Acute hypoxic pulmonary vasoconstriction in man is attenuated by type I angiotensin II receptor blockade.

OBJECTIVES: We examined the hypothesis that angiotensin II (ANG II) is a modulator of acute hypoxic pulmonary vasoconstriction (HPV) by looking at the effect of losartan, a selective type 1 ANG II receptor antagonist, on acute HPV in man. METHODS: Ten normal volunteers were studied on two separate days. They either received pre-treatment with losartan 25, 50, 100, 100 mg respectively on four consecutive days or matched placebo. They were then rendered hypoxaemic, by breathing an N2/O2 mixture for 20 min to achieve an SaO2 of 85-90% adjusted for a further 20 min to achieve an SaO2 of 75-80%. Pulsed wave Doppler echocardiography was used to measure mean pulmonary artery pressure (MPAP), cardiac output and hence pulmonary vascular resistance (PVR). RESULTS: Baseline MPAP and PVR (during normoxaemia) were unaffected by losartan pre-treatment compared with placebo. However, losartan significantly reduced MPAP at both levels of hypoxaemia compared with placebo: 14.7 +/- 0.7 vs 19.0 +/- 0.7 mmHg at an SaO2 85-90% (P < 0.01) and 20.0 +/- 0.7 vs 25.7 +/- 0.8 mmHg at an SaO2 75-80% (P < 0.05) respectively. Similarly losartan significantly reduced PVR compared to placebo: 191 +/- 9 vs 246 +/- 10 dyne.s.cm-5 at an SaO2 85-90% (P < 0.005) and 233 +/- 12 vs 293 +/- 18 dyne.s.cm-5 at an SaO2 75-80% (P < 0.05), respectively. Pre-treatment with losartan, however, had no significant effect on systemic vascular resistance although losartan compared to placebo resulted in a significant (P < 0.05) reduction in mean arterial pressure at an SaO2 75-80%: 78 +/- 2 vs 87 +/- 2 mmHg. CONCLUSIONS: Losartan had no effect on baseline pulmonary haemodynamics but significantly attenuated acute hypoxic pulmonary vasoconstriction, suggesting that angiotensin II plays a role in modulating this response in man via its effects on the type 1 angiotensin II receptor.

Human C-type natriuretic peptide: effects on the haemodynamic and endocrine responses to angiotensin II.

OBJECTIVE: The aim was to study the effects of high dose systemic human C-type natriuretic peptide (CNP) infusion in man on systemic and pulmonary haemodynamics and the renin-angiotensin system before and after infusion of angiotensin II. METHODS: Eight normal male volunteers were studied on two separate occasions when, after the subjects had been rested to reach a baseline haemodynamic state (T0), infusions of either human CNP (10 pmol.kg-1.min-1) or placebo (5% dextrose) were begun. After 30 min (T30) on each study day, a concomitant infusion of angiotensin II (6 ng.kg-1.min-1) was started, and both infusions ran together for a further 30 min (until T60). Measurements of systemic and pulmonary haemodynamic variables and the activity of the renin-angiotensin system were made at baseline (T0), after 30 min of CNP or placebo (T30), and after angiotensin II (T60). RESULTS: Infusion of CNP had no significant effects on systemic or pulmonary haemodynamics or on baseline renin-angiotensin system activity compared with placebo. Infusion of angiotensin II produced significant systemic and pulmonary pressor effects and also stimulated aldosterone secretion. There were, however, no significant differences between the changes induced by angiotensin II (expressed as the difference between T30 and T60) when CNP was infused compared with placebo: change in mean systemic arterial pressure with CNP 26.6(SEM 2.3) mm Hg v placebo 30.3(3.6) mm Hg; change in mean pulmonary artery pressure with CNP 11.7(2.5) mm Hg v placebo 10.9(1.0) mm Hg; change in aldosterone concentration with CNP 219(40) pmol.litre-1 v placebo 242(40) pmol.litre-1. CONCLUSIONS: At a dose of CNP which has previously been found to have marked haemodynamic effects in dogs, no effect on systemic or pulmonary haemodynamics was observed in man. Furthermore, CNP had no effect on the aldosterone or pressor responses to infused angiotensin II. The present study would suggest that CNP does not have a circulating endocrine role in cardiovascular homeostasis, although a paracrine role within vascular endothelium is perhaps more likely.

