Left Pulmonary Vascular Pressure-flow Research Articles

Effects of halothane and enflurane anesthesia on sympathetic beta-adrenoreceptor-mediated pulmonary vasodilation in chronically instrumented dogs.

The authors previously reported that the pulmonary vasodilator response to the sympathetic beta-adrenoreceptor agonist isoproterenol is potentiated during isoflurane anesthesia compared with the conscious state. In the present in vivo study, the authors tested the hypothesis that halothane and enflurane anesthesia also enhance sympathetic beta adrenoreceptor-mediated pulmonary vasodilation. The authors also used the membrane-permeable analog of cyclic adenosine monophosphate (cAMP), dibutyryl cAMP, to help delineate the site in the signaling pathway for an anesthesia-induced effect on beta adrenoreceptor-mediated pulmonary vasodilation. Mongrel dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LPQ) relationship. LPQ plots were measured on separate days in the conscious, halothane-, and enflurane-anesthetized states at baseline, after preconstriction with the thromboxane analog U46619, and during the cumulative intravenous administration of isoproterenol. LPQ plots were also measured in conscious, halothane-, and isoflurane-anesthetized dogs after U46619 preconstriction and during the cumulative intravenous administration of dibutyryl cAMP. Compared with the conscious state, neither halothane nor enflurane had an effect on the baseline LPQ relationship. The magnitude of the pulmonary vasodilator response to isoproterenol was potentiated during halothane anesthesia but unchanged during enflurane anesthesia. The pulmonary vasodilator response to dibutyryl cAMP was not altered during either halothane or isoflurane anesthesia compared with the conscious state. These results indicate that inhalational anesthetic agents can exert differential effects on the pulmonary vasodilator response to sympathetic beta-adrenoreceptor activation. The potentiated vasodilator response observed during halothane and isoflurane anesthesia is the result of effects proximal to cAMP accumulation in the beta-adrenoreceptor signaling pathway.

Pulmonary vascular effects of propofol at baseline, during elevated vasomotor tone, and in response to sympathetic alpha- and beta-adrenoreceptor activation.

This in vivo study had two primary objectives. The first goal was to determine whether the pulmonary vascular effects of propofol depend on the preexisting level of vasomotor tone, and the second was to investigate the effects of propofol on the pulmonary vascular responses to sympathetic alpha- and beta-adrenoreceptor activation. Thirty-one mongrel dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LPQ) relation. Left lung autotransplantation (LLA) was also performed in eight additional dogs to induce a long-term increase in pulmonary vascular resistance. LPQ plots were measured on separate days in the conscious state and during propofol anesthesia. LPQ plots were measured at baseline and when vasomotor tone was acutely increased with the alpha agonist, phenylephrine, or the thromboxane mimetic, U46619. In separate experiments, cumulative dose-response curves to alpha- (phenylephrine) and beta- (isoproterenol) adrenoreceptor agonists were generated in conscious and propofol-anesthetized dogs. Compared with the conscious state, propofol had no effect on the baseline LPQ relation in normal or post-LLA dogs. However, propofol caused pulmonary vasoconstriction (P < 0.05) when vasomotor tone was acutely increased with either phenylephrine or U46619 in normal or post-LLA dogs. The pulmonary vasoconstrictor response to alpha-adrenoreceptor activation was potentiated (P < 0.05) during propofol anesthesia, whereas the pulmonary vasodilator response to beta-adrenoreceptor activation was not altered. These results indicate that the pulmonary vascular response to propofol anesthesia is tone-dependent. During sympathetic activation, propofol may favor alpha-adrenoreceptor-mediated vasoconstriction over beta-adrenoreceptor-mediated vasodilation.

Pulmonary vasoregulation by endothelin in conscious dogs after left lung transplantation.

