Splanchnic disposal of human atrial natriuretic peptide in humans

In healthy men (n = 6), the splanchnic fractional extraction of human atrial natriuretic peptide (hANP), as determined by the hepatic venous catheter technique, was 75% under basal conditions resulting in a splanchnic uptake of hANP of 8.5 +/- 5.0 pmol/min. In spite of a drop (P less than .05) in splanchnic fractional extraction to about 50%, splanchnic uptake of hANP rose to 56 to 99 pmol/min (P less than .01) when pharmacologic plasma concentrations of hANP were induced during a bolus (100 micrograms)-primed intravenous (IV) infusion (100 micrograms/h; time, one hour) of hANP. This was accompanied by a fall in estimated hepatic blood flow (P less than .05), in pulmonary arterial pressure (P less than .01), and, in each individual, in systemic BP. Total metabolic clearance rates, splanchnic clearance rates, and production rates of hANP were 4.5 +/- 2.2 L/min, 0.4 +/- 0.1 L/min, and 46.1 +/- 20.1 pmol/min, respectively. Thus, in healthy men, the splanchnic area accounts for approximately 10% of total hANP clearance.     

Coronary hemodynamic effects of atrial natriuretic peptide in humans

Studies of the effects of atrial natriuretic peptide on the coronary circulation have yielded conflicting results in animals and have not been fully investigated in human subjects. To further characterize the direct coronary hemodynamic actions of atrial natriuretic peptide in humans and to assess the safety of its administration in patients with coronary artery disease, incremental doses of synthetic atrial natriuretic peptide and nitroglycerin were infused into the left coronary artery in 14 patients, 11 of whom had coronary artery disease. Both agents caused dose-related increases in total coronary sinus blood flow. The largest dose of atrial natriuretic peptide given to all patients (100 micrograms) increased mean coronary sinus blood flow from 127 +/- 7 to 149 +/- 9 ml/min (p less than 0.05) and decreased coronary vascular resistance from 0.93 +/- 0.07 to 0.81 +/- 0.05 mm Hg/ml per min (p less than 0.05); mean arterial blood pressure and heart rate were not affected by this dose of atrial natriuretic peptide. The greatest changes in coronary sinus blood flow (+25%) and coronary vascular resistance (-18%) after atrial natriuretic peptide administration occurred in the patients with coronary artery disease and no other associated cardiovascular disease. The maximal effects of atrial natriuretic peptide were similar to those of nitroglycerin, and no untoward effects were observed. Thus, atrial natriuretic peptide is a direct coronary vasodilator in humans. Its maximal dose effects are similar to those of nitroglycerin and were well tolerated in this small group of patients. The physiologic importance and therapeutic potential of atrial natriuretic peptide in patients with coronary artery disease merit further investigation.     

Effects of atrial natriuretic peptide on the coronary arterial vasculature in humans

The effects of the synthetic 28-amino-acid alpha-human atrial natriuretic peptide (ANP) on the proximal coronary arteries and coronary blood flow were evaluated in 17 patients. Proximal coronary dimension was quantitated by digital angiography, and coronary flow was quantitated with 3F Doppler flow catheters. ANP, when given as a 2.5-micrograms/kg bolus in the left ventricle, caused sustained significant proximal coronary dilations from 3.49 +/- 0.57 to 4.09 +/- 0.76 mm, lasting more than 30 minutes. The proximal coronary diameter did not increase further after intracoronary injection of 0.3 mg nitroglycerin (4.08 +/- 0.79 mm). Coronary flow (resistance coronary dilation) was not significantly increased at 5 minutes after ANP (87 +/- 55 to 102 +/- 54 vol flow units), indicating that the proximal coronary dilations were not flow dependent. The persistent proximal coronary dilations were associated with minor and transient decreases in aortic pressure and left ventricular end-diastolic pressure and with minor and transient increases in heart rate, cardiac output, and left ventricular contractility. Plasma ANP level increased significantly by more than sixfold from 39.8 +/- 8.8 to 245.8 +/- 168.5 pg/ml. The time course of proximal coronary dilations was related more closely to the time course of increase in plasma cyclic guanosine monophosphate than that of plasma ANP. This study demonstrates that bolus injection of ANP (2.5 micrograms/kg), an endogenous vasodilator, caused marked sustained preferential proximal coronary dilations and brief minor changes in cardiac and systemic hemodynamics. Although additional studies are needed to assess its clinical efficacy as a coronary dilator in the treatment of coronary artery disease, these data suggest a potential of ANP in the therapy of ischemia.     

