Carperitide Infusion Research Articles

Effect of atrial natriuretic peptide on adiponectin in patients with heart failure

The adipocyte-specific cytokine adiponectin, has cardioprotective effects, correlates with endogenous cardiac natriuretic peptides and adipocyte has guanylyl cyclase-A receptors of natriuretic peptides. To evaluate the effect of carperitide (atrial natriuretic peptide; ANP) on plasma adiponectin in patients with heart failure. Seventy-five patients admitted to our hospital with decompensated heart failure were randomised (1:2) to nitroglycerin (group I: n = 23) or carperitide infusion (group II: n = 52). Blood samples were collected at baseline and after 7 days. Plasma levels of total and high-molecular weight (HMW) adiponectin, ANP and brain natriuretic peptide (BNP) were measured. There were no differences in baseline characteristics between the two groups. In group I, plasma levels of total and HMW adiponectin were significantly decreased (21.1+/-2.5 to 18.6+/-2.5 microg/mL, p<0.05, 12.3+/-1.8 to 10.8+/-1.7 microg/mL, p<0.05, respectively) concomitant with the decrease in plasma levels of ANP and BNP. In group II, plasma levels of total and HMW adiponectin were significantly increased (17.3+/-1.3 to 19.7+/-1.6 microg/mL, p<0.0001, 9.8+/-1.0 to 10.5+/-1.0 microg/mL, p<0.05, respectively) concomitant with the increase in ANP. These findings indicate that carperitide infusion increases plasma levels of total and HMW adiponectin in patients with heart failure.

Effects of Carperitide on the Long-Term Prognosis of Patients With Acute Decompensated Chronic Heart Failure The PROTECT Multicenter Randomized Controlled Study

Carperitide is used to treat acute decompensated heart failure (ADHF), but its effects on long-term prognosis have not been studied. A multicenter randomized controlled study of 49 patients with ADHF was performed to clarify the drug's effects on long-term prognosis. Low-dose carperitide (0.01-0.05 microg x kg(-1 ) x min(-1)) was infused for 72 h as the initial treatment (n=26), whereas in the control group (n=23), standard medical treatment other than carperitide was given without limitation. Anti-aldosterone drugs were prohibited in both groups. During carperitide infusion, significant increases of the atrial natriuretic peptide and cyclic GMP levels and a significant decrease in the heart-type fatty acid-binding protein/serum creatinine ratio were observed, suggesting inhibition of myocyte cell membrane damage. On the other hand, no significant differences in the plasma brain natriuretic peptide, troponin T, and creatinine levels were noted in either group. During 18-month follow-up, significant reductions of death and rehospitalization occurred in the carperitide vs control group (11.5% vs 34.8%; p=0.0359). Cox regression analysis revealed that randomization to carperitide (p=0.020), pretreatment systolic blood pressure >or=140 mmHg (p=0.043), and beta-blocker therapy (p=0.016) were independent predictors for freedom from cardiac events. Acute-phase low-dose carperitide infusion improved the long-term prognosis of patients with ADHF.

Abstract 1690: Prevention of Contrast-Induced Nephropathy by Carperitide

Introduction: Contrast-induced nephropathy (CIN) remains as a common complication of angiographic procedure. Carperitide, an antagonist of secretion of rennin, aldosterone and vasopressin with natriuretic effects, has renal protective effects. Hypothesis: Carperitide may be effective in preventing CIN. Methods: We prospectively studied 170 consecutive patients with chronic renal failure (serum creatinine(SCr) concentration &gt;1.3mg/dl)who underwent coronary angiography. The patients were randomly assigned to either 1.3ml/kg/hr of lactated Ringer’s infusion plus carperitide 0.042μg/kg/min (Carperitide group N=86) or lactated Ringer’s infusion alone (Control group N=84). The administration was initiated 6 hours prior to the procedure and continued for 48 hours after angiography. The concentration of SCr and cystatin C were measured at baseline, 24 hours, 48 hours, 1 week, and 1 month following the angiography. Results: The SCr concentration increased gradually up to one month in the Control group, whereas remained almost unchanged in the Carperitide group (p=0.001 for the trend, Figure ). The cystatin C concentration also showed the same trend (p=0.013 for the trend, Figure ). When CIN was defined as an increase of ≥0.5 mg/dl or ≥25% in the SCr at 48 hours after angiography, CIN developed in 7 of 84 patients (8%) in the Control group and 1 of 86 patients (1%) in the Carperitide group (P=0.047). Multivariate analysis disclosed that carperitide infusion (OR 0.097, P=0.041) and quantity of contrast media (OR 14.06, P=0.004) were significantly related to the development of CIN. Conclusions: Carperitide is effective in preventing CIN in patients with chronic renal failure.

