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Biomedical subjects

S Mukaddam-Daher

Publications and source records attributed to S Mukaddam-Daher.

At least 19 recordsLinked to original sources
PubMed2005

Pregnancy alters nitric oxide synthase and natriuretic peptide systems in the rat left ventricle.

Cyclic guanosine monophosphate (cGMP), which is implicated in cardiac cell growth and function, is synthesized by cytoplasmic soluble guanylyl cyclase (GC) stimulated via nitric oxide (NO) and by particulate membrane-bound GC activated via natriuretic peptides. We investigated possible cGMP elevation in the left ventricle (LV) of rats developing physiologic LV hypertrophy during gestation. Furthermore, expression of estrogen receptors (ER) and oxytocin receptors (OTR) was evaluated because their activation stimulates NO and atrial natriuretic peptide (ANP) release from the heart. Compared with nonpregnant controls, Sprague-Dawley rats on day 7 of gestation had similar heart weights, but, on days 14 and 21, ventricular mass increased by 12% and 28% respectively (P< 0.05). LV cGMP concentration was elevated at day 14 of gestation (3.25 +/- 0.12 vs 4.65 +/- 0.17 pmol/g wet weight, P< 0.01) but decreased at day 21 (2.45 +/- 0.09 pmol/g, P< 0.05) to increase again on postpartum day 1 (6.01 +/- 0.15 pmol/g) and day 4 (9.21 +/- 1.79 pmol/g). Changes in endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), OTR and ERalpha, but not ERbeta, proteins paralleled the pregnancy-related cGMP changes in the LV. In contrast, ANP mRNA of the LV remained at control level throughout gestation but increased postpartum, whereas brain natriuretic peptide (BNP) expression declined at term and increased postpartum. The particulate GC natriuretic peptide receptors (GC-A and GC-B) transcripts were already lower at day 14 of gestation. Natriuretic peptide clearance receptor (NPR-C) transcript was not altered on days 7 and 14, but increased at term. We conclude that cGMP concentration in the rat LV is influenced by both NOS and natriuretic peptide systems and may be involved in the changes of LV contractility and hypertrophy that occur during rat gestation.

Animals↗
PubMed2004

Imidazoline receptors in the heart: a novel target and a novel mechanism of action that involves atrial natriuretic peptides.

Chronic stimulation of sympathetic nervous activity contributes to the development and maintenance of hypertension, leading to left ventricular hypertrophy (LVH), arrhythmias and cardiac death. Moxonidine, an imidazoline antihypertensive compound that preferentially activates imidazoline receptors in brainstem rostroventrolateral medulla, suppresses sympathetic activation and reverses LVH. We have identified imidazoline receptors in the heart atria and ventricles, and shown that atrial I1-receptors are up-regulated in spontaneously hypertensive rats (SHR), and ventricular I1-receptors are up-regulated in hamster and human heart failure. Furthermore, cardiac I1-receptor binding decreased after chronic in vivo exposure to moxonidine. These studies implied that cardiac I1-receptors are involved in cardiovascular regulation. The presence of I1-receptors in the heart, the primary site of production of natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), cardiac hormones implicated in blood pressure control and cardioprotection, led us to propose that ANP may be involved in the actions of moxonidine. In fact, acute iv administration of moxonidine (50 to 150 microg/rat) dose-dependently decreased blood pressure, stimulated diuresis and natriuresis and increased plasma ANP and its second messenger, cGMP. Chronic SHR treatment with moxonidine (0, 60 and 120 microg kg(-1) h(-1), sc for 4 weeks) dose-dependently decreased blood pressure, resulted in reversal of LVH and decreased ventricular interleukin 1beta concentration after 4 weeks of treatment. These effects were associated with a further increase in already elevated ANP and BNP synthesis and release (after 1 week), and normalization by 4 weeks. In conclusion, cardiac imidazoline receptors and natriuretic peptides may be involved in the acute and chronic effects of moxonidine.

