Analysis of pulmonary vasodilator responses to the Rho-kinase inhibitor fasudil in the anesthetized rat

2008 ◽  
Vol 295 (5) ◽  
pp. L828-L836 ◽  
Author(s):  
Adeleke M. Badejo ◽  
Jasdeep S. Dhaliwal ◽  
David B. Casey ◽  
Thomas B. Gallen ◽  
Anthony J. Greco ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Systemic Arterial Pressure ◽  
Prior Exposure ◽  
Intravenous Injections ◽  
Pulmonary Vasodilator

The small GTP-binding protein Rho and its downstream effector, Rho-kinase, are important regulators of vasoconstrictor tone. Rho-kinase is upregulated in experimental models of pulmonary hypertension, and Rho-kinase inhibitors decrease pulmonary arterial pressure in rodents with monocrotaline and chronic hypoxia-induced pulmonary hypertension. However, less is known about responses to fasudil when pulmonary vascular resistance is elevated on an acute basis by vasoconstrictor agents and ventilatory hypoxia. In the present study, intravenous injections of fasudil reversed pulmonary hypertensive responses to intravenous infusion of the thromboxane receptor agonist, U-46619 and ventilation with a 10% O2 gas mixture and inhibited pulmonary vasoconstrictor responses to intravenous injections of angiotensin II, BAY K 8644, and U-46619 without prior exposure to agonists, which can upregulate Rho-kinase activity. The calcium channel blocker isradipine and fasudil had similar effects and in small doses had additive effects in blunting vasoconstrictor responses, suggesting parallel and series mechanisms in the lung. When pulmonary vascular resistance was increased with U-46619, fasudil produced similar decreases in pulmonary and systemic arterial pressure, whereas isradipine produced greater decreases in systemic arterial pressure. The hypoxic pressor response was enhanced by 5–10 mg/kg iv nitro-l-arginine methyl ester (l-NAME), and fasudil or isradipine reversed the pulmonary hypertensive response to hypoxia in control and in l-NAME-treated animals, suggesting that the response is mediated by Rho-kinase and L-type Ca2+ channels. These results suggest that Rho-kinase is constitutively active in regulating baseline tone and vasoconstrictor responses in the lung under physiological conditions and that Rho-kinase inhibition attenuates pulmonary vasoconstrictor responses to agents that act by different mechanisms without prior exposure to the agonist.

Rho kinase and Ca2+ entry mediate increased pulmonary and systemic vascular resistance in l-NAME-treated rats

2007 ◽  
Vol 293 (5) ◽  
pp. L1306-L1313 ◽  
Author(s):  
Jasdeep S. Dhaliwal ◽  
David B. Casey ◽  
Anthony J. Greco ◽  
Adeleke M. Badejo ◽  
Thomas B. Gallen ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Arterial Pressure ◽  
Systemic Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Arterial Pressure ◽  
Rho Kinase ◽  
Systemic Arterial Pressure ◽  
Intravenous Injections ◽  
Pulmonary Arterial ◽  
Dose Dependent

The small GTP-binding protein and its downstream effector Rho kinase play an important role in the regulation of vasoconstrictor tone. Rho kinase activation maintains increased pulmonary vascular tone and mediates the vasoconstrictor response to nitric oxide (NO) synthesis inhibition in chronically hypoxic rats and in the ovine fetal lung. However, the role of Rho kinase in mediating pulmonary vasoconstriction after NO synthesis inhibition has not been examined in the intact rat. To address this question, cardiovascular responses to the Rho kinase inhibitor fasudil were studied at baseline and after administration of an NO synthesis inhibitor. In the intact rat, intravenous injections of fasudil cause dose-dependent decreases in systemic arterial pressure, small decreases in pulmonary arterial pressure, and increases in cardiac output. l-NAME caused a significant increase in pulmonary and systemic arterial pressures and a decrease in cardiac output. The intravenous injections of fasudil after l-NAME caused dose-dependent decreases in pulmonary and systemic arterial pressure and increases in cardiac output, and the percent decreases in pulmonary arterial pressure in response to the lower doses of fasudil were greater than decreases in systemic arterial pressure. The Ca++ entry blocker isradipine also decreased pulmonary and systemic arterial pressure in l-NAME-treated rats. Infusion of sodium nitroprusside restored pulmonary arterial pressure to baseline values after administration of l-NAME. These data provide evidence in support of the hypothesis that increases in pulmonary and systemic vascular resistance following l-NAME treatment are mediated by Rho kinase and Ca++ entry through L-type channels, and that responses to l-NAME can be reversed by an NO donor.

