Cardiac Atrial Natriuretic Peptide Research Articles

Dilatory and inotropic effects of corticotropin-releasing factor (CRF) on the isolated heart. Effects on atrial natriuretic peptide (ANP) release.

The effects of CRF administration on cardiac performance, coronary flow and ANP release were investigated in the rat heart. Isolated hearts were perfused at a constant filling pressure according to working heart model with a Krebs-Henseleit solution containing glucose and insulin, saturated with a gas mixture containing 95% O2 and 5% CO2. Administration of CRF via a cannula into the left atrium elicited a prolonged increase in the coronary flow rate and a transient increase in the aortic pressure resulting in an overall increase in the pressure-volume work. The oxygen consumption, after the administration of CRF, increased in accordance with the cardiac effort. No changes were observed in the spontaneous heart rate. Furthermore, administration of CRF induced a short-term increase of ANP release into the coronary perfusate. Our experiments suggest that administration of CRF produces a prolonged dilatory effect on the coronary arteries while producing a transient positive inotropic effect and a transient increase of ANP release on the isolated rat heart.

Diabetes-induced alterations in atrial natriuretic peptide gene expression in Wistar-Kyoto and spontaneously hypertensive rats.

We investigated the effects of streptozotocin-induced diabetes on atrial natriuretic peptide (ANP) synthesis, hemodynamic parameters, blood volume, and histopathology, as well as the reversibility of such effects with insulin therapy in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The biatrial ANP messenger RNA (mRNA) levels in the diabetic WKY rats increased by 16-17% compared with those in the age-matched WKY rats at 12 weeks after the onset of diabetes, whereas their ventricular ANP mRNA levels showed increases of 190% in left ventricles and 160% in right ventricles at 8 weeks. In the diabetic SHRs, the left atrial ANP mRNA levels increased by 36% compared with those in the age-matched SHRs, as early as 4 weeks after diabetes onset. Their ventricular ANP mRNA levels also showed 80-82% increases in left and right ventricles at 4 weeks. In proportion to changes in cardiac ANP synthesis, the biventricular end-diastolic pressures were significantly elevated at 8 weeks in the diabetic WKY rats and at 4 weeks in the diabetic SHRs. The blood volume significantly increased at 8 weeks in the diabetic WKY rats and remained higher thereafter, whereas it did not change in the diabetic SHRs throughout the experimental period. The left ventricular peak dP/dt was depressed in the 8-week diabetic SHRs, whereas in the diabetic WKY rats, its depression was observed at 12 weeks after diabetes onset. Histopathological studies showed that diabetic changes in ANP synthesis and hemodynamic parameters described above occurred before the cardiomyopathic histological changes. Cardiac ANP synthesis in the diabetic rats completely reverted to control levels after insulin therapy, accompanied by normalization of hemodynamic parameters. The present study indicates that 1) ANP synthesis is significantly augmented in the streptozotocin-induced diabetic rat compared with that in the normal rat, and the combination of diabetes and hypertension produces an earlier and greater effect in stimulating cardiac ANP synthesis than does either disease alone; 2) an elevation in the intraventricular filling pressure that occurs before observable cardiomyopathic histopathological alterations might be involved partially in the augmented ANP synthesis; and 3) the reversibility with insulin therapy suggests that the streptozotocin-induced alterations observed in cardiac ANP synthesis and hemodynamics result from insulin-deficient diabetes mellitus, not from cardiac toxicity of streptozotocin.

Prostaglandins regulate the synthesis and secretion of the atrial natriuretic peptide.

We have examined the effects of several PGs on the synthesis and release of the atrial natriuretic peptide (ANP) in vivo and in vitro. PGF2 alpha infusion in anesthetized rats resulted in a significant increase in plasma immunoreactive (ir) ANP levels in vivo despite effecting only modest changes in hemodynamics. The PGs were also effective at promoting irANP secretion in primary cultures of neonatal rat atrial and ventricular cardiocytes. PGF2 alpha increased irANP release with half-maximal induction seen at approximately 10(-8) M; PGE2 was somewhat less effective and prostacyclin (PGI2) was without effect. The PGs also increased ANP mRNA levels in these cells, suggesting that these agents exert a major effect on the synthesis as well as the secretion of the prohormone. Transient expression analysis of atrial cells transfected with 2,500 bp of human (h) ANP 5' flanking sequence linked to a chloramphenicol acetyltransferase (CAT) reporter demonstrated that PGF2 alpha (10(-5) M) increased hANP promoter activity approximately twofold relative to the control. PGF2 alpha had no effect on the promoterless control (pSV0-lamin CAT). Treatment of cultured atriocytes with high concentrations of a cyclooxygenase inhibitor resulted in a significant suppression of ANP secretion in vitro and a truncation of the plasma ANP response to volume infusion in vivo. Taken together these studies support a role for PGs as regulators of cardiac ANP synthesis and secretion, and suggest an additional mechanism whereby eicosanoids may act to control cardiovascular and renal homeostasis.