Animals↗
PubMed2004

The cardiovascular and renal effects of the potent and highly selective mu opioid agonist [Dmt1]DALDA.

The cardiovascular and renal effects of a mu opioid agonist, [Dmt]DALDA, were studied in conscious Sprague-Dawley rats. During the first hour postinjection, [Dmt]DALDA (0.025-250 microg/rat, IV) evoked a dose-dependent diuresis. The dose of 2.5 microg increased urine volume from 1.0 +/- 0.2 to 3.4 +/- 0.3 mL/h (P < 0.001, n = 30), urinary excretion of sodium, potassium, and cGMP, and induced a mild antihypertensive effect. This dose increased cumulative 4-hour urine volume but significantly inhibited sodium and potassium excretions. The renal and cardiovascular effects were abolished by naloxone (4 mg/kg), but not by naloxonazine (35 mg/kg SC), a selective mu-1 receptor antagonist. Pretreatment with 8 mg/kg naloxone methiodide, an opioid antagonist with limited access to the brain, partially inhibited the renal effects of [Dmt]DALDA. Inhibition of nitric oxide synthases with L-NAME (1 mg/kg) had no effect on the renal and cardiovascular actions of [Dmt]DALDA. Plasma ANP and AVP, measured at 20 and 120 minutes after injection, were not altered by 2.5 and 25 microg [Dmt]DALDA. Therefore, [Dmt]DALDA evokes renal and cardiovascular effects that may primarily be mediated by central naloxonazine-insensitive mu opioid receptors (non-mu-1). These findings indicate that the central mu opioid system is involved in the regulatory mechanism of renal handling of sodium and water.

Animals↗
PubMed2003

Cardiac effects of moxonidine in spontaneously hypertensive obese rats.

Moxonidine, an imidazoline receptor agonist that acts centrally to inhibit sympathetic activity, has been shown to reduce effectively blood pressure, fasting insulin levels, and free fatty acids. In this study, we investigated the long-term effects of moxonidine treatment on cardiac natriuretic peptides (ANP and BNP) in Spontaneously Hypertensive Obese Rats (SHROBs), a rat model that resembles human Syndrome X. SHROBs expressing spontaneous hypertension, insulin resistance, and genetic obesity (weight 590 +/- 20 g, at 30 weeks) received moxonidine in chow at 4 mg/kg/day for 15 days. Moxonidine significantly reduced not only systolic blood pressure (187 +/- 6 versus 156 +/- 5 mm Hg, P < 0.05) but also plasma ANP (1595 +/- 371 versus 793 +/- 131 pg/mL, P < 0.05) and BNP (22 +/- 3 versus 14 +/- 1 pg/mL, P < 0.04), without influencing cardiac content of either peptide. Semi-quantitative PCR revealed that atrial ANPmRNA/GAPDHmRNA decreased to 39% 6 10% of pair-fed controls, P < 0.03. In left ventricles, moxonidine also decreased ANP mRNA to 69% +/- 7% and BNP mRNA to 74% +/- 6% of control, P < 0.02, but right ventricular ANP and BNP mRNA were not affected. These findings indicate that chronic inhibition of sympathetic activity with moxonidine in SHROB is associated with decreased ventricular natriuretic peptide transcription, consistent with the cardioprotective effects of moxonidine given the role of ANP and BNP as markers of cadiac disease. Moxonidine also improves the metabolic profile in these rats, thus it may be considered the drug of choice in treatment of metabolic syndrome X.

Animals↗
PubMed2003

Normalization of up-regulated cardiac imidazoline I(1)-receptors and natriuretic peptides by chronic treatment with moxonidine in spontaneously hypertensive rats.

