Robyn L. Woods

Effects of intravenous brain natriuretic peptide on regional sympathetic activity in patients with chronic heart failure as compared with healthy control subjects.

OBJECTIVES We sought to assess the effects of brain natriuretic peptide (BNP) on systemic and regional sympathetic nervous activity (SNA) in both patients with congestive heart failure (CHF) and healthy control subjects. BACKGROUND Although the response of SNA to atrial natriuretic peptide (ANP) has been well documented, the response of SNA to BNP is largely unknown. METHODS We assessed cardiac and whole-body SNA using the norepinephrine (NE) tracer dilution method before and after infusion of two doses of BNP (3 and 15 ng/kg body weight per min) in 11 patients with stable CHF (ejection fraction 24 +/- 2%) and 12 age-matched healthy control subjects. In addition, renal SNA and hemodynamic variables were assessed at baseline and after the higher BNP dose. RESULTS Low dose BNP did not change blood pressure or whole-body NE spillover, but reduced cardiac NE spillover in both groups by 32 +/- 13 pmol/min (p < 0.05). In both groups, high dose BNP reduced pulmonary capillary pressure by 5 +/- 1 mm Hg (p < 0.001) and mean arterial pressure by 6 +/- 3 mm Hg (p < 0.05), without a concomitant increase in whole-body NE spillover; however, cardiac NE spillover returned to baseline levels. Renal NE spillover remained virtually unchanged in healthy control subjects (501 +/- 120 to 564 +/- 115 pmol/min), but was reduced in patients with CHF (976 +/- 133 to 656 +/- 127 pmol/min, p < 0.01). CONCLUSIONS Our results demonstrate a sympathoinhibitory effect of BNP. Cardiac sympathetic inhibition was observed at BNP concentrations within the physiologic range, whereas high dose BNP, when arterial and filling pressures fell and reflex sympathetic stimulation was expected, systemic and cardiac SNA equated to baseline values. There was inhibition of renal SNA in patients with CHF, but not in healthy control subjects. Whether this effect is specific to BNP or related to reduced filling pressure remains to be determined.

Antihypertrophic actions of the natriuretic peptides in adult rat cardiomyocytes: importance of cyclic GMP.

UNLABELLED Atrial natriuretic peptide (ANP) prevents hypertrophy of neonatal cardiomyocytes. However, whether this effect is retained in the adult phenotype or if other members of the natriuretic peptide family exhibit similar antihypertrophic properties, has not been elucidated. OBJECTIVE Our objective was to examine whether the natriuretic peptides protect against adult cardiomyocyte hypertrophy in vitro. METHODS Adult rat cardiomyocytes were incubated with angiotensin II (Ang II)+/-ANP, B-type (BNP) or C-type (CNP) natriuretic peptides for determination of [3H]phenylalanine incorporation, c-fos mRNA expression and cyclic GMP. The effects of 8-bromo-cyclic GMP (cyclic GMP analogue), HS-142-1 (particulate guanylyl cyclase inhibitor) and KT5823 (cyclic GMP-dependent protein kinase inhibitor) were also investigated. RESULTS Ang II-stimulated increases in markers of hypertrophy, [3H]phenylalanine incorporation (to 136+/-3% of control, n=9) and c-fos mRNA expression (4.3+/-1.4-fold, n=5), were completely prevented by each of ANP, BNP or CNP. This protective action was accompanied by increased cardiomyocyte cyclic GMP. Inhibitory actions on [3H]phenylalanine incorporation were mimicked by 8-bromo-cyclic GMP, and were abolished by HS-142-1. KT5823 blocked the response to BNP and CNP, but not to ANP. CONCLUSION ANP prevents hypertrophy of adult rat cardiomyocytes. This protective action is shared by BNP and CNP and involves activation of particulate guanylyl cyclase receptors. Antihypertrophic effects of BNP and CNP are mediated through cyclic GMP-dependent protein kinase, but ANP can activate additional pathways independent of cyclic GMP to prevent adult cardiomyocte hypertrophy. These novel findings are of interest particularly since BNP appears to exert antifibrotic rather than antihypertrophic actions in vivo, while CNP is thought to act at least in part via the endothelium.

CARDIOPROTECTIVE FUNCTIONS OF ATRIAL NATRIURETIC PEPTIDE AND B‐TYPE NATRIURETIC PEPTIDE: A BRIEF REVIEW

1. If one was to design a hormone to protect the heart, it would have a number of features shown by the cardiac natriuretic peptides atrial natriuretic peptide (ANP) and B‐type natriuretic peptide (BNP). These hormones are made in cardiomyocytes and are released into the circulation in response to atrial and ventricular stretch, respectively. Atrial natriuretic peptide and BNP can reduce the preload and after‐load in normal and failing hearts. They reduce blood volume over the short term by sequestering plasma and over the longer term by promoting renal salt and water excretion and by antagonizing the renin–angiotensin–aldosterone system at many levels. Each of these actions affords indirect benefit to a volume‐ or pressure‐threatened heart.