Haemodynamic and endocrine effects of type 1 angiotensin II receptor blockade in patients with hypoxaemic cor pulmonale.

OBJECTIVES: Angiotensin II (ANG II) is known to be a potent vasoconstrictor agent in the pulmonary circulation. Furthermore, type 1 ANG II receptor blockade with losartan attenuates acute hypoxic pulmonary vasoconstriction in normal subjects. The aim of this study was therefore to evaluate the haemodynamic and endocrine sequelae of type 1 ANG II receptor blockade in patients with hypoxaemic cor pulmonale. METHODS: Nine patients with chronic obstructive pulmonary disease (COPD) age 67 +/- 3 years with pulmonary hypertension and normal left ventricular systolic function were studied on two separate occasions in a double-blind, placebo-controlled, crossover study. They were randomised to receive either 50 mg of oral losartan or matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Haemodynamic measurements and venous blood samples were taken at baseline and after 2 and 4 h. RESULTS: Maximal effects were observed at 4 h where losartan compared to placebo resulted in a significant reduction in both MPAP (28.6 +/- 2.0 vs 32.4 +/- 1.5 mmHg) and TPR (428 +/- 40 vs 510 +/- dyn.s.cm-5), respectively. Similarly losartan compared to placebo resulted in a significant reduction in MAP (87 +/- 4.5 vs 93 +/- 3.2 mmHg) and SVR (1293 +/- 94 vs 1462 +/- 112 dyn.s.cm-5), and significantly increased CO (5.58 +/- 0.43 vs 5.31 +/- 0.42 l/min). In addition, plasma aldosterone was significantly lower after treatment with losartan compared to placebo: 76 +/- 23 vs 164 +/- 43 pg/ml respectively. CONCLUSIONS: Thus, selective type 1 ANG II receptor blockade appears to have beneficial pulmonary and endocrine effects, suggesting a possible therapeutic role in the management of hypoxaemic cor pulmonale.

Cardiopulmonary effects of endothelin-1 in man.

OBJECTIVES: Endothelin-1 levels are elevated in a number of conditions characterised by impaired cardiovascular performance and abnormal vasoconstriction such as congestive cardiac failure and primary and secondary pulmonary hypertension. The aim of the present study was to assess the effects of the vasoconstrictor peptide endothelin-1 on pulmonary and systemic haemodynamics and cardiovascular performance in normal man. METHODS: Ten healthy male volunteers were studied on two occasions in a randomised, double-blind, placebo-controlled, cross-over study and received systemic infusions of either endothelin-1 (0.75, 1.5 and 3 pmol.kg-1.min-1 for 30 min each) or saline placebo. Systemic and pulmonary haemodynamic parameters were monitored non-invasively by pulsed-wave Doppler, as were parameters of left and right ventricular diastolic filling and inotropic state. Effects on renin-angiotensin and natriuretic peptide system activity were also measured. RESULTS: Endothelin-1 infusion produced dose-related falls in heart rate, stroke volume and cardiac output. Systemic vascular resistance (SVR) increased from 1156 +/- 57 to 1738 +/- 115 dyn.s.cm-5, and total pulmonary vascular resistance (TPR) increased from 142 +/- 12 to 329 +/- 22 dyn.s.cm-5. Endothelin-1 caused significant impairment of left and right ventricular diastolic filling, even at a low dose which had no pulmonary or systemic pressor effects. Electromechanical and Doppler acceleration indices of inotropic state were also significantly impaired. Activity of the renin-angiotensin system was suppressed by endothelin-1 whilst plasma levels of atrial natriuretic peptide (ANP) were unchanged. CONCLUSIONS: Thus, in addition to systemic and pulmonary pressor effects our results suggest that endothelin-1 impairs overall cardiovascular performance by causing diastolic dysfunction and acting as a negatively inotropic agent. These effects were associated with compensatory changes in the renin-angiotensin system.

Atrial natriuretic peptide and brain natriuretic peptide in cor pulmonale. Hemodynamic and endocrine effects.

