糖尿病胃动力障碍大鼠胃窦平滑肌组织中CNP和NPR-B蛋白含量变化

目的探讨糖尿病胃动力障碍大鼠胃窦平滑肌组织中C型钠尿肽（CNP）和B型钠尿肽受体（NPR-B）的蛋白含量变化。方法腹腔注射链脲佐菌素（STZ）（65 mg/kg）4周,制备糖尿病动物模型。利用多道生理信号记录系统记录糖尿病大鼠胃窦平滑肌收缩活动,将发生胃窦平滑肌收缩活动紊乱的大鼠列入糖尿病胃动力障碍模型。采用免疫组织化学方法观察糖尿病大鼠胃窦平滑肌中CNP和NPR-B的分布。结果糖尿病胃动力障碍组大鼠与正常对照组相比胃窦平滑肌组织CNP表达无明显差异,但NPR-B表达明显增多（P〈0.01）。结论糖尿病大鼠发生胃动力障碍可能与胃窦平滑肌中NPR-B上调有关,提示糖尿病大鼠胃CNP-NPR-B/pGC-cGMP转导系统的改变可能参与胃动力障碍的发生。     

C-type natriuretic-peptide-potentiated relaxation response of gastric smooth muscle in streptozotocin-induced diabetic rats

AIM： To study the sensitivity of gastric smooth muscle to C-type natriuretic peptide （CNP） in streptozotocin（STZ）-induced diabetic rats.METHODS： The spontaneous contraction of a gastric smooth muscle strip was recorded by using physiological methods in rats. The expressions of CNP and natriuretic peptide receptor-B （NPR-B） in gastrictissue were examined by using immunohistochemistry techniques in the diabetic rat.RESULTS： At 4 wk after injection of STZ and vehicle,the frequency of spontaneous contraction of gastric smooth muscle was significantly reduced in diabeticrats, and the frequency was decreased from 3.10 ±0.14 cycle/min in controls to 2.23± 0.13 cycle/min（n = 8, P 〈 0.01）. However, the amplitude of spontaneous contraction was not significant different from the normal rat. CNP significantly inhibited spontaneous contraction of gastric smooth musclein normal and diabetic rats, but the inhibitory effect was significantly potentiated in the diabetic rats.The amplitudes of spontaneous contraction were suppressed by 75.15% ± 0.71% and 58.92% ±1.32% while the frequencies were decreased by 53.33% ±2.03% and 26.95% ± 2.82% in diabetic and normal rats, respectively （n = 8, P 〈 0.01）. The expression ofCNP in gastric tissue was not changed in diabetic rats,however the expression of NPR-B was significantlyincreased in diabetic rats, and the staining indexes of NPR-B were 30.67± 1.59 and 17.63 ± 1.49 in diabeticand normal rat, respectively （n = 8, P 〈 0.01）.CONCLUSION： The results suggest that CNP inducedan inhibitory effect on spontaneous contraction ofgastric smooth muscle, potentiated in diabetic ratvia up-regulation of the natriuretic peptides-NPR-B-particulate guanylyl cyclase-cyclic GMP signal pathway.     

Comparative study in the effect of C-type natriuretic peptide on gastric motility in various animals