The effect of treatment with moxonidine (120 mg/kg/h sc, 4 weeks) on cardiac I(1)-receptors and natriuretic peptide synthesis was evaluated in spontaneously hypertensive rats (SHR). I(1)-receptor protein (85 kD) was up-regulated in SHR atria, and normalized in right and left atria by moxonidine. Similarly, moxonidine normalized atrial and ventricular atrial natriuretic peptide messenger RNA (mRNA) and brain natriuretic peptide mRNA. This study shows that cardiac I(1)-receptors are functional, being regulated by hypertension and by chronic exposure to agonist, and that cardiac natriuretic peptides may be regulated by I(1)-receptor-mediated mechanisms.

Animals↗
PubMed2002

Regulation of cardiac oxytocin system and natriuretic peptide during rat gestation and postpartum.

We have recently uncovered the presence of an oxytocin system in the heart and found that oxytocin is a physiological regulator of atrial natriuretic peptide (ANP), a diuretic, natriuretic and vasodilator cardiac hormone. However, dynamic changes in these systems during gestation, when mechanisms of volume and pressure homeostasis are altered, are not clear. Accordingly, ANP, oxytocin and oxytocin receptors were evaluated in rat hearts and plasma at three stages of gestation (7, 14 and 21 days) and at 2 and 5 days postpartum. Compared with non-pregnant controls, plasma ANP was elevated in mid-gestation, but significantly decreased at term (21 days), to increase again postpartum. Right and left atrial ANP mRNA levels were not altered throughout gestation but increased by 1.5- to 2-fold postpartum (P<0.01). At term, ANP content in right (8.7+/-1.2 vs 12.7+/-1.1 micro g/mg protein, P<0.04) and left (3.5+/-0.6 vs 8.5+/-2.0 micro g/mg protein, P<0.01) atria increased. These findings imply that decreased plasma ANP at term results from inhibition of release rather than decreased synthesis. In parallel, oxytocin, a stimulator of ANP release, decreased in left atria at day 7 to 50% of non-pregnant levels and remained low throughout gestation. Oxytocin receptor mRNA increased in left atria at 7 and 14 days of gestation by 2- and 5-fold respectively, but decreased at 21 days to lower than non-pregnant levels to increase again (3-fold) postpartum. The changes in oxytocin receptor expression at term and postpartum paralleled oxytocin receptor protein determined by Western blot. These results imply that pregnancy is associated with dynamic changes in the cardiac oxytocin system (peptide and/or receptors), which may influence natriuretic peptide release. Together, these peptides would act on their receptors in the heart, vasculature and kidneys to maintain vascular tone and renal function throughout gestation and postpartum.

Animals↗
PubMed2001

Negative inotropic and chronotropic effects of oxytocin.

We have previously shown that oxytocin receptors are present in the heart and that perfusion of isolated rat hearts with oxytocin results in decreased cardiac flow rate and bradycardia. The mechanisms involved in the negative inotropic and chronotropic effects of oxytocin were investigated in isolated dog right atria in the absence of central mechanisms. Perfusion of atria through the sinus node artery with 10(-6) mol/L oxytocin over 5 minutes (8 mL/min) significantly decreased both beating rate (-14.7+/-4.9% of basal levels, n=5, P<0.004) and force of contraction (-52.4+/-9.1% of basal levels, n=5, P<0.001). Co-perfusion with 10(-6) mol/L oxytocin receptor antagonist (n=3) completely inhibited the effects of oxytocin on frequency (P<0.04) and force of contraction (P<0.004), indicating receptor specificity. The effects of oxytocin were also totally inhibited by co-perfusion with 5x10(-8) mol/L tetrodotoxin (P<0.02) or 10(-6) mol/L atropine (P<0.03) but not by 10(-6) mol/L hexamethonium, which implies that these effects are neurally mediated, primarily by intrinsic parasympathetic postganglionic neurons. Co-perfusion with 10(-6) mol/L NO synthase inhibitor (L-NAME) significantly inhibited oxytocin effects on both beating rate (-1.85+/-1.27% versus -14.7+/-4.9% in oxytocin alone, P<0.05) and force of contraction (-24.9+/-4.4% versus -52.4+/-9.1% in oxytocin alone, n=4, P<0.04). The effect of oxytocin on contractility was further inhibited by L-NAME at 10(-4) mol/L (-8.1+/-1.8%, P<0.01). These studies imply that the negative inotropic and chronotropic effects of oxytocin are mediated by cardiac oxytocin receptors and that intrinsic cardiac cholinergic neurons and NO are involved in these actions.

