Time course of release of atrial natriuretic peptide in the anaesthetized dog

In 12 chloralose anaesthetized dogs plasma concentration of immunoreactive atrial natriuretic peptide (IR-ANP) was measured using a radioimmunoassay. Plasma IR-ANP was 74 +/- 4.8 pg/mL (mean +/- SE) and increased by 39 +/- 4.1 pg/mL when left atrial pressure was increased by 10 cm H2O during partial mitral obstruction. Observation of the time course of the changes in IR-ANP during atrial distension showed that IR-ANP was increased within 2 min of atrial distension and declined after atrial distension, with a half-time of 4.5 min. The time course of the changes in IR-ANP was unaffected by vagotomy or administration of atenolol. Maximum electrical stimulation of the right ansa subclavia failed to produce any change in IR-ANP. IR-ANP was higher in coronary sinus plasma than in femoral arterial plasma confirming that the heart was the source of the IR-ANP. The results support the hypothesis that IR-ANP is released from the heart by a direct effect of stretch of the atrial wall rather than by a neural or humoral mechanism involving a reflex from atrial receptors.     

Exercise induced increase in plasma atrial natriuretic peptide and effect of sodium loading in normal man

Atrial tachyarrhythmias and atrial pacing are associated with increased cardiac secretion of atrial natriuretic peptide (ANP) in man. Using treadmill exercise to exhaustion, we have studied the effect of exercise induced tachycardia on plasma immunoreactive ANP (IR-ANP) and vasoactive hormones in 6 normal men before and after 6 days of sodium loading (salt supplements and 0.4 mg 9 alpha fludro hydrocortisone daily for 4 days). Similar increases in heart rate and plasma catecholamine levels occurred during exercise in both studies. Sodium loading increased resting supine plasma IR-ANP (P less than 0.037) and suppressed plasma renin and aldosterone, including the renin-aldosterone response to exercise. Plasma IR-ANP increased more than 3-fold during exercise to 48 +/- 7 before and 66 +/- 12 pmol/l after sodium loading (P greater than 0.1). When the response of individual subjects was examined, there was no significant correlation between change in plasma IR-ANP and change in heart rate or catecholamine levels in either exercise study. Exercise induces greater increments in plasma IR-ANP than either acute or chronic sodium loading in normal men and may be a useful and rapid means of assessing the heart's ability to secrete ANP.     

Chronic and acute volume expansion in normal man: effect on atrial diameter and plasma atrial natriuretic peptide

Plasma levels of immunoreactive alpha human atrial natriuretic peptide (IR-ANP) and left atrial diameter were measured in 6 normal subjects before and after 6 days of sodium loading using salt supplements and 9-alpha-fluorohydrocortisone. During chronic sodium loading, which increased mean body weight by 1.5 kg and markedly reduced plasma renin and aldosterone levels, plasma IR-ANP increased from 21 +/- 3 to 36 +/- 7 pmol/l (P less than 0.02). Increase in atrial diameter correlated with gains in body weight (r = 0.93, P less than 0.01) but not with increase in plasma IR-ANP. After chronic sodium loading for 6 days, further volume expansion (2 litres of saline infused over 2 hours) significantly increased left atrial diameter but did not affect plasma IR-ANP levels. We conclude that chronic sodium loads increase plasma IR-ANP. However, the failure of further acute atrial distension to increase hormone levels suggests that factors in addition to atrial stretch are important in regulating atrial peptide secretion in man.     

A possible contribution of endogenous atrial natriuretic peptide to proteinuria in patients with chronic renal failure.

Plasma levels of immunoreactive atrial natriuretic peptide (IR-ANP) were measured with a specific radioimmunoassay in 19 undialysed patients with chronic renal failure. At the beginning, an extremely high level of plasma hANP (50 fmol/ml) seen in a patient was rejected with Smirnov's test and was excluded from further statistics. The plasma IR-ANP levels in these patients were significantly higher than those of 19 normal subjects matched with age and sex (10.9 +/- 1.6 vs 5.3 +/- 0.6 fmol/ml, mean +/- SEM, p less than 0.01), and positively correlated with mean blood pressure (r = 0.44, p less than 0.05) and the cardiothoracic ratio (r = 0.65, p less than 0.01), but did not correlate with creatinine clearance (r = -0.38, n.s.). Further, a significant correlation was observed between plasma IR-ANP and urinary protein output (r = 0.47, p less than 0.05). On the other hand, urinary protein output did not correlate significantly with variables such as mean blood pressure, the cardiothoracic ratio or creatinine clearance. Since it has been suggested that ANP enhances glomerular capillary permeability, increased ANP responding to volume overload in those patients may play an important role in increasing urinary protein excretion.     