We have studied the hemodynamic and hormonal effects of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in eight patients with cor pulmonale. Subjects were studied twice and were given a 20-min placebo infusion followed by either ANP or BNP (3 pmol/kg/min then 10 pmol/kg/ min for 20 min each). Responses were measured after placebo infusion and following low-dose then high-dose ANP or BNP. Placebo infusion had no significant effects on either study day. Low-dose ANP and BNP significantly reduced mean pulmonary artery pressure (MPAP) from baseline by 3.7 mm Hg (95% confidence interval [CI], 1.4 to 6.1) and 3.0 mm Hg (95% CI, 0.6 to 5.4), respectively. High-dose ANP and BNP further reduced MPAP from baseline by 7.1 mm Hg (95% CI, 4.8 to 9.4) and 7.1 mm Hg (95% CI, 4.7 to 9.6), respectively. Effects on total pulmonary vascular resistance were similar. ANP and BNP had no confounding systemic hemodynamic effects. Plasma aldosterone was significantly suppressed from baseline by ANP: 156 pmol/L (95% CI, 93 to 220) after low dose, 275 pmol/L (95% CI, 207 to 343) after high dose; and by BNP: 92 pmol/L (95% CI, 30 to 153) after low dose, 159 pmol/L (95% CI, 98 to 220) after high dose. ANP and BNP produced dose-related pulmonary vasodilatation in patients with cor pulmonale, without worsening oxygen saturation or affecting systemic hemodynamics. ANP and BNP also exerted favorable neurohormonal effects by suppressing aldosterone.

Lisinopril attenuates acute hypoxic pulmonary vasoconstriction in humans.

OBJECTIVE: We have studied the effects of angiotensin-converting enzyme (ACE) inhibition with lisinopril on acute hypoxic pulmonary vasoconstriction (HPV). DESIGN: Randomized, double-blind, placebo-controlled study in ten healthy volunteers. Subjects received four daily doses of lisinopril or matched placebo before attending the laboratory 5 h after taking the final dose. After reaching a resting hemodynamic state, subjects were made hypoxemic (SaO2, 75 to 80%) for 30 min. MEASUREMENTS: Pulmonary and systemic hemodynamic parameters were measured noninvasively at baseline and after 30 min of hypoxemia. RESULTS: Mean pulmonary artery pressure (MPAP) and total pulmonary vascular resistance (TPR) were similar at baseline on both study days. The increase in MPAP induced by hypoxemia was significantly blunted by pretreatment with lisinopril (means and 95% confidence interval [CI] for difference) 13.4 mm Hg vs placebo 19.6 mm Hg (95% CI, 2.5, 9.9). Likewise, the TPR response to hypoxemia was significantly blunted by lisinopril: 124 dyne.s.cm-5 vs placebo 179 dyne.s.cm-5 (95% CI, 11, 99). Lisinopril had no confounding systemic effects on mean arterial pressure, cardiac output, or systemic vascular resistance at baseline or in response to hypoxemia. CONCLUSIONS: Lisinopril therefore significantly attenuated the pulmonary pressor response to hypoxemia without decreasing baseline MPAP or TPR. This suggests that angiotensin II might play a modulatory role during HPV in man and that ACE inhibition may be a useful adjunctive treatment in hypoxemic pulmonary hypertension.

Effects of hypercapnia on hemodynamic, inotropic, lusitropic, and electrophysiologic indices in humans.