We tested the hypothesis that regulation of the pulmonary circulation by endogenous endothelin (ET) during normoxia and hypoxia was altered in conscious dogs 1 mo after left lung autotransplantation (LLA). Sham-operated control and post-LLA dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LP-Q) relationship. LP-Q plots were generated on separate days during normoxia and hypoxia (arterial PO(2) approximately 50 Torr) in the intact condition, after selective ET(A)-receptor inhibition (BQ-485), and after combined ET(A+B)-receptor inhibition (bosentan). Although LLA resulted in a chronic increase in pulmonary vascular resistance, the ET-receptor antagonists had no effect on the LP-Q relationship during normoxia in either group. The magnitude of hypoxic pulmonary vasoconstriction (HPV) was flow dependent in both groups, and the HPV response was potentiated post-LLA compared with control. ET(A)-receptor inhibition attenuated the HPV response to the same extent in both groups. ET(A+B)-receptor inhibition attenuated the HPV response to a greater extent than did ET(A)-receptor inhibition alone, and this effect was greater post-LLA compared with control. Plasma ET-1 concentration only increased during hypoxia in the LLA group. These results indicate that ET does not regulate the baseline LP-Q relationship in either group. Both ET(A)- and ET(B)-receptor activation mediate a component of HPV in conscious dogs, and the vasoconstrictor influence of ET(B)-receptor activation is enhanced post-LLA.

PROPOFOL ANESTHESIA RESULTS IN PROFOUND PULMONARY VASOCONSTRICTION IN CHRONICALLY-INSTRUMENTED DOGS FOLLOWING LEFT LUNG AUTOTRANSPLANTATION

S546 Introduction: Left lung autotransplantation (LLA) results in a chronic increase in pulmonary vascular resistance. [1] The effects of propofol anesthesia on the pulmonary circulation are controversial. In normal dogs, propofol can induce profound pulmonary vasoconstriction in the setting of acutely elevated vasomotor tone. [2] In this study, we investigated the effects of propofol anesthesia on the left pulmonary vascular pressure-flow (LPQ) relationship in chronically-instrumented dogs with elevated vasomotor tone resulting from LLA. Methods: We utilized 8 dogs that had undergone LLA 3 to 7 weeks earlier. LPQ plots were generated by continuously measuring the pulmonary vascular pressure gradient (PAP-LAP) and left pulmonary flow (LQ) during gradual ([similar]1 min) inflation of a hydraulic occuder implanted around the right pulmonary artery. In protocol 1, LPQ plots were measured in the conscious state and during the cumulative intravenous administration of propofol anesthesia (5 mg/kg bolus plus 0.25, 0.5, 1.0 mg[center dot]kg-1 [center dot]min-1 maintenance dose). In protocol 2, LPQ plots were obtained in the conscious state, following preconstriction with the thromboxane analog, U46619 ([similar]0.2 [micro sign]g[center dot]kg-1 [center dot]min-1, iv), to acutely increase pulmonary vasomotor tone, and during propofol anesthesia as described in protocol 1. Two-way ANOVA was used to assess the effects of propofol on the LPQ relationship. Values are means +/- SEM. Results: LLA resulted in a chronic increase (p < 0.01) in pulmonary vascular resistance. Compared to the conscious state, propofol anesthesia had no effect on the baseline LPQ relationship post-LLA (Figure 1). In contrast, when pulmonary vasomotor tone was acutely increased (p < 0.01) with U46619, propofol resulted in marked dose-dependent pulmonary vasoconstriction (Figure 1).Figure 1Discussion: Despite the chronic increase in pulmonary vasomotor tone post-LLA, propofol did not exert a vasodilator influence on the baseline pulmonary circulation post-LLA. However, in the setting of acutely elevated vasomotor tone, propofol induced profound dose-dependent pulmonary vasoconstriction post-LLA.

Selective endothelial dysfunction in conscious dogs after cardiopulmonary bypass.

It has previously been demonstrated that cardiopulmonary bypass (CPB) causes prolonged pulmonary vascular hyperreactivity (D.P. Nyhan, J.M. Redmond, A.M. Gillinov, K. Nishiwaki, and P.A. Murray. J. Appl. Physiol. 77: 1584-1590, 1994). This study investigated the effects of CPB on endothelium-dependent (acetylcholine and bradykinin) and endothelium-independent (sodium nitroprusside) pulmonary vasodilation in conscious dogs. Continuous left pulmonary vascular pressure-flow (LP-Q) plots were generated in conscious dogs before CPB and again in the same animals 3-4 days post-CPB. The dose of U-46619 used to acutely preconstrict the pulmonary circulation to similar levels pre- and post-CPB was decreased (0.13 +/- 0.01 vs. 0.10 +/- 0.01 mg.kg-1.min-1, P < 0.01) after CPB. Acetylcholine, bradykinin, and sodium nitroprusside all caused dose-dependent pulmonary vasodilation pre-CPB. The pulmonary vasodilator response to acetylcholine was completely abolished post-CPB. For example, at left pulmonary blood flow of 80 ml.kg-1.min-1 acetylcholine (10 micrograms.kg-1.min-1) resulted in 72 +/- 15% reversal (P < 0.01) of U-46619 preconstriction pre-CPB but caused no change post-CPB. However, the responses to bradykinin and sodium nitroprusside were unchanged post-CPB. The impaired pulmonary vasodilator response to acetylcholine, but not to bradykinin, suggests a selective endothelial defect post-CPB. The normal response to sodium nitroprusside indicates that cGMP-mediated vasodilation is unchanged post-CPB.

