Selective inhibition of cGMP-inhibitable cAMP phosphodiesterase decreases pulmonary vasoreactivity

1991 ◽  
Vol 261 (2) ◽  
pp. H487-H492 ◽  
Author(s):  
J. Haynes ◽  
P. A. Kithas ◽  
A. E. Taylor ◽  
S. J. Strada
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Muscle Relaxation ◽  
Selective Inhibition ◽  
Smooth Muscle Relaxation ◽  
Ang Ii ◽  
Camp Phosphodiesterase ◽  
Cyclic Monophosphate ◽  
Pressor Responses ◽  
Camp Hydrolysis

Guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) are mediators of smooth muscle relaxation. In this study, selective inhibitors of phosphodiesterase (PDE) isozymes were used to assess the role of cyclic nucleotide hydrolysis in angiotensin II (ANG II) and hypoxic pulmonary vasoconstriction. In isolated rat lungs, the hypoxic pressor response (HPR) was induced with a 95% N2-5% CO2 gas mixture. When administered during the plateau of the HPR, trequinsin (nonselective PDE inhibitor) and indolidan (cGMP-inhibitable cAMP PDE inhibitor) significantly (P = 0.01) decreased the pulmonary arterial pressure (Ppa) by 60 +/- 7 and 53 +/- 3%, respectively, compared with zaprinast (cGMP PDE inhibitor), rolipram (cGMP-insensitive cAMP PDE inhibitor), and the 0.1% dimethyl sulfoxide (DMSO) vehicle control, which decreased the Ppa by 6 +/- 3, 4 +/- 3, and 0%, respectively. In the trequinsin and indolidan groups, the subsequent ANG II pressor responses and HPRs were significantly (P = 0.01) decreased when compared with the zaprinast, rolipram, and DMSO groups. During normoxia, none of the PDE inhibitor (0.3-30 microM) had an effect on the baseline Ppa. These results suggest that cAMP hydrolysis by the cGMP-inhibitable cAMP PDE play a significant role in pulmonary vascular tone regulation.

Selective inhibition of angiotensin II-mediated vasoconstriction by lipoxygenase blockade

1989 ◽  
Vol 257 (2) ◽  
pp. H434-H443 ◽  
Author(s):  
N. Stern ◽  
M. Golub ◽  
K. Nozawa ◽  
M. Berger ◽  
E. Knoll ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
High Performance ◽  
Pressor Response ◽  
Selective Inhibition ◽  
Ang Ii ◽  
Vascular Effects ◽  
Pressor Responses ◽  
Radiometric Detection

We have previously demonstrated that the lipoxygenase (LO) pathway has a specific role in the effect of angiotensin II (ANG II) on aldosterone secretion. To elucidate whether the LO pathway also participates in the vascular effects of ANG II, the nonselective LO inhibitor phenidone (PHE; 30 mg/kg) was administered to rats 1 h before graded dose ANG II infusion. PHE reduced the LO product 12-hydroxyeicosatetraenoic acid (12-HETE) in deendothelialized aortas by an average of 36% as determined by radiometric detection with high-performance liquid chromatography and radioimmunoassay methods. In parallel, the peak systolic pressor response to ANG II was lowered from 36.2 +/- 3.7 to 16.8 +/- 2.0 mmHg. The peak pressor responses to ANG II were also reduced by two other LO inhibitors, baicalein (30 mg/kg) and esculetin (60 mg/kg) (13.9 +/- 2.4 and 22.1 +/- 4.7 mmHg, respectively; P less than 0.01 compared with control rats for both), but not by the cyclooxygenase inhibitor indomethacin. The LO inhibitors baicalein (7.5 X 10(-5) M) and PHE (10(-4) M) markedly attenuated the in vitro contractile response to ANG II of femoral artery rings. In contrast, neither the in vivo nor in vitro constrictor responses to norepinephrine were affected by baicalein. Thus lipoxygenase blockade induces a direct and selective inhibition of ANG II-induced vasoconstriction. The LO pathway may have an important role in mediating the pressor effect of ANG II.