Animals↗
PubMed2000

Oxytocin and its receptors are synthesized in the rat vasculature.

Produced and released by the heart, oxytocin (OT) acts on its cardiac receptors to decrease the cardiac rate and force of contraction. We hypothesized that it might also be produced in the vasculature and regulate vascular tone. Consequently, we prepared acid extracts of the pulmonary artery and vena cava of female rats. OT concentrations in dog and sheep aortae were equivalent to those of rat aorta (2745 +/- 180 pg/mg protein), indicating that it is present in the vasculature of several mammalian species. Reverse-phase HPLC of aorta and vena cava extracts revealed a single peak corresponding to the amidated OT nonapeptide. Reverse-transcribed PCR confirmed OT synthesis in these tissues. Using the selective OT receptor ligand compound VI, we detected a high number of OT-binding sites in the rat vena cava and aorta. Furthermore, OT receptor (OTR) mRNA was found in the vena cava, pulmonary vein, and pulmonary artery with lower levels in the aorta, suggesting vessel-specific OTR distribution. The abundance of OTR mRNA in the vena cava and pulmonary vein was associated with high atrial natriuretic peptide mRNA. In addition, we have demonstrated that diethylstilbestrol treatment of immature female rats increased OT significantly in the vena cava but not in the aorta and augmented OTR mRNA in both the aorta (4-fold) and vena cava (2-fold), implying regulation by estrogen. Altogether, these data suggest that the vasculature contains an intrinsic OT system, which may be involved in the regulation of vascular tone as well as vascular regrowth and remodeling.

Animals↗
PubMed2000

Corticotropin-releasing hormone causes antidiuresis and antinatriuresis by stimulating vasopressin and inhibiting atrial natriuretic peptide release in male rats.

In both normally hydrated and volume-expanded rats, there was a biphasic effect of corticotropin-releasing hormone (CRH) (1-10 microgram, i.v.) on renal function. Within the first hour, CRH caused antidiuresis, antinatriuresis, and antikaliuresis together with reduction in urinary cGMP output that, in the fourth hour, were replaced by diuresis, natriuresis, and kaliuresis accompanied by increased cGMP output. Plasma arginine vasopressin (AVP) concentrations increased significantly within 5 min, reached a peak at 15 min, and declined by 30 min to still-elevated values maintained for 180 min. Changes in plasma atrial natriuretic peptide (ANP) were the mirror image of those of AVP. Plasma ANP levels were correlated with decreased ANP in the left ventricle at 30 min and increased ANP mRNA in the right atrium at 180 min. All urinary changes were reversed by a potent AVP type 2 receptor (V(2)R) antagonist. Control 0.9% NaCl injections evoked an immediate increase in blood pressure and heart rate measured by telemetry within 3-5 min. This elevation of blood pressure was markedly inhibited by CRH (5 microgram). We hypothesize that the effects are mediated by rapid, direct vasodilation induced by CRH that decreases baroreceptor input to the brain stem, leading to a rapid release of AVP that induces the antidiuresis by direct action on the V(2)Rs in the kidney. Simultaneously, acting on V(2)Rs in the heart, AVP inhibits ANP release and synthesis, resulting in a decrease in renal cGMP output that is responsible for the antinatriuretic and antikaliuretic effects.

Animals↗
PubMed2000

Atrial natriuretic peptide is involved in renal actions of moxonidine.