STUDY OBJECTIVE: The inotropic, lusitropic, and electrophysiologic effects of acute hypercapnia in humans are not known. Although the effects of hypercapnia on the systemic circulation have been well documented, there is still some debate as to whether hypercapnia causes true pulmonary vasoconstriction in vivo. We have therefore evaluated the effects of acute hypercapnia on these cardiac indices and the interaction of hypercapnia with the systemic and pulmonary vascular beds in humans. PARTICIPANTS AND INTERVENTIONS: Eight healthy male volunteers were studied using Doppler echocardiography. After resting for at least 30 min to achieve baseline hemodynamic parameters (T(0)), they were rendered hypercapnic to achieve an end-tidal carbon dioxide (CO2) of 7 kPa for 30 min by breathing a variable mixture of CO2/air (T1). They were restudied after 30 min recovery breathing air (T2). Hemodynamic, diastolic, and systolic flow parameters, QT dispersion (maximum-minimum QT interval measured in a 12-lead ECG), and venous blood samples for plasma renin activity (PRA), angiotensin II (ANG II), and aldosterone (ALDO) were measured at each time point. RESULTS: Hypercapnia compared with placebo significantly increased mean pulmonary artery pressure 14 +/- 1 vs 9 +/- 1 mm Hg and pulmonary vascular resistance 171 +/- 17 vs 129 +/- 17 dyne.s.cm-5, respectively. Heart rate, stroke volume, cardiac output, and mean arterial BP were increased by hypercapnia. Indexes of systolic function, namely peak aortic velocity and aortic mean and peak acceleration, were unaffected by hypercapnia. Similarly, hypercapnia had no effect on lusitropic indexes reflected by its lack of effect on isovolumic relaxation time, mitral E-wave deceleration time, and mitral E/A wave ratio. Hypercapnia was found to significantly increase both QTc interval and QT dispersion: 428 +/- 8 vs 411 +/- 3 ms and 48 +/- 2 vs 33 +/- 4 ms, respectively. There was no significant effect of hypercapnia on PRA, ANG II, or ALDO. CONCLUSION: Thus, acute hypercapnia appears to have no adverse inotropic or lusitropic effects on cardiac function, although repolarization abnormalities, reflected by an increase in QT dispersion, and its effects on pulmonary vasoconstriction may have important sequelae in man.

Left ventricular systolic performance during acute hypoxemia.

STUDY OBJECTIVE: Although some of the cardiovascular responses to hypoxemia are well described, effects on myocardial contractility have not been defined. Such effects are readily assessed by noninvasive techniques and we have therefore evaluated Doppler-phonocardiographic parameters of systolic left ventricular contractility in normal humans rendered hypoxemic. DESIGN: Eight healthy male volunteers were studied. Parameters were measured after resting to achieve baseline haemodynamics, after 20 min moderate hypoxemia (SaO2 85 to 90%), and after a further 20 min of severe hypoxemia (SaO2 75 to 80%). Hypoxemia was induced by breathing a variable N2/O2 mixture. MEASUREMENTS: Pulsed-wave Doppler analysis of ascending aortic blood flow was combined with phonocardiography to measure indices of systolic left ventricular function at baseline and at the end of each period of hypoxemia. RESULTS: There was a significant, dose-related increase in cardiac output in response to hypoxemia, from 5.5 +/- 0.26 L/min at baseline to 6.1 +/- 0.08 L/min during moderate hypoxemia and to 7.0 +/- 0.23 L/min during severe hypoxemia. Likewise, heart rate increased significantly in dose-related fashion although stroke volume was not affected by either level of hypoxemia. Hypoxemia had no significant effects on systolic or diastolic blood pressures, but caused a significant reduction in systemic vascular resistance. Aortic peak and mean acceleration and acceleration time were not affected by moderate or severe hypoxemia. Although the systolic time intervals measured shortened significantly during severe hypoxemia, these were no longer significant when appropriate corrections were made for heart rate. CONCLUSIONS: Although cardiac output increases during hypoxemia, this is due to increases in heart rate but not to any effect on stroke volume. Parameters of left ventricular systolic function and myocardial inotropic state were also not affected by severe hypoxemia. Systolic left ventricular function and myocardial contractility are thus well preserved in normal humans during hypoxemia.

Angiotensin II receptor blockade and effects on pulmonary hemodynamics and hypoxic pulmonary vasoconstriction in humans.