AIM: To investigate the effect of natriuretic peptides on gastric motility in various animals, and the effect of C-type natriuretic peptide (CNP) on spontaneous contraction of gastric smooth muscle in rat, guinea-pig and human in vitro was compared.METHODS: Spontaneous contraction of gastric smooth muscle was recorded by four channel physiograph.RESULTS: In the guinea-pig and rat gastric antral circular smooth muscle, CNP markedly decreased the amplitude of spontaneous contraction but it didn't affect the frequency,however, the contractile activity was completely inhibited by CNP in gastric antral longitudinal smooth muscle. In the human gastric antral circular and longitudinal smooth musie, CNP completely inhibited spontaneous contraction. In the circular smooth muscle of guinea-pig and rat gastric fundus,CNP obviously decreased the amplitude of spontaneous contraction but it didn't affect the frequency, however, the contractile activity was completely inhibited by CNP in smooth muscle of fundus longitudinal. In the circular and longitudinal smooth muscle of guinea-pig gastric body, CNP at first induced a relaxation and then an increase in amplitude of spontaneous contraction (rebound contraction), but the frequency was not changed. After the circular smooth muscle of gastric body was pretreated with atropine, an M receptor blocker, the rebound contraction was abolished; In circular and longitudinal smooth muscle of rat gastric body, CNP induced a transient and slight relaxation and successively followed by the recovery in amplitude of spontaneous contraction but it also didn't affect the frequency. After the smooth muscle was pretreated with atropine, the transient and slight relaxation was replaced by long term and complete inhibition; The percentage of CNP-induced inhibition was 76.77±6.21% (fundus), 67.21±5.32 % (body) and 58.23±6.21% (antral) in the gastric circular muscle, however, the inhibitory percentage was 100±0.00 % (fundus), 68.66±3.55 % (body) and 100±0.00 % (antrum) in the gastric longitudinal smooth muscle of guinea-pigs; In the rat, the percentage of CNP-induced inhibition was 95.87±4.12 %(fundus), 94.91±5.08 % (body) and 66.32±7.32 % (antrum)in the gastric circular smooth muscle, but in the longitudinal smooth muscle, CNP completely inhibited the spontaneous contraction. Using LY83583, a guanylate cyclase inhibitor, and zaparinast as a phosphoesterase inhibitor to inhibit the generation of cGMP, the effect of CNP on the spontaneous contraction was markedly weakened by LY83583, however, the inhibitory effect was enhanced by zaparinast.CONCLUSION: (1) CNP can obviously inhibit the spontaneous contraction of gastric antral circular and longitudinal smooth muscle in the rat, guinea-pig and human.The order of inhibitory potency is human ＞rat＞ guinea-pig.(2) In the same animals, the inhibitory effect of CNP on spontaneous contraction is the most powerful in fundus and the weakest in antrum, in the same position, the inhibitory effect on the circular smooth muscle is more powerful than that on longitudinal smooth muscle. (3) The inhibitory effect of CNP on spontaneous contraction in the gastric smooth muscle is mediated by a cGMP dependent pathway.     

Role of calcium-activated potassium currents in CNP-induced relaxation of gastric antral circular smooth muscle in guinea pigs

AIM: To investigate ion channel mechanism in CNP-induced relaxation of gastric circular smooth muscle in guinea pigs.METHODS: Spontaneous contraction of gastric smooth muscle was recorded by a four -channel physiograph. The whole cell patch-damp technique was used bo record calcium-activated potassium currents and membrane potential in the gastric myocytes isolated by collagenase.RESULTS: C-type natriuretic peptide (CNP) markedly inhibited the spontaneous contraction in a dose-dependent manner in gastric circular smooth muscle in guinea pigs.Ly83583, an inhibitor of guanylate cyclase, weakened CNP-induced inhibition on spontaneous contraction but Zaparinast, an inhibitor of cGMP sensitive phosphoesterase,potentiated CNP-induced inhibition in gastric circular smooth muscles. The inhibitory effects of CNP on spontaneous contraction were blocked by tetrathylammonium (TEA), a nonselective potassium channel blocker. CNP hyperpolarized membrane potential from -60.0 mV±2.0 mV to -68.3 mV±3.0 mV in a single gastric myocyte. CNP increased calcium-activated potassium currents (IK（ca)) in a dose-dependent manner in gastric circular myocytes. CNP also increased the spontaneously transient outward currents(STOCs). Ly83583 partly blocked CNP-induced increase of calcium-activated potassium currents, but Zaparinast potented the effect.CONCLUSION:CNP inhibits spontaneous contraction,and potassium channel may be involved in the process in gastric circular smooth muscle of guinea pigs.CNP-induced increase of IK(ca) mediated by a cGMP dependent pathway.     

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.     

High and low gain switches for regulation of cAMP efflux concentration: distinct roles for particulate GC- and soluble GC-cGMP-PDE3 signaling in rabbit atria