Predominant Effect of A-Type Natriuretic Peptide on Reduction of Oxidative Stress During the Treatment of Patients With Heart Failure

Oxidative stress plays an important role in the pathogenesis of heart failure and was investigated in the present study of the role of exogenous A-type natriuretic peptide (ANP) in the patients with heart failure and in cultured neonatal rat cardiomyocytes. The first protocol was to examine if an infusion of human ANP (carperitide) changed serum levels of TRX (thioredoxin) during the treatment of patients with heart failure compared with conventional therapy using furosemide. Protocol 2 investigated whether ANP had a direct antioxidant action on the failing heart by measuring TRX gene expression and reactive oxygen species (ROS) production in cultured neonatal rat cardiomyocytes. In Protocol 1, 8 patients were treated with only an intravenous bolus of furosemide and 11 patients with only an intravenous infusion of carperitide for 24 h. Serum TRX levels significantly decreased at 4 h (p<0.03) and at 24 h (p<0.05) in the carperitide group, whereas they decreased slightly but were not significantly different in the furosemide group. In Protocol 2, it was found that a low dose of exogenous ANP of 10(-9) mol/L significantly suppressed TRX expression and ROS production in cardiomyocytes. Carperitide infusion has a predominantly antioxidant action, in addition to improving the hemodynamics of patients with acute heart failure. Furthermore, carperitide infusion should have a direct antioxidant effect on the failing heart.

Effect of prophylactic bronchodilator treatment with i.v. carperitide on airway resistance and lung compliance after tracheal intubation

Lung resistance increases after induction of anaesthesia. We hypothesized that prophylactic bronchodilation with i.v. carperitide before tracheal intubation would decrease airway resistance and increase lung compliance after placement of the tracheal tube in both smokers and nonsmokers. Ninety-seven adults aged between 24 and 59 yr were randomized to receive i.v. normal saline (0.9% saline) (control) or carperitide, 0.2 microg kg(-1) min(-1) throughout the study. The 97 patients included smokers and nonsmokers. Thus the patients were allocated to one of the four groups: smokers who received normal saline (n=21), nonsmokers who received normal saline (n=27), smokers who received carperitide (n=19) or nonsmokers who received carperitide (n=30). Thirty minutes after starting normal saline or carperitide infusion, we administered thiamylal 5 mg kg(-1) and fentanyl 5 microg kg(-1) to induce general anaesthesia and vecuronium 0.3 mg kg(-1) for muscle relaxation. Continuous infusion of thiamylal 15 mg kg(-1) h(-1) followed anaesthetic induction. Mean airway resistance (R(awm)), expiratory airway resistance (R(awe)) and dynamic lung compliance (C(dyn)) were determined 4, 8, 12 and 16 min after tracheal intubation and compared between the four groups. At 4 min after intubation, R(awm) and R(awe) were higher and C(dyn) lower in smokers than in nonsmokers in the control group. R(awm) and R(awe) were lower and C(dyn) higher in smokers in the carperitide group than in smokers in the control group. R(awm) and R(awe) were lower in nonsmokers in the carperitide group than in nonsmokers in the control group. Marked bronchoconstriction occurred in the control groups (smokers and nonsmokers) 4 min after tracheal intubation. Prophylactic treatment with carperitide before induction of anaesthesia and tracheal intubation was advantageous, particularly in smokers.

Inhibition of Aldosterone and Endothelin-1 by Carperitide Was Attenuated With More Than 1 Week of Infusion in Patients With Congestive Heart Failure

Short-term infusion of carperitide (atrial natriuretic peptide) has beneficial effects on neurohumoral factors; however, it remains unclear whether the effects are sustained for long-term infusion. To evaluate the effects of long-term infusion of carperitide on neurohumoral factors in patients with chronic congestive heart failure (CHF), we measured neurohumoral factors before and 1 hour after stopping carperitide infusion in 42 CHF patients. Carperitide infusion was continued for more than 2 days until there was symptomatic improvement of CHF. Patients were divided into 2 groups by the median value of infusion duration: group 1 (less than 7 days, n=21) and group 2 (more than 7 days, n=21). In group 1, aldosterone (ALD) and endothelin-1 (ET-1) were significantly increased after stopping carperitide. In contrast, ALD and ET-1 did not change after stopping carperitide in group 2. The molar ratio of cyclic guanosine monophosphate/atrial natriuretic peptide before stopping carperitide was significantly lower in group 2 than in group 1. Suppression of ALD and ET-1 was maintained for 7 days of carperitide infusion, but the beneficial effect on neurohumoral factors was attenuated after more than 7 days, probably through down-regulation of biologic receptors coupled with guanylate cyclase in CHF patients.