Therapeutic actions of alpha-human atrial natriuretic polypeptide in 16 clinical cases

Alpha-human atrial natriuretic polypeptide (alpha-hANP) was applied to 16 clinical patients, 6 patients with essential hypertension, 7 patients with congestive heart failure and 3 patients with cirrhosis. Following intravenous bolus injection of 400 micrograms of synthetic alpha-hANP, a hypotensive effect of very rapid onset was found, which was more potent in the hypertensive patients than in the normotensive cases. Cardiac functions were improved significantly with a similar time course as the depressor response in the cases of heart failure or hypertension. Hemodynamic observations showed a marked increase in cardiac output, cardiac index, stroke volume, ejection fraction and ejection rate, and a concomitant decrease of the pressure in the right side of the heart and pulmonary circulation in these subjects. In addition, the renal response to alpha-hANP induced obvious increases in urine volume, electrolytes and creatinine excretions in all the subjects. Finally, plasma levels of aldosterone, Arg-vasopressin and noradrenaline were also altered by alpha-hANP. No significant side effects were registered. The above result confirms the therapeutic actions of alpha-hANP in human subjects and opens the possibility to research alpha-hANP as a powerful pharmacological tool as well as potential new medicine for human disorders.     

Adrenomedullin and heart failure

Evidence suggests that adrenomedullin (AM) plays a role in the pathophysiology of heart failure. Circulating concentrations of AM are elevated in cardiovascular disease in proportion to the severity of cardiac and hemodynamic impairment. Raised plasma AM levels following acute cardiac injury and in heart failure provide prognostic information on adverse outcomes. In heart failure, elevated circulating AM also identifies patients likely to receive long-term benefit from inclusion of additional anti-failure therapy (carvedilol). Administration of AM in experimental and human heart failure induces reductions in arterial pressure and cardiac filling pressures, and improves cardiac output, in association with inhibition of plasma aldosterone (despite increased renin release) and sustained (or augmented) renal glomerular filtration and sodium excretion. Furthermore, AM in combination with other therapies (angiotensin-converting enzyme inhibition and augmentation of the natriuretic peptides) results in hemodynamic and renal benefits greater than those achieved by the agents separately. Manipulation of the AM system holds promise as a therapeutic strategy in cardiac disease.     

Recent Advances in Hypertension

The possible relationship between the renal mechanism of volume control and blood pressure regulation is discussed. Expansion of the extracellular fluid (ECF) and plasma volumes was demonstrated following renal artery constriction in the rat; after about one month ECF volume returned to normal although hypertension persisted. Measurements of cardiac output in the unanesthetized rat by an implanted electromagnetic flowmeter showed an initial rise in cardiac output after renal artery constriction, returning to normal in 10 to 15 days. A homeostatic hypothesis for the production of renal hypertension is put forward in which changes in ECF volume, capacity vessel tone and myocardial contractility participate in the development of hypertension by elevating cardiac output. Autoregulation of peripheral flow then occurs and the consequent restoration of blood pressure at a renal pressure receptor results in return to normal of cardiac output by negative feedback. Thus in chronic hypertension the high peripheral resistance is maintained by autoregulation.     

Can the heart initiate some forms of hypertension?

An active role for the heart in the initiation of hypertension can be postulated in two different sets of conditions. 1) Activation of pressor reflexes from the ventricles, coronary arteries, or aorta has been shown to produce substantial rises of arterial pressure; experience with postcoronary bypass hypertension suggests that these reflexes could be responsible for some types of paroxysmal hypertension. 2) Increased cardiac action caused by either neural or humoral factors can initiate a rise in cardiac output and blood pressure; sustained hypertension could be produced experimentally in conscious dogs by electrical stimulation of the stellate ganglion or by continuous infusion of dobutamine in the left coronary artery. Evidence suggesting that this could occur in humans was derived from a study of the relationship of cardiac output to cardiopulmonary volume in essential hypertension.     