This study tests the hypothesis that particulate (p) guanylyl cyclase (GC) and soluble (s) GC are involved in the distinct roles for the regulation of cGMP-PDE-cAMP signaling and of mechanical and secretory functions in the heart. Experiments were performed in perfused beating rabbit atria. C-type natriuretic peptide (CNP) and SIN-1, an NO donor, or BAY 41-2272 (BAY), a direct activator for sGC, were used to activate pGC and sGC, respectively. CNP and SIN-1 increased cGMP and cAMP efflux in a concentration-dependent manner. Increase in cAMP was a function of cGMP. The changes in cAMP efflux concentration in terms of cGMP were much more prominent in the atria treated with CNP than in the atria treated with SIN-1. Increase in cAMP efflux concentration was blocked by milrinone but not changed by EHNA. BAY increased cGMP but not cAMP in a concentration-dependent manner. CNP and SIN-1 decreased atrial stroke volume and myocytic ANP release. The decreases in terms of cGMP efflux concentration were much more prominent in the atria treated with CNP than in the atria treated with SIN-1 or BAY. Milrinone accentuated GC agonist-induced decreases in atrial stroke volume and ANP release. In the presence of ODQ, SIN-1 or BAY induced effects were not observed. These data suggest that pGC and sGC activations have distinct roles via cGMP-PDE3-cAMP signaling in the cardiac atrium: high and low gain switches, respectively, for the regulation of cAMP levels and contractile and secretory functions.     

Atrial natriuretic peptide signal pathway upregulated in stomach of streptozotocin-induced diabetic mice

AIM:To investigate atrial natriuretic peptide(ANP) secretion from gastric mucosa and the relationship between the ANP/natriuretic peptide receptor type A (NPR-A)pathway and diabetic gastroparesis. METHODS:Male imprinting control region(ICR)mice (4 wk old)were divided into two groups:control mice, and streptozotocin-induced diabetic mice.Eight weeks after injection,spontaneous gastric contraction was recorded by using physiography in control and streptozotocin-induced diabetic mice.The ANP-positive cells in ...     

Atrial natriuretic peptide signal pathway upregulated in stomach of streptozotocin-induced diabetic mice

AIM:To investigate atrial natriuretic peptide(ANP) secretion from gastric mucosa and the relationship between the ANP/natriuretic peptide receptor type A (NPR-A)pathway and diabetic gastroparesis. METHODS:Male imprinting control region(ICR)mice (4 wk old)were divided into two groups:control mice, and streptozotocin-induced diabetic mice.Eight weeks after injection,spontaneous gastric contraction was recorded by using physiography in control and streptozotocin-induced diabetic mice.The ANP-positive cells in ...     

Phenotype-related alteration in expression of natriuretic peptide receptors in aortic smooth muscle cells.

To elucidate the physiological and pathophysiological roles of the natriuretic peptide family in vascular smooth muscle cells, in which the natriuretic peptide family is implicated in growth inhibition as well as vasorelaxation, we have examined the phenotype-related expression of three kinds of natriuretic peptide receptors in rat aortic smooth muscle cells. The expression of natriuretic peptide receptors at the mRNA level was studied by Northern blot hybridization, and the expression at the protein level was determined by the cGMP production method and receptor binding assay. In intact aortic media, atrial natriuretic peptide (ANP)-A receptor mRNA and ANP-B receptor mRNA were detected, and the potency of cGMP production by ANP was at least two orders of magnitude stronger than that by C-type natriuretic peptide. Clearance receptor mRNA was undetectable, and only a small amount of the clearance receptor was detected by the binding assay in intact aortic media. By contrast, in cultured aortic smooth muscle cells at the first, fifth, and 17th passages, the ANP-B receptor mRNA level markedly increased; meanwhile, the expression of the ANP-A receptor mRNA became undetectable. C-type natriuretic peptide was one order of magnitude more potent than ANP in cGMP production in cultured aortic smooth muscle cells. The clearance receptor density and its mRNA level increased tremendously in these cultured cells. These results demonstrate that the marked phenotype-related alteration occurs in the expression of natriuretic peptide receptors in rat aortic smooth muscle cells.     

高浓度葡萄糖对CNP致大鼠胃窦环形肌舒张的影响

目的探讨高浓度葡萄糖（简称高糖）对C型钠尿肽（CNP）致胃窦环形肌舒张的影响及其可能机制。方法取大鼠40只制备胃窦环形肌条,肌条收缩活动稳定后,对照1、2组分别加入不同浓度CNP（1×10^-8、3×10^-8、1×10^-7mol/L）及硝普钠（SNP）（1×10^-7、3×10^-7、1×10^-6mol/L）,观察其效应,每次加药观察20 m in,冲洗3次;高糖1、2组预加葡萄糖使浴槽终浓度为30 mmol/L,其后操作同对照1、2组;甘露醇组预加甘露醇30mmol/L,其后操作同对照1组;均采用多道生理信号采集处理系统计算CNP（SNP）致平滑肌张力的抑制率。结果对照1、2组产生浓度依赖的胃窦环形肌平滑肌舒张效应,高糖1组可明显抑制CNP和硝普钠产生的平滑肌条舒张效应明显减弱;甘露醇（30 mmol/L）组CNP产生的平滑肌条舒张效应明显减弱。结论高糖抑制CNP引起的胃窦环形肌舒张效应;该效应可能与细胞内外渗透压改变有关。     

