Mechanism of the acute pressor effect and bradycardia elicited by diaspirin crosslinked hemoglobin in anesthetized rats

1998 ◽  
Vol 76 (4) ◽  
pp. 434-442 ◽  
Author(s):  
Steve Moisan ◽  
Guy Drapeau ◽  
Kenneth E Burhop ◽  
Francis Rioux
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Heart Rate ◽  
Pressor Effect ◽  
Endogenous Nitric Oxide ◽  
Pressor Activity ◽  
Vagal Reflex ◽  
Generating System ◽  
Hypertensive Episode ◽  
Diaspirin Crosslinked Hemoglobin

Diaspirin crosslinked hemoglobin (DCLHb) is a chemically stabilizedhemoglobin (Hb) that induces an increase in blood pressure and a decrease of heart rate wheninjected intravenously in some animals. The mechanism by which DCLHb elicits thesehemodynamic effects was studied in pentobarbital-anesthetized, vagotomized rats using a varietyof drugs known for their inhibitory action towards endogenous hemodynamically active systems.The hypertensive episode elicited by DCLHb (100 or 400 mg·kg–1) was attenuatedin animals pretreated with NG-nitro-L-arginine (inhibitor of nitric oxidesynthases) throughout the 30-min period of observation, but it was not reduced in thosepretreated with a variety of sympatholytic drugs (e.g., prazosin), atropine, BIBP-3226(neuropeptide Y antagonist), indomethacin,[1-(Beta-mercapto-Beta,Beta-cyclopentanemethylene propionic acid), 2-(0-methyl)tyrosine]-Arg8 vasopressin (vasopressin antagonist), losartan (angiotensin antagonist),bosentan (endothelin antagonist), or L-arginine- (nitric oxide precursor), compared withcontrol animals. With the exception of propranolol and BIBP-3226, none of the aforenamedinhibitors reduced the amplitude of the bradycardia associated with the pressor effect of DCLHb.These results suggest that: (i) the acute (<30 min) pressor activity of DCLHb inour animal model requires the presence of an endogenous nitric oxide generating system to beexpressed; (ii) the bradycardia elicited by DCLHb might involve the participation ofneuropeptide Y and (or) its NPY-1 receptors, but it is unlikely to involve abaroreceptor-mediated vagal reflex, at least in our animal model.Key words: hemoglobin, nitric oxide, blood pressure, heart rate,DCLHb.

Nonpeptide endothelin receptor antagonists attenuate the pressor effect of diaspirin-crosslinked hemoglobin in rat

1999 ◽  
Vol 77 (3) ◽  
pp. 188-194 ◽  
Author(s):  
Francis Rioux ◽  
Nathalie Harvey ◽  
Steve Moisan ◽  
Richard Larivière ◽  
Marcel Lebel ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
No Synthase ◽  
Endothelin Receptor Antagonists ◽  
Pressor Effect ◽  
Endothelin Receptor ◽  
Hemodynamic Effects ◽  
Receptor Antagonists ◽  
Pressor Activity ◽  
Diaspirin Crosslinked Hemoglobin

Endothelin 1 (ET-1) is a potent vasoactive and mitogenic peptide that is thought to participate in the hemodynamic effects elicited by drugs that block the biosynthesis and release of endothelium-derived nitric oxide (NO), such as NO synthase inhibitors. Using the nonpeptide endothelin receptor antagonists bosentan and LU-135252, we tested the hypothesis that endothelins contribute to the pressor activity of diaspirin-crosslinked hemoglobin (DCLHb), a hemoglobin-based oxygen carrier, whose pressor activity in mammals is attributed primarily to a scavenging action towards NO. The NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME), ET-1, and noradrenaline (NA) were used as reference drugs. Bosentan markedly reduced the pressor effects elicited by DCLHb, L-NAME, and ET-1, but not those evoked by NA. LU-135252 attenuated the pressor effect elicited by DCLHb and ET-1, but not that produced by L-NAME or NA. The decreases in heart rate associated with the pressor effect of DCLHb and L-NAME were reduced by LU-135252, whereas only those elicited by DCLHb were attenuated by bosentan. In contrast with bosentan, LU-135252 caused a decrease in the baseline blood pressure and heart rate. These results suggest that endothelins may participate in the pressor activity of DCLHb. They suggest also that nonpeptide endothelin receptor antagonists such as bosentan or LU-135252 may be useful to counteract endothelin-mediated undesirable hemodynamic effects of drugs that inhibit the activity of the NO system.Key words: hemoglobin, endothelin, nitric oxide, blood pressure, diaspirin-crosslinked hemoglobin (DCLHb).