SIMULATION OF ACUTE HAEMORRHAGE IN UNANAESTHETIZED RABBITS

1. We have shown that it is feasible to match the linear rate of fall of cardiac output that occurs during haemorrhage at 2.7 ml/kg per min in unanaesthetized rabbits by constricting the thoracic inferior vena cava so as to decrease venous return.

Acute Antihypertrophic Actions of Bradykinin in the Rat Heart: Importance of Cyclic GMP

Abstract—The antihypertrophic action of angiotensin (Ang)-converting enzyme (ACE) inhibitors in the heart is attributed in part to potentiation of bradykinin. Bradykinin prevents hypertrophy of cultured cardiomyocytes by releasing nitric oxide (NO) from endothelial cells, which increases cardiomyocyte guanosine 3′5′-cyclic monophosphate (cyclic GMP). It is unknown whether cyclic GMP is essential for the action of bradykinin, or whether findings in isolated cardiomyocytes apply in whole hearts, in the presence of other cell types and mechanical/dynamic activity. We now examine the contribution of cyclic GMP to the antihypertrophic action of bradykinin in cardiomyocytes and perfused hearts. In adult rat isolated cardiomyocytes cocultured with bovine aortic endothelial cells, the inhibitory action of bradykinin (10 &mgr;mol/L) against Ang II (1 &mgr;mol/L)–induced [3H]phenylalanine incorporation was abolished by the soluble guanylyl cyclase inhibitor [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (10 &mgr;mol/L). In Langendorff-perfused rat hearts, Ang II (10 nmol/L)–induced increases in [3H]phenylalanine incorporation and atrial natriuretic peptide mRNA expression were prevented by bradykinin (100 nmol/L), the NO donor sodium nitroprusside (3 &mgr;mol/L), and the ACE inhibitor ramiprilat (100 nmol/L). The acute antihypertrophic action of bradykinin was accompanied by increased left ventricular cyclic GMP, and the ramiprilat effect was attenuated by HOE 140 (1 &mgr;mol/L, a B2-kinin receptor antagonist) or [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (100 nmol/L). In conclusion, bradykinin exerts a direct inhibitory action against the acute hypertrophic response to Ang II in rat isolated hearts, and elevation of cardiomyocyte cyclic GMP may be an important antihypertrophic mechanism used by bradykinin and ramiprilat in the heart.

Atrial, B-type, and C-type natriuretic peptides cause mesenteric vasoconstriction in conscious dogs.

Cardiovascular responses were compared with equimolar infusions of B-type (BNP) and C-type (CNP) with atrial natriuretic peptide (ANP) in conscious, instrumented dogs. On separate days, each natriuretic peptide or vehicle was infused (intravenously) at step-up doses of 2, 5, 10, and 20 pmol. kg-1. min-1 (20 min each dose) to increase circulating levels of the infused peptide from approximately 2- to 20-fold. Like ANP, infusions of BNP caused dose-related increases (P < 0.05) in mesenteric vascular resistance, urine flow, natriuresis, and hematocrit (changes at highest doses were 60 +/- 9, 334 +/- 113, 313 +/- 173, and 12 +/- 2%, respectively). BNP also lowered (P < 0. 05) plasma renin activity (-43 +/- 11%) and arterial pressure (-10 +/- 3%). Effects of BNP were independent of reflex sympathetic activation, since autonomic ganglion blockade did not attenuate the responses. CNP infusions had little effect except to increase (P < 0. 05) mesenteric vascular resistance (27 +/- 10%) and plasma ANP (41 +/- 7%). Cardiovascular actions of BNP, like those of ANP, counteract the renin-ANG system and may protect the heart by lowering cardiac preload (venous return) and afterload (arterial pressure) while maintaining blood flow to extrasplanchnic regions.Cardiovascular responses were compared with equimolar infusions of B-type (BNP) and C-type (CNP) with atrial natriuretic peptide (ANP) in conscious, instrumented dogs. On separate days, each natriuretic peptide or vehicle was infused (intravenously) at step-up doses of 2, 5, 10, and 20 pmol ⋅ kg-1 ⋅ min-1(20 min each dose) to increase circulating levels of the infused peptide from ∼2- to 20-fold. Like ANP, infusions of BNP caused dose-related increases ( P < 0.05) in mesenteric vascular resistance, urine flow, natriuresis, and hematocrit (changes at highest doses were 60 ± 9, 334 ± 113, 313 ± 173, and 12 ± 2%, respectively). BNP also lowered ( P < 0.05) plasma renin activity (-43 ± 11%) and arterial pressure (-10 ± 3%). Effects of BNP were independent of reflex sympathetic activation, since autonomic ganglion blockade did not attenuate the responses. CNP infusions had little effect except to increase ( P < 0.05) mesenteric vascular resistance (27 ± 10%) and plasma ANP (41 ± 7%). Cardiovascular actions of BNP, like those of ANP, counteract the renin-ANG system and may protect the heart by lowering cardiac preload (venous return) and afterload (arterial pressure) while maintaining blood flow to extrasplanchnic regions.

Haemodynamic action of B-type natriuretic peptide substantially outlasts its plasma half-life in conscious dogs.