Bioactivity of adrenomedullin and proadrenomedullin N-terminal 20 peptide in man.

Although the biological effects of adrenomedullin (AM) and PAMP have been reported extensively in animal studies and from in-vitro experiments, relatively little information is available on responses to the hormone administered to man. This review summarizes data from the few studies carried out in man. In healthy volunteers, i.v. infusion of AM reduces arterial pressure, probably at a lower rate of administration than is required to elicit other responses. AM stimulates heart rate, cardiac output, plasma levels of cAMP, prolactin, norepinephrine and renin whilst inhibiting any concomitant response in plasma aldosterone. Little or no increase in urine volume or sodium excretion has been observed. Patients with essential hypertension differ only in showing a greater fall in arterial pressure and in the development of facial flushing and headache. In patients with heart failure or chronic renal failure, i.v. AM has similar effects to those seen in normal subjects but also induces a diuresis and natriuresis, depending on the dose administered. Infusion of AM into the brachial artery results in a dose-related increase in forearm and skin blood flow, more prominent and more dependent on endogenous nitric oxide in healthy volunteers than in patients with cardiac failure. When infused into a dorsal hand vein, AM partially reversed the venoconstrictor action of norepinephrine. Although much more information is required to clarify the role of AM under physiological and pathophysiological circumstances, it is clear that it has prominent hemodynamic and neurohormonal effects, though generally lesser urinary effects when administered short-term in doses sufficient to raise its levels in plasma to those seen in a number of clinical disorders. The only study of PAMP in man showed that its skeletal muscle vasodilator potency, when infused into the brachial artery of healthy volunteers, was less than one hundredth that of AM, and it was without effect on skin blood flow.     

The influence of carotid sinus pressure on plasma atrial natriuretic peptide in anaesthetized rabbits

The effect of changes in carotid sinus perfusion pressure on plasma immunoreactive atrial natriuretic peptide (IR-ANP) was examined in anaesthetized rabbits, and the role of arterial pressure in mediating the changes in IR-ANP was assessed. Plasma IR-ANP was significantly greater (101.7 +/- 24.3 pg ml-1) when carotid sinus pressure was 60 mmHg than when it was 160 mmHg (27.1 +/- 8.6 pg ml-1). Mean arterial pressure (MAP) was significantly greater when carotid sinus pressure was controlled at 60 mmHg compared to when it was 160 mmHg, but right atrial pressure (RAP) was not significantly different at the two carotid sinus pressures. The administration of hexamethonium attenuated the changes in MAP and heart rate (HR) which occurred in response to alterations in carotid sinus pressure, and abolished the change in plasma IR-ANP. The results suggest that an inverse relationship exists between carotid sinus pressure and plasma IR-ANP, and that the release of ANP in response to a reduction of carotid sinus pressure is mediated by the associated haemodynamic changes.     

Alteration of humoral and peripheral vascular responses during graded exercise in heart failure

We hypothesized that performanceof exercise during heart failure (HF) would lead to hypoperfusion ofactive skeletal muscles, causing sympathoactivation at lower workloadsand alteration of the normal hemodynamic and hormonal responses. Wemeasured cardiac output, mean aortic and right atrial pressures,hindlimb and renal blood flow (RBF), arterial plasma norepinephrine(NE), plasma renin activity (PRA), and plasma arginine vasopressin(AVP) in seven dogs during graded treadmill exercises and at rest. Incontrol experiments, sympathetic activation at the higher workloadsresulted in increased cardiac performance that matched the increasedmuscle vascular conductance. There were also increases in NE, PRA, and AVP. Renal vascular conductance decreased during exercise, such thatRBF remained at resting levels. After control experiments, HF wasinduced by rapid ventricular pacing, and the exercise protocols wererepeated. At rest in HF, cardiac performance was significantly depressed and caused lower mean arterial pressure, despite increased HR. Neurohumoral activation was evidenced by renal and hindlimb vasoconstriction and by elevated NE, PRA, and AVP levels, but it didnot increase at the mildest workload. Beyond mild exercise, sympathoactivation increased, accompanied by progressive renal vasoconstriction, a fall in RBF, and very large increases of NE, PRA,and AVP. As exercise intensity increased, peripheral vasoconstriction increased, causing arterial pressure to rise to near normal levels, despite depressed cardiac output. However, combined with redirection ofRBF, this did not correct the perfusion deficit to the hindlimbs. Weconclude that, in dogs with HF, the elevated sympathetic activity observed at rest is not exacerbated by mild exercise. However, withheavier workloads, sympathoactivation begins at lower workloads andbecomes progressively exaggerated at higher workloads, thus alteringdistribution of blood flow.

