibitor, zaprinast (0.1-30 microM) both induced a concentration-dependent inhibition of the electrical field stimulation-induced vasoconstriction, while atrial natriuretic peptide (ANP; 100 nM) produced only a slight decrease of the vasoconstrictor response. Methylene blue (3 microM), a known inhibitor of soluble guanylate cyclase increased the electrical field stimulation-induced vasoconstriction. SIN-1 and methylene blue when administered simultaneously, antagonized each others effect. None of the compounds tested (SIN-1, zaprinast, ANP or methylene blue) had any significant effect on the stimulation-evoked [3H]-noradrenaline overflow. 4. 8-Bromo-cyclic GMP, a potent activator of cyclic GMP-dependent protein kinase, markedly and concentration-dependently (3-300 microM) increased [3H]-noradrenaline overflow but decreased field stimulation-induced vasoconstriction. Dibutyryl-cyclic GMP (100 JM), a weak activator of cyclic GMP-dependent protein kinase, affected neither the pre- nor the postjunctional response to electrical field stimulation.5. These data show that an NO-like substance of endothelial origin, derived from L-arginine, attenuates vasoconstriction in the rat tail artery, whether neurally-induced or evoked by exogenous noradrenaline.Since noradrenaline release was unaltered by compounds modifying NO production, this NO-like compound acted through a postjunctional mechanism. The lack of prejunctional effects of both soluble and membrane-associated guanylate cyclase activators, despite a large effect of 8-bromo-cyclic GMP,suggests that endogenou Topics: Animals; Arginine; Arteries; Atrial Natriuretic Factor; Cyclic GMP; Electric Stimulation; Endothelium, Vascular; In Vitro Techniques; Male; Methylene Blue; Molsidomine; NG-Nitroarginine Methyl Ester; Nitric Oxide; Norepinephrine; Purinones; Rats; Tail; Vasoconstriction; Vasodilator Agents | 1992 |
Nitrovasodilators as a new class of ocular hypotensive agents.
Because of recent evidence indicating that hormone regulation of particulate guanylate cyclase in the eye may modulate aqueous humor dynamics, we have investigated the possibility that exogenous activators of soluble guanylate cyclase may be useful in altering intraocular pressure (IOP). A variety of nitrovasodilators known to activate guanylate cyclase were evaluated for their topical effects on IOP, outflow resistance and systemic cardiovascular parameters. In both young and older rabbits, topically applied nitroglycerin (0.003-0.1 g %) rapidly lowered IOP in a dose-dependent fashion, with a peak effect at 1 to 2 hr. Topically applied 0.1% isosorbide dinitrate, sodium nitrite, hydralazine, minoxidil and sodium nitroprusside mimicked the ocular hypotensive actions of nitroglycerin. Ipsilateral effects on IOP were greater than contralateral effects and, at the doses applied, there was little or no alteration in heart rate or systemic blood pressure, or signs of ocular irritation. Higher doses (0.5-2.0 g %) of nitroglycerin, hydralazine and sodium nitroprusside were less effective in lowering IOP. Topically applied molsidomine (0.1%), a prodrug which requires hepatic metabolism to 3-morpholino-sydnonimin hydrochloride for guanylate cyclase stimulatory activity, was ineffective in lowering IOP, whereas topical 0.1% 3-morpholino-sydnonimin hydrochloride was effective. After chronic administration, rabbits receiving nitroglycerin showed diminished ocular response, whereas repeated doses of hydralazine (56 days) did not elicit tolerance. Tonographic studies showed that topically applied nitroglycerin and hydralazine increased the facility (decreased the resistance) of aqueous humor leaving the eye. These data indicate that topically applied nitrovasodilators can effectively lower IOP at doses which have little effect on systemic blood pressure. Because these IOP-lowering effects appear to result, to a significant degree, from local actions on the eye, further investigation of these agents in conditions of elevated intraocular pressure may be warranted. Topics: Administration, Topical; Animals; Aqueous Humor; Atrial Natriuretic Factor; Blood Pressure; Dose-Response Relationship, Drug; Intraocular Pressure; Isosorbide Dinitrate; Male; Molsidomine; Nitroglycerin; Nitroprusside; Rabbits; Vasodilator Agents | 1992 |