Effects of NADPH oxidase inhibitors on hypoxic vasoconstriction in buffer-perfused rabbit lungs

1995 ◽  
Vol 268 (5) ◽  
pp. L747-L752 ◽  
Author(s):  
F. Grimminger ◽  
N. Weissmann ◽  
R. Spriestersbach ◽  
E. Becker ◽  
S. Rosseau ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Selective Inhibition ◽  
Ang Ii ◽  
Selective Blockade ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction ◽  
On Line ◽  
Test Specificity

The involvement of NADPH oxidase in hypoxic pulmonary vasoconstriction (HPV) was investigated in buffer-perfused rabbit lungs, employing the inhibitors diphenyleneiodonium (DPI) and apocynin. Responses to the vasoconstrictors U-46619 and angiotensin II (ANG II) were used to test specificity. Lung nitric oxide (NO) generation was assessed by on-line monitoring of NO exhalation (chemiluminescence), and the efficacy of DPI and apocynin on the NADPH oxidase-dependent O2- generation was quantified in alveolar macrophages by fluorescent-activated cell sorter technique. In a concentration range between 1 and 5 mM, apocynin inhibited macrophage respiratory burst and HPV but similarly suppressed U-46619-induced vasoconstrictor responses. DPI inhibited macrophage O2- generation in concentrations > or = 0.5 microM. At doses between 0.5 and 1.5 microM, DPI blocked lung NO generation, thereby increasing HPV. At higher doses (4 microM), in contrast, DPI fully blocked the hypoxia-induced pressor responses, whereas the vasoconstrictor responses to U-46619 and [Asn1, Val5] ANG II were not diminished. In the presence of NG-monomethyl-L-arginine, used to block lung NO generation throughout, DPI exhibited only the monophasic selective inhibition of HPV. We conclude that apocynin lacks specificity for HPV, but DPI, in addition to inhibiting lung NO generation, causes selective blockade of the hypoxia-induced vasoconstriction. This finding supports the hypothesis that an NADPH oxidase is involved in hypoxia sensing or specific signal transduction events underlying HPV.

Metabolic clearance of angiotensin II in pregnant and nonpregnant sheep

1985 ◽  
Vol 249 (1) ◽  
pp. E49-E55 ◽  
Author(s):  
R. P. Naden ◽  
S. Coultrup ◽  
B. S. Arant ◽  
C. R. Rosenfeld
Keyword(s):  
Angiotensin Ii ◽  
Pressor Response ◽  
Plasma Concentrations ◽  
Metabolic Clearance ◽  
Ang Ii ◽  
Pressor Responses ◽  
Pregnant Sheep ◽  
Vascular Responsiveness ◽  
Arterial Plasma ◽  
In Pregnancy

Reduced vascular responsiveness to infused angiotensin II (ANG II) has been observed during pregnancy. It has been proposed that infusions produce lower circulating concentrations of ANG II in pregnancy, due to an increase in the metabolic clearance rate of ANG II (MCRangii). We have evaluated the MCRangii and the arterial plasma concentrations of ANG II during constant infusions of 1.15 micrograms ANG II/min into chronically instrumented pregnant (n = 6) and nonpregnant (n = 9) sheep. Although the pressor responses were significantly less in the pregnant than in the nonpregnant sheep (17.5 +/- 0.5 vs. 34.9 +/- 3.2 mmHg, P less than 0.001), the values for MCRangii were not different: 56.2 +/- 6.3 ml X min-1 X kg-1 in nonpregnant and 55.9 +/- 4.3 ml X min-1 X kg-1 in pregnant sheep. The steady-state plasma ANG II concentrations during the infusions were slightly less in pregnant than in nonpregnant sheep (388 +/- 36 vs. 454 +/- 36 pg/ml); however, this difference would be responsible for only a 2-mmHg reduction in the pressor response. We conclude that the reduced pressor response to infused ANG II in pregnancy is not due to an increase in MCRangii nor to lower plasma ANG II concentrations.