Prostaglandin D2 inhibits hypoxic pulmonary vasoconstriction in neonatal lambs

1983 ◽  
Vol 54 (6) ◽  
pp. 1585-1589 ◽  
Author(s):  
J. B. Philips ◽  
R. K. Lyrene ◽  
M. McDevitt ◽  
W. Perlis ◽  
C. Satterwhite ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Inferior Vena ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Vena Cava ◽  
Systemic Arterial Pressure ◽  
Prostaglandin D2 ◽  
Pulmonary Vasoconstriction ◽  
Neonatal Lambs

Intrapulmonary injections of prostaglandin D2 (PGD2) reduce pulmonary arterial pressure and resistance in fetal and hypoxic neonatal lambs without affecting systemic arterial pressure. This apparently specific pulmonary effect of PGD2 could be explained by inactivation of the agent during passage through the pulmonary capillary bed. We therefore studied the effects of both pulmonary and systemic infusions of PGD2 on the acute vascular response to a 1-min episode of hypoxia in newborn lambs. Since PGD2 has been reported to be a pulmonary vasoconstrictor in normoxic lambs, we also evaluated its effects during normoxemia. Pulmonary vascular pressures were not affected by either 1- or 10-micrograms . kg-1 . min-1 infusions into the left atrium or inferior vena cava during normoxia. Infusion of 1 microgram . kg-1 . min-1 PGD2 into the inferior vena cava decreased pulmonary vascular resistance and increased systemic arterial pressure. These two parameters were unchanged with the other three infusion regimens. Mean pulmonary vascular resistance rose 83% with hypoxia and no PGD2. PGD2 prevented any change in pulmonary vascular resistance with hypoxia, while systemic arterial pressure increased (1-microgram . kg-1 . min-1 doses) or was unchanged. Thus PGD2 specifically prevents hypoxic pulmonary vasoconstriction while maintaining systemic pressures, regardless of infusion site. PGD2 may be indicated in treatment of persistent pulmonary hypertension of the newborn and other pulmonary hypertensive disorders.

Inhaled nitric oxide partially reverses hypoxic pulmonary vasoconstriction in the dog

1994 ◽  
Vol 76 (3) ◽  
pp. 1350-1355 ◽  
Author(s):  
J. A. Romand ◽  
M. R. Pinsky ◽  
L. Firestone ◽  
H. A. Zar ◽  
J. R. Lancaster
Keyword(s):  
Nitric Oxide ◽  
Arterial Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Canine Model ◽  
Systemic Arterial Pressure ◽  
Vasomotor Tone ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial

Nitric oxide (NO) inhaled during a hypoxia-induced increase in pulmonary vasomotor tone decreases pulmonary arterial pressure (Ppa). We conducted this study to better characterize the hemodynamic effects induced by NO inhalation during hypoxic pulmonary vasoconstriction in 11 anesthetized ventilated dogs. Arterial and venous systemic and pulmonary pressures and aortic flow probe-derived cardiac output were recorded, and nitrosylhemoglobin (NO-Hb) and methemoglobin (MetHb) were measured. The effects of 5 min of NO inhalation at 0, 17, 28, 47, and 0 ppm during hyperoxia (inspiratory fraction of O2 = 0.5) and hypoxia (inspiratory fraction of O2 = 0.16) were observed. NO inhalation has no measurable effects during hyperoxia. Hypoxia induced an increase in Ppa that reached plateau levels after 5 min. Exposure to 28 and 47 ppm NO induced an immediate (< 30 s) decrease in Ppa and calculated pulmonary vascular resistance (P < 0.05 each) but did not return either to baseline hyperoxic values. Increasing the concentration of NO to 74 and 145 ppm in two dogs during hypoxia did not induce any further decreases in Ppa. Reversing hypoxia while NO remained at 47 ppm further decreased Ppa and pulmonary vascular resistance to baseline values. NO inhalation did not induce decreases in systemic arterial pressure. MetHb remained low, and NO-Hb was unmeasurable. We concluded that NO inhalation only partially reversed hypoxia-induced increases in pulmonary vasomotor tone in this canine model. These effects are immediate and selective to the pulmonary circulation.