Halothane and Enflurane Attenuate Pulmonary Vasodilation Mediated by Adenosine Triphosphate-sensitive Potassium Channels Compared to the Conscious State

Adenosine triphosphate (ATP)-sensitive potassium (k+ATP) channels play an important role in pulmonary vasoregulation. However, the effects of volatile anesthetics on k+ATP channel-mediated pulmonary vasoregulation have not been elucidated. The purpose of the present study was to investigate the effects of halothane and enflurane anesthesia on the pulmonary vasodilator response to the selective k+ATP channel agonist lemakalim (BRJ38227) compared with that measured in the conscious state. The authors also investigated the extent to which endogenous neurohumoral vasoconstrictor mechanisms modulate the vasodilator response to k+ATP channel activation. Nineteen conditioned, male mongrel dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LPQ) relationship. LPQ plots were generated by continuously measuring the pulmonary vascular pressure gradient (pulmonary arterial pressure-left atrial pressure) and left pulmonary blood flow during gradula (approximately 1 min) inflation of a hydraulic occluder implanted around the right main pulmonary artery. After preconstriction with the thromboxane analog, U46619 (9,11-dideoxy-11 alpha, 9 alpha-epoxymethano-prostaglandin F2 alpha), the pulmonary vascular dose-response relationship for the k+ATP agonist lemakalim was assessed in the conscious and halothane-anesthetized states and also in the conscious and enflurane-anesthetized states. This protocol was repeated in conscious and halothane-anesthetized dogs after combined neurohumoral block with antagonists of sympathetic alpha 1 adrenoreceptors, arginine vasopressin V1-receptors, and angiotensin II receptors. The effect of the k+ATP antagonist glybenclamide on the baseline LPQ relationship and on the lemakalim dose-response relationship also was assessed in conscious dogs. Compared with the conscious state, halothane, enflurane and glybenclamide had no net effect on the baseline LPQ relationship. In contrast, halothane and enflurane attenuated (P < 0.05) the pulmonary vasodilator response to lemakalim compared with the conscious state. Glybenclamide also caused a rightward shift (P < 0.05) in the lemakalim dose-response relationship. Combined neurohumoral block did not modulate the vasodilator response to lemakalim in the conscious state. The halothane-induced attenuation of the vasodilator response to lemakalim was apparent after combined neurohumoral block. These results indicate that halothane and enflurane act to reduce the magnitude of K+ATP channel-mediated pulmonary vasodilation. Reflex pulmonary vasoconstriction resulting from K+ATP mediated systematic hypotension does not alter the magnitude of the pulmonary vasodilator response to lemakalim nor is it responsible for the attenuated response to K+ATP channel activation during halothane anesthesia.

Endothelium-dependent pulmonary vasodilation is selectively attenuated during isoflurane anesthesia.