Hormonal responses to synthetic atrial natriuretic peptide in patients on regular hemodialysis

The effects of atrial natriuretic peptide (ANP) on mean arterial blood pressure, heart rate, plasma renin activity, aldosterone, cortisol, norepinephrine, epinephrine and arginine vasopressin were studied in 6 anuric subjects receiving regular hemodialysis. An iv bolus injection of 8 nmol of ANP followed by infusion at 32 pmol.kg-1.min-1 for 1 h in the pre- and posthemodialysis period was performed. Basal plasma ANP was higher before than after hemodialysis. ANP administration produced a reduction in mean arterial blood pressure accompanied by an elevation of norepinephrine and of plasma renin activity (from 2.49 +/- 0.52 to 3.39 +/- 0.85 nmol.1-1.h-1 predialysis and from 2.78 +/- 0.71 to 3.15 +/- 0.86 nmol.l-1.h-1 postdialysis, respectively, mean +/- SEM; P less than 0.05). Plasma aldosterone and cortisol were significantly decreased. Plasma epinephrine and AVP remained unchanged. These hemodynamic and hormonal changes were similar in the pre- and the postdialysis period. These results suggest that 1) ANP causes a fall in mean arterial blood pressure, which in turn induces reflex tachycardia and activation of the sympathetic nervous system without diuresis; 2) the activated sympathetic nervous system as reflected in elevation of plasma norepinephrine may increase plasma renin activity; 3) reduced plasma aldosterone is not influenced by enhancement of the renin-angiotensin system; therefore, 4) reduction of plasma aldosterone as well as cortisol is probably due to direct action of ANP, and finally 5) AVP had no direct relation with ANP administration.     

Effect of induced ventricular tachycardia on atrial natriuretic peptide in humans

The effects of induced sustained ventricular tachycardia on the release of plasma-immunoreactive atrial natriuretic peptide were evaluated in 11 adult patients undergoing diagnostic electrophysiologic study. Plasma concentrations of atrial natriuretic peptide withdrawn from the right atrium before and during sustained ventricular tachycardia (mean tachycardia cycle length 320 +/- 68 ms, duration greater than 30 s) were determined by radioimmunoassay. Hemodynamic measurements included phasic femoral artery blood pressure and mean right atrial blood pressure before and during ventricular tachycardia. During ventricular tachycardia, atrial natriuretic peptide increased from 93 +/- 49 pg/ml to 234 +/- 195 pg/ml (p less than 0.05), systolic arterial blood pressure decreased from 120 +/- 16 to 70 +/- 23 mm Hg (p less than 0.001), diastolic arterial blood pressure decreased from 63 +/- 8 to 51 +/- 16 mm Hg (p = NS) and mean right atrial blood pressure increased from 3 +/- 1 to 8 +/- 5 mm Hg (p less than 0.02). In six patients, all hemodynamic variables and the atrial natriuretic peptide were measured during repeated stimulation protocols to investigate the effect of ventricular stimulation for ventricular tachycardia induction on atrial natriuretic factor release. Compared with the values obtained during sinus rhythm, there was no significant increase in atrial natriuretic factor during ventricular stimulation at a cycle length of 600 ms (45 +/- 20 versus 52 +/- 21 pg/ml) or at a cycle length of 400 ms (45 +/- 20 versus 57 +/- 18 pg/ml). No significant linear relation could be found among the changes in mean right atrial pressure, systolic arterial blood pressure and the increase in atrial natriuretic peptide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of atrial natriuretic peptide on mammalian large intestine