Abstract 421: The Subfornical Organ (SFO) Mediates CSF Na+ -induced Pressor Response via Activation of AT1 Receptors

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Missale A Tiruneh ◽  
Bing S Huang ◽  
Frans H Leenen
Keyword(s):  
Crucial Role ◽  
Major Part ◽  
Wistar Rats ◽  
Pressor Response ◽  
Electrolytic Lesion ◽  
Induced Responses ◽  
Ang Ii ◽  
At1 Receptors ◽  
Pressor Responses ◽  
The Brain

In salt-sensitive rats on high salt or rats with icv infusion of Na + , the increase in CSF [Na + ] leads to activation of the brain renin-angiotensin-aldosterone system and thereby to sympatho-excitation and hypertension. We tested whether the SFO and AT 1 receptors in the SFO play a crucial role in mediating the Na + -induced responses. In conscious Wistar rats, intra-SFO infusion of Na + -rich aCSF increased BP in a dose-related manner, whereas mannitol with the same osmolarity had no effects. Intra-SFO infusion of the AT 1 receptor blocker candesartan (cand.,10 μg) abolished pressor responses to intra-SFO infusion of Ang II (80 ng) or Na + -rich aCSF (0.45-0.6 M NaCl), and prevented 50% of the BP increase induced by icv infusion of Na + -rich aCSF (0.3 M NaCl, 4 μl/min for 6 min). In another set of Wistar rats, electrolytic lesion of the SFO prevented 50-65% of BP increases induced by icv infusion of Na + -rich aCSF or Ang II (5 ng/min). These data suggest that the SFO neurons are Na + -sensitive and via AT 1 receptors mediate a major part of the pressor response to CSF Na + . Data=means±SE (n=5-7). *p<.05 vs vehicle or sham lesion.

Central effects of angiotensins I and II in conscious streptozotocin-treated rats

1990 ◽  
Vol 258 (5) ◽  
pp. R1147-R1156 ◽  
Author(s):  
K. C. Tomlinson ◽  
S. M. Gardiner ◽  
T. Bennett
Keyword(s):  
Pressor Response ◽  
Cardiovascular Responses ◽  
Brattleboro Rats ◽  
Ang Ii ◽  
Angiotensin I ◽  
Enhanced Sensitivity ◽  
Drinking Response ◽  
Pressor Responses ◽  
Long Evans ◽  
Residual Response

Responses to intracerebroventricular (icv) angiotensin II (ANG II) were measured in Long-Evans rats treated with the diabetogenic agent, streptozotocin (STZ), or saline 28 days earlier. STZ-treated Long-Evans rats showed normal pressor responses to ANG II in the absence of drinking water, but bradycardic responses were impaired although there was no reduction in baroreflex sensitivity. When allowed to drink, saline-treated, but not STZ-treated, rats showed an enhanced pressor response to icv ANG II and a tachycardia. Peripheral V1-receptor antagonism attenuated the pressor response to icv ANG II, leaving a residual response that was greater in saline-treated than in STZ-treated rats. STZ-treated rats had attenuated pressor and heart rate responses to icv angiotensin I (ANG I). Although some cardiovascular responses to icv ANG I and ANG II were reduced in STZ-treated rats, these animals showed enhanced sensitivity to the dipsogenic effects of the peptides. Vasopressin-deficient Brattleboro rats showed little pressor response to icv ANG II unless drinking was allowed, in which case the pressor response was less in STZ-treated than in saline-treated Brattleboro rats, although there was no difference in drinking response.

scholarly journals Evidence for a role of protein kinase C in hypoxic pulmonary vasoconstriction

1999 ◽  
Vol 276 (1) ◽  
pp. L90-L95 ◽  
Author(s):  
Norbert Weissmann ◽  
Robert Voswinckel ◽  
Thorsten Hardebusch ◽  
Simone Rosseau ◽  
Hossein Ardeschir Ghofrani ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nadph Oxidase ◽  
Superoxide Anion ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Ang Ii ◽  
Pkc Inhibitor ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation, thus optimizing gas exchange. NADPH oxidase-related superoxide anion generation has been suggested as part of the signaling response to hypoxia. Because protein kinase (PK) C activation can occur during hypoxia and PKC activation is known to be critical for NADPH oxidase stimulation in different cell types, we probed the role of PKC in hypoxic vasoconstriction in intact rabbit lungs. Control vasoconstrictor responses were elicited by angiotensin II (ANG II) and the stable thromboxane analog U-46619. Portions of the experiments were performed while NO synthesis and prostanoid generation were blocked with N G-monomethyl-l-arginine and acetylsalicylic acid to avoid confounding effects due to interference with these vasoactive mediators. The PKC inhibitor H-7 (10–50 μM) caused dose-dependent inhibition of HPV, but this agent lacked specificity because ANG II- and U-46619-induced vasoconstrictions were correspondingly suppressed. In contrast, low concentrations of the specific PKC inhibitor bisindolylmaleimide I (BIM; 1–15 μM) strongly inhibited the hypoxic vasoconstriction without any interference with the responses to the pharmacological agents. Superimposable dose-inhibition curves were also obtained for BIM when lung NO synthesis and prostanoid generation were blocked throughout the experiments. Under either condition, BIM did not affect normoxic vascular tone. The PKC activator farnesylthiotriazole (FTT), ascertained to stimulate rabbit NADPH oxidase by provocation of alveolar macrophage superoxide anion generation in vitro, caused rapid-onset, transient pressor responses in normoxic lungs. After FTT, the hypoxic vasoconstrictor response was totally suppressed, in contrast to the largely maintained pressor responses to ANG II and U-46619. The lungs became refractory even to delayed hypoxic challenges after FTT application. In conclusion, these data support the concept that activation of PKC is involved in the transduction pathway forwarding pulmonary vasoconstriction in response to alveolar hypoxia.