We have recently reported that halothane (Hal) anesthesia attenuates the pulmonary vasodilator responses to both bradykinin (BK) and sodium nitroprusside (SNP) compared with responses measured in the conscious state. These agonists have been classically used to activate endothelium-dependent and -independent vasodilator pathways, respectively. Our present goal was to assess the effect of isoflurane (Iso) anesthesia on pulmonary vasodilation activated via these pathways. Left pulmonary vascular pressure-flow (P-Q) plots were used to measure the pulmonary vascular responses to cumulative intravenous doses of BK, SNP, and 3-morpholinosydonimine-N-ethylcarbamide (SIN-1), a nitric oxide donor, in chronically instrumented dogs in the conscious state and during Iso anesthesia after matched preconstriction with the thromboxane analogue U-46619. Iso attenuated the vasodilator response to BK (P < 0.05). However, Iso had a differential effect on the responses to SIN-1 and SNP. Iso potentiated the vasodilator response to SIN-1 (P < 0.05), whereas Iso attenuated the response to SNP (P < 0.05). The vasodilator response to SIN-1 was unchanged during Hal anesthesia. The ATP-sensitive potassium (KATP)-channel inhibitor glibenclamide attenuated the vasodilator response to SNP (P < 0.05) but not to SIN-1. Thus Iso and Hal selectively attenuate the endothelium-dependent pulmonary vasodilator response to BK. Both anesthetics attenuate vasodilation induced by SNP but not by SIN-1. Moreover, a component of SNP-induced vasodilation involves KATP-channel activation.

Pulmonary vascular effects of isoflurane anesthesia after left lung autotransplantation in chronically instrumented dogs.

Single lung transplantation has become a viable therapy for treatment of end-stage pulmonary disease. We previously observed that left lung autotransplantation (LLA) results in a chronic increase in pulmonary vascular resistance and enhanced pulmonary vascular reactivity to sympathetic alpha adrenoreceptor activation. The effects of inhalational anesthetics on the pulmonary circulation after lung transplantation have not been investigated. In the current study, the authors tested the hypothesis that isoflurane anesthesia, known to cause systemic vasodilation, would exert a vasodilator influence on the baseline pulmonary circulation after LLA. In addition, they tested the hypothesis that isoflurane anesthesia, known to attenuate the systemic vasoconstrictor response to sympathetic alpha adrenoreceptor agonists, would reduce the magnitude of the pulmonary vasoconstrictor response to sympathetic alpha adrenoreceptor activation after LLA. Left pulmonary vascular pressure-flow (LPQ) plots were generated in chronically instrumented dogs by measuring the pulmonary vascular pressure gradient (pulmonary arterial pressure-left atrial pressure) and left pulmonary blood flow during inflation of a hydraulic occluder implanted around the right main pulmonary artery. Left pulmonary vascular pressure-flow plots were generated in 8 dogs 2-5 weeks after LLA in the conscious and isoflurane-anesthetized states at baseline, after beta adrenoreceptor block with propranolol, and during the cumulative administration of the alpha agonist, phenylephrine. Left pulmonary vascular pressure-flow plots also were generated in eight conscious, sham-operated control dogs at baseline, after beta block, and during phenylephrine administration. Compared with conscious control dogs, LLA resulted in a leftward shift (P < 0.01) in the baseline left pulmonary vascular pressure-flow relation, indicating chronic pulmonary vasoconstriction. Despite the enhanced level of pulmonary vasomotor tone after LLA, isoflurane did not exert a vasodilator influence on the baseline left pulmonary vascular pressure-flow relation. The pulmonary vasoconstrictor response to phenylephrine was enhanced (P < 0.01) after LLA compared with the response measured in conscious control dogs. The magnitude of the pulmonary vasoconstrictor response to phenylephrine after LLA was not attenuated during isoflurane anesthesia. Isoflurane anesthesia does not exert a vasodilator influence on the pulmonary circulation in the setting of increased pulmonary vascular resistance after LLA. In addition, in contrast to previous studies of the systemic circulation, isoflurane does not attenuate the enhanced pulmonary vasoconstrictor response to sympathetic alpha adrenoreceptor activation after LLA.

Isoflurane and the pulmonary vascular pressure-flow relation at baseline and during sympathetic alpha- and beta-adrenoreceptor activation in chronically instrumented dogs.