Reversal of reflex pulmonary vasoconstriction induced by main pulmonary arterial distension

1985 ◽  
Vol 58 (4) ◽  
pp. 1107-1114 ◽  
Author(s):  
C. E. Juratsch ◽  
R. F. Grover ◽  
C. E. Rose ◽  
J. T. Reeves ◽  
W. F. Walby ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arachidonic Acid ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Bolus Injection ◽  
Main Pulmonary Artery ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Vasodilator ◽  
Anesthetized Dogs ◽  
The Right

Distension of the main pulmonary artery (MPA) induces pulmonary hypertension, most probably by neurogenic reflex pulmonary vasoconstriction, although constriction of the pulmonary vessels has not actually been demonstrated. In previous studies in dogs with increased pulmonary vascular resistance produced by airway hypoxia, exogenous arachidonic acid has led to the production of pulmonary vasodilator prostaglandins. Hence, in the present study, we investigated the effect of arachidonic acid in seven intact anesthetized dogs after pulmonary vascular resistance was increased by MPA distention. After steady-state pulmonary hypertension was established, arachidonic acid (1.0 mg/min) was infused into the right ventricle for 16 min; 15–20 min later a 16-mg bolus of arachidonic acid was injected. MPA distension was maintained throughout the study. Although the infusion of arachidonic acid significantly lowered the elevated pulmonary vascular resistance induced by MPA distension, the pulmonary vascular resistance returned to control levels only after the bolus injection of arachidonic acid. Notably, the bolus injection caused a biphasic response which first increased the pulmonary vascular resistance transiently before lowering it to control levels. In dogs with resting levels of pulmonary vascular resistance, administration of arachidonic acid in the same manner did not alter the pulmonary vascular resistance. It is concluded that MPA distension does indeed cause reflex pulmonary vasoconstriction which can be reversed by vasodilator metabolites of arachidonic acid. Even though this reflex may help maintain high pulmonary vascular resistance in the fetus, its function in the adult is obscure.

Atrial natriuretic factor attenuates the pulmonary pressor response to hypoxia

1988 ◽  
Vol 65 (5) ◽  
pp. 1975-1983 ◽  
Author(s):  
S. Adnot ◽  
P. E. Chabrier ◽  
C. Brun-Buisson ◽  
I. Viossat ◽  
P. Braquet
Keyword(s):  
Arterial Pressure ◽  
Vascular Resistance ◽  
Atrial Natriuretic Factor ◽  
Pressor Response ◽  
Systemic Arterial Pressure ◽  
Pulmonary Hemodynamics ◽  
Natriuretic Factor ◽  
Pulmonary Vasodilator ◽  
Pulmonary Arterial ◽  
Atrial Natriuretic

The influence of endogenous and exogenous atrial natriuretic factor (ANF) on pulmonary hemodynamics was investigated in anesthetized pigs during both normoxia and hypoxia. Continuous hypoxic ventilation with 11% O2 was associated with a uniform but transient increase of plasma immunoreactive (ir) ANF that peaked at 15 min. Plasma irANF was inversely related to pulmonary arterial pressure (Ppa; r = -0.66, P less than 0.01) and pulmonary vascular resistance (PVR; r = -0.56, P less than 0.05) at 30 min of hypoxia in 14 animals; no such relationship was found during normoxia. ANF infusion after 60 min of hypoxia in seven pigs reduced the 156 +/- 20% increase in PVR to 124 +/- 18% (P less than 0.01) at 0.01 microgram.kg-1.min-1 and to 101 +/- 15% (P less than 0.001) at 0.05 microgram.kg-1.min-1. Cardiac output (CO) and systemic arterial pressure (Psa) remained unchanged, whereas mean Ppa decreased from 25.5 +/- 1.5 to 20.5 +/- 15 mmHg (P less than 0.001) and plasma irANF increased two- to nine-fold. ANF infused at 0.1 microgram.kg-1.min-1 (resulting in a 50-fold plasma irANF increase) decreased Psa (-14%) and reduced CO (-10%); systemic vascular resistance (SVR) was not changed, nor was a further decrease in PVR induced. No change in PVR or SVR occurred in normoxic animals at any ANF infusion rate. These results suggest that ANF may act as an endogenous pulmonary vasodilator that could modulate the pulmonary pressor response to hypoxia.

scholarly journals Analysis of responses to the Rho-kinase inhibitor Y-27632 in the pulmonary and systemic vascular bed of the rat

