Suhayla Mukaddam-Daher

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.

Negative Inotropic and Chronotropic Effects of Oxytocin

Abstract—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 5×10−8 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.

Clonidine and ST-91 May Activate Imidazoline Binding Sites in the Heart to Release Atrial Natriuretic Peptide

It is well established that the antihypertensive drug clonidine acts through specific imidazoline receptors in the brain and kidney to increase diuresis, natriuresis, and kaliuresis. We have previously shown that the effects of clonidine are associated with elevated plasma atrial natriuretic peptide (ANP). Similar to clonidine, ST-91, a clonidine analogue that does not cross the blood-brain barrier, evokes renal responses that are also associated with elevated plasma ANP. The mechanisms of ANP increase elicited by these imidazoline drugs are unclear. Since ANP is primarily released from the cardiac atria, we investigated the direct effect of the imidazoline drugs on ANP release by incubating left and right atrial sections with 10(-6) mol/L ST-91 in the presence and absence of efaroxan, a selective imidazoline I1 receptor antagonist, for 30 minutes at 37 degrees C. ST-91 significantly stimulated ANP release, and the effect was inhibited by 10(-6) mol/L efaroxan. Further studies using heart perfusion with the imidazoline drugs with and without antagonists over 30 minutes revealed that both clonidine and ST-91 gradually stimulated ANP release. Also, perfusion with these compounds resulted in a gradual decrease in heart rate, but bradycardia was significant only with clonidine. The effects of ST-91 were inhibited by 10(-6) mol/L efaroxan and to a lesser extent by 10(-6) mol/L yohimbine, implying that the actions of ST-91 were mainly mediated by I1 receptors. On the other hand, the actions of clonidine were inhibited by 10(-5) mol/L efaroxan and by 10(-6) mol/L yohimbine, an alpha2-adrenoceptor antagonist, which may suggest that the actions of clonidine were preferentially mediated by alpha2-adrenoceptors in the heart. These results indicate that the peripheral actions of clonidine are probably mediated by alpha2 and imidazoline receptors and may involve direct stimulation of ANP release by the cardiac atria--an effect that may account for the increase in plasma ANP levels and diuresis and natriuresis observed in vivo after administration of clonidine and its analogues.

Urinary responses to acute moxonidine are inhibited by natriuretic peptide receptor antagonist

1 We have previously shown that acute intravenous injections of moxonidine and clonidine increase plasma atrial natriuretic peptide (ANP), a vasodilator, diuretic and natriuretic hormone. We hypothesized that moxonidine stimulates the release of ANP, which would act on its renal receptors to cause diuresis and natriuresis, and these effects may be altered in hypertension. 2 Moxonidine (0, 10, 50, 100 or 150 μg in 300 μl saline) and clonidine (0, 1, 5 or 10 μg in 300 μl saline) injected intravenously in conscious normally hydrated normotensive Sprague–Dawley rats (SD, ∼200 g) and 12–14‐week‐old Wistar‐Kyoto (WKY) and spontaneously hypertensive rats (SHR) dose‐dependently stimulated diuresis, natriuresis, kaliuresis and cGMP excretion, with these effects being more pronounced during the first hour post‐injection. The actions of 5 μg clonidine and 50 μg moxonidine were inhibited by yohimbine, an α2‐adrenoceptor antagonist, and efaroxan, an imidazoline I1‐receptor antagonist. 3 Moxonidine (100 μg) stimulated (P<0.01) diuresis in SHR (0.21±0.04 vs 1.16±0.06 ml h−1 100 g−1), SD (0.42±0.06 vs 1.56±0.19 ml h−1 100 g−1) and WKY (0.12±0.04 vs 1.44±0.21 ml h−1 100 g−1). Moxonidine‐stimulated urine output was lower in SHR than in SD and WKY. Moxonidine‐stimulated sodium and potassium excretions were lower in SHR than in SD, but not WKY, demonstrating an influence of strain but not of pressure. Pretreatment with the natriuretic peptide antagonist anantin (5 or 10 μg) resulted in dose‐dependent inhibition of moxonidine‐stimulated urinary actions. Anantin (10 μg) inhibited (P<0.01) urine output to 0.38±0.06, 0.12±0.01, and 0.16±0.04 ml h−1 100 g−1 in SD, WKY, and SHR, respectively. Moxonidine increased (P<0.01) plasma ANP in SD (417±58 vs 1021±112 pg ml−1) and WKY (309±59 vs 1433±187 pg ml−1), and in SHR (853±96 vs 1879±229 pg ml−1). 4 These results demonstrate that natriuretic peptides mediate the urinary actions of moxonidine through natriuretic peptide receptors.

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.

