Role of atrial natriuretic peptides and neuropeptide Y in blood pressure regulation

Atrial natriuretic peptides (ANP) are released into the circulation in response to enhanced atrial stretching. These peptides not only have diuretic and natriuretic properties, but also exert a relaxing effect on the vasculature. Moreover, they antagonize the contractions induced by norepinephrine and angiotensin II. Neuropeptide Y (NPY) is also a vasoactive peptide. It is widely distributed throughout the central and peripheral nervous systems. NPY is coreleased with norepinephrine by perivascular nerve endings. At high concentrations, this peptide has a direct vasoconstrictor effect. In addition, it enhances the vascular effect of various agonists, including norepinephrine and angiotensin II. Both ANP and NPY have an inhibitory effect on renin secretion. This effect may have important implications for the role of these peptides in cardiovascular regulation.     

Central natriuretic peptides regulation of peripheral atrial natriuretic factor release

Atrial natriuretic factor (ANF) and C-type natriuretic peptide (CNP) receptors have been described in encephalic areas and nuclei related to the regulation of cardiovascular as well as sodium and water homeostasis. Stimulation of the anterior ventral third ventricular region of the brain modifies plasma ANF concentration, suggesting the participation of the central nervous system in the regulation of circulating ANF. The aim of this work was to study the effect of centrally applied ANF or CNP on plasma ANF. Normal and blood volume expanded rats (0.8 ml isotonic saline/100 g body weight) were intra cerebralventricularly injected with 1, 10 or 100 ng/μl/min ANF. Blood volume expanded animals were also centrally injected with the same doses of CNP. Blood samples were collected at 5 and 15 min. after intracerebralventricular administration of either ANF or CNP. Centrally applied ANF did not affect circulating ANF in normal blood volume rats. In blood volume expanded animals both ANF (1, 10 or 100 ng/μl/min) and CNP (1 ng/μl/min) decreased plasma ANF concentration after 15 min. Moreover, CNP (10 and 100 ng/μl/min) lowered circulating ANF levels not only at 15 min but also at 5 min. Neither ANF nor CNP elicited any change in mean arterial pressure and heart rate in normal and blood volume expanded rats. These results suggest the existence of a central regulation exerted by natriuretic peptides on circulating ANF levels. Furthermore, this is the first study reporting an effect on plasma ANF induced by centrally applied CNP.     

Effect of natriuretic peptides on cerebral artery blood flow in healthy volunteers

The natriuretic peptides (NPs), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), have vasoactive functions that concern humans and most animals, but their specific effects on cerebral circulation are poorly understood. We therefore examined the responsiveness of cerebral arteries to different doses of the natriuretic peptides in animals and humans. We conducted a dose-response experiment in guinea pigs (in vitro) and a double-blind, three-way cross-over study in healthy volunteers (in vivo). In the animal experiment, we administered cumulative doses of NPs to pre-contracted segments of cerebral arteries. In the main study, six healthy volunteers were randomly allocated to receive two intravenous doses of ANP, BNP or CNP, respectively, over 20 min on three separate study days. We recorded blood flow velocity in the middle cerebral artery (V_MCA) by transcranial Doppler. In addition, we measured temporal and radial artery diameters, headache response and plasma concentrations of the NPs. In guinea pigs, ANP and BNP but not CNP showed significant dose-dependent relaxation of cerebral arteries. In healthy humans, NP infusion had no effect on mean V_MCA, and we found no difference in hemodynamic responses between the NPs. Furthermore, natriuretic peptides did not affect temporal and radial artery diameters or induce headache. In conclusion, natriuretic peptides in physiological and pharmacological doses do not affect blood flow velocity in the middle cerebral artery or dilate extracerebral arteries in healthy volunteers.     

Role of gamma-MSH peptides in the regulation of adrenal steroidogenesis

Alpha-, beta- and gamma-melanocyte stimulating hormones (MSHs) are peptides derived from the ACTH precursor, pro-opiomelanocortin. All three peptides have been highly conserved throughout evolution but their exact biological function in mammals is still largely obscure. In recent years, there has been a surge of interest in alpha-MSH and its role in the regulation of feeding. Gamma-MSH by contrast has been shown to be involved in the regulation of adrenal steroidogenesis and also has effects on the cardiovascular and renal systems. This review will provide an overview of the role that gamma-MSH peptides play in the regulation of adrenal steroidogenesis.     