     

Endothelin-1 in chronic renal failure and hypertension

Investigation into the role of endothelin-1 (ET-1) in renal function has revealed two major direct actions leading to the control of extracellular volume and blood pressure. These are the regulation of renal hemodynamics and glomerular filtration rate and the modulation of sodium and water excretion. In the rat remnant kidney model of chronic renal failure, ET-1 production is increased in blood vessels and renal tissues. These changes are related to an increase in preproET-1 expression and correlate with the rise in blood pressure, the development of cardiovascular hypertrophy, and the degree of renal insufficiency and injury. Selective ETA receptor blockade prevents the progression of hypertension and the vascular and renal damage, supporting a role for ET-1 in chronic renal failure progression. The increase in ET-1 production can be associated with other local mediators, including angiotensin II, transforming growth factor-beta1 and nitric oxide, the local production of which is also altered in chronic renal failure. In human patients with essential hypertension, atherosclerosis, and nephrosclerosis, plasma ET-1 levels are increased compared with patients with uncomplicated essential hypertension. Similarly, plasma ET-1 concentrations are markedly increased in patients with end-stage renal disease undergoing dialysis, and this correlates with blood pressure, suggesting that ET-1 may contribute to hypertension in these patients. The treatment of anemia in patients with renal failure with human recombinant erythropoietin increases blood pressure by accentuating the underlying endothelial dysfunction and the elevated vascular ET-1 production. Overall, these results support a role for ET-1 in hypertension and the end-organ damage associated with chronic renal failure. ETA receptor blockade may then represent a potential target for the management of hypertension and cardiovascular and renal protection.     

Hemodynamic effects of arginine vasopressin in rats adapted to chronic hypoxia

Acute and chronic pulmonary and systemic hemodynamic responses to arginine vasopressin (AVP) were examined in 4-wk hypoxia-adapted and air control rats. AVP, administered intravenously as bolus injections or sustained infusions, produced major dose-dependent V1-receptor-mediated reductions in mean pulmonary arterial pressure in hypoxia-adapted rats. These effects were comparable in pentobarbital-anesthetized, thoracotomized animals and in conscious, intact rats. Chronic infusions of AVP induced a sustained reduction in mean pulmonary arterial pressure and partially prevented the development of pulmonary hypertension without changing systemic arterial pressure. AVP induced significant decreases in cardiac output in both groups; the cardiac output response was not significantly different in hypoxia-adapted and air control animals. AVP induced almost no change in MPAP in air control rats. Furthermore the systemic pressor effects of AVP were significantly blunted in hypoxia-adapted rats compared with air controls. We conclude that the pulmonary depressor and blunted systemic pressor effects of AVP observed in hypoxia-adapted rats may be related to release of a vasodilator, such as endothelium-derived relaxing factor, vasodilator prostaglandins, or atrial natriuretic peptides. Further study is needed to elucidate these mechanisms and assess the usefulness of AVP and/or its analogues in the treatment and prevention of hypoxia-induced pulmonary hypertension.     