Atrial natriuretic peptide is distributed in a number of organs including the large intestine. Atrial natriuretic peptide has potent diuretic and natriuretic properties and appears to play a central role in fluid and electrolyte homeostasis by an action on the kidney. We examined the influence of atrial natriuretic peptide on mammalian colon because this organ is also intimately involved in homeostasis. Segments of the distal colons of male Sprague-Dawley rats were stripped of muscle layers and mounted in flux chambers. Atrial natriuretic peptide, when added to the serosal side of the mucosa, in concentrations ranging from 10(-8)-10(-5) M, caused a rapid, concentration-dependent increase in short-circuit current, transmucosal electrical potential difference, and conductance. The response to atrial natriuretic peptide was inhibited by (a) chloride-free solution on the serosal surface; (b) pretreatment of the tissues with the chloride channel blocker, diphenylamine-2-carboxylate (10(-3) M mucosally); (c) pretreatment with d,l-verapamil (10(-4) M mucosally and serosally); (d) calcium-free solution on the serosal surface; (e) pretreatment with tetrodotoxin (10(-7) M to serosal surface); and (f) pretreatment with atropine (10(-5) M serosally). However, the response to atrial natriuretic peptide was not influenced by pretreatment with amiloride (10(-4) M to mucosal and serosal surfaces) or piroxicam (10(-5) M serosally). Atrial natriuretic peptide did not elicit an increase in short-circuit current and potential difference across T84 cells derived from a human colonic carcinoma cell line, suggesting that the response to atrial natriuretic peptide is not due to a direct effect on colonocytes. These findings suggest that atrial natriuretic peptide acts by a calcium-mediated secretory mechanism involving cholinergic nerves and is likely to be involved in the endogenous neurohumoral regulation of ion transport in the mammalian colon.     

Pressure dependence of atrial natriuretic peptide during norepinephrine infusion in humans

The relative contribution of increased blood pressure (BP) or norepinephrine (NE), or both, to the stimulatory effect of an NE pressor infusion on circulating immunoreactive atrial natriuretic peptide (ANP) was evaluated in 10 healthy young men. They were studied during an infusion of NE, which was applied initially alone and then in combination with sodium nitroprusside. NE infusion rate was increased in four 30-minute intervals to a final dose of 200 ng/kg body weight per minute, leading to 12-fold higher plasma NE levels than were seen during control conditions. This increased mean BP (from a mean basal value of 94 +/- 3 to 119 +/- 4 [SEM] mm Hg; p less than 0.001) and plasma immunoreactive ANP (from 50 +/- 7 to 112 +/- 17 pg/ml; p less than 0.001), whereas heart rate decreased (p less than 0.001). The NE infusion was continued at the highest dose and an additional infusion of sodium nitroprusside was started to titrate mean BP in 30-minute intervals down to control values; a mean sodium nitroprusside dose of 0.95 micrograms/kg/min restored mean BP to 93 +/- 4 mm Hg (p less than 0.001), decreased plasma immunoreactive ANP to basal values (51 +/- 4 pg/ml; p less than 0.001), increased heart rate (p less than 0.001), and left plasma levels of NE largely unchanged. Plasma protein and hematocrit rose about 5 to 6% (p less than 0.001) during the NE infusion and then decreased about 3 to 4% (p less than 0.001 and p less than 0.01) when sodium nitroprusside was added.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pressure-dependent distal tubular action of atrial natriuretic peptide in healthy humans