Moxonidine, an antihypertensive imidazoline compound, reduces blood pressure by selective activation of central imidazoline I(1)-receptors and inhibition of sympathetic nerve activity and by direct actions on the kidney, with both mechanisms resulting in diuresis and natriuresis. We hypothesized that the hypotensive and renal actions of moxonidine may be mediated by atrial natriuretic peptide (ANP), a cardiac peptide involved in pressure and volume homeostasis through its vasodilatory, diuretic, and natriuretic actions. Renal parameters were measured on an hourly basis over a period of 4 hours in conscious rats that received bolus intravenous injections of moxonidine (1 to 150 microg/300 microL saline). During the first hour, moxonidine dose-dependently stimulated diuresis, natriuresis, kaliuresis, and urinary cGMP, the index of ANP activity. Moxonidine (50 microg) significantly (P<0.001) stimulated urinary volume (0.35+/-0.04 versus 1.05+/-0.09 mL/h per 100 g), sodium (14. 3+/-2.5 versus 51.8+/-6.5 micromol/h per 100 g), potassium (10.5+/-2. 3 versus 32.3+/-3.2 micromol/h per 100 g), and cGMP (325+/-52 versus 744+/-120 pmol/h per 100 g). Pretreatment with a selective imidazoline receptor antagonist, efaroxan, dose-dependently inhibited moxonidine-stimulated renal parameters. Efaroxan (25 microg per rat) significantly inhibited moxonidine-stimulated diuretic and natriuretic effects and urinary cGMP excretion (744+/-120 versus 381+/-137 pmol/h per 100 g, P<0.02). The alpha(2)-adrenoceptor antagonist yohimbine (50 microg per rat) partially yet significantly inhibited moxonidine-stimulated diuresis and natriuresis but not cGMP excretion. Plasma ANP was dose-dependently increased by moxonidine and was inhibited by pretreatment with efaroxan (220.8+/-36.9 versus 100.3+/-31.7 pg/mL, P<0.03) but not by yohimbine. In conclusion, selective in vivo activation of imidazoline receptors by moxonidine is associated with dose-dependent diuresis, natriuresis, and kaliuresis as well as stimulated plasma ANP and urinary cGMP excretion, thus implicating ANP in the renal actions of moxonidine.

Adrenergic alpha-Antagonists↗
PubMed2000

Oxytocin is a cardiovascular hormone.

Oxytocin (OT), a nonapeptide, was the first hormone to have its biological activities established and chemical structure determined. It was believed that OT is released from hypothalamic nerve terminals of the posterior hypophysis into the circulation where it stimulates uterine contractions during parturition, and milk ejection during lactation. However, equivalent concentrations of OT were found in the male hypophysis, and similar stimuli of OT release were determined for both sexes, suggesting other physiological functions. Indeed, recent studies indicate that OT is involved in cognition, tolerance, adaptation and complex sexual and maternal behaviour, as well as in the regulation of cardiovascular functions. It has long been known that OT induces natriuresis and causes a fall in mean arterial pressure, both after acute and chronic treatment, but the mechanism was not clear. The discovery of the natriuretic family shed new light on this matter. Atrial natriuretic peptide (ANP), a potent natriuretic and vasorelaxant hormone, originally isolated from rat atria, has been found at other sites, including the brain. Blood volume expansion causes ANP release that is believed to be important in the induction of natriuresis and diuresis, which in turn act to reduce the increase in blood volume. Neurohypophysectomy totally abolishes the ANP response to volume expansion. This indicates that one of the major hypophyseal peptides is responsible for ANP release. The role of ANP in OT-induced natriuresis was evaluated, and we hypothesized that the cardio-renal effects of OT are mediated by the release of ANP from the heart. To support this hypothesis, we have demonstrated the presence and synthesis of OT receptors in all heart compartments and the vasculature. The functionality of these receptors has been established by the ability of OT to induce ANP release from perfused heart or atrial slices. Furthermore, we have shown that the heart and large vessels like the aorta and vena cava are sites of OT synthesis. Therefore, locally produced OT may have important regulatory functions within the heart and vascular beds. Such functions may include slowing down of the heart or the regulation of local vascular tone.