The extent to which isoflurane anesthesia alters systemic vascular regulation has received considerable attention. In contrast, the pulmonary vascular effects of isoflurane have not been elucidated. Our initial objective was to investigate the net effect of isoflurane on the baseline left pulmonary vascular pressure-flow (LPQ) relation compared with values measured in the conscious state. In addition, we assessed the extent to which isoflurane alters the pulmonary vascular responses to sympathetic alpha- and beta-adrenoreceptor activation. Twelve conditioned mongrel dogs were chronically instrumented to measure the LPQ relation. LPQ plots were generated by continuously measuring the pulmonary vascular pressure gradient (pulmonary arterial pressure--left atrial pressure) and left pulmonary blood flow during gradual (approximately 1 min) inflation of a hydraulic occluder implanted around the right main pulmonary artery. LPQ plots were generated at baseline in the conscious and isoflurane-anesthetized states (n = 12). The pulmonary vascular dose-response relation to the sympathetic alpha-adrenoreceptor agonist phenylephrine also was investigated in conscious and isoflurane-anesthetized dogs (n = 6). Finally, after preconstriction with the thromboxane analogue U46619, the dose-response relation to the sympathetic beta-adrenoreceptor agonist isoproterenol was assessed in the conscious and isoflurane-anesthetized states (n = 8). Compared with values measured in the conscious state, isoflurane anesthesia had no net effect on the baseline LPQ relation. The magnitude of the pulmonary vasoconstrictor response to phenylephrine observed in conscious dogs was not altered during isoflurane anesthesia. In contrast, the pulmonary vasodilator response to isoproterenol was markedly potentiated (P < 0.01) during isoflurane anesthesia compared with that in the conscious state. These results indicate that isoflurane does not exert a net vasodilator influence on the pulmonary circulation at baseline. In contrast to the systemic circulation, the pulmonary vasoconstrictor response to sympathetic alpha-adrenoreceptor activation is maintained during isoflurane anesthesia. Surprisingly, the pulmonary vasodilator response to sympathetic beta-adrenoreceptor activation is actually potentiated during isoflurane. Thus, isoflurane anesthesia has differential effects on the canine pulmonary vascular responses to sympathetic alpha- and beta-adrenoreceptor activation.

Pulmonary Vasoregulation by Arginine Vasopressin in Conscious, Halothane-anesthetized, and Pentobarbital-anesthetized Dogs with Increased Vasomotor Tone

Arginine vasopressin (AVP) is an important "stress" hormone that is known to play a key role in cardiovascular homeostasis of the systemic circulation. In contrast, the effects of AVP on the pulmonary circulation have not been extensively investigated, and the extent to which general anesthesia alters the pulmonary vascular response to AVP is entirely unknown. Our first objective was to assess the effects of AVP on the pulmonary vascular pressure-flow relation in chronically instrumented conscious dogs in the setting of an acute elevation in pulmonary vasomotor tone. Our second objective was to investigate the effects of halothane and pentobarbital anesthesia on the pulmonary vascular response to AVP after inducing the same degree of pulmonary preconstriction achieved in the conscious state. Conditioned, mongrel dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LPQ) relation. LPQ plots were generated by continuously measuring the pulmonary vascular pressure gradient (pulmonary arterial pressure minus left atrial pressure) and left pulmonary blood flow during gradual (approximately 1 min) inflation of a hydraulic occluder around the right pulmonary artery, which directed total pulmonary blood flow through the left pulmonary circulation. LPQ plots were generated in conscious (n = 10), halothane-anesthetized (n = 9) and pentobarbital-anesthetized (n = 7) dogs. In each condition, LPQ plots were measured at baseline, during the intravenous administration of the thromboxane analog U46619 and during the cumulative administration of AVP (2-19 ng.kg-1.min-1, intravenous) in the presence of U46619 preconstriction. U46619 caused acute pulmonary vasoconstriction (P < 0.01) in conscious dogs. In this setting of U46619 preconstriction, AVP caused pulmonary vasodilation (P < 0.05) in the conscious state. In contrast, despite identical levels of U46619 preconstriction, the pulmonary vasodilator response to AVP was either reversed to vasoconstriction (P < 0.05) or abolished during halothane and pentobarbital anesthesia. These results indicate that AVP exerts a significant pulmonary vasodilator response in the setting of acute pulmonary vasoconstriction in conscious dogs. However, the pulmonary vascular response to this stress hormone is markedly altered during halothane and pentobarbital anesthesia.

Humoral pulmonary vasoregulation in conscious dogs after left lung autotransplantation.