STUDY OBJECTIVE: We examined the hypothesis that angiotensin II (ANG II) is a modulator of pulmonary vascular tone by examining the effects of ANG II blockade on pulmonary hemodynamics during normoxemia and hypoxemia in normal volunteers with an activated renin angiotensin system (RAS). PARTICIPANTS AND INTERVENTIONS: Eight normal volunteers, pretreated with furosemide, were studied on two separate occasions and received either an infusion of saralasin, 5 micrograms/kg/min, or placebo. After 20 min, they were rendered hypoxemic, by breathing N2/O2 mixture for 20 min to achieve arterial oxygen saturation (SaO2) of 85 to 90% adjusted for a further 20 min to achieve SaO2 of 75 to 80%. Doppler echocardiography was used to measure mean pulmonary artery pressure (MPAP), cardiac output, and hence total pulmonary vascular resistance (TPR). RESULTS: Saralasin compared with placebo resulted in a significant (p < 0.05) reduction in MPAP during normoxemia, 6.70 +/- 1.0 vs 11.7 +/- 1.3 mm Hg; at SaO2 of 85 to 90%, 14.7 +/- 1.4 vs 20.5 +/- 1.0 mm Hg; and at SaO2 of 75 to 80%, 18.1 +/- 1.9 vs 27.8 +/- 1.9 mm Hg, respectively. Likewise saralasin compared with placebo resulted in a significant reduction in TPR during normoxemia, 104 +/- 14 vs 180 +/- 20 dyne.s.cm-5; at SaO2 of 85 to 90%, 222 +/- 24 vs 295 +/- 21 dyne.s.cm-5; and at SaO2 of 75 to 80%, 238 +/- 21 vs 362 +/- 11 dyne.s.cm-5, respectively. The delta MPAP response to hypoxemia was likewise significantly (p < 0.01) attenuated by saralasin infusion compared with placebo: mean difference 5.0 mm Hg, 95% confidence interval (CI) 1.9 to 8.08, and there was a trend toward attenuation of the delta TPR response to hypoxemia (0.05 < p < 0.10): mean difference 47 dyne.s.cm-5, 95% CI, -10 to 105. CONCLUSION: In addition to causing pulmonary vasodilatation in the presence of an activated RAS, our results suggest that ANG II receptor blockade attenuates acute hypoxic pulmonary vasoconstriction and that ANG II may play a role in modulating this response in normal man.

Effects of inhaled fluticasone propionate and oral prednisolone on lymphocyte beta 2-adrenoceptor function in asthmatic patients.

The aim of the study was to evaluate the facilitatory effects of inhaled corticosteroid on in vitro parameters of lymphocyte beta 2-adrenoceptor function in asthmatic patients. Serum cortisol level was also evaluated as a measure of systemic bioactivity. Ten (four female) asthmatic subjects were evaluated, mean (SEM) age was 28.6(2.0) years, and FEV1 was 79.9%(8.7) predicted. Single doses of inhaled placebo (PL), fluticasone propionate, 1,000 micrograms (F1000), fluticasone propionate, 2,000 micrograms(F2000), or oral prednisolone, 50 mg(PRED), were given at 10 PM the previous night and measurements were made 10 h later. Values for beta 2-receptor density (logBmax: fmol/10(6)cells) were significantly (p < 0.05) greater than PL with PRED but not with inhaled fluticasone (as means and 95% confidence interval [CI] for difference vs PL): PL, 0.27; F1000, 0.30; F2000, 0.32; and PRED, 0.48 (95% CI vs PL, 0.075 to 0.341). Maximal cyclic adenosine monophosphate (cAMP) responses to isoproterenol hydrochloride (isoprenaline (Emax; pmol/10(6)cells) mirrored those for Bmax: PL, 4.00; F1000, 4.68; F2000, 4.26; and PRED, 7.46 (95% CI vs PL, -0.01 to 6.91). Receptor affinity (Kd) was not significantly altered by any treatment. There was significant (p < 0.05) suppression of serum cortisol (nmol/L) with F2000 and PRED compared with PL: PL, 307.9; F1000, 323.2; F2000, 130.1 (95% CI vs PL, 69.76 to 285.8) and PRED, 51.8 (95% CI vs PL, 144.11 to 368.01). Thus, high-dose inhaled fluticasone propionate did not have any facilitatory effects on lymphocyte beta 2-adrenoceptor parameters as compared with oral prednisolone which upregulated beta 2-receptor density and increased cAMP response. In contrast, high-dose inhaled fluticasone (2,000 micrograms) significantly suppressed serum cortisol. In conclusion, there would appear to be a dissociation in systemic sensitivity between effects of inhaled corticosteroid on adrenal suppression and lymphocyte beta 2-adrenoceptor regulation.

Left atrial thrombus as an early consequence of blunt chest trauma.