Cardiac Hypotensive Extract: Responses of Single Comb White Leghorn Hens Fed Low- or High-Sodium Diets

Experiments were conducted to determine if hypotensive responses to chicken cardiac hypotensive extract (CHE) or synthetic rat atrial natriuretic peptide (ANP) are affected by dietary sodium. The CHE was significantly more hypotensive in chickens fed high-sodium diets than in chickens fed low-sodium diets. Atrial natriuretic peptide was equally hypotensive in both groups. Experiments were also conducted to determine whether CHE inhibits the hypertensive response to arginine vasotocin (AVT), the avian antidiuretic hormone. The acute hypertensive response to AVT was inhibited by CHE; and CHE reversed the AVT-induced increase in the baseline mean arterial blood pressure.

Cardiac Atrial Natriuretic Peptide Concentrations in Experimental Obese Mice.

Obesity is usually associated with expansion of blood volume. Therefore, we studied whether obesity affects cardiac and plasma atrial natriuretic peptide (ANP) levels in experimental animal model. Mice made obese with gold thioglucose developed cardiac hypertrophy associated with increases in ANP in atrial tissue and plasma. There were significant (p less than 0.01) correlations between the cardiac ANP concentration and body weight or cardiac weight. These data suggest that enhanced synthesis of atrial ANP in obese mice can be mainly ascribed to increased blood volume associated with cardiac hypertrophy.

Atrial Natriuretic Peptide in Plasma, Atria, Ventricles, and Hypothalamus of Long-Evans and Vasopressin- Deficient Brattleboro Rats*

To evaluate the role of vasopressin in the regulation of atrial natriuretic peptide (ANP) secretion, the plasma, atrial, ventricular, and hypothalamic levels of ANP were measured in Long-Evans (LE) and vasopressin-deficient Brattleboro (DI) rats. Total atrial immunoreactive ANP (IR-ANP) as well as right auricular IR-ANP concentration were higher in the DI than in the LE rats, whereas no significant difference was noted in left auricular IR-ANP concentration. In the left ventricle of DI rats, the IR-ANP concentration was 82% greater than that in the LE rats, while no substantial difference was found in the right ventricular IR-ANP concentration between the strains. Normal LE rats had low levels of left ventricular ANP mRNA and barely detectable ANP mRNA in the right ventricle, DI rats showed a 3-fold greater ANP mRNA concentration in the left ventricle than age-matched LE controls, and ANP mRNA levels were also increased in the left auricle of DI rats. The hypothalamic IR-ANP content, but not the concentration, was significantly increased in the DI compared to the LE rats. Despite increased cardiac IR-ANP and ANP mRNA levels, plasma IR-ANP concentrations were similar in the conscious DI rats (97 +/- 9 pg/ml; n = 13) and the LE rats (95 +/- 8 pg/ml; n = 15). Volume expansion (1.1 ml/100 g BW of 0.9% saline, iv) increased right atrial pressure and caused a significant rise in plasma IR-ANP in both strains (P less than 0.01). Elevations of plasma IR-ANP concentrations caused by volume loading were comparable in LE and DI rats in either the absence or presence of exogenous vasopressin (5 ng/kg.min, iv), which, when infused alone, did not significantly influence the plasma IR-ANP concentration. However, the relation between the change in IR-ANP concentration and the change in right atrial pressure shifted to the left, and thus, for a given increase in right atrial pressure, a greater amount of IR-ANP was released in the vasopressin-treated rats than in the control animals. These results demonstrate that although acute volume expansion does not necessarily require endogenous vasopressin for the ANP secretory response, vasopressin increased the ability of volume expansion to induce ANP release, thus modulating the direct mechanical stimulus-induced ANP secretion. The increased left ventricular levels of immunoreactive ANP and augmentation of ANP mRNA levels in Brattleboro rats despite normal left ventricular weight to body weight ratio show that increased ANP gene expression may occur in the ventricles independently of hypertrophy.