OBJECTIVE: To study the influence of blood pressure reduction with sodium nitroprusside on the renal glomerular and tubular actions of atrial natriuretic peptide. DESIGN: Forty-nine healthy subjects were examined in four different groups receiving placebo, sodium nitroprusside alone, atrial natriuretic peptide alone (10 ng/kg per min), or sodium nitroprusside and atrial natriuretic peptide in combination. The infusion rate of sodium nitroprusside was gradually increased until a 10 mmHg decrease in diastolic blood pressure was obtained. METHODS: Lithium clearance was used to evaluate segmental tubular reabsorption. RESULTS: In the placebo group neither renal nor hormonal parameters were changed. Except for a fall in urinary flow, sodium nitroprusside alone had no effect on renal parameters. Urinary excretion of cyclic GMP (cGMP) was slightly increased, whereas the plasma cGMP level was not changed in response to sodium nitroprusside. The plasma aldosterone level was elevated during sodium nitroprusside infusion, although neither the plasma angiotensin II level nor the plasma atrial natriuretic peptide level were changed. Atrial natriuretic peptide alone caused an increase in filtration fraction and a decrease in renal plasma flow. Urinary sodium excretion, fractional sodium excretion, and urinary flow were increased, and distal fractional tubular sodium absorption decreased, whereas lithium clearance and proximal fractional tubular re-absorption were not changed by atrial natriuretic peptide. Atrial natriuretic peptide alone caused a decrease in plasma aldosterone and an increase in plasma and urinary cGMP levels. During blood pressure reduction with sodium nitroprusside, atrial natriuretic peptide caused no changes in the renal parameters except for an increase in filtration fraction. Thus, the increase in urinary sodium excretion (-8 versus +37 micromol/min) and the decrease in distal fractional sodium excretion (0.0 versus -2.4%) caused by atrial natriuretic peptide were attenuated. The atrial natriuretic peptide-induced changes in proximal fractional tubular reabsorption (-0.5 versus +0.6%) and cGMP were not changed by blood pressure reduction. CONCLUSIONS: Blood pressure reduction causes an attenuation of the natriuretic action of atrial natriuretic peptide in normotensive humans that is at least partly caused by attenuation of the distal tubular action of atrial natriuretic peptide. The results support the hypothesis that the action of atrial natriuretic peptide on distal tubular sodium reabsorption is pressure-dependent in humans.     

Influence of betaxolol on renal function and atrial natriuretic peptide in essential hypertension.

The hypotensive action of beta-adrenoreceptor blockers is not fully understood, there being a lack of studies focusing on possible relationships between beta-blockers and the secretion of atrial natriuretic peptide (ANP). In 10 patients with essential hypertension, we investigated the influence of betaxolol, a selective beta 1-adrenergic blocking agent, on renal function and on plasma levels of ANP during exercise, volume depletion and volume expansion. Chronic therapy with betaxolol (mean 14.5 mg/day) did not alter glomerular filtration rate and renal blood flow although blood pressure was reduced. Renal vascular resistance decreased from 12795 +/- 1064 dyn/s per cm5 to 10614 +/- 833 dyn/s per cm5 (P less than 0.005). Under betaxolol, basal ANP levels increased from 39 +/- 10 pg/ml to 80 +/- 19pg/ml (P less than 0.01). ANP increased during exercise and volume expansion but was decreased during volume depletion. ANP values observed under betaxolol treatment showed significantly higher values while preserving their dynamic features. We believe that the stimulating effect of betaxolol on ANP may at least partly account for its hypotensive action.     

Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide.

To elucidate the ligand-receptor relationship of the natriuretic peptide system, which comprises at least three endogenous ligands, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), and three receptors, the ANP-A receptor or guanylate cyclase-A (GC-A), the ANP-B receptor or guanylate cyclase-B (GC-B), and the clearance receptor (C-receptor), we characterized the receptor preparations from human, bovine, and rat tissues and cultured cells with the aid of the binding assay, Northern blot technique, and the cGMP production method. Using these receptor preparations, we examined the binding affinities of ANP, BNP, and CNP for the C-receptor and their potencies for cGMP production via the ANP-A receptor (GC-A) and the ANP-B receptor (GC-B). These analyses revealed the presence of a marked species difference in the receptor selectivity of the natriuretic peptide family, especially among BNPs. Therefore, we investigated the receptor selectivity of the natriuretic peptide family using the homologous assay system with endogenous ligands and receptors of the same species. The rank order of binding affinity for the C-receptor was ANP greater than CNP greater than BNP in both humans and rats. The rank order of potency for cGMP production via the ANP-A receptor (GC-A) was ANP greater than or equal to BNP much greater than CNP, but that via the ANP-B receptor (GC-B) was CNP greater than ANP greater than or equal to BNP. These findings on the receptor selectivity of the natriuretic peptide family provide a new insight into the understanding of the physiological and clinical implications of the natriuretic peptide system.     