We investigated the roles of cyclooxygenase metabolites, arginine vasopressin (AVP) and angiotensin II (ANG II), as mediators of the chronic increase in pulmonary vascular resistance associated with left lung autotransplantation (LLA) in conscious dogs. Continuous left pulmonary vascular pressure-flow (LP-Q) plots were generated in conscious dogs 2- to 5-wk post-LLA and in sham-operated control conscious dogs. LLA resulted in a marked shift (P < 0.01) in the LP-Q relationship as reflected by an approximate doubling of the pulmonary vascular pressure gradient at each common value of left pulmonary blood flow compared with the control group. Cyclooxygenase pathway inhibition (indomethacin) and AVP V1-receptor block had no effect on the LP-Q relationship post-LLA. Angiotensin-converting enzyme inhibition (captopril) also failed to reverse the increase in pulmonary vascular resistance post-LLA. Because captopril has the dual effect of inhibiting the production of ANG II and the degradation of bradykinin, additional studies utilizing a selective ANG II receptor antagonist were performed. ANG II receptor block (saralasin) significantly altered the LP-Q relationship post-LLA to cause active pulmonary vasodilation (P < 0.01). Thus, the chronic increase in pulmonary vascular resistance post-LLA is not mediated by metabolites of the cyclooxygenase pathway or AVP V1-receptor activation. A significant component of the increase in pulmonary vascular resistance resulting from LLA is mediated by ANG II. The differential responses to captopril and saralasin may imply a pulmonary vasoregulatory role for bradykinin post-LLA.

Pulmonary vascular beta-adrenoreceptor activity in conscious dogs after left lung autotransplantation

Our objective was to determine whether chronic denervation associated with left lung autotransplantation (LLA) results in an alteration in sympathetic beta-adrenoreceptor regulation of the pulmonary circulation in conscious dogs. Continuous left pulmonary vascular pressure-flow (LPQ) plots were generated in conscious dogs 2-4 wk post-LLA and in sham-operated control conscious dogs. We tested the hypothesis that endogenous sympathetic beta-adrenoreceptor activation via circulating catecholamines acted to attenuate the chronic increase in pulmonary vascular resistance post-LLA. Administration of the sympathetic beta-adrenoreceptor antagonist propranolol had no significant effect on the LPQ relationship post-LLA. We also tested the hypothesis that pulmonary vascular reactivity to sympathetic beta-adrenoreceptor activation would be increased post-LLA. The thromboxane analogue U-46619 was used to acutely preconstrict (P < 0.01) the pulmonary circulation in control dogs; this preconstriction shifted the LPQ relationship to the same position measured post-LLA. Under these conditions, cumulative doses of the beta-adrenoreceptor agonist isoproterenol caused pulmonary vasodilation (P < 0.01) in the control group but had no effect post-LLA. However, after acute preconstriction with U-46619, the pulmonary vasodilator response (P < 0.01) to isoproterenol post-LLA was not significantly different from that in the control group. These differential responses to isoproterenol with and without acute preconstriction indicate that a significant component of the chronic increase in pulmonary vascular resistance post-LLA is mediated by passive nonvasoactive mechanisms. Moreover, sympathetic beta-adrenoreceptor reactivity of the pulmonary circulation is not enhanced by chronic denervation resulting from the LLA procedure.

Amrinone and the Pulmonary Vascular Pressure–Flow Relationship in Conscious Control Dogs and Following Left Lung Autotransplantation