Atrial natriuretic peptides in man

Research on the physiological role of atrial peptides in man is limited, and the potential for these peptides, or more stable analogues, in therapeutics is uncertain. It is clear, however, that plasma levels of immunoreactive atrial natriuretic peptide (IR-ANP) are increased in volunteers taking a high sodium diet, and are elevated in patients with heart failure, chronic renal failure, and primary aldosteronism. There is suggestive evidence that IR-ANP levels are increased also in essential hypertension, although overlap with normotensives is considerable. Injection or infusion of atrial peptides into man results in a diuresis, an increased output of urine electrolytes, a fall in blood pressure and a rise in heart rate, suppression of aldosterone and sometimes of renin also, and stimulation of norepinephrine. In essential hypertensives, urinary effects may be greater than in normotensives. Heart failure patients show a rise in cardiac output and falls in both systemic and pulmonary arterial pressure. Over the next few years and especially if specific antagonists can be developed, the physiologic and pathophysiologic roles of atrial peptides in normal man and in clinical disorders should be clarified. It is possible that stable analogues of atrial peptides will find a place in the treatment of cardiac failure, renal failure, and perhaps hypertension.     

Effects of longitudinal stretch on VSM tone and distensibility of muscular conduit arteries

With progressing age, large arteries diminish their longitudinal stretch, which in extreme cases results in tortuosity. Increased age is also associated with loss of vessel distensibility. We measured pressure-diameter curves from muscular porcine carotid arteries ex vivo at different longitudinal stretch ratios (lambda(z) = 1.4 and 1.8) and under different vascular smooth muscle (VSM) conditions (fully relaxed, normal VSM tone, and maximally contracted). Distensibility was found to be halved by decreasing longitudinal stretch from lambda(z) = 1.8 to 1.4 at physiological pressures. This counterintuitive observation is possible because highly nonlinear elastic modulus of the artery and anisotropic properties. Furthermore, a significantly larger basal VSM contraction was observed at lambda(z) = 1.8 than 1.4, although this was clearly not related to a myogenic response during inflation. This dependence of VSM tone to longitudinal stretch may have possible implications on the functional characteristics of the arterial wall.     

Role of the vagus in control of the major conduit coronary artery in the dog.

Using El Badawi and Schenk's modification of Karnovski's method for the demonstration of acetylcholinesterase, the authors found cholinergic fibres both in the perivascular connective tissue and directly in the wall (in the adventitia) of the major coronary arteries; the fibres were distributed regularly around the circumference of the arteries. In the case of the smaller intramyocardial arteries, the cholinergic fibres were concentrated at two poles of the blood vessel; none were present in the wall of the veins. The shape and topography of the coronary cholinergic arterial plexus resemble the shape and topography of the coronary sympathetic adrenergic system. In apparent contradiction of this finding, stimulation of the cervical vagus did not affect the diameter of the large coronary arteries. Since acetylcholine (6--10 micrograms/kg i.v.) produced a mean 7.4% increase in the diameter of the ramus interventricularis ventralis, we concluded that there are no postgangliar cholinergic fibres of vasomotor significance for the large coronary arteries in the cervical vagus. The specific acetylcholinesterase activity found in the wall of these vessels belongs either to cholinergic terminals whose ganglion cells are not located in the vagal ganglion, or to cholinergic axones terminating outside the wall of the large coronary arteries.     

Role of peptides in regulation of the contractile activity of lymphatic vessels

The review sums up our own and literature data on effects of regulatory peptides upon contractility of lymphatic vessels and lymph flow. Some specific features of the peptides activity: the efficiency in ultra-low concentrations and the biphasic effects, are analyzed.     

Molecular aspects of atrial natriuretic peptides

Peptides possessing both natriuretic and smooth muscle relaxant activities have been isolated from heart atria and their structures have been determined. The peptides designated ANP (atrial natriuretic peptide) regulate salt and water balance and blood pressure. The scope of this article is to provide a summary of recent research developments directed towards understanding the molecular nature of atrial natriuretic peptides.     