Altered Orcadian Rhythms of Blood Pressure and Heart Rate in Non-Hemodialysis Chronic Renal Failure

The extended use of ambulatory monitoring has permitted the identification of many conditions in which the circadian rhythm of blood pressure is altered. The common denominator seems to be an impairment of the autonomic nervous system function. We examined whether the circadian blood pressure rhythm is altered in chronic renal failure (where autonomic dysfunction is usually present) by using a standardized chronobiological inferential statistical method in hospitalized subjects. For this purpose, a group of 30 non-hemodialysis hypertensive patients with chronic renal failure was compared with a second group of 30 patients affected by uncomplicated mild-to-moderate essential hypertension. The two groups were matched by age, sex and circadian mesors of blood pressure. Diet, meal times, sleep and activity logs were standardized. Blood pressure and heart rate recordings were obtained by using an automatic oscillometric recorder and subsequently analyzed according to the cosinor method. A mean circadian rhythm of blood pressure was documented in both groups, but while the mean acrophases occurred between 2 and 3 p.m. in essential hypertension, in renal failure they were between 11 p.m. and midnight for blood pressure and around 7 p.m. for heart rate. In addition, the mean circadian amplitudes were significantly lower in renal failure, while the mean circadian mesor of heart rate was significantly higher. Our data demonstrate that the circadian rhythms of blood pressure and heart rate are altered also in hypertension due to chronic renal failure.     

Altered Orcadian Rhythms of Blood Pressure and Heart Rate in Non-Hemodialysis Chronic Renal Failure

The extended use of ambulatory monitoring has permitted the identification of many conditions in which the circadian rhythm of blood pressure is altered. The common denominator seems to be an impairment of the autonomic nervous system function. We examined whether the circadian blood pressure rhythm is altered in chronic renal failure (where autonomic dysfunction is usually present) by using a standardized chronobiological inferential statistical method in hospitalized subjects. For this purpose, a group of 30 non-hemodialysis hypertensive patients with chronic renal failure was compared with a second group of 30 patients affected by uncomplicated mild-to-moderate essential hypertension. The two groups were matched by age, sex and circadian mesors of blood pressure. Diet, meal times, sleep and activity logs were standardized. Blood pressure and heart rate recordings were obtained by using an automatic oscillometric recorder and subsequently analyzed according to the cosinor method. A mean circadian rhythm of blood pressure was documented in both groups, but while the mean acrophases occurred between 2 and 3 p.m. in essential hypertension, in renal failure they were between 11 p.m. and midnight for blood pressure and around 7 p.m. for heart rate. In addition, the mean circadian amplitudes were significantly lower in renal failure, while the mean circadian mesor of heart rate was significantly higher. Our data demonstrate that the circadian rhythms of blood pressure and heart rate are altered also in hypertension due to chronic renal failure.     

Plasma and atrial levels of atrial natriuretic peptide (ANP) in pulmonary hypertensive rats

Immunoreactive atrial natriuretic peptide (IR-ANP) was measured in plasma and atrium of normal and monocrotaline induced pulmonary hypertensive rats (PH rats). In these animals, there was right ventricular hypertrophy and right ventricular systolic pressure was elevated. Fourteen days after a single dose of monocrotaline (40 mg/kg), plasma IR-ANP concentrations were significantly elevated (964.3 +/- 63.0 pg/ml vs. 521.0 +/- 81.9 pg/ml in controls, p less than 0.001). Tissue levels of IR-ANP in the right atrium in PH rats was significantly lower than those in the controls (45.1 +/- 3.9 ng/mg vs. 240.5 +/- 10.4 ng/mg, p less than 0.001), while there was no significant difference in tissue levels of atrial IR-ANP in the left atrium between the two groups. Thus, development of pulmonary hypertension led to an increase in release of ANP from the right atrium.     

Changes in the proportion of A- and B-types of granules containing atrial and brain natriuretic peptides in atrial myocytes in vasorenal hypertension in rats

The system of cardiac natriuretic peptides (NP) is a very important factor opposing the effects of the rennin-angiotensin-aldosterone system (RAAS), sympathoadrenal system and vasopressin to reduce blood pressure. In the present study, we analyzed the release of atrial and brain natriuretic peptides in the myocytes of the right atrium in rats by the quantitative morphometric method using double immunocytochemical labeling of atrial granules comprising NP in vasorenal hypertension induced by the renal artery ligation. The decrease in the total amount of secretory granules in atrium myocytes by 18% was detected on the 30th day after the operation. The number of the A-type granules was reduced by 53%, and the number of B-type granules was increased by 64% in comparison with the intact animals. Our data indicate activation of NP secretion in vasorenal hypertension. The results suggest that high arterial pressure might be explained by reduced expression of NP receptors in this pathology.     