Discordant atrial natriuretic peptide and brain natriuretic peptide levels in lone atrial fibrillation

OBJECTIVES: We sought to characterize natriuretic peptide levels in a cohort of rigorously characterized subjects with lone atrial fibrillation (AF). BACKGROUND: Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are sensitive biomarkers of cardiac contractile dysfunction. Both peptides have been reported to be elevated in cohorts with AF, but previous studies have included subjects with underlying structural heart disease. We studied these hormones in 150 subjects with lone AF. METHODS: Study subjects had electrocardiographic evidence of at least one episode of AF and a structurally normal heart on echocardiography. Subjects were excluded if they had a history of a myocardial infarction, rheumatic heart disease, cardiomyopathy, significant valvular disease, hyperthyroidism, or hypertension that preceded the onset of AF. Control subjects were obtained from a healthy outpatient primary care population. Plasma pro-ANP and N-terminal pro-BNP (nt-pro-BNP) levels were determined using commercially available immunoassays. RESULTS: A total of 150 serial subjects with lone AF were enrolled and studied, the majority during normal sinus rhythm. Median levels of nt-pro-BNP were significantly elevated in subjects with lone AF as compared with control subjects (166 vs. 133 fmol/ml, p=0.0003). There was no significant difference in pro-ANP levels between subjects with lone AF and control subjects (1,730 vs. 1,625 fmol/ml, p=0.90). CONCLUSIONS: Discordant natriuretic peptide levels were observed in this homogeneous population of subjects with lone AF. This biomarker pattern, which is present even in sinus rhythm, may represent an underlying subclinical predisposition to this common arrhythmia.     

Hemodynamic and sympathetic responses to human atrial natriuretic peptide infusion in patients with cirrhosis

To determine the potential usefulness of atrial natriuretic peptide (ANP) in patients with cirrhosis, we examined the effects of the infusion of a low dose of alpha-human ANP (alpha hANP, 25 ng.kg-1.min-1 for 30 min) on renal, splanchnic, systemic hemodynamics and sympathetic outflow in eight patients. Pulmonary arterial plasma ANP concentrations increased from 59 +/- 9 to 328 +/- 41 pg/ml (mean +/- S.E., p less than 0.05). Mean values of glomerular filtration rate and renal plasma flow were not significantly changed. Individual renal plasma flow responses differed from one patient to another. Renal plasma flow increased in two patients, decreased in three and did not change in the other patients. Renal plasma flow changes were correlated with basal renal plasma flow values (r = -0.938, p less than 0.05) but not with arterial pressure changes or renal vein plasma norepinephrine concentration changes. Azygos blood flow increased from 0.43 +/- 0.10 to 0.63 +/- 0.13 l/min (p less than 0.05) and the hepatic-venous pressure gradient decreased from 19.9 +/- 1.5 to 17.5 +/- 2.9 mmHg in post-infusion (p less than 0.05). Mean arterial pressure decreased significantly by 18% and cardiac output by 12%. Systemic vascular resistance and pulmonary arterial plasma norepinephrine concentrations were not significantly modified. Thus, in patients with cirrhosis, alpha hANP appears to have a direct vasodilating action on renal arterioles when basal renal vascular tone is high. In addition, although alpha hANP might exert a portal hypotensive action, alpha hANP induced arterial hypotension as a result of both low cardiac output and a lack of increased sympathetic vascular tone. The arterial hypotensive action may, thus, limit the therapeutic use of low doses of alpha hANP in cirrhotic patients.     

Influence of angiotensin converting enzyme inhibition on relation of atrial natriuretic peptide concentration to atrial pressure in heart failure.