Preischemic infusion of alpha-human atrial natriuretic peptide elicits myoprotective effects against ischemia reperfusion in isolated rat hearts.

Carperitide, a synthetic alpha-human atrial natriuretic peptide (ANP) is a newly developed drug for the treatment of heart failure. However, effects of carperitide on susceptibility to ischemia reperfusion injury are left to be determined. Isolated rat hearts were subjected to Langendorff perfusion. Six hearts received 0.1 microM of carperitide for 10 min, 6 hearts received 1 mM of a NO synthetase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) for 5 min before the infusion of carperitide, 6 hearts received 0.02 microM of a PKC synthetase inhibitor chelerythrine chloride for 5 min before the infusion of carperitide, 6 hearts received 100 microM of a selective mitochondrial ATP-sensitive potassium (KATP) channel blocker 5-dehydroxydecanoate (5HD) before the infusion of carperitide, 6 hearts received 10 microM of a soluble guanylate cyclase inhibitor methylene blue for 5 min before the infusion of carperitide, and 6 hearts served as a control with no drug infusion. All hearts were then subjected to 20 min of global ischemia followed by 120 min of reperfusion. Left ventricular pressures and coronary flow were measured throughout the experiment and infarct size was detected at the end of experiment. Both plasma and tissue cGMP levels were also determined. The results showed: (1) Carperitide significantly reduced infarct size compared to control (26.1 +/- 2.8 vs. 42.7 +/- 2.3%, carperitide vs. control, p < 0.05). This effect was reversed by L-NAME, chelerythrine and 5HD, but not methylene blue. (2) Plasma cGMP levels were increased in carperitide-treated group. This effect was reversed by L-NAME (0.16 +/- 0.03 vs. 1.04 +/- 0.09* vs. 0.28 +/- 0.02 nmol/L, control vs. carperitide vs. L-NAME, *p < 0.01 vs. control). We conclude that preischemic infusion of carperitide exerts cardioprotective effects possibly through NO-PKC dependent pathway followed by mitochondrial KATP channel activation.

Usefulness of carperitide for the treatment of refractory heart failure due to severe acute myocardial infarction.

Carperitide (synthetic atrial natriuretic peptide) is a newly developed drug for the treatment of heart failure. Although this drug has been used for various types of heart failure, it remains unknown whether it has additive effects on hemodynamic parameters or renal excretory function during intensive treatment for acute refractory heart failure. We have examined the cardiorenal and hormonal effects of carperitide (0.05-0.10 microg / min / kg) in 9 patients (mean age: 67+/-8 years) with severe heart failure complicated with acute myocardial infarction, in which a range of intensive treatments have already been started. Hemodynamic parameters were determined before and 4, 24 and 48 hours after initiation of carperitide. Pulmonary capillary wedge pressure (mean+/-SD) had decreased dramatically from 21+/-6 to 11+/-5 mmHg (p<0.01) 4 hours after the treatment without significant renal effects. Heart rate and systemic blood pressure were not significantly changed. These beneficial effects were maintained for at least 24 hours. Plasma aldosterone levels fell significantly in response to the drug (from 148+/-68 to 56+/-29 pg / ml; p<0.05). However, mean hourly urine output remained unchanged after carperitide. In conclusion, intravenous infusion of carperitide promptly and persistently reduces left ventricular filling pressure without diuresis, hypotension, reflex tachycardia, or neurohormonal activation in patients with refractory heart failure due to severe acute myocardial infarction.

Alpha-human atrial natriuretic peptide, carperitide, reduces infarct size but not arrhythmias after coronary occlusion/reperfusion in dogs.