利钠肽家族基因与心血管疾病研究新进展

利钠肽家族是一组由心肌细胞分泌的激素,主要包括A型、B型和C型利钠肽,具有相似的基因结构和生理学效应,可对心血管系统产生血压调节、抗心肌肥厚、抗心肌纤维化和抗心肌弛缓等保护作用。利钠肽受体A、B和C亦介导多种生理活性,调节心血管稳态。利钠肽受体A选择性结合A型、B型利钠肽。利钠肽受体B结合C型利钠肽。利钠肽受体C结合各型利钠肽,通过受体介导的内化和退化作用清除血液循环中利钠肽。对利钠肽家族及其受体基因单核甘酸多态性及功能研究显示,其与多种心血管疾病(房颤、高血压、心力衰竭等)的易感性相关。利钠肽家族及其受体基因缺失的转基因小鼠表现为心肌肥厚、心肌纤维化,与高血压、心肌病及心力衰竭的发生发展相关。各种导致心肌肥厚和缺血性损伤的刺激均参与利钠肽及其受体基因的表达调控。临床将脑钠肽作为左室功能障碍和心力衰竭失代偿的一个预测指标。静脉注射重组脑钠肽已经成为治疗急性心力衰竭的有效手段。深入了解利钠肽家族基因变异及其信号调控有助于探索心血管疾病的病理生理机制,为临床诊疗开辟新思路。     

利钠肽家族基因与心血管疾病研究新进展

利钠肽家族是一组由心肌细胞分泌的激素, 主要包括A型、B型和C型利钠肽, 具有相似的基因结构和生理学效应, 可对心血管系统产生血压调节、抗心肌肥厚、抗心肌纤维化和抗心肌弛缓等保护作用。利钠肽受体A、B和C亦介导多种生理活性, 调节心血管稳态。利钠肽受体A选择性结合A型、B型利钠肽。利钠肽受体B结合C型利钠肽。利钠肽受体C结合各型利钠肽, 通过受体介导的内化和退化作用清除血液循环中利钠肽。对利钠肽家族及其受体基因单核甘酸多态性及功能研究显示, 其与多种心血管疾病(房颤、高血压、心力衰竭等)的易感性相关。利钠肽家族及其受体基因缺失的转基因小鼠表现为心肌肥厚、心肌纤维化, 与高血压、心肌病及心力衰竭的发生发展相关。各种导致心肌肥厚和缺血性损伤的刺激均参与利钠肽及其受体基因的表达调控。临床将脑钠肽作为左室功能障碍和心力衰竭失代偿的一个预测指标。静脉注射重组脑钠肽已经成为治疗急性心力衰竭的有效手段。深入了解利钠肽家族基因变异及其信号调控有助于探索心血管疾病的病理生理机制, 为临床诊疗开辟新思路。     

Hemodynamic and plasma atrial natriuretic factor responses to cardiac volume loading in young versus older normotensive humans.

To assess the effects of age on responsiveness of atrial natriuretic factor (ANF) release, and the possible contribution of cardiac sympathetic activity, in young (n = 8) and older normotensives (n = 7), the effects of cardiac volume load on plasma ANF, central venous pressure, and general hemodynamics were evaluated. Studies were performed after pretreatment with placebo or 80 mg propranolol. Cardiac volume loading increased central venous pressure by 3-5 mmHg (1 mmHg = 133.3 Pa); beta-blockade did not affect this response. Cardiac volume load caused significant increases in heart rate (10-15 beats/min) and cardiac index (by 0.7-0.8 L.min-1.m-2) and decreases in plasma catecholamines. Propranolol attenuated the increases in heart rate and cardiac index. These hemodynamic responses did not differ significantly between the two groups of subjects. Cardiac volume load significantly increased plasma ANF, by 87 +/- 21 pg/mL in the young normotensives and by 212 +/- 33 pg/mL in the older normotensives (p < 0.01, young vs. older). beta-Blockade did not affect this different response. Our results show that the plasma ANF response to volume loading is potentiated by aging. Although differences in atrial stretch cannot be excluded, this effect may relate to the decrease in clearance of plasma ANF occurring with aging.