The role of natriuretic peptide receptor-A signaling in unilateral lung ischemia-reperfusion injury in the intact mouse

Ischemia-reperfusion (IR) causes human lung injury in association with the release of atrial and brain natriuretic peptides (ANP and BNP), but the role of ANP/BNP in IR lung injury is unknown. ANP and BNP bind to natriuretic peptide receptor-A (NPR-A) generating cGMP and to NPR-C, a clearance receptor that can decrease intracellular cAMP. To determine the role of NPR-A signaling in IR lung injury, we administered the NPR-A blocker anantin in an in vivo SWR mouse preparation of unilateral lung IR. With uninterrupted ventilation, the left pulmonary artery was occluded for 30 min and then reperfused for 60 or 150 min. Anantin administration decreased IR-induced Evans blue dye extravasation and wet weight in the reperfused left lung, suggesting an injurious role for NPR-A signaling in lung IR. In isolated mouse lungs, exogenous ANP (2.5 nM) added to the perfusate significantly increased the filtration coefficient sevenfold only if lungs were subjected to IR. This effect of ANP was also blocked by anantin. Unilateral in vivo IR increased endogenous plasma ANP, lung cGMP concentration, and lung protein kinase G (PKG(I)) activation. Anantin enhanced plasma ANP concentrations and attenuated the increase in cGMP and PKG(I) activation but had no effect on lung cAMP. These data suggest that lung IR triggered ANP release and altered endothelial signaling so that NPR-A activation caused increased pulmonary endothelial permeability.

Moxonidine improves cardiac structure and performance in SHR through inhibition of cytokines, p38 MAPK and Akt

BACKGROUND AND PURPOSE Regression of left ventricular hypertrophy by moxonidine, a centrally acting sympatholytic imidazoline compound, results from a sustained reduction of DNA synthesis and transient stimulation of DNA fragmentation. Because apoptosis of cardiomyocytes may lead to contractile dysfunction, we investigated in spontaneously hypertensive rats (SHR), time‐ and dose‐dependent effects of in vivo moxonidine treatment on cardiac structure and function as well as on the inflammatory process and signalling proteins involved in cardiac cell survival/death.

Natriuretic peptides as therapeutic targets

Natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide and C-type natriuretic peptide) are cardiac and vascular peptides with vasodilatory, diuretic, natriuretic, anti-inflammatory, antifibrotic and antimitogenic actions. Natriuretic peptides are implicated in normal pressure and volume homeostasis and in the defence against excessive increases in overload-related factors, vasopressive and cardiotoxic factors and their impact on the heart, blood vessels and brain. Genetic manipulation studies confirmed the importance of natriuretic peptides in these functions. Natriuretic peptides are metabolised by NPR-C (clearance receptors) and by enzymatic degradation by neutral endopeptidase. Natriuretic peptide levels (mainly brain natriuretic peptide) correlate with left ventricular hypertrophy and with the severity of heart failure, and are reduced by effective treatment, thus used as diagnostic and prognostic tools. Based on the multiple protective effects of natriuretic peptides, pharmacological therapy has been approved and includes potentiating natriuretic peptide levels by intravenous infusion or by inhibition of endogenous natriuretic peptide degradation. Because each approach has its limitations, the field remains open for improvement.

Control of left ventricular mass by moxonidine involves reduced DNA synthesis and enhanced DNA fragmentation

Left ventricular hypertrophy (LVH) is a maladaptive process associated with increased cardiovascular risk. Regression of LVH is associated with reduced complications of hypertension. Moxonidine is an antihypertensive imidazoline compound that reduces blood pressure primarily by central inhibition of sympathetic outflow and by direct actions on the heart to release atrial natriuretic peptide, a vasodilator and an antihypertrophic cardiac hormone. This study investigated the effect of moxonidine on LVH and the mechanisms involved in this effect.

Functional and molecular effects of imidazoline receptor activation in heart failure.

AIMS Heart failure is a progressive deterioration in heart function associated with overactivity of the sympathetic nervous system. The benefit of inhibition of sympathetic activity by moxonidine, a centrally acting imidazoline receptor agonist, was questioned based on the outcome of a failing clinical trial. The following studies measured cardiac structure and hemodynamics and mechanisms underlying moxonidine-induced changes, in cardiomyopathic hamsters, where the stage of the disease, dose, and compliance were controlled. MAIN METHODS Male BIO 14.6 hamsters (6 and 10 months old, with moderate and advanced heart failure, respectively) received moxonidine at 2 concentrations: low (2.4 mg/kg/day) and high (9.6 mg/kg/day), or vehicle, subcutaneously, for 1month. Cardiac function was measured by echocardiography, plasma and hearts were collected for histological determination of fibrosis and apoptosis, as well as for measurement cytokines by Elisa and cardiac proteins by Western blotting. KEY FINDINGS Compared to age-matched vehicle-treated BIO 14.6, moxonidine did not reduce blood pressure but significantly reduced heart rate and improved cardiac performance. Moxonidine exerted anti-apoptotic effect with differential inflammatory/anti-inflammatory responses that culminate in attenuated cardiac apoptosis and fibrosis and altered protein expression of collagen types. Some effects were observed regardless of treatment onset, although the changes were more significant in the younger group. Interestingly, moxonidine resulted in upregulation of cardiac imidazoline receptors. SIGNIFICANCE These studies imply that in addition to centrally mediated sympathetic inhibition, the effects of moxonidine may, at least in part, be mediated by direct actions on the heart. Further investigation of imidazolines/imidazoline receptors in cardiovascular diseases is warranted.