Hideo Oya

Hemodynamic, Renal, and Hormonal Effects of Adrenomedullin Infusion in Patients With Congestive Heart Failure

BACKGROUND Experimental studies have shown that adrenomedullin (AM) causes vasodilatation, diuresis, and a positive inotropic effect. In humans, however, whether infusion of AM has beneficial effects in congestive heart failure (CHF) remains unknown. METHODS AND RESULTS Hemodynamic, renal, and hormonal responses to intravenous infusion of human AM (0.05 microg. kg(-1). min(-1)) were examined in 7 patients with CHF and 7 normal healthy subjects (NL). In NL group, AM significantly decreased mean arterial pressure (-16 mm Hg, P<0. 05) and increased heart rate (+12 bpm, P<0.05). In CHF group, AM also decreased mean arterial pressure (-8 mm Hg, P<0.05) and increased heart rate (+5 bpm, P<0.05), but to a much lesser degree (P<0.05 versus NL). AM markedly increased cardiac index (CHF, +49%; NL, +39%, P<0.05) while decreasing pulmonary capillary wedge pressure (CHF, -4 mm Hg; NL, -2 mm Hg, P<0.05). AM significantly decreased mean pulmonary arterial pressure only in CHF (-4 mm Hg, P<0.05). AM increased urine volume (CHF, +48%; NL, +62%, P<0.05) and urinary sodium excretion (CHF, +42%; NL, +75%, P<0.05). Only in CHF, plasma aldosterone significantly decreased during (-28%, P<0.05) and after (-36%, P<0.05) AM infusion. These parameters remained unchanged in 7 patients with CHF and 6 healthy subjects who received placebo. CONCLUSIONS Intravenous infusion of AM has beneficial hemodynamic and renal effects in patients with CHF.

Vasodilatory Effect of Ghrelin, an Endogenous Peptide From the Stomach

Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, which is identified as an endogenous ligand for GH secretagogues receptor. Although both ghrelin and its specific receptor are expressed in blood vessels, the cardiovascular effects of ghrelin remain unknown. To clarify whether ghrelin has a vasodilatory effect in humans, the response of forearm blood flow (FBF) to intra-arterial infusion of ghrelin was examined in eight healthy volunteers using a plethysmograph. In addition, hormonal responses to ghrelin were studied. Ghrelin increased FBF in a dose-dependent manner. Pretreatment with NG-monomethyl-l-arginine (l-NMMA), a nitric oxide synthase inhibitor, did not inhibit the FBF response to ghrelin, although l-NMMA significantly inhibited GH release. Serum insulin-like growth factor-I (IGF-I) level was not altered by ghrelin administration. Plasma cyclic guanosine 3´,5´-monophosphate level, a second messenger of nitric oxide, was also not altered. These results suggest that ghrelin has vasodilatory effects possibly through GH/IGF-I/nitric oxide–independent mechanisms.

Cardiovascular and hormonal effects of subcutaneous administration of ghrelin, a novel growth hormone-releasing peptide, in healthy humans.

Ghrelin is a novel GH (growth hormone)-releasing peptide isolated from the stomach. The cardiovascular and hormonal effects of the subcutaneous administration of ghrelin in humans remain unknown. Six healthy volunteers each received subcutaneous administration of three doses of ghrelin (1, 5 or 10 microg/kg) and placebo; the order of administration was randomized, and separate doses were given at least 24 h apart. The serum GH level dose-dependently increased from 0.5 +/- 0.4 to 3.6 +/- 2.1 ng/ml (1 microg/kg ghrelin; P=0.99 compared with baseline), 27.1 +/- 12.0 ng/ml (5 microg/kg; P<0.01 compared with baseline) and 45.4 +/- 12.8 ng/ml (10 microg/kg; P<0.01 compared with baseline) 30 min after ghrelin administration. Subcutaneous administration of ghrelin did not significantly alter circulating levels of corticotropin, cortisol, insulin-like growth factor-1, noradrenaline or adrenaline, although 10 microg/kg ghrelin slightly increased the prolactin level. No significant changes in heart rate or mean arterial pressure were observed. In contrast, the left ventricular ejection fraction, as assessed by echocardiography, increased dose-dependently from 63.5 +/- 0.6% to 65.1 +/- 0.9% (1 microg/kg ghrelin; P=0.97 compared with baseline), 69.6 +/- 1.3% (5 microg/kg; P<0.01 compared with baseline) and 71.5 +/- 0.9% (10 microg/kg; P<0.01 compared with baseline) 30 min after ghrelin administration. These haemodynamic and hormonal changes were still apparent 60 min after ghrelin injection. In conclusion, subcutaneous administration of ghrelin dose-dependently induced relatively specific GH release and enhanced cardiac performance in humans.