OBJECTIVE--To examine the influence of the duration of follow up on the values of heart rate variability (HRV) and the left ventricular ejection fraction (LVEF) for predicting mortality after infarction. BACKGROUND--HRV is an index of autonomic balance that identifies patients at a high risk of arrhythmic events. The index is most depressed during the first few weeks after myocardial infarction whereas left ventricular function tends to deteriorate with time. HYPOTHESIS--The value of depressed HRV measured before discharge from hospital for predicting mortality after infarction should decline with time. METHODS--The HRV and the LVEF were assessed in 433 survivors of a first acute myocardial infarction: HRV < 20 units and LVEF < 40% were taken as cut off points. Kaplan-Meier survival functions for total cardiac mortality and sudden cardiac death were calculated for the whole five year follow up period and for different intervening periods. RESULTS--During follow up of four weeks to five years there were 46 (10.6%) deaths and 15 (3.5%) patients died suddenly. Within the whole follow up period, HRV < 20 units and LVEF < 40% were both strongly associated with total cardiac mortality (p < 0.0001), but HRV was an independent predictor of total cardiac mortality only during the first six months of follow up. There were no deaths predicted by HRV < 20 units after the first year of follow up whereas LVEF < 40% had a sensitivity of 43% and a positive predictive accuracy of 9% for predicting death during this period. HRV < 20 units was better than LVEF < 40% in predicting sudden deaths during the first year of follow up but was an independent predictor only of those sudden deaths occurring within six months of infarction. CONCLUSIONS--The duration of follow up affects the prediction of sudden death and total cardiac mortality from HRV. Reduced HRV as measured before discharge from hospital does not seem to retain independent prognostic value after six months of follow up. These findings have potential implications for the serial evaluation of HRV and for the prevention of sudden death after myocardial infarction.     

Hormone and hemodynamic responses to atrial natriuretic peptide in conscious sheep and effect of hemorrhage

The effect of rat atrial natriuretic peptide (ANP) on basal hemodynamic and hormonal function and on the response to acute hemorrhage was studied in eight conscious sheep. ANP infusions (3 micrograms/kg BW bolus, followed by 50 ng/kg.min for 70 min) increased plasma immunoreactive ANP levels from less than 12 pmol/liter to steady state levels of 523 +/- 20 pmol/liter, reduced arterial pressure by 14% (P less than 0.002), increased heart rate by 26% (P less than 0.06), and increased plasma norepinephrine levels (P less than 0.015) compared to control values. These changes were associated with a significant increase in plasma cortisol (P less than 0.05) and smaller increases in plasma ACTH and arginine vasopressin (AVP), but plasma angiotensin II (AII) and aldosterone were unaffected. When hemorrhage (15 ml/kg BW over 10 min) was performed during ANP or control infusions, hypotension was greater (P less than 0.0004) during ANP treatment and the responses of plasma ACTH, AVP, catecholamines, and AII were enhanced compared with those to control hemorrhage. Plasma immunoreactive ANP during ANP infusions was significantly higher after hemorrhage (mean, 833 +/- 46; P less than 0.003), but the disappearance rate after the termination of ANP infusion was the same (3.1 min) with or without hemorrhage. These studies show that ANP infusions, achieving plasma levels observed in pathological states such as congestive heart failure, inhibit the expected responses of plasma AII and aldosterone to mild acute hypotension, but do not inhibit the responses of plasma AVP, ACTH, AII, and aldosterone associated with acute moderate hemorrhage in conscious sheep.     

普萘洛尔及其对映体血药浓度对血浆心钠素水平的影响

本文研究８名健康志愿者口服单剂量普萘洛尔（４０ｍｇ）和１２名健康志愿者口服多剂量普萘洛尔（８０ｍｇ／ｄａｙ×３）后；静息状态和踏车兴奋状态时血浆心钠素（ＡＮＰ）水平的变化。口服单剂量普萘洛尔后３ｈ，静息状态时血浆ＡＮＰ水平升高１９．４±１１．１ｎｇ／Ｌ（Ｐ＜０．０５）；而运动状态时血浆ＡＮＰ升高更为明显，为６４．８±４０．９ｎｇ／Ｌ（Ｐ＜０．０５）。血浆ＡＮＰ的变化与普萘洛尔对映体Ｓ（－）－ＰＰＬ和Ｒ（＋）－ＰＰＬ浓度均具有良好的线性相关性，相关系数分别为０．８５６３和０．７１９２。口服多剂量普萘洛尔停药后１２ｈ，血浆ＡＮＰ仍可维持较高水平，较基础对照值升高３９．９±２８．３ｎｇ／Ｌ（Ｐ＜０．０５）。此结果提示，普萘洛尔参与了血浆ＡＮＰ水平的调控，这种作用尚难以用β肾上腺素能效应进行解释，可能与抑制ＡＮＰ的体内降解过程有关。     