Nimodipine inhibits the pressor activity of diaspirin-crosslinked hemoglobin (DCLHb) in the rat

1998 ◽  
Vol 76 (10-11) ◽  
pp. 983-988 ◽  
Author(s):  
Francis Rioux ◽  
Mélanie St-Pierre ◽  
Nathalie Harvey ◽  
Steve Moisan ◽  
Kenneth E Burhop ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Calcium Channels ◽  
Calcium Antagonists ◽  
Pressor Response ◽  
Pressor Effect ◽  
Adrenoceptor Agonist ◽  
Pressor Activity ◽  
Tonic Phase ◽  
Diaspirin Crosslinked Hemoglobin

Impaired nitric oxide (NO) activity is associated with an increase in blood pressure in rats. Voltage-regulated calcium channels are believed to participate in this hemodynamic event. To further test this hypothesis, we examined the effect of nimodipine and verapamil (calcium antagonists) on the pressor activity of diaspirin-crosslinked hemoglobin (DCLHb), a well-known NO scavenger, in anesthetized rats. Nimodipine, the most potent of the two calcium antagonists used, was also tested against phenylephrine (alpha1-adrenoceptor agonist). The pressor effect of DCLHb was reduced markedly by nimodipine and verapamil, whereas that elicited by phenylephrine, particularly the tonic phase of its pressor response, was resistant to blockade by nimodipine. The bradycardia and tachycardia associated with the pressor effects of DCLHb and phenylephrine, respectively, were not affected by nimodipine. The pressor effect elicited by DCLHb and its alteration by nimodipine were also examined in rats pretreated with 100% O2. This treatment was found to potentiate the pressor effect of DCLHb. However, this synergism did not impair the inhibitory action of nimodipine towards the pressor activity of DCLHb. Altogether these results suggest that the pressor activity of DCLHb in our animal model might involve the participation of voltage-regulated calcium channels.Key words: hemoglobin, nitric oxide, calcium channels, blood pressure, diaspirin-crosslinked hemoglobin.

Characterization of the role of endogenous nitric oxide in myogenic vascular oscillations during cooling-evoked hemodynamic perturbations of rats

2017 ◽  
Vol 95 (7) ◽  
pp. 803-810 ◽  
Author(s):  
Yi-Hsien Lin ◽  
Yia-Ping Liu ◽  
Yu-Chieh Lin ◽  
Po-Lei Lee ◽  
Che-Se Tung
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Heart Rate ◽  
Cold Stress ◽  
Low Frequency ◽  
Sympathetic Activation ◽  
Nitric Oxide Synthase Inhibitor ◽  
Dicrotic Notch ◽  
Endogenous Nitric Oxide

Rapid immersion of a rat’s limbs into 4 °C water, a model of cold stress, can elicit hemodynamic perturbations (CEHP). We previously reported that CEHP is highly relevant to sympathetic activation and nitric oxide production. This study identifies the role of nitric oxide in CEHP. Conscious rats were pretreated with the nitric oxide synthase inhibitor L-NAME (NG-nitro-l-arginine methyl ester) alone or following the removal of sympathetic influences using hexamethonium or guanethidine. Rats were then subjected to a 10 min cold-stress trial. Hemodynamic indices were telemetrically monitored throughout the experiment. The analyses included measurements of systolic blood pressure; heart rate; dicrotic notch; short-term cardiovascular oscillations and coherence between blood pressure variability and heart rate variability in regions of very low frequency (0.02–0.2 Hz), low frequency (0.2–0.6 Hz), and high frequency (0.6–3.0 Hz). We observed different profiles of hemodynamic reaction between hexamethonium and guanethidine superimposed on L-NAME, suggesting an essential role for a functional adrenal medulla release of epinephrine under cold stress. These results indicate that endogenous nitric oxide plays an important role in the inhibition of sympathetic activation and cardiovascular oscillations in CEHP.

Short-term and long-term blood pressure and heart rate variability in the mouse

2000 ◽  
Vol 278 (1) ◽  
pp. R215-R225 ◽  
Author(s):  
Ben J. A. Janssen ◽  
Peter J. A. Leenders ◽  
Jos F. M. Smits
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Heart Rate ◽  
Pressure Fluctuations ◽  
Sympathetic Nerves ◽  
Pulse Interval ◽  
Control Mechanisms ◽  
Short Term ◽  
Endogenous Nitric Oxide ◽  
Short Term Variability