C-type natriuretic peptide (CNP) effects in anterior pituitary cell lines: evidence for homologous desensitisation of CNP-stimulated cGMP accumulation in alpha T3-1 gonadotroph-derived cells

C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, has been found at its highest tissue concentrations in the anterior pituitary, where it is localised in gonadotrophs. Its specific guanylyl cyclase-containing receptor, GC-B, is also expressed on several anterior pituitary cell types, and CNP potently stimulates cGMP accumulation in rat pituitary cell cultures and pituitary cell lines. The mouse gonadotroph-derived alpha T3-1 cell line has been shown to express CNP as well as GC-B (but not GC-A) receptors, suggesting that CNP may well be an autocrine regulator of gonadotrophs. Comparing effects of three natriuretic peptides (atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and CNP) on cGMP accumulation in four pituitary cell lines (alpha T3-1, TtT-GF, AtT-20 and GH(3)) we find that CNP is most potent and effective in alpha T3-1 cells. In these cells, CNP-stimulated cGMP accumulation was found to desensitise during a 30 min exposure to CNP. Pretreatment with CNP for up to 6 h also caused a significant reduction in the ability of CNP to subsequently stimulate cGMP accumulation. This effect was receptor specific, because pretreatment with sodium nitroprusside (an activator of nitric oxide-sensitive guanylyl cyclase), or with ANP or BNP, did not cause desensitisation of CNP-stimulated cGMP accumulation. Protein kinase C activation with phorbol esters also inhibited CNP-stimulated cGMP accumulation and such inhibition was also seen in cells desensitised by pretreatment with CNP. Thus it appears that the endogenous GC-B receptors of alpha T3-1 cells are subject to both homologous and heterologous desensitisation, that the mechanisms underlying these forms of desensitisation are distinct, and that cGMP elevation alone is insufficient to desensitise GC-B receptors.     

Guanylyl cyclase receptors mediate cardiopulmonary vagal reflex actions of ANP

Atrial natriuretic peptide (ANP) potentiates vagal cardiopulmonary reflexes due to chemosensory (Bezold-Jarisch [B-J] reflex) or mechanosensory (ramp baroreflex) activation. The ANP receptor mediating these actions is unknown. We examined the role of particulate guanylyl-cyclase (pGC) receptors in ANP-induced enhancement of cardiopulmonary vagal reflexes. Cardiopulmonary baroreceptor reflex function was assessed by bradycardic responses to ramp blood pressure rises after rapid intravenous methoxamine (100 micro g/kg bolus dose). The B-J reflex was evoked by 3 intravenous doses of serotonin (1 to 10 micro g/kg). In conscious, chronically instrumented rats (n=9), these tests were performed on each animal during randomized infusions of rat ANP (150 ng/kg per minute IV), saline (270 micro L/h IV), the pGC receptor antagonist HS-142-1 (3 mg/kg IV), or combined HS-142-1+ANP treatment. HS-142-1 alone attenuated normal B-J reflex (by 33+/-8%, P<0.05) but not ramp baroreflex responses. As we showed previously, ANP enhanced baroreflex and B-J reflex bradycardia (by approximately 140% and approximately 30%, respectively, P<0.05), compared with saline infusion. These ANP effects were completely blocked by HS-142-1, demonstrating that the cardiopulmonary vagal reflex actions of ANP occurred through pGC natriuretic peptide receptors. Additionally, we have provided evidence for the first time that pGC natriuretic peptide receptors are essential for the full expression of the B-J reflex but not for that of cardiopulmonary vagal baroreflexes. This tonic interaction between pGC natriuretic peptide receptors and cardiopulmonary chemosensitive receptors may be important during pathophysiological activation of B-J reflex, such as with myocardial infarction.     