Pulmonary venous responses to thromboxane A2 analogue and atrial natriuretic peptide in lambs

To characterize pulmonary venous vasoactivity and the factors that modulate it, we determined venous responses to a vasoconstrictor agent, thromboxane A2 (TXA2) analogue U46619, and to a vasodilator agent, atrial natriuretic peptide (ANP), in 28 isolated blood-perfused lamb lungs under conditions of varying vascular tone and intraluminal pressures. TXA2 was given in a 5 micrograms/kg bolus followed by a steady infusion of 1 micrograms/kg/min to three groups of lungs: group 1, n = 4, with low vasomotor tone; group 2, n = 8, with moderate vasomotor tone; and group 3, n = 7, with moderate vasomotor tone and high venous intraluminal pressures. Group 3 lungs were reverse-perfused to obtain high venous pressures. ANP was given as two 10 micrograms/kg bolus injections, 5 minutes apart, to three groups of lungs: group 4, n = 4, with low vasomotor tone; group 5, n = 5, with moderate vasomotor tone; and group 6, n = 8, with high vasomotor tone. Group 6 lungs were vasoconstricted with TXA2 infusion. In all lungs, we measured blood flow and pressures in the pulmonary artery and left atrium and partitioned the venous segment by measuring pressures in 20-80-microns venules by micropuncture. We found that the venous constrictor response to TXA2 was greatest in lungs with moderate basal vasomotor tone and low venous intraluminal pressures. In lungs with low vasomotor tone or high venous intraluminal pressures, the venous response to TXA2 was attenuated. The vasodilator response to ANP was negligible in lungs with low vasomotor tone, probably because they were already maximally vasodilated, but similar in lungs with moderate and high vasomotor tone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cell biology of atrial natriuretic peptide.

Atrial natriuretic peptide (ANP) exhibits a wide spectrum of cardiovascular, endocrine, metabolic and renal actions. cGMP is the major mediator of ANP at the cellular level and only tissues possessing particulate guanylate cyclase appear to present ANP-induced actions. Three types of ANP receptors have recently been cloned. Two of them (A and B receptors) are homologous and contain guanylate cyclase catalytic domains. The C receptor could possibly regulate the metabolic fate of ANP. Data obtained by the radiation inactivation method suggest the presence of an inter- or intramolecular inhibitory component of nearly 90 kilodaltons that represses the catalytic activity of guanylate cyclase within its membrane environment. The mechanism of guanylate cyclase stimulation by ANP could involve this inhibitory component. Preliminary data suggest that the hyperresponsiveness of the particulate guanylate cyclase/cGMP system in hypertension occurs through modulation of the inhibitory component.     

Haemodynamic responses to a ring-deleted analogue of atrial natriuretic peptide in rats with cirrhosis

AIMS: In cirrhosis, the effects of selective activation of atrial natriuretic peptide (ANP) R2-receptors on haemodynamics, endogenous ANP (ANP1-28) and sodium excretion are unknown. The aim of the present study was to examine the effects of selective activation of ANP-R2 receptors by ANP4-23 (a ring-deleted analogue of endogenous ANP) on haemodynamics, plasma ANP1-28 concentrations and urinary sodium excretion in conscious cirrhotic and normal rats. METHODS: Haemodynamics and sodium excretion were measured prior to and following administration of ANP4 23. Plasma ANP1-28 concentrations were also measured. RESULTS: In cirrhotic rats, ANP4-23 significantly decreased portal pressure and tributary blood flow by 15% and 25% respectively but significantly increased portal territory vascular resistance by 30%. Systemic and renal haemodynamics were not altered by ANP4-23. In normal rats, ANP4-23 did not significantly change splanchnic, renal and systemic haemodynamics. In both groups of rats, ANP4-23 increased plasma ANP1-28 concentrations but did not change sodium excretion. CONCLUSIONS: ANP4-23 administration induced splanchnic vasoconstriction in cirrhotic but not in normal rats. ANP4-23-elicited vasoconstriction caused a portal hypotensive effect in cirrhotic rats. Finally, in both groups, ANP4-23 caused an increase in plasma ANP1-28 concentrations but did not increase sodium excretion.