Knowledge on murine blood pressure and heart rate control mechanisms is limited. With the use of a tethering system, mean arterial pressure (MAP) and pulse interval (PI) were continuously recorded for periods up to 3 wk in Swiss mice. The day-to-day variation of MAP and PI was stable from 5 days after surgery. Within each mouse ( n = 9), MAP and PI varied by 21 ± 6 mmHg and 17 ± 4 ms around their respective 24-h averages (97 ± 3 mmHg and 89 ± 3 ms). Over 24-h periods, MAP and PI were bimodally distributed and clustered around two preferential states. Short-term variability of MAP and PI was compared between the resting (control) and active states using spectral analysis. In resting conditions, variability of MAP was mainly confined to frequencies <1 Hz, whereas variability of PI was predominantly linked to the respiration cycle (3–6 Hz). In the active state, MAP power increased in the 0.08- to 3-Hz range, whereas PI power fell in the 0.08- to 0.4-Hz range. In both conditions, coherence between MAP and PI was high at 0.4 Hz with MAP leading the PI fluctuations by 0.3–0.4 s, suggesting that reflex coupling between MAP and PI occurred at the same frequency range as in rats. Short-term variability of MAP and PI was studied after intravenous injection of autonomic blockers. Compared with the resting control state, MAP fell and PI increased after ganglionic blockade with hexamethonium. Comparable responses of MAP were obtained with the α-blocker prazosin, whereas the β-blocker metoprolol increased PI similarly. Muscarinic blockade with atropine did not significantly alter steady-state levels of MAP and PI. Both hexamethonium and prazosin decreased MAP variability in the 0.08- to 1-Hz range. In contrast, after hexamethonium and metoprolol, PI variability increased in the 0.4- to 3-Hz range. Atropine had no effect on MAP fluctuations but decreased those of PI in the 0.08- to 1-Hz range. These data indicate that, in mice, blood pressure and its variability are predominantly under sympathetic control, whereas both vagal and sympathetic nerves control PI variability. Blockade of endogenous nitric oxide formation by N G-nitro-l-arginine methyl ester increased MAP variability specifically in the 0.08- to 0.4-Hz range, suggesting a role of nitric oxide in buffering blood pressure fluctuations.

scholarly journals Serum levels of NG, NG-dimethyl-L-arginine, a potential endogenous nitric oxide inhibitor in dialysis patients.

1997 ◽  
Vol 8 (9) ◽  
pp. 1437-1442
Author(s):  
B Anderstam ◽  
K Katzarski ◽  
J Bergström
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Serum Levels ◽  
Model Systems ◽  
Dialysis Dose ◽  
Control Subjects ◽  
Before And After ◽  
Endogenous Nitric Oxide ◽  
Experimental Model Systems ◽  
The One

Nitric oxide (NO) is involved in blood pressure regulation, and its synthesis is inhibited by methylarginines. It has been hypothesized that one of these, asymmetrical dimethylarginine (ADMA), may contribute to dialysis-associated hypertension because it accumulates in the plasma of hemodialysis (HD) patients in a concentration high enough (4 mumol/L) to inhibit NO synthesis in experimental model systems. A precolumn HPLC technique was used to quantify methylarginines (ADMA and symmetrical dimethylarginine [SDMA]) in plasma from HD patients before and after dialysis, from continuous ambulatory peritoneal dialysis (CAPD) patients, and from healthy subjects. Plasma ADMA concentrations were 0.59 +/- 0.22 (SD) mumol/L in HD patients predialysis (n = 19) and 0.70 +/- 0.27 mumol/L in CAPD patients (n = 11), versus about half of the concentration in control subjects (0.36 +/- 0.08 mumol/L, n = 7). The concentrations of SDMA (not an inhibitor of NO formation) were approximately four to five times the ADMA concentrations in both HD and CAPD patients, in contrast to a ratio of 1:1 in the control subjects. Methylarginine concentrations were reduced by 23% and 40% postdialysis, as calculated from ADMA and SDMA values, respectively. No significant correlations were observed between ADMA concentrations, on the one had, and blood pressure, creatinine and dialysis dose (Kt/V urea), on the other hand. It is concluded that plasma levels of ADMA are considerably lower than those reported earlier in patients treated with HD and also below the levels that hitherto have been thought to have clinical relevance. The role of ADMA in inhibiting NO in dialysis-associated hypertension is questioned.

L-NAME antagonizes vasopressin V2-induced vasodilatation in dogs

1994 ◽  
Vol 266 (1) ◽  
pp. H99-H106 ◽  
Author(s):  
J. F. Liard
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Heart Rate ◽  
Endothelial Cells ◽  
Cardiac Output ◽  
Arginine Vasopressin ◽  
Electromagnetic Flowmeter ◽  
Hemodynamic Effects ◽  
Blood Pressure Responses ◽  
Chronically Instrumented Dogs