Estrogen replacement increases coronary artery distensibility in ovariectomized rats.

The effect of estrogen on the passive characteristics of arteries is not known. We hypothesized that estrogen would increase arterial distensibility as part of its protective effect on the vasculature. Female Sprague-Dawley rats were ovariectomized at 11 weeks of age. One group received a placebo (n = 6), while two other groups (n = 5 each) of rats received a 17beta-estradiol pellet (0.15 mg or 0.5 mg with 60-day release). After 4 weeks of estrogen replacement, coronary and mesenteric arteries (<200 microm diameter) were dissected and mounted on a dual-chamber arteriograph. Lumen diameter and wall thickness were measured in pressurized arteries. The relative changes in diameter (distensibility) as well as wall thickness per unit change in pressure were significantly increased (p < 0.05) in the coronary arteries of the 0.5 mg estradiol replaced rats compared with the ovariectomized control animals and the 0.15 mg estradiol replaced rats. Surprisingly, in the mesenteric arteries from the same animals, there was no difference in distensibility or pressure - wall thickness among the groups. This study provides experimental data of a novel hypothesis that estrogen may afford part of its protection through vascular remodeling of the coronary circulation.     

Intraoperative in situ radial artery conduit flow assessment

A technique is described for simple flow assessment of the in situ radial artery conduit during coronary bypass via a small incision. This technique allows morphologic and physiologic direct intraoperative assessment of radial artery quality and expands the use of radial artery during coronary artery surgery.     

Vasorelaxant effects of and receptors for atrial natriuretic peptides in the mesenteric artery and aorta of the rat

Vasorelaxant effects of different atrial natriuretic peptides (ANP) were measured on rat aortic strips and mesenteric artery rings. These results were compared with the potency of the same peptides to displace 125I-labelled ANP (101-126) on membrane preparations of aorta and of mesenteric vascular bed. In aortic strips and mesenteric artery rings precontracted with phenylephrine (3 X 10(-8) and 10(-6) M, respectively), the order of potency of ANP was as follows: ANP (99-126) greater than ANP (101-126) greater than ANP (103-126) = ANP (103-125) much greater than ANP (103-123). In the displacement binding assays, the order of potency of ANP peptides was similar to that of the relaxation experiments: ANP (99-126) = ANP (101-126) greater than ANP (103-126) = ANP (103-125) much greater than ANP (103-123). When the vessels were precontracted by a smaller concentration of phenylephrine (10(-7) M in mesenteric artery and 10(-8) M in aorta), the IC50 of ANP (101-126) was significantly lower than when the higher concentration of phenylephrine was used. These results show that ANP receptors in the mesenteric artery and in the aorta have similar structural requirements, according to the order of potency of different length ANP, both for binding and myotropic responses.     

Atrial natriuretic peptides stimulate renal gluconeogenesis

Atrial natriuretic peptide (5-28AA; ANP) and atrial extract (ANS) stimulated rat renal gluconeogenesis in cortical tubule suspension in a dose dependent fashion only from substrates that enter gluconeogenesis via phosphoenol-pyruvate carboxylase. The effects of ANP and ANS were significantly potentiated by cAMP and cGMP, whereas methoxamine showed no effect. Extracellular calcium revealed a key role for ANP and ANS response to gluconeogenesis: a concentration of calcium higher than 1 mM was essential. Isolated cells from cortex which lost cell membrane polarity by warming but responded solely to cAMP and cGMP showed no effect by ANP nor ANS. These data suggest that ANP or ANS may act mainly from the basolateral site in the proximal tubule cell and promote gluconeogenesis through cAMP and/or cGMP system.     