Amrinone, a bipyridine compound, is known to improve left ventricular function via its positive inotropic and afterload-reducing effects. The goal of this study was to assess the efficacy of amrinone as a pulmonary vasodilator, an effect that could be beneficial in the setting of right heart failure associated with pulmonary hypertension. Investigated were the effects of intravenous amrinone (750 micrograms/kg loading dose plus 1-20 micrograms.kg-1.min-1 maintenance dose) on the left pulmonary vascular pressure-flow (LPQ) relationship in chronically instrumented, conscious dogs. The effects of amrinone on the LPQ relationship were assessed in a series of conscious control dogs with (n = 10) and without (n = 9) acute preconstriction with the thromboxane analog U46619 and in a series of conscious dogs 2-4 weeks after left lung autotransplantation (LLA) with (n = 8) and without (n = 8) acute U46619 preconstriction. Left pulmonary vascular pressure-flow plots were generated by continuously measuring the pulmonary vascular pressure gradient (pulmonary arterial pressure/left atrial pressure [PAP/LAP]) and left pulmonary blood flow during gradual (approximately 1 min) inflation of a hydraulic occluder implanted around the right pulmonary artery. Amrinone had no effect on the baseline LPQ relationship in control dogs. U46619 caused acute pulmonary vasoconstriction. For example, PAP/LAP at left pulmonary blood flow of 70 ml.min-1.kg-1 was increased (P < 0.01) from 16 +/- 2 to 37 +/- 2 mmHg during U46619 administration. In this setting of acute preconstriction, amrinone caused pulmonary vasodilation, i.e., PAP/LAP was decreased (P < 0.05) from 37 +/- 2 to 32 +/- 2 mmHg. Left lung autotransplantation was associated with a marked shift in the LPQ relationship, indicating a chronic increase in pulmonary vascular resistance, i.e., PAP/LAP was increased (P < 0.01) from 15 +/- 2 to 32 +/- 3 mmHg. Despite the chronic increase in pulmonary vascular resistance after LLA, amrinone had no effect on the baseline LPQ relationship. However, after acute preconstriction with U46619 after LLA, amrinone caused pulmonary vasodilation, i.e., PAP/LAP was decreased (P < 0.05) from 45 +/- 4 to 39 +/- 4 mmHg. These results indicate that amrinone exerts a significant, although relatively modest pulmonary vasodilator influence in the setting of acute pulmonary vasoconstriction in conscious control dogs and in conscious dogs after LLA. However, amrinone did not reverse the chronic increase in pulmonary vascular resistance associated with LLA.

Abnormal responses to pulmonary vasodilators in conscious dogs after left lung autotransplantation.

We investigated the extent to which left lung autotransplantation (LLA) alters endothelium-dependent (bradykinin and acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilation in the pulmonary circulation of conscious dogs. Continuous left pulmonary vascular pressure-flow (LPQ) plots were generated in conscious dogs 3-4 wk post-LLA and in sham-operated controls. LLA resulted in a marked upward shift in the baseline LPQ relationship compared with the control group (P < 0.01), i.e., LLA caused a chronic increase in pulmonary vascular resistance. The thromboxane analogue, U-46619, was used to acutely preconstrict the pulmonary circulation in control dogs, which shifted the control LPQ relationship to the same position measured post-LLA. Under these circumstances, bradykinin, acetylcholine, and nitroprusside caused pulmonary vasodilation in the control group, whereas these responses were either attenuated or reversed to vasoconstriction post-LLA. After acute preconstriction with U-46619 post-LLA, the pulmonary vasodilator responses to bradykinin and acetylcholine were again attenuated, but the response to nitroprusside was unaltered compared with control. These results indicate that a significant component of the chronic increase in pulmonary vascular resistance post-LLA is passively mediated and does not reflect an active increase in baseline vasomotor tone. Moreover, LLA results in an impairment in endothelium-dependent, but not endothelium-independent, pulmonary vasodilation in conscious dogs.

Acute and chronic pulmonary vasoconstriction after left lung autotransplantation in conscious dogs.

We investigated the acute and chronic effects of left lung autotransplantation (LLA) on the left pulmonary vascular pressure-flow (LP/Q) relationship in conscious dogs. Continuous LP/Q plots were generated in chronically instrumented conscious dogs 2 days, 2 wk, 1 mo, and 2 mo after LLA. Identically instrumented normal conscious dogs were studied at equal time points post-surgery. LLA had little or no effect on baseline systemic hemodynamics or blood gases. In contrast, compared with normal conscious dogs, striking active flow-independent pulmonary vasoconstriction was observed 2 days post-LLA. The slope of the LP/Q relationship was increased from a normal value of 0.275 +/- 0.021 to 0.699 +/- 0.137 mmHg.ml-1.min-1.kg-1 2 days post-LLA. Pulmonary vasoconstriction of similar magnitude was also observed on a chronic basis at 2 wk, 1 mo, and even 2 mo post-LLA. Pulmonary vasoconstriction post-LLA was not due to fixed resistance at the left pulmonary arterial or venous anastomotic sites. Finally, systemic arterial blood gases were unchanged when total pulmonary blood flow was directed to exclusively perfuse the transplanted left lung. Thus, LLA results in both acute and chronic pulmonary vasoconstriction in conscious dogs. LLA should serve as a useful stable experimental model to assess the specific effects of surgical transplantation on pulmonary vascular regulation.