Interactions between nitroglycerin and endothelium in vascular smooth muscle relaxation

1991 ◽  
Vol 260 (3) ◽  
pp. H698-H701 ◽  
Author(s):  
J. L. Dinerman ◽  
D. L. Lawson ◽  
J. L. Mehta
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
No Production ◽  
Cyclic Monophosphate ◽  
The Mean ◽  
Smooth Muscle Relaxant ◽  
Vascular Smooth Muscle Relaxation

To evaluate the role of endothelium in nitroglycerin (NTG)-mediated vascular relaxation, epinephrine-contracted rat thoracic aortic segments with and without intact endothelium were exposed to NTG (10(-10) to 10(-5) M). Aortic segments with intact (endo+, n = 15) and denuded endothelium (endo-, n = 9) exhibited typical NTG-induced relaxation. However, the mean effective concentration of NTG was lower for endo- than for endo+ segments (P less than 0.001). To determine if this phenomenon related to nitric oxide (NO) generation by endothelium, six endo+ segments were treated with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO production. These endo+ segments exhibited greater (P less than 0.001) relaxation in response to NTG than the untreated endo+ segments. Oxyhemoglobin, an inhibitor of guanylate cyclase activation, greatly diminished NTG-mediated relaxation of all aortic segments. To determine if the enhanced NTG-mediated relaxation of endo- segments was unique to the guanosine 3',5'-cyclic monophosphate-dependent vasodilator NTG, other endo+ and endo- segments were exposed to adenosine 3',5'-cyclic monophosphate-dependent vasodilator papaverine (10(-8) to 10(-4) M), and no difference in EC50 was noted between endo+ and endo- segments. Thus endothelium attenuates NTG-mediated vasorelaxation, and this attenuation is abolished by inhibition of endothelial NO production with L-NMMA. These observations indicate that endothelium is a dynamic modulator of vascular smooth muscle relaxant effects of NTG. This modulation appears to result from a competitive interaction between endothelial NO and NTG.

Prostaglandin synthetase inhibitors do not decrease hypoxic pulmonary vasoconstriction

1976 ◽  
Vol 41 (5) ◽  
pp. 714-718 ◽  
Author(s):  
E. K. Weir ◽  
I. F. McMurtry ◽  
A. Tucker ◽  
J. T. Reeves ◽  
R. F. Grover
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Prostaglandin Synthesis ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction ◽  
Before And After ◽  
Anesthetized Dogs ◽  
Prostaglandin Antagonists ◽  
The Stability

Prostaglandins are naturally occurring substances with powerful vasoactive effects that are released from tissues during hypoxia or ischemia. Several workers have suggested that a prostaglandin may help to mediate the pulmonary vascular pressor response to alveolar hypoxia. To investigate this possibility, we have measured the pressor responses to hypoxia before and after prostaglandin synthesis antagonism with meclofenamate in eight anesthetized dogs, two groups of awake calves (n=10 and =5), and nine isolated, perfused rat lungs. In addition, synthesis was inhibited by the use of indomethacin in nine additional dogs. The stability of the pulmonary vascular response to repeated hypoxic challenges was demonstrated in nine other dogs. In each species and with both prostaglandin antagonists, the pulmonary pressorresponses to hypoxia were significantly increased rather than reduced. We conclude that prostaglandins do not mediate the pulmonary vasoconstriction caused by hypoxia. The consistent increase observed suggests that hypoxic vasoconstriction stimulates prostaglandin synthesis, the net effect of which is pulmonary vasodilatation which opposes the constriction.