2010 ◽  
Vol 299 (1) ◽  
pp. H184-H192 ◽  
Author(s):  
David B. Casey ◽  
Adeleke M. Badejo ◽  
Jasdeep S. Dhaliwal ◽  
James L. Sikora ◽  
Alex Fokin ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Guanylate Cyclase ◽  
Kinase Inhibitor ◽  
Pulmonary Arterial Pressure ◽  
Rho Kinase ◽  
Hypoxic Exposure ◽  
Intravenous Injections ◽  
Vasoconstrictor Response ◽  
Rho Kinase Inhibitor ◽  
Pulmonary Arterial

Responses to the Rho kinase inhibitor Y-27632 were investigated in the anesthetized rat. Under baseline conditions intravenous injections of Y-27632 decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressures were enhanced when baseline tone was increased with U-46619, and under elevated tone conditions Y-27632 produced similar percent decreases in pulmonary and systemic arterial pressures. Injections of Y-27632 prevented and reversed the hypoxic pulmonary vasoconstrictor response. The increase in pulmonary arterial pressure in response to ventilation with a 10% O2-90% N2 gas mixture was not well maintained during the period of hypoxic exposure. Treatment with the nitric oxide (NO) synthase (NOS) inhibitor nitro-l-arginine methyl ester (l-NAME) increased pulmonary arterial pressure and prevented the decline or fade in the hypoxic pulmonary vasoconstrictor response. The hypoxic pulmonary vasoconstrictor response was reversed by Y-27632 in control and in l-NAME-treated animals. The Rho kinase inhibitor attenuated increases in pulmonary arterial pressures in response to intravenous injections of serotonin, angiotensin II, and Bay K 8644. Y-27632, sodium nitrite, and BAY 41-8543, a guanylate cyclase stimulator, decreased pulmonary and systemic arterial pressures and vascular resistances in monocrotaline-treated rats. These data suggest that Rho kinase is involved in the regulation of baseline tone and in the mediation of pulmonary vasoconstrictor responses. The present data suggest that the hypoxic pulmonary vasoconstrictor response is modulated by the release of NO that mediates the nonsustained component of the response in the anesthetized rat. These data suggest that Rho kinase and NOS play important roles in the regulation of vasoconstrictor tone in physiological and pathophysiological states and that monocrotaline-induced pulmonary hypertension can be reversed by agents that inhibit Rho kinase, generate NO, or stimulate soluble guanylate cyclase.

The Rho kinase inhibitor azaindole-1 has long-acting vasodilator activity in the pulmonary vascular bed of the intact chest rat

2012 ◽  
Vol 90 (7) ◽  
pp. 825-835 ◽  
Author(s):  
Edward A. Pankey ◽  
Ryuk J. Byun ◽  
William B. Smith ◽  
Manish Bhartiya ◽  
Franklin R. Bueno ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Kinase Inhibitor ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Rho Kinase ◽  
Rock Inhibitor ◽  
Vasodilator Activity ◽  
Pulmonary Arterial ◽  
Vascular Beds

Responses to a selective azaindole-based Rho kinase (ROCK) inhibitor (azaindole-1) were investigated in the rat. Intravenous injections of azaindole-1 (10–300 µg/kg), produced small decreases in pulmonary arterial pressure and larger decreases in systemic arterial pressure without changing cardiac output. Responses to azaindole-1 were slow in onset and long in duration. When baseline pulmonary vascular tone was increased with U46619 or L-NAME, the decreases in pulmonary arterial pressure in response to the ROCK inhibitor were increased. The ROCK inhibitor attenuated the increase in pulmonary arterial pressure in response to ventilatory hypoxia. Azaindole-1 decreased pulmonary and systemic arterial pressures in rats with monocrotaline-induced pulmonary hypertension. These results show that azaindole-1 has significant vasodilator activity in the pulmonary and systemic vascular beds and that responses are larger, slower in onset, and longer in duration when compared with the prototypical agent fasudil. Azaindole-1 reversed hypoxic pulmonary vasoconstriction and decreased pulmonary and systemic arterial pressures in a similar manner in rats with monocrotaline-induced pulmonary hypertension. These data suggest that ROCK is involved in regulating baseline tone in the pulmonary and systemic vascular beds, and that ROCK inhibition will promote vasodilation when tone is increased by diverse stimuli including treatment with monocrotaline.

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