Atrial and brain natriuretic peptides share binding sites in the kidney and heart

We examined the distribution of binding sites for atrial natriuretic peptide (ANP) and the recently discovered brain natriuretic peptide (BNP) in rat kidney and heart by receptor autoradiography. In frozen kidney sections, both 125I-ANP and 125I-BNP exhibited localized binding to cortical glomeruli. The binding of each radiolabeled peptide was abolished by inclusion of either excess (1 ωM) unlabeled ANP or excess unlabeled BNP, suggesting that ANP and BNP share cortical glomerular binding sites. In frozen cardiac sections, ANP and BNP binding sites were localized to the endothelium of the endomural channels and endocardium. As was the case for kidney, binding of each peptide at these sites was abolished by the presence of excess unlabeled ANP or BNP, suggesting that these natriuretic peptides share binding sites in the heart as well. To explore further the possibility that ANP and BNP utilize the same receptor(s), we performed competitive binding experiments using cultured pulmonary artery endothelial (CPAE) cells. ANP and BNP competitively displaced one another with equivalent IC 50 values from CPAE cell binding sites. Furthermore, both ANP and BNP elevated the levels of cGMP, a putative second messenger for ANP, in these cells. These data are consistent with the observation that BNP, like ANP, causes a natriuresis and diuresis in rats, and suggest that BNP may posses other biological activities known for ANP.

Release and regulation of atrial natriuretic peptide (ANP).

Mammalian atrial cardiocytes synthesize and secrete a hormone called atrial natriuretic peptide (ANP), which causes natriuresis, diuresis and inhibition of smooth muscle contraction, aldosterone and renin release. Volume loading, vasoconstrictor agents, immersion in water, atrial tachycardia and high salt diets have been reported to increase the release of cardiac ANP, thereby suggesting that the peptide is released in response to an increase in atrial pressure. That stretch is an important stimulus for ANP release is also suggested by clinical studies demonstrating a direct correlation between secretion rate and atrial pressure. The experiments using isolated perfused rat heart provide direct evidence that distension of the right atrium stimulates the release of ANP. Pharmacological studies in the isolated heart point to roles of cytosolic calcium, the phosphoinositide system and the cyclic AMP pathway in the regulation of ANP release. The concentration of calcium in heart muscle cells, in addition to the length of the muscle fibers, depends on many factors such as the action of humoral substances, cardiac nerve activity and heart rate, which may all contribute to the regulation of ANP secretion.

Increased synthesis and release of atrial peptide during DOCA escape in conscious dogs.

The escape from the sodium-retaining effects of prolonged mineralocorticoid treatment in animals and humans was first noted over 40 yr ago, but despite intense study the mechanisms responsible for the escape phenomenon have not been identified. Putative "natriuretic hormones" have been proposed to account for the escape phenomenon. To determine whether atrial natriuretic peptides (ANP) could participate in the escape phenomenon, the mineralocorticoid deoxycorticosterone acetate (DOCA) was administered to conscious dogs for 14 days. Escape was accompanied by a doubling of plasma ANP concentration and four- to sevenfold increases in cardiac ANP messenger RNA. There were also significant increases in mean arterial blood pressure during the last 8 days of DOCA treatment. Thus increases in the synthesis and secretion of ANP and increases in atrial pressure may represent mechanisms that contribute to the escape from mineralocorticoid-induced sodium retention.

Atrial natriuretic peptide mRNA is regulated by glucocorticoids invivo

In these studies glucocorticoids were found to increase the plasma levels of atrial natriuretic peptide (ANP) as well as the expression of the ANP gene in the Sprague-Dawley rat. Plasma ANP rose two-fold after 48 hrs. of exposure to dexamethasone (1 mg/day) in both intact and adrenalectomized animals. This was accompanied by a 1.5-2.0 fold increase in the levels of atrial and ventricular ANP transcripts. Deoxycorticosterone acetate (5 mg/day), administered on the same schedule, failed to increase either plasma ANP levels or cardiac ANP mRNA accumulation. These effects suggest that ANP may have a potential role as a mediator of glucocorticoid activity in the cardiovascular system and support the hypothesis that ANP is a glucocorticoid-regulated gene.