Serum levels of natriuretic peptides in patients with Behcet’s disease

The objective of our study was to elucidate serum levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) in Behcet’s disease (BD) patients with active and inactive period. The multicenter study included 53 patients with active (n = 28) and inactive (n = 25) BD (mean age, 34.3 ± 9 years; 15 men and 38 women) satisfying the International Study Group criteria and 26 healthy controls (mean age, 34.4 ± 6.1 years; seven men and 19 women) matched for age and gender from a similar ethnic background. Serum natriuretic peptides levels were determined by enzyme immunoassay kit. Mean serum ANP concentrations in the active patients (4.01 ± 1.21 ng/ml) were significantly lower than in the healthy controls (5.76 ± 1.99 ng/ml, p = 0.004). Mean serum BNP levels were found to be significantly higher in both the active (6.19 ± 2.97 ng/ml) and inactive (6.49 ± 2.88 ng/ml) BD groups compared with the control group (3.82 ± 1.1 ng/ml, p = 0.004 and p = 0.001, respectively). Mean serum CNP concentrations in the active patients (0.49 ± 0.12 ng/ml) were significantly lower than in the inactive patients (0.65 ± 0.2 ng/ml, p = 0.017) and the healthy controls (0.8 ± 0.27 ng/ml, p < 0.001). Our results suggest that changes in natriuretic peptide levels may be associated with vasculitis that play role in the etiopathogenesis of the BD.     

Chimeric natriuretic peptide ACNP stimulates both natriuretic peptide receptors,the NPRA and NPRB

Here, we investigated the receptor profile of the newly designed natriuretic peptide (NP) ACNP consisting of the N- and C-terminus of human ANP and the ring structure of CNP, its potency/efficacy in stimulating cGMP generation in primary cells, and its stability towards peptidase activity. ACNP stimulated both human natriuretic peptide receptors (NPRs), NPRA and NPRB, as potent as their native ligands in receptor transfected cells. Consequently, ACNP was more efficient in generating cGMP compared to ANP, BNP, and CNP, in primary cells expressing both NPRs. All NPs have been similarly degraded by neprilysin, except the neprilysin-resistant BNP. However, ACNP was fastest degraded in serum, while CNP was most stable. Congruently, CNP but not ACNP reduced blood pressure most significantly after acute peptide infusion in normotensive mice. Our data identify ACNP as the first compound being able to stimulate both natriuretic receptors with similar potency and efficacy as their respective ligands.     

C-type natriuretic peptide induces redifferentiation of vascular smooth muscle cells with accelerated reendothelialization

We recently reported that C-type natriuretic peptide (CNP) occurs in vascular endothelial cells and acts as a vascular-type natriuretic peptide. In the present study, we stimulated the cGMP cascade in proliferating smooth muscle cells (SMCs), in which particulate guanylate cyclase-B, the specific receptor for CNP, is predominantly expressed, by use of an adenovirus encoding rat CNP cDNA (Ad.CNP). In the Ad.CNP-treated cultured SMCs, CNP caused the growth inhibition of SMCs at G(1) phase with an early increase of p21(CIP1/WAF1) expression and subsequent upregulation of p16(INK4a). The expression of smooth muscle myosin heavy chain-2, which is the molecular marker of highly differentiated SMCs, was reinduced in the Ad.CNP-treated SMCs. The Ad.CNP-treated SMCs also reexpressed particulate guanylate cyclase-A, which shows high affinity to atrial and brain natriuretic peptide and is exclusively expressed in well-differentiated SMCs. CNP, which was overexpressed in rabbit femoral arteries in vivo at the time of balloon injury, significantly suppressed neointimal formation. Furthermore, an enhancement of the expression of smooth muscle myosin heavy chain-2 occurred in the residual neointima. In addition, early regeneration of endothelial cells was observed in the Ad.CNP-infected group. Thus, stimulation of cGMP cascade in proliferating dedifferentiated SMCs can induce growth inhibition and redifferentiation of SMCs with accelerated reendothelialization.     

