L-ANAP

HIF-1α-l-PGDS-PPARγ regulates hypoxia-induced ANP secretion in beating rat atria

Lipocalin-type prostaglandin D synthase (L-PGDS) and peroxisome proliferator activated receptor γ (PPARγ) play important roles in cardiovascular diseases. Nevertheless, effects of hypoxia-inducible factor 1α (HIF-1α) on L-PGDS and PPARγ protein levels and its role in hypoxia-induced atrial natriuretic peptide (ANP) secretion are unclear. In perfused beating rat atria, we observed that hypoxia significantly increased HIF-1α protein levels and stimulated ANP secretion, while upregulating L-PGDS. Hypoxia-induced ANP secretion was clearly attenuated by HIF-1α antagonist 2-methoxyestradiol, downregulating both HIF-1α and L-PGDS protein levels. It was also attenuated by L-PGDS antagonists, AT-56 and HQL-49, downregulating L-PGDS protein levels. In addition, hypoxia-induced ANP secretion was accompanied by increased PPARγ protein levels and was strongly attenuated by PPARγ antagonist GW9662. Hypoxia-induced increase in atrial PPARγ protein levels were dramatically inhibited by both 2-methoxyestradiol and AT-56. These results indicated that hypoxia promotes ANP secretion, at least in part, by activating HIF-1α-l-PGDS-PPARγ signaling in beating rat atria.

Endogenous ET-1 promotes ANP secretion through activation of COX2-L-PGDS-PPARγ signaling in hypoxic beating rat atria

Endothelin-1 (ET-1) is a potent stimulus for the secretion of atrial natriuretic peptide (ANP) and hypoxia stimulates the release of ET-1, which is involved in the regulation of atrial ANP secretion. However, the precise mechanism of endogenous ET-1 in the regulation of hypoxia-induced ANP secretion is unclear. Therefore, this study aimed to investigate the mechanism of hypoxia-induced endogenous ET-1 regulation of ANP secretion in isolated perfused hypoxic beating rat atria. The results of this study showed that acute hypoxia significantly stimulated ET-1 release and upregulated the expression of its type A as well as type B receptors (ETA and ETB receptors). Endogenous ET-1 induced by hypoxia markedly upregulated the expression of cyclooxygenase 2 (COX2) through activation of its two receptors, leading to an increase in lipocalin-type prostaglandin D synthase (L-PGDS) expression and prostaglandin D2 (PGD2) production. L-PGDS-derived PGD2 activated peroxisome proliferator-activated receptor γ (PPARγ), ultimately promoting hypoxia-induced ANP secretion. Conversely, L-PGDS-derived PGD2 may in turn regulate L-PGDS expression by a nuclear factor erythroid-2-related factor 2 (NRF2)-mediated feedback mechanism. These results indicate that endogenous ET-1 induced by hypoxia promotes hypoxia-induced ANP secretion by activation of COX2-L-PGDS-PPARγ signaling in beating rat atria. In addition, the positive feedback loop between L-PGDS-derived PGD2 and L-PGDS expression induced by hypoxia is part of the mechanism of hypoxia-induced ANP secretion by endogenous ET-1.

Plasma L-ENK, AVP, ANP and serum gastrin in patients with syndrome of Liver-Qi-stagnation

AIM:To investigate the pathophysiologic basis of syndrome of Liver-Qi stagnation and parameters for clinical differentiation.METHODS:Plasma L-ENK, AVP, ANP and serum gastrin were determined by RIA in 84 patients with neurasthenia, mastodynia,chronic gastritis, and chronic cholecystitis presenting the same syndrome of Liver-Qi stagnation in traditional Chinese medicine (TCM). Healthy subjects served as controls in comparison with patients having the same syndrome but with different diseases.RESULTS:Among the patients with Liver-Qi stagnation, the plasma L-ENK, ANP and gastrin levels were 38.83ng/L ± 6.32ng/L, 104.11ng/L ± 29.01ng/L and 32.20ng/L ± 6.68ng/L, being significantly lower than those in the healthy controls (P < 0.01, t = 3.34, 6.17, 4.48). The plasma AVP of the patient group (52.82ng/L ± 19.09ng/L) was significantly higher than that of the healthy controls (P <0.01, t = 5.79 =. The above changes in patients having the same symptom complex but different diseases entities showed no significant differences, P >0.05.CONCLUSION:The syndrome of Liver-Qi stagnation is closely related to the emotional modulatory abnormality of the brain, with decrease of plasma L-ENK, ANP and gastrin, and increase of plasma AVP as the important pathophysiologic basis.