Animals↗
PubMed1999

Hormonal regulation of natriuretic peptide system during induced ovarian follicular development in the rat.

All components of the natriuretic peptide (NP) system have been found in the ovary. The purpose of this study was to determine the hormonal regulation of the NP system during follicular growth and ovulation induced by gonadotropins eCG and hCG. Ovarian membrane binding, before and after treatment, revealed the presence of guanylyl cyclase-type receptors exclusively. Equine CG treatment increased Bmax from 225 +/- 50 fmol/mg protein in control animals to 354 +/- 51 fmol/mg protein, and additional hCG treatment increased it further to 492 +/- 130 fmol/mg protein (p < 0.05), without changing receptor affinity. The increased binding was consistent with increased ability of atrial natriuretic peptide (ANP) to activate guanylyl cyclase in the ovarian cells obtained from hormone-treated animals. In confirmation, autoradiography of 125I-tyroCNP and 125I-ANP binding to the rat ovary showed that both guanylyl cyclase GC-A and GC-B receptor subtypes are localized to the granulosa cells of antral follicles. Quantitative analysis of GC-A and GC-B receptors by reverse transcription-polymerase chain reaction showed that the expression level of both receptors started to increase at 2 h and reached maximal levels at 6 h following eCG treatment. Increased levels of GC-B mRNA were also observed 12 h after eCG injection. At 24 and 48 h the receptor levels were below basal. Stimulation of NP receptors by eCG was paralleled by activation of both ovarian ANP and C-type natriuretic peptide (CNP) gene expression. ANP mRNA increased as early as 1 h after eCG injection and remained elevated up to 6 h. CNP mRNA increased at 2 h after eCG injection, peaked (5-fold) at 6 h, and remained elevated 48 h later, a stage at which follicular maturation continues. Incubation of ovaries with ANP significantly decreased eCG-induced estradiol level, indicating the functionality of the ovarian NP system. These results implicate the NP system in the induction and maintenance of fluid balance in the rapidly developing ovarian follicle.

Animals↗
PubMed1999

Pulmonary natriuretic peptide system during rat development.

Maturational changes in the rat lung natriuretic peptide system were studied postnatally in 1-, 4-, and 22-day-old rats. Lung atrial natriuretic factor (ANF) content increased significantly from day 1 to day 4 (712+/-188 vs. 1905+/-520 pg/mg protein; p<0.01) but decreased to 532+/-41 pg/mg protein, on day 22. These changes paralleled ANF messenger RNA (mRNA) detected by reverse transcribed polymerase chain reaction (RT-PCR). Rat pulmonary development also was associated with quantitative and qualitative alterations in ANF receptors. Competitive-binding radioreceptor assays of lung membranes with 125I-ANF and increasing concentrations of unlabeled ANF revealed that the natriuretic peptide receptor-binding sites (Bmax) progressively increased with age from 112 +/-21 fmol/mg protein at day 1 to 211+/-16 (p<0.02) and 326+/-62 fmol/mg protein (p<0.04) in 4- and 22-day-old rats, respectively. Autoradiographic studies of 125I-tyr(0)CNP binding to lung sections revealed that the levels of the natriuretic peptide receptor B (NPR-B) were undetectable. On the other hand, binding of 125I-ANF increased with age, and the higher binding at 4 days was mainly due to increased density of the clearance receptor-C (NPR-C), and at 22 days due to increased natriuretic peptide receptor-A (NPR-A). The increase in natriuretic peptide binding was confirmed at the level of synthesis, where RT-PCR revealed that NPR-A mRNA significantly increased (p<0.01) in 22-day-old rats. In conclusion, these studies demonstrate that the rat pulmonary natriuretic peptide system is altered during development. The altered synthesis of lung natriuretic peptides and their receptors may play a role in the postnatal adaptation of pulmonary circulation.