Metabolic and respiratory hydrogen ion effects on hypoxic pulmonary vasoconstriction

1984 ◽  
Vol 57 (2) ◽  
pp. 545-550 ◽  
Author(s):  
C. Marshall ◽  
L. Lindgren ◽  
B. E. Marshall
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Respiratory Acidosis ◽  
Hydrogen Ion ◽  
Regression Equations ◽  
Rat Lung ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Ion Effects

Hypoxic pulmonary vasoconstriction (HPV) was studied in the ventilated-perfused rat lung in vitro. Respiratory acidosis and alkalosis were obtained by ventilating with 2, 7, or 10% CO2 (21% O2-balance N2). Metabolic acidosis and alkalosis were produced by the addition of 0.9 N NaHCO3 or 1 N lactic acid to the perfusate at constant PCO2. At each pH the pressor responses to 2 and 4% O2 were compared with the maximum pressor response (R%max) obtained with zero O2 and 5% CO2 at a normal pH (approximately 7.35). HPV was maximal when the [H+] was between 38 and 50 nM and was attenuated by changes of pH in either direction. Both respiratory and metabolic pH changes had similar effects. The combined linear regression equations were as follows: with 2% O2 the response to acidosis was R%max = 101.37 – 0.52 [H+] and to alkalosis was R%max = 2.03 [H+] - 3.85; with 4% O2 the response to acidosis was R%max = 56.88 – 0.3 [H+] and to alkalosis was R%max = 1.16 [H+] - 4.95. These effects were not due to changes of ionized calcium.

Plasma level, urinary excretion, and metabolic production of cGMP during gestation in rats

1989 ◽  
Vol 257 (4) ◽  
pp. R847-R853 ◽  
Author(s):  
K. P. Conrad ◽  
K. A. Vernier
Keyword(s):  
Plasma Level ◽  
Urinary Excretion ◽  
Muscle Relaxation ◽  
Late Pregnancy ◽  
Fractional Excretion ◽  
Significant Rise ◽  
Smooth Muscle Relaxation ◽  
Metabolic Clearance ◽  
Cyclic Monophosphate ◽  
The Face

We postulated that guanosine 3',5'-cyclic monophosphate (cGMP), a cellular mediator of vascular smooth muscle relaxation, might mediate maternal renal and cardiovascular hemodynamic adaptation to pregnancy. Because extracellular levels of cGMP most likely reflect intracellular production, we began our investigation of this hypothesis by measuring the plasma concentration, urinary excretion, and metabolic clearance rates of cGMP during pregnancy in rats. Plasma cGMP was significantly elevated during mid- and late pregnancy, whereas urinary excretion of cGMP was increased throughout pregnancy. The fractional excretion of cGMP by the kidneys was 0.90 +/- 0.15 in the nonpregnant condition. In contrast, plasma levels of adenosine 3',5'-cyclic monophosphate were unchanged during pregnancy, and its urinary excretion rose slightly, reaching significance only on gestational day 20. There was also a significant rise in urinary excretion of cGMP throughout pseudopregnancy. The metabolic clearance rate of cGMP measured in chronically instrumented rats before, during, and after pregnancy was not significantly altered during gestation. The elevated plasma level of cGMP during gestation in rats, in the face of an unchanged metabolic clearance, reflects augmented tissue(s) production of cGMP, although enhanced cellular efflux may contribute. Because cGMP is a second messenger for several vasodilatory hormones, our data are consistent with the hypothesis that vascular production of cGMP may increase during pregnancy and thereby contribute to maternal renal and cardiovascular vasodilation. (Most investigators have not observed increment of plasma atrial natriuretic peptide in rat gestation; therefore this hormone is an unlikely first messenger for the elevated extracellular levels of cGMP that we have observed. Finally, pseudopregnant rats also showed enhanced urinary excretion of cGMP, which suggests that the proliferative activity that accompanies fetoplacental maturation, as well as hormones elaborated by the fetoplacental unit, is not necessary for the rise in urinary excretion of cGMP observed during pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

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