Experiments were performed in conscious chronically instrumented dogs to study the mechanism of hemodynamic effects mediated by selective vasopressin V2 agonists. In one group of dogs (n = 5) instrumented for the measurement of arterial pressure and cardiac output (electromagnetic flowmeter), the infusion of NG-nitro-L-arginine methyl ester (L-NAME; 20 or 40 micrograms.kg-1 x min-1) prevented or significantly inhibited the increase in cardiac output, heart rate and systemic conductance induced by injections of 1-desamino-8-D-arginine vasopressin (DDAVP, desmopressin) and 4-valine-8-D-arginine vasopressin (VDAVP), two selective V2 agonists. L-NAME infusion did not modify the aortic adenosine 3',5'-cyclic monophosphate increase induced by DDAVP infusion. In a second group of dogs similarly prepared (n = 4), the administration of L-arginine (10 mg.kg-1 x min-1) at the same time as that of L-NAME (20 micrograms.kg-1 x min-1) completely prevented the hemodynamic effects of L-NAME and restored the response to DDAVP administration. In a third group of dogs (n = 4), the infusion of a bradykinin B2 antagonist, at a rate that significantly inhibited the cardiac output, heart rate, and blood pressure responses to bradykinin, did not modify the hemodynamic response to DDAVP infusion. We conclude that the hemodynamic effects of selective V2 agonists in dogs are not mediated by bradykinin release but instead via a V2-like receptor on endothelial cells that triggers the release of nitric oxide.

ON THE HYPERTENSIVE ACTION OF TOLAZOLINE AND HYDERGINE

1963 ◽  
Vol 41 (1) ◽  
pp. 941-946 ◽  
Author(s):  
B. G. Benfey ◽  
D. R. Varma
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Cardiac Contractility ◽  
Pressure Rise ◽  
Pressor Effect ◽  
Blood Pressure Rise ◽  
Chronotropic Effects

The effects of tolazoline and Hydergine on blood pressure, cardiac contractility, and heart rate have been studied in dogs under pentobarbitone anesthesia. Whereas in the absence of reserpine, tolazoline had a pressor effect in two of four dogs, following reserpine it had a marked pressor action in each of eight dogs. The blood pressure rise was associated with positive inotropic and negative chronotropic effects. Phenoxybenzamine abolished these effects of tolazoline. Hydergine had pressor and negative chronotropic effects in the absence of reserpine. Following reserpine these effects were associated with positive inotropic actions. Phenoxybenzamine reduced these effects of Hydergine. It is concluded that the pressor action of tolazoline is wholly due to adrenergic vasoconstriction, whereas that of Hydergine is only partly an adrenergic effect.

Neither endogenous nor inhaled nitric oxide influences the function of circulating platelets in healthy volunteers

1999 ◽  
Vol 97 (3) ◽  
pp. 345-353 ◽  
Author(s):  
Johanna ALBERT ◽  
N. Håkan WALLÉN ◽  
Nailin LI ◽  
Claes FROSTELL ◽  
Paul HJEMDAHL
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Heart Rate ◽  
Healthy Volunteers ◽  
Thrombin Generation ◽  
Bleeding Time ◽  
Flow Cytometric ◽  
Fibrinogen Binding ◽  
Inhaled No

Experimental models have indicated prothrombotic effects of inhibition of nitric oxide (NO) production, and anti-thrombotic effects of inhaled NO, but the influence of NO on platelet function in vivo in humans is not well established. We therefore investigated the effects of systemic inhibition of NO synthesis by NG-monomethyl-⌊-arginine (⌊-NMMA) and of NO inhalation on platelet function in vivo. On two occasions, ⌊-NMMA (13.5 mg/kg) or saline infusion was administered to 14 healthy volunteers in a double-blind cross-over study. After a 30 min infusion of ⌊-NMMA or placebo, NO inhalation (30 p.p.m) was added during the remaining 30 min of infusion, on both occasions. Measurements included filtragometry ex vivo (reflecting platelet aggregability), flow-cytometric evaluation of platelets in whole blood (fibrinogen binding and P-selectin expression), plasma β-thromboglobulin (reflecting platelet secretion), cGMP in platelets and plasma, thrombin generation markers (thrombin fragment 1+2 and thrombin–antithrombin complexes) in plasma, and bleeding time. l-NMMA increased blood pressure and decreased heart rate. NO inhalation did not influence blood pressure or heart rate, but caused a 3-fold elevation in plasma cGMP levels (P < 0.001). Neither ⌊-NMMA nor NO influenced filtragometry readings or flow-cytometric determinations of platelet fibrinogen binding and P-selectin expression. Furthermore, plasma β-thromboglobulin, platelet cGMP and thrombin generation markers were not influenced by either treatment. Bleeding time was not influenced by ⌊-NMMA compared with placebo, but was increased by ≈ 25% during NO inhalation (P < 0.01), whether NO synthesis had been inhibited or not. The prolongation of bleeding time by inhaled NO was not accompanied by any effect on the platelet variables assessed. The present results indicate that circulating platelets are not influenced by endogenous or inhaled NO, presumably due to the rapid inactivation of NO in the blood. This does not exclude possible effects of endothelial NO in the interface between the blood and the vessel wall.

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