Animals↗
PubMed1999

Renal effects of prolonged intrarenal infusions of angiotensin II and atrial natriuretic peptide in sheep.

Angiotensin II (AngII) and atrial natriuretic peptide (ANP) are two hormones that have antagonistic effects on volume and pressure regulation. Plasma levels of both hormones are elevated in sheep pregnancy. However, during pregnancy, volume expansion occurs despite elevated plasma ANP, implying an overriding role of AngII. In addition to counteracting the effects of ANP on the physiological level, AngII also may act on the receptor level. Therefore this study was designed to investigate the hemodynamic and renal effects of ANP and AngII separately and to define their selective effects on the renal natriuretic peptide receptor types in the various segments of the nephron. Eight unilaterally nephrectomized nonpregnant sheep received separately for 10 days, low doses of AngII (1 ng/kg/min) and ANP (0.5 ng/kg/min) directly infused into the renal arteries to avoid systemic effects. Intrarenal AngII infusion decreased sodium excretion (UNaV) from 111+/-11 to 36 +/-8 and 45+/-6 mmol/day (p<0.05) on days 3 and 8-10, respectively. Mean arterial pressure (MAP) increased from 94 +/-6 mm Hg to a maximum of 107+/-8 mm Hg on day 5 of infusion and stabilized at 101+/-7 mm Hg on days 8-10 (p<0.05). Intrarenal ANP infusion significantly increased UNaV on day 1 from 93+/-9 to 188+/-20 mmol/day (p<0.05), followed by sodium retention on days 4-6 (average, 60+/-13 mmol/day; p<0.05). UNaV again increased above control levels on days 8-10 to an average level of 111+/-15 mmol/day. MAP decreased from 99+/-4 to 90+/-5 mm Hg (p<0.05) on days 1-3, and remained lower than control throughout the infusion period. The kidneys were collected at control nephrectomy and at the end of infusion. The natriuretic peptide receptors were characterized by competitive-binding radioreceptor assays on glomerular, outer medullary, and inner medullary membranes. AngII infusion increased the dissociation constant (Kd) of inner medullary natriuretic peptide receptors from 186 +/-11 to 267+/-22 pM (p<0.05), and ANP infusion decreased maximal binding capacity (Bmax) of inner medullary receptors from 134+/-10 to 89+/-15 fmol/mg protein (p<0.05). Glomerular and outer medullary natriuretic peptide receptors were not affected by either AngII or ANP infusion. In conclusion, AngII stimulates antinatriuresis and counteracts the hemodynamic and renal effects of ANP in part by downregulating the renal inner medullary natriuretic peptide receptors.

Angiotensin II↗
PubMed1998

Rat heart: a site of oxytocin production and action.

We report here that the rat heart is a site of oxytocin (OT) synthesis and release. Oxytocin was detected in all four chambers of the heart. The highest OT concentration was in the right atrium (2128 +/- 114 pg/mg protein), which was 19-fold higher than in rat uterus but 3.3-fold lower than in the hypothalamus. OT concentrations were significantly greater in the right and left atria than in the corresponding ventricles. Furthermore, OT was released into the effluent of isolated, perfused rat heart (34.5 +/- 4.7 pg/min) and into the medium of cultured atrial myocytes. Reverse-phase HPLC purification of the heart extracts and heart perfusates revealed a main peak identical with the retention time of synthetic OT. Southern blots of reverse transcription-PCR products from rat heart revealed gene expression of specific OT mRNA. OT immunostaining likewise was found in atrial myocytes and fibroblasts, and the intensity of positive stains from OT receptors paralleled the atrial natriuretic peptide stores. Our findings suggest that heart OT is structurally identical, and therefore derived from, the same gene as the OT that is primarily found in the hypothalamus. Thus, the heart synthesizes and processes a biologically active form of OT. The presence of OT and OT receptor in all of the heart's chambers suggests an autocrine and/or paracrine role for the peptide. Our finding of abundant OT receptor in atrial myocytes supports our hypothesis that OT, directly and/or via atrial natriuretic peptide release, can regulate the force of cardiac contraction.