Effects of ANP on pulmonary vein electrophysiology, Ca2+ homeostasis and adrenergic arrhythmogenesis via PKA

Atrial fibrillation (AF) is the most common form of arrhythmia and increases the risk of stroke and heart failure (HF). Pulmonary veins (PVs) are important sources of triggers that generate AF, and calcium (Ca²⁺ ) overload participates in PV arrhythmogenesis. Neurohormonal activation is an important cause of AF. Higher atrial natriuretic peptide (ANP) level predicts paroxysmal AF occurrence in HF patients. However, it is not clear if ANP directly modulates electrophysiological characteristics and Ca²⁺ homeostasis in the PVs. Conventional microelectrodes, whole-cell patch-clamp, and the Fluo-3 fluorimetric ratio technique were performed using isolated rabbit PV preparations or single isolated PV cardiomyocytes before and after ANP administration. We found that ANP (1, 10, and 100 nmol/L) concentration-dependently decreased spontaneous activity in PV preparations. ANP (100 nmol/L) decreased isoproterenol (1 μmol/L)-induced PV spontaneous activity and burst firing. AP811 (100 nmol/L, NPR-C agonist), H89 (1μmol/L, PKA inhibitor) decreased isoproterenol-induced PV spontaneous activity or burst firing, but successive administration of ANP had no further effect on PV activity. KT5823 (1 μmol/L, PKG inhibitor) decreased isoproterenol-induced PV spontaneous activity but did not change isoproterenol-induced PV burst firing, whereas successive administration of ANP did not change isoproterenol-induced PV burst firing. ANP decreased intracellular Ca²⁺ transient and sarcoplasmic reticulum Ca²⁺ content in single PV cardiomyocytes. ANP decreased the late sodium current, L-type Ca²⁺ current, but did not change nickel-sensitive Na⁺ -Ca²⁺ exchanger current in single PV cardiomyocytes. In conclusion, ANP directly regulates PV electrophysiological characteristics and Ca²⁺ homeostasis and attenuates isoproterenol-induced arrhythmogenesis through NPR-C/cAMP/PKA signal pathway.

Distinct roles for L- and T-type Ca(2+) channels in regulation of atrial ANP release

Atrial secretion of atrial natriuretic peptide (ANP) has been shown to be regulated by atrial workload. Although modulating factors for the secretion of ANP have been reported, the role for intracellular Ca(2+) on the secretion of ANP has been controversial. The purpose of the present study was to define roles for L- and T-type Ca(2+) channels in the regulation of ANP secretion in perfused beating rabbit atria. BAY K 8644 (BAY K) increased atrial stroke volume and pulse pressure. BAY K suppressed ANP secretion and ANP concentration in terms of extracellular fluid (ECF) translocation concomitantly with an increase in atrial dynamics. BAY K shifted the relationship between ANP secretion and ECF translocation downward and rightward. These results indicate that BAY K inhibits myocytic release of ANP. In the continuous presence of BAY K, diltiazem reversed the effects of BAY K. Diltiazem alone increased ANP secretion and ANP concentration along with a decrease in atrial dynamics. Diltiazem shifted relationships between ANP secretion and atrial stroke volume or ECF translocation leftward. The T-type Ca(2+) channel inhibitor mibefradil decreased atrial dynamics. Mibefradil inhibited ANP secretion and ANP concentration in contrast with the L-type Ca(2+) channel inhibitor. These results suggest that activation of L- and T-type Ca(2+) channels elicits opposite effects on atrial myocytic release of ANP.