Differential regulation of membrane guanylyl cyclases in congestive heart failure: natriuretic peptide receptor (NPR)-B, Not NPR-A, is the predominant natriuretic peptide receptor in the failing heart

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) bind natriuretic peptide receptor (NPR)-A and decrease blood pressure and cardiac hypertrophy by elevating cGMP concentrations. Physiological responses to ANP and BNP are diminished in congestive heart failure (CHF) by an unknown mechanism. C-type natriuretic peptide (CNP) binding to NPR-B decreases cardiac hypertrophy, but the effect of CHF on NPR-B is unknown. Here, we measured ANP/NPR-A-dependent and CNP/NPR-B-dependent guanylyl cyclase activities in membranes from failing and nonfailing hearts. Transaortic banding of mice resulted in marked CHF as indicated by increased heart/body weight ratios, increased left ventricular diameters, and decreased ejection fractions. In nonfailed hearts, saturating ANP concentrations increased particulate guanylyl cyclase activity almost 10-fold, whereas saturating CNP concentrations increased activity 6.9-fold, or to about 70% of the ANP response. In contrast, in failed heart preparations, CNP elicited twice as much activity as ANP due to dramatic reductions in NPR-A activity without changes in NPR-B activity. For the first time, these data indicate that NPR-B activity represents a significant and previously unappreciated portion of the natriuretic peptide-dependent guanylyl cyclase activity in the normal heart and that NPR-B accounts for the majority of the natriuretic peptide-dependent activity in the failed heart. Based on these findings, we suggest that drugs that target both NPRs may be more beneficial than drugs like nesiritide (Natrecor) that target NPR-A alone.     

Similar baroreflex bradycardic actions of atrial natriuretic peptide and B and C types of natriuretic peptides in conscious rats.

OBJECTIVE: We have previously shown that atrial natriuretic peptide (ANP) modulates cardiac barosensitive afferent pathways to enhance reflex bradycardia in rats. The present study examined whether B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) also modulate heart rate reflex function. DESIGN: Baroreflex bradycardia was evoked by rapid (over 4-6 s) intravenous (i.v.) infusions of methoxamine (100 microg/kg; 'ramp' baroreflex technique) in the presence of infused i.v. natriuretic peptide and of vehicle (0.9% saline, 270 microl/h) in conscious adult Munich-Wistar rats. Initially a dose-response study to ANP (infused at 25, 50 and 100 pmol/kg per min i.v.) was performed in 10 rats to determine an appropriate dose for subsequent experiments with the other peptides. In a separate group of 11 animals, rat BNP-32 and rat CNP-22 were infused at 50 pmol/kg per min i.v. RESULTS: Reflex responses to ANP were dose-related, with a significant increase in baroreflex sensitivity of 50+/-15% at the 25 pmol dose, 102+/-10% at the 50 pmol dose and 117+/-11% at 100 pmol dose (all P<0.05). BNP and CNP (50 pmol/kg/min i.v.) substantially increased baroreflex bradycardia (by 115+/-17% and 62+/-15%, respectively; P<0.05) compared to vehicle infusion. CONCLUSIONS: Both BNP and CNP augmented baroreflex slowing of heart rate in response to rapid increases in blood pressure in rats. Whereas other reports have shown marked differences in cardiovascular responses between the natriuretic peptides, particularly with CNP, our findings demonstrate an important common action of ANP, BNP and CNP to facilitate vagal heart rate baroreflexes.     

The genetic contribution of the natriuretic peptide system to cardiovascular diseases

Three types of natriuretic peptides (NP) have been isolated: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). The NP family elicits a number of vascular, renal and endocrine effects that help to maintain blood pressure and extracellular fluid volume. These effects are mediated by the specific binding of NP to cell surface receptors that have been characterized, purified and cloned from cells of the vasculature, kidney, adrenal gland and brain. There are 3 subtypes of NP receptors: type A natriuretic peptide receptor (NPRA), type B natriuretic peptide receptor (NPRB), and type C natriuretic peptide receptor (NPRC). All 3 subtypes affect cellular second messenger activity. NPRA and NPRB are guanylyl cyclase receptors, and their activation increases cGMP levels. Activation of NPRC results in inhibition of adenylyl cyclase activity. Human NPRA has a high structural homology with human NPRB, and contains a highly-conserved guanylyl cyclase domain. ANP and BNP bind primarily to NPRA, which is found in the vasculature, causing vasodilation and inhibition of vascular smooth muscle cell proliferation. The present paper contains a review of NPs and their receptors and the genetic contribution of the NP system to cardiovascular diseases such as essential hypertension and myocardial infarction.