Animals↗
PubMed1998

Altered regulation of natriuretic peptides in the rat heart by prenatal exposure to morphine.

1. Both endogenous and exogenous opioids modulate blood pressure and cardiac function by stimulating cardiac synthesis of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). Since morphine crosses the placental barrier, it could alter the ANF-BNP system in the fetal heart. The aim of this study was to characterize cardiac natriuretic peptides in normal rat development and in rats prenatally exposed to morphine. 2. Female rats received either saline or morphine (10 or 20 mg kg-1 day-1) via osmotic minipumps during gestation. The effects of this treatment were investigated in offspring at 1, 4 and 22 days of age. 3. During maturation, atrial ANF and ANF mRNA increased by 3-fold from birth to 3 weeks of age, but BNP and BNP mRNA tended to decrease. In the ventricles, both ANF and BNP content decreased at 3 weeks after birth, from 25.11 +/- 3.6 to 0.81 +/- 0.1 ng (mg protein)-1 (P < 0.001), and from 3.36 +/- 0.33 to 0.19 +/- 0.01 ng (mg protein)-1 (P < 0.001), respectively. However, whereas ventricular ANF mRNA decreased, BNP mRNA levels did not change during maturation. Prenatal exposure to morphine significantly increased ANF content in the left atria of 22-day-old rats, and in the right atria of 1-, 4- and 22-day-old rats compared with age-matched saline controls. In contrast, prenatal exposure to 20 mg kg-1 day-1 morphine significantly inhibited BNP and BNP mRNA in the ventricles at all ages studied. 4. These observations suggest that alterations in mRNA synthesis or stability and/or post-translational processing of ANF and BNP occur in the heart during maturation, and that prenatal exposure to morphine alters cardiac production, and possibly release, of both peptides.

Analgesics, Opioid↗
PubMed1997

Oxytocin releases atrial natriuretic peptide by combining with oxytocin receptors in the heart.

Previous studies indicated that the central nervous system induces release of the cardiac hormone atrial natriuretic peptide (ANP) by release of oxytocin from the neurohypophysis. The presence of specific transcripts for the oxytocin receptor was demonstrated in all chambers of the heart by amplification of cDNA by the PCR using specific oligonucleotide primers. Oxytocin receptor mRNA content in the heart is 10 times lower than in the uterus of female rats. Oxytocin receptor transcripts were demonstrated by in situ hybridization in atrial and ventricular sections and confirmed by competitive binding assay using frozen heart sections. Perfusion of female rat hearts for 25 min with Krebs-Henseleit buffer resulted in nearly constant release of ANP. Addition of oxytocin (10(-6) M) significantly stimulated ANP release, and an oxytocin receptor antagonist (10(-7) and 10(-6) M) caused dose-related inhibition of oxytocin-induced ANP release and in the last few minutes of perfusion decreased ANP release below that in control hearts, suggesting that intracardiac oxytocin stimulates ANP release. In contrast, brain natriuretic peptide release was unaltered by oxytocin. During perfusion, heart rate decreased gradually and it was further decreased significantly by oxytocin (10(-6) M). This decrease was totally reversed by the oxytocin antagonist (10(-6) M) indicating that oxytocin released ANP that directly slowed the heart, probably by release of cyclic GMP. The results indicate that oxytocin receptors mediate the action of oxytocin to release ANP, which slows the heart and reduces its force of contraction to produce a rapid reduction in circulating blood volume.

Animals↗