Increased Plasma P-Selectin and Decreased Thrombomodulin in Pulmonary Arterial Hypertension Were Improved by Continuous Prostacyclin Therapy

BackgroundThrombosis in situ related to endothelial cell injury may contribute to the development of pulmonary hypertension (PH). P-selectin, a leukocyte adhesion receptor present in endothelial cells and platelets, reflects endothelial injury and platelet activation, and thrombomodulin (TM), a receptor for thrombin and a major anticoagulant proteoglycan on the endothelial membrane, reflects the anticoagulant activity of the endothelium. Methods and ResultsTo assess abnormal coagulation due to endothelial injury in patients with PH, plasma levels of soluble P-selectin and TM were measured in 32 patients with primary PH (PPH), 25 with secondary pulmonary arterial hypertension (sPAH), 31 with pulmonary venous hypertension (PVH), and 17 healthy subjects (Control). These measurements were repeated after continuous infusion of prostacyclin in 15 patients with PPH and 3 with sPAH. P-selectin levels in both the sPAH and PPH groups were significantly higher than those in the Control and PVH groups (P <0.05). Plasma TM level in the PPH group was significantly lower than those in the other groups (P <0.01). After prostacyclin therapy, the lower TM level was increased and the higher P-selectin level was decreased (P <0.05). ConclusionsDecreased TM and increased P-selectin in PPH and sPAH may reflect in situ thrombosis due to endothelial injury. Prostacyclin may act not only as a vasodilator but also as an agent that improves endothelial injury and altered hemostasis in pulmonary arterial injury.

Increased plasma monocyte chemoattractant protein‐1 level in idiopathic pulmonary arterial hypertension

Objective:  Monocyte chemoattractant protein‐1 (MCP‐1), a pro‐inflammatory chemokine, has potent chemoattractant activity for monocytes/macrophages. We sought to investigate the clinical significance of MCP‐1 in idiopathic pulmonary arterial hypertension (IPAH).

Effects of Adrenomedullin Inhalation on Hemodynamics and Exercise Capacity in Patients With Idiopathic Pulmonary Arterial Hypertension

Background—Adrenomedullin (AM) is a potent pulmonary vasodilator peptide. However, whether intratracheal delivery of aerosolized AM has beneficial effects in patients with idiopathic pulmonary arterial hypertension remains unknown. Accordingly, we investigated the effects of AM inhalation on pulmonary hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension. Methods and Results—Acute hemodynamic responses to inhalation of aerosolized AM (10 &mgr;g/kg body wt) were examined in 11 patients with idiopathic pulmonary arterial hypertension during cardiac catheterization. Cardiopulmonary exercise testing was performed immediately after inhalation of aerosolized AM or placebo. The work rate was increased by 15 W/min until the symptom-limited maximum, with breath-by-breath gas analysis. Inhalation of AM produced a 13% decrease in mean pulmonary arterial pressure (54±3 to 47±3 mm Hg, P <0.05) and a 22% decrease in pulmonary vascular resistance (12.6±1.5 to 9.8±1.3 Wood units, P <0.05). However, neither systemic arterial pressure nor heart rate was altered. Inhalation of AM significantly increased peak oxygen consumption during exercise (peak &OV0312;o2, 14.6±0.6 to 15.7±0.6 mL · kg−1 · min−1, P <0.05) and the ratio of change in oxygen uptake to that in work rate (&Dgr;&OV0312;o2/&Dgr;W ratio, 6.3±0.4 to 7.0±0.5 mL · min−1 · W−1, P <0.05). These parameters remained unchanged during placebo inhalation. Conclusions—Inhalation of AM may have beneficial effects on pulmonary hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension.

Plasma brain natriuretic peptide as a noninvasive marker for efficacy of pulmonary thromboendarterectomy

BACKGROUND Plasma brain natriuretic peptide (BNP), a cardiac hormone secreted mainly by the cardiac ventricles, has been shown to increase in proportion to the degree of cardiac overload. However, whether plasma BNP may serve as a marker for the efficacy of pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension remains unknown. METHODS Plasma BNP level was measured in 34 patients with chronic thromboembolic pulmonary hypertension before and 1 month after pulmonary thromboendarterectomy. Right heart catheterization was also performed before and 1 month after the operation. RESULTS Preoperative plasma BNP level was significantly elevated in patients with chronic thromboembolic pulmonary hypertension compared with control patients (246 +/- 40 vs 13 +/- 2 pg/mL; p < 0.001; n = 34) and was positively correlated with total pulmonary resistance (r = 0.57; p < 0.001). After pulmonary thromboendarterectomy, plasma BNP level in survivors markedly decreased (220 +/- 31 to 54 +/- 9 pg/mL; p < 0.001; n = 32) in association with a reduction of total pulmonary resistance (15.6 +/- 1.0 to 4.5 +/- 0.3 Wood units; p < 0.001). The change in plasma BNP level was closely correlated with that in total pulmonary resistance (r = 0.63; p < 0.001). Importantly, a sustained elevation of plasma BNP (> or = 50 pg/mL) indicated the presence of residual pulmonary hypertension (> or = 5 Wood units) after operation (sensitivity = 73%; specificity = 81%). CONCLUSIONS Plasma BNP level was strongly associated with the severity of pulmonary hypertension in patients with chronic thromboembolic pulmonary hypertension and thereby may serve as a noninvasive marker for the efficacy of pulmonary thromboendarterectomy.