1. The objective of the present study was to determine the plasma half‐life of B‐type natriuretic peptide (BNP) in conscious dogs after intravenous administration and to compare this with its haemodynamic effects. In six chronically instrumented dogs, plasma BNP concentrations were measured under basal conditions, during a constant infusion of canine BNP‐32 (10 pmol/kg per min; 25 min) to steady state and at nominated time points up to 75 min after stopping the infusion. Concomitant, continuous measurements of mean arterial blood pressure (MAP), heart rate (HR), central venous pressure (CVP) and mesenteric blood flow (MBF) were obtained.

EVIDENCE FOR A RENOMEDULLARY VASODEPRESSOR HORMONE

1. Recent physiological experiments have established that increasing the perfusion pressure of the kidney causes the release of a vasodepressor substance from the renal medulla.

ANP and Bradycardic Reflexes in Hypertensive Rats: Influence of Cardiac Hypertrophy

In previous studies we demonstrated that in normotensive rats, but not in spontaneously hypertensive rats (SHR), atrial natriuretic peptide (ANP) enhances bradycardic reflexes through an action on cardiac vagal afferent pathways. The present study aimed to determine whether cardiac hypertrophy, hypertension, or a nonreversible genetic factor accounted for the insensitivity of SHR to ANP action on cardiac reflex pathways. SHR were treated with the angiotensin-converting enzyme (ACE) inhibitor perindopril (3 mg/kg per day) for 6 weeks from 4 to 9 weeks of age (SHR-S, n=10) or for 9 weeks from 4 to 12 weeks of age (SHR-L, n=10) or were untreated (SHR, n=10) to produce differential effects on blood pressure and left ventricle/body weight ratio (LV/BW). Untreated normotensive Wistar-Kyoto rats (WKY, n=10) were also studied. At 13 weeks of age, all rats were instrumented with aortic and jugular catheters, and at 14 weeks we measured heart rate reflexes to rapid intravenous infusions of methoxamine (100 microg/kg, cardiac baroreflex) and serotonin (5 to 60 microg/kg, von Bezold-Jarisch cardiac chemosensitive reflex), with either alpha-rat ANP (150 ng/kg per minute IV) or saline vehicle (270 microL/h IV) infusion. Perindopril treatment for 6-week (SHR-S) and 9-week (SHR-L) durations maintained blood pressure at normotensive levels in both groups. SHR-S exhibited a small degree of cardiac hypertrophy (LV/BW was 8% higher than in WKY but 11% less than in untreated SHR), but LV/BW was normalized in SHR-L (to within 1% of WKY LV/BW). In WKY, ANP significantly (P<0.05) enhanced bradycardic responses to both the cardiac baroreflex (by 42+/-10%) and von Bezold-Jarisch chemosensitive reflex (by 17+/-5%) activation but had no effect in SHR. The cardiac reflex action of ANP was restored in SHR-L (ANP enhanced reflex bradycardia by 28+/-12% and 36+/-8%, baroreflex and von Bezold-Jarisch reflex, respectively; P<0.05), but SHR-S, which developed some cardiac hypertrophy, remained unresponsive to ANP. Our results suggest that the inability of ANP to sensitize cardiac vagal (nonarterial) afferents in SHR was not due to an inherited irreversible component, or the hypertension per se, but was associated with the presence of cardiac hypertrophy. A functional consequence of hypertension-induced cardiac hypertrophy may be the inhibition of the cardioprotective action of ANP through cardiac vagal reflexes.

Aspirin for the prevention of cognitive decline in the elderly: rationale and design of a neuro-vascular imaging study (ENVIS-ion).

BackgroundThis paper describes the rationale and design of the ENVIS-ion Study, which aims to determine whether low-dose aspirin reduces the development of white matter hyper-intense (WMH) lesions and silent brain infarction (SBI). Additional aims include determining whether a) changes in retinal vascular imaging (RVI) parameters parallel changes in brain magnetic resonance imaging (MRI); b) changes in RVI parameters are observed with aspirin therapy; c) baseline cognitive function correlates with MRI and RVI parameters; d) changes in cognitive function correlate with changes in brain MRI and RVI and e) whether factors such as age, gender or blood pressure influence the above associations.Methods/DesignDouble-blind, placebo-controlled trial of three years duration set in two Australian academic medical centre outpatient clinics. This study will enrol 600 adults aged 70 years and over with normal cognitive function and without overt cardiovascular disease. Subjects will undergo cognitive testing, brain MRI and RVI at baseline and after 3 years of study treatment. All subjects will be recruited from a 19,000-patient clinical outcome trial conducted in Australia and the United States that will evaluate the effects of aspirin in maintaining disability-free longevity over 5 years. The intervention will be aspirin 100 mg daily versus matching placebo, randomized on a 1:1 basis.DiscussionThis study will improve understanding of the mechanisms at the level of brain and vascular structure that underlie the effects of aspirin on cognitive function. Given the limited access and high cost of MRI, RVI may prove useful as a tool for the identification of individuals at high risk for the development of cerebrovascular disease and cognitive decline.Trial Registrationclinicaltrials.gov Identifier: NCT01038583