Carperitide, a recombinant form of alpha-hANP, possesses potent diuretic, natriuretic, and vasodilatory activity, and inhibits the renin-aldosterone system and sympathetic nervous activity. However, its beneficial effects on ischemic myocardium have not been studied fully. We examined carperitide's effects on infarct size, hemodynamics, and arrhythmia frequency in anesthetized dogs (n = 20) subjected to a 90-min coronary artery occlusion/6-h reperfusion protocol. Intravenous infusion of carperitide (0.2 microg/kg/min) commenced 15 min after occlusion and continued during occlusion/reperfusion. Ventricular fibrillation developed in two of 10 control versus three of 10 treated dogs (p = NS). Hemodynamics, collateral blood flow to the ischemic wall measured 10 min after occlusion, and extent of area at risk were comparable for the two groups. Infarct size/area at risk was smaller in treated than in control dogs (4.5 +/- 2.1% vs. 27.8 +/- 7.8%, respectively; p < 0.05). During occlusion, carperitide tended to increase collateral blood flow (+39%) and significantly decreased left ventricular systolic pressure (-13%) and end-diastolic pressure (-40%) compared with baseline. In control dogs, collateral blood flow tended to decrease (-8.3%), whereas most hemodynamic parameters did not change significantly with respect to baseline. The number of arrhythmias recorded during occlusion/reperfusion was similar in the two groups. Intravenous administration of carperitide limited infarct size, but did not reduce incidence of ventricular arrhythmias after 90-min coronary occlusion/6-h reperfusion in anesthetized dogs. Although the beneficial effects of carperitide may be attributable to concomitant changes in hemodynamics and collateral blood flow, the precise mechanisms require further investigation.

Ｃａｒｐｅｒｉｔｉｄｅ（ＳＵＮ ４９３６：α‐ヒト心房性ナトリウム利尿ペプチド）投与による運動誘発左心機能障害の改善

Effects of carperitide on cardiac function during dynamic exercise were studied in 11 patients, aged 50 to 68 years, with chronic heart failure.Changes in hemodynamic parameters during symptom-limited supine multistage bicycle ergometer exercise testing, in which initial work load of 25 w was increased stepwise by 25 w every 3 min, were compared before and after intra-pulmonary artery infusion of carperitide (0.05 or 0.1μg/kg/min, for 30 min).Following carperitide infusion at rest, systolic and diastolic blood pressure, systemic vascular resistance and pulmonary artery wedge pressure decreased significantly, while the heart rate increased signficantly.At the time of peak exercise, the pulmonary artery wedge pressure remained at a lower level (13.5±2.9mmHg ; mean±SEM) after the infusion of carperitide as compared to the case of placebo infusion (25.1±2.4mmHg, p<0.001). Other hemodynamic parameters including blood pressure, heart rate, cardiac index, coronary sinus flow, systemic vascular resistance, coronary vascular resistance, and myocardial oxygen consumption showed no significant diffe- rences between the carperitide and placebo groups.One of 2 patients receiving 0.1μg/kg/min of carperitide was withdrawn from the study due to the occurrence of abrupt hypotension. None of 9 patients receiving 0.05μg/kg/min experienced any adverse effect.These results suggest that infusion of carperitide at a moderate dose can exert some beneficial hemodynamic effects on exercise-induced impairment of left ventricular function in patients with chronic heart failure.

Effect of carperitide (alpha-human atrial natriuretic polypeptide) on the cardiovascular system in experimental animals

The cardiovascular and diuretic actions of carperitide were studied in experimental animals. Carperitide relaxed various canine arteries and veins that were contracted by high K+ or norepinephrine. Carperitide stimulated particulate guanylate cyclase from rat thoracic aortas. Carperitide had almost no effect on coronary perfusion pressure or heart rate, but caused a slight decrease in contractile force in isolated guinea pig hearts. Carperitide tended to decrease isoproterenol-induced renin release from isolated rat kidney slices and elicited decreases in angiotensin II-induced aldosterone release from bovine zona glomerulosa cells. Intravenous injection of carperitide elicited decreases in arterial blood pressure and total peripheral resistance in the anesthetized and conscious dogs. Carperitide also elicited transient increases in cardiac output and coronary blood flow followed by slight decreases in them. Intravenous infusion of carperitide elicited decreases in pulmonary capillary wedge pressure, pulmonary pressure and right atrial pressure in association with elevating plasma carperitide (ANP like immuno-reactivity) level in dogs with heart failure induced by coronary artery occlusion and saline loading. These results suggest that carperitide decreases both preload and afterload and can improve the untoward hemodynamic alterations in animals with acute experimental heart failure.