Thromboembolism is rarely considered in discussions of the complications of blunt chest trauma. The few cases of thromboembolism that have been reported in this setting have occurred in association with significant myocardial damage. A previously fit 23 year old woman was admitted to the intensive care unit following a road traffic accident. A day later, left atrial thrombus was demonstrated by transoesophageal echocardiography in the absence of any other evidence of important myocardial injury. Anticoagulation with heparin was cautiously introduced in spite of her extensive injuries, and there were no consequent bleeding complications. At hospital discharge on day 18 she was entirely well. Full anticoagulation with warfarin was continued for a further eight weeks at which time follow up transoesophageal echocardiography showed complete resolution of the thrombus.

Pulmonary vasorelaxant activity of atrial natriuretic peptide and brain natriuretic peptide in humans.

BACKGROUND: Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) exhibit in vitro pulmonary vasodilator activity, but little information is available regarding their effects in the human pulmonary vasculature. Their effects in the human pulmonary circulation and their ability to modulate the pulmonary pressor effects of angiotensin II have therefore been evaluated. METHODS: Eight healthy volunteers were studied on three separate occasions. Infusions of either ANP, BNP, or placebo were given for 60 minutes with a concomitant infusion of angiotensin II given for the final 30 minutes. Pulmonary haemodynamics were measured by pulsed wave Doppler echocardiography at baseline (T0), before commencing angiotensin II (T30), and at the end of the infusion period (T60). RESULTS: Mean pulmonary artery pressure (MPAP) showed a fall with ANP and BNP infusion at T30 compared with placebo. Although angiotensin II infusion had significant pulmonary pressor effects on all three study days, MPAP at T60 was lower when ANP (18.3 (2.0) mm Hg) and BNP (16.1 (1.5) mm Hg) were given concomitantly compared with placebo (21.8 (1.6) mm Hg). CONCLUSIONS: These findings indicate that both ANP and BNP exhibit pulmonary vasorelaxant activity in humans in terms of antagonism of the pulmonary pressor effects of angiotensin II. This would support the hypothesis that ANP and BNP act as circulating counter-regulatory hormones in states of pathological pulmonary vasoconstriction.

Acute effects of hypoxaemia and angiotensin II in the human pulmonary vascular bed.

Hypoxaemia and angiotensin II both cause pulmonary vasoconstriction and co-exist as pathophysiological pulmonary pressor stimuli in patients with cor pulmonale. Evidence from animal studies, however, suggests that angiotensin II may modulate the hypoxic pulmonary vasoconstrictor response. We have therefore studied how hypoxaemia and angiotensin II interact in the human pulmonary vascular bed. Eight male volunteers were studied on two occasions. From baseline (T0) onwards, subjects breathed room air at one visit, and on the other, a nitrogen/oxygen mixture which rendered arterial oxygen saturation between 75% and 80%. After 30 min (T30), angiotensin II was infused for a further 30 min (until T60). Mean pulmonary artery pressure (MPAP) and total pulmonary vascular resistance (PVR) were determined by pulsed-wave Doppler echocardiography at T0, T30 and T60. The change in MPAP (delta MPAP) due to hypoxaemia and angiotensin II together was 18.0 +/- 1.3 mmHg, significantly greater than the delta MPAP response to either hypoxaemia alone (13.4 +/- 1.1 mmHg) or angiotensin II alone (10.3 +/- 1.1 mmHg). In terms of change in PVR (delta PVR), the response to hypoxaemia and angiotensin II together (230 +/- 25 dyne.s/cm5) was no different from the response to ANG II alone (214 +/- 31 dyne.s/cm5), although both these were significantly greater than delta PVR with hypoxaemia alone (114 +/- 12 dyne.s/cm5). The delta MPAP and delta PVR responses to angiotensin II were significantly greater when normoxaemic than when hypoxaemic: delta MPAP mean difference 5.6 mmHg (95% confidence interval (CI) 3.0-8.2); delta PVR mean difference 98 dyne.s/cm5 (95% CI 16-181). Angiotensin II therefore produced significantly less pulmonary vasoconstriction when hypoxaemic compared with normoxaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute effects of ANP and BNP on hypoxic pulmonary vasoconstriction in humans.

1. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have pulmonary vasorelaxant activity with plasma concentrations being elevated in patients with hypoxaemic pulmonary hypertension. However, their effects on acute hypoxic pulmonary vasoconstriction (HPV), the initiating stimulus for pulmonary hypertension have not to date been investigated. We have therefore studied the effects of ANP and BNP on acute HPV in humans. 2. Eight healthy volunteers were studied on three separate occasions. After reaching a resting haemodynamic state (t0), an infusion of either ANP (10 pmol kg-1 min-1), BNP (10 pmol kg-1 min-1) or placebo (5% dextrose) was commenced. This was given alone for 30 min (t30) before subjects were rendered hypoxaemic (SaO2 75-80%) for a further 30 min (t60), with the initial infusion continuing to t60. Pulsed-wave Doppler analysis of pulmonary artery flow was used to measure mean pulmonary arterial pressure (MPAP) and hence total pulmonary vascular resistance (PVR) was calculated. 3. MPAP and PVR both tended to decrease in response to ANP and BNP infusion, although compared with placebo, the difference at t30 was only statistically significant for PVR. Hypoxaemia increased MPAP and PVR, although values at t60 were significantly lower following both ANP and BNP compared with placebo. 4. In terms of the actual change in PVR (delta PVR) induced by hypoxaemia (from t30 to t60), BNP (146(16) dyn s cm-5), but not ANP (183(21) dyn s cm-5) significantly attenuated delta PVR compared with placebo (194(26) dyns s cm-5): mean difference BNP versus placebo 48 dyn s cm-5, 95% Cl 3-93. An identical pattern was observed for delta MPAP where BNP (15.9(1.1) mmHg), but not ANP (18.0(1.2) mmHg) significantly attenuated delta MPAP compared with placebo (19.0(1.7) mmHg): mean difference BNP versus placebo 3.1 mmHg, 95% Cl 0.7-5.5. 5. Thus, although both ANP and BNP exhibit pulmonary vasorelaxant activity, only BNP significantly attenuated the MPAP and PVR responses to acute hypoxaemia. This suggests that the natriuretic peptides may have a role in attenuating pulmonary hypertension secondary to hypoxaemia.

The role of the renin-angiotensin and natriuretic peptide systems in the pulmonary vasculature.

1. The role of vasoactive peptide systems in the pulmonary vasculature has been studied much less extensively than systemic vascular and endocrine effects. The current understanding of the role of the renin-angiotensin (RAS) and natriuretic peptide systems (NPS) in the pulmonary circulation is therefore reviewed. 2. Plasma concentrations of angiotensin II, the main vasoactive component of the RAS, are elevated in pulmonary hypertension and may interact with hypoxaemia to cause further pulmonary vasoconstriction. Pharmacological manipulation of angiotensin II can attenuate hypoxic pulmonary vasoconstriction but larger studies are needed to establish the efficacy of this therapeutic strategy in established pulmonary hypertension. 3. Although all the known natriuretic peptides, ANP, BNP and CNP are elevated in cor pulmonale, only ANP and BNP appear to have pulmonary vasorelaxant activity in humans. ANP and BNP can also attenuate hypoxic pulmonary vasoconstriction, suggesting a possible counter-regulatory role for these peptides. Inhibition of ANP/BNP metabolism by neutral endopeptidase has been shown to attenuate development of hypoxic pulmonary hypertension but this property has not been tested in humans. 4. It is also well established that there are potentially important endocrine and systemic circulatory interactions between the RAS and NPS. This also occurs in the pulmonary circulation and in humans, where at least BNP acts to attenuate angiotensin II induced pulmonary vasoconstriction. This interaction may be particularly relevant as a mechanism to counter-regulate overactivity of the RAS.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of frusemide and hypoxia on the pulmonary vascular bed in man.