Role of histidine for charge regulation of unstructured peptides at interfaces and in bulk

Histidine‐rich, unstructured peptides adsorb to charged interfaces such as mineral surfaces and microbial cell membranes. At a molecular level, we investigate the adsorption mechanism as a function of pH, salt, and multivalent ions showing that (1) proton charge fluctuations are—in contrast to the majority of proteins—optimal at neutral pH, promoting electrostatic interactions with anionic surfaces through charge regulation and (2) specific zinc(II)‐histidine binding competes with protons and ensures an unusually constant charge distribution over a broad pH interval. In turn, this further enhances surface adsorption. Our analysis is based on atomistic molecular dynamics simulations, coarse grained Metropolis Monte Carlo, and classical polymer density functional theory. This multiscale modeling provides a consistent picture in good agreement with experimental data on Histatin 5, an antimicrobial salivary peptide. Biological function is discussed and we suggest that charge regulation is a significant driving force for the remarkably robust activity of histidine‐rich antimicrobial peptides. Proteins 2014; 82:657–667. © 2013 Wiley Periodicals, Inc.     

Biology of natriuretic peptides and their receptors

Increasing evidence suggests that natriuretic peptides (NPs) play diverse roles in mammals, including renal hemodynamics, neuroendocrine, and cardiovascular functions. Collectively, NPs are classified as hypotensive hormones; the main actions of NPs are implicated in eliciting natriuretic, diuretic, steroidogenic, antiproliferative, and vasorelaxant effects, important factors in the control of body fluid volume and blood pressure homeostasis. One of the principal loci involved in the regulatory actions of NPs is their cognate plasma membrane receptor molecules, which are activated by binding with specific NPs. Interaction of NPs with their receptors plays a central role in physiology and pathophysiology of hypertension and cardiovascular disorders. Gaining insight into the intricacies of NPs-specific receptor signaling pathways is of pivotal importance for understanding both hormone-receptor biology and the disease states arising from abnormal hormone receptor interplay. During the last decade there has been a surge in interest in NP receptors; consequently, a wealth of information has emerged concerning molecular structure and function, signaling mechanisms, and use of transgenics and gene-targeted mouse models. The objective of this present review is to summarize and document the previous findings and recent discoveries in the field of the natriuretic peptide hormone family and receptor systems with emphasis on the structure-function relationship, signaling mechanisms, and the physiological and pathophysiological significance in health and disease.     

Role of atrial natriuretic factor in regulation of blood pressure in normotensive rats having reduced renal mass

Experiments were carried out in normotensive, saline-drinking, 60% reduced renal mass rats to determine the effect of an in vivo blockade of endogenous atrial natriuretic factor (ANF) on blood pressure. We used a 60% reduction in renal mass because blood pressure in these normotensive animals is extremely sensitive to any slight further reduction of renal excretory function. Six weeks following the reduction of renal mass and documentation of normotension, rats were injected intraperitoneally twice daily for 12 days with ANF antibody prepared against the C-terminal heptapeptide of AP III conjugated to bovine thyroglobulin. Control rats similarly prepared, received normal rabbit serum (NRS). Blood pressure progressively increased in rats receiving the antibody, and its withdrawal returned blood pressure to control levels within 4-5 days. Serum from either normal rabbits or rabbits immunized with bovine thyroglobulin or peptides unrelated to ANF had no effect on blood pressure in the control animals. These experiments show that in the normotensive saline-drinking rat with reduced renal mass, an antibody to AP III raises blood pressure. This suggests that ANF here is acting to prevent the rise in blood pressure.     

Identification of new atrial natriuretic peptides in frog heart

It has been observed that mammalian atrial natriuretic peptide (ANP)-like immunoreactivity is found in frog heart, but to date the natriuretic factors have not yet been identified. Isolation from bull-frog heart extract was performed mainly by immunoaffinity chromatography on a column linked with anti-hANP IgG. From the low molecular weight fraction, 24- and 21-amino acid peptides were purified to homogeneity. Both peptides were found to elicit diuretic-natriuretic as well as vasorelaxant activity, and were named "frog ANP-24" and "frog ANP-21", respectively. Complete amino acid sequences of the peptides were established by microsequencing and confirmed by syntheses. Frog ANP-21 was identified as an N-terminally three amino acid deleted form of frog ANP-24. Remarkable sequence homology was observed between frog ANP and mammalian ANP, especially in the regions flanked by two half-cystine residues.