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The novel peptide dwarf open reading frame (DWORF), highly conserved across species and expressed almost exclusively in cardiac ventricular muscle, may play a role in cardiac physiology and pathophysiology. The effect of direct administration of DWORF in the intact heart has not previously been examined. Accordingly, we investigated the cardiac effects of DWORF (1-30 nM) in normal isolated perfused rat hearts and hearts undergoing ischaemia/reperfusion (I/R) injury, and evaluated potential mechanisms of action. Exogenous DWORF at the top dose (30 nM) increased perfusion pressure (PP) in normal hearts, which indicates coronary vasoconstriction; and during post-ischaemic reperfusion, DWORF increased PP in a dose-dependent manner. In I/R hearts, DWORF at the top dose also increased left ventricular end-diastolic pressure and maximum and minimum derivatives of left ventricular pressure noted dP/dt(max) and dP/dt(min), respectively, without affecting developed pressure (DP). Co-infusion of DWORF with Diltiazem, an l-type Ca 2+ channel blocker (1μM), in I/R hearts attenuated the falls in DP, dP/dt(max) and dP/dt(min) observed with Diltiazem alone. DWORF co-infusion with both Diltiazem and Y27632 (1μM) (a Rho-Kinase inhibitor) reversed the coronary vasodilator effect of the inhibitors administered alone. In conclusion, we provide the first evidence that DWORF has coronary vasoconstrictor actions in normal hearts and when administered during reperfusion in an ex-vivo model of cardiac I/R injury, and also exhibits positive cardiac inotropic activity in the latter setting. DWORF's effect on ventricular contractile function appears to be dependent on the l-type Ca 2+ channel, whereas Rho-Kinase activity may be related to the coronary vasoconstrictor effects of DWORF., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Biological actions attributed to the adrenomedullin (AM) peptides, AM and AM2, include reduction of arterial pressure and peripheral resistance. While AM has been shown to reduce aldosterone secretion from the adrenal, little information is available regarding possible actions of AM2 on aldosterone. Evidence suggests that AM may act as a functional antagonist to angiotensin II (Ang II) but such a role has not been investigated for AM2. Accordingly, we have examined hemodynamic and adrenal responses to stepped Ang II infusions with or without co-infusions of AM2 (33ng/(kgmin)) in conscious sheep under controlled conditions of a low sodium intake. The dose-dependent pressor