AIMS: Diuretic therapy is conventionally used to treat oedema in patients with hypoxic cor pulmonale. This condition is associated with activation of the renin angiotensin system (RAS) with elevated levels of angiotensin II (ANG II), a potent pulmonary pressor agent. We explored the hypothesis that RAS activation by diuretic therapy might therefore worsen hypoxic pulmonary vasoconstriction via the effects of ANG II on the pulmonary vascular bed. METHODS: Eight normal volunteers were studied on 2 separate days. They either received 40 mg frusemide daily or placebo for 4 days and were then rendered hypoxaemic, by breathing an N2/O2 mixture for 20 min to achieve an SaO2 of 85-90% adjusted for a further 20 min to achieve an SaO2 of 75-80%. Pulsed wave doppler echocardiography was used to measure mean pulmonary artery pressure, cardiac output and hence pulmonary vascular resistance (PVR). RESULTS: Plasma renin activity (PRA) was significantly (P < 0.01) increased after prior treatment with frusemide compared with placebo at all time points. Prior treatment with frusemide significantly (P < 0.05) increased PVR compared with placebo at baseline: 185 +/- 17 vs 132 +/- 10 dyn s cm-5 at an SaO2 of 85-90%: 291 +/- 18 vs 229 +/- 16 dyn s cm-5 and at SaO2 of 75-80%: 356 +/- 12 vs 296 +/- 17 dyn s cm-5 respectively. However, the delta-PVR response to hypoxaemia was not significantly altered by frusemide compared with placebo. In contrast to its effect on the pulmonary vasculature prior treatment with frusemide did not significantly alter systemic haemodynamic parameters either at baseline or during hypoxia. CONCLUSIONS: Thus, prior treatment with frusemide increased baseline pulmonary vascular resistance and significantly augmented the hypoxaemic pulmonary vascular response in additive fashion. It is hypothesised that this effect of frusemide may be due to RAS activation with ANG II mediated pulmonary vasoconstriction.

The effects of angiotensin II on circulating levels of natriuretic peptides.

We have evaluated the differential release of A, B and C-type natriuretic peptides in response to incremental doses of angiotensin II (2, 4 and 6 ng kg-1 min-1). Baseline plasma concentrations of ANP (5.99 +/- 0.74 pmol 1-1) were significantly (P < 0.05) higher than BNP (1.53 +/- 0.48 pmol 1-1) or CNP (0.41 +/- 0.11 pmol 1-1). Angiotensin II infusion caused a significant (P < 0.05) increase in plasma ANP to 53.76 +/- 17.3 pmol 1-1 at 6 ng kg-1 min-1. Plasma concentrations of BNP and CNP were not significantly affected by angiotensin II. Arterial blood pressures and systemic vascular resistance increased (P < 0.001) in response to angiotensin II infusion. Thus, ANP, unlike BNP or CNP, is released acutely in response to the pressor stimulus of angiotensin II. This may represent a dissociation in release of the natriuretic peptides, in terms of short and long term responses to activation of the renin-angiotensin system.

Adverse effects of hypoxaemia on diastolic filling in humans.

1. Abnormalities of myocardial relaxation may occur as a consequence of myocyte hypoxia. We have therefore examined the effects of hypoxaemia on right and left ventricular diastolic function in 10 healthy male subjects. 2. After resting to reach baseline haemodynamics, subjects were rendered hypoxaemic by breathing a variable nitrogen/oxygen mixture. Oxygen saturation (SaO2) was maintained at 85-90% for 20 min and then at 75-80% for a further 20 min. Haemodynamic and diastolic filling parameters were measured noninvasively at baseline and at the end of each period of hypoxaemia. 3. Diastolic filling of both ventricles was significantly impaired by hypoxaemia. In comparison with baseline, left ventricular isovolumic relaxation time and transmitral E-wave deceleration time corrected for heart rate were significantly prolonged at SaO2 75-80%: mean difference in corrected relaxation time, 9.8 ms (95% confidence interval 1-19); mean difference in corrected deceleration time, 34 ms (95% confidence interval 11-56). Similarly, right ventricular isovolumic relaxation time and transtricuspid E-wave deceleration time were significantly prolonged at SaO2 values of 75-80% compared with baseline: mean difference in relaxation time, 20.3 ms (95% confidence interval 3-38); mean difference in deceleration time, 33 ms (95% confidence interval 11-55). 4. During hypoxaemia there were dose-related increases in heart rate, cardiac output and mean pulmonary artery pressure, but no effects on mean arterial pressure. 5. Hypoxaemia significantly impairs relaxation of left and right ventricles in normal humans. These changes may reflect impairment of intracellular calcium transport secondary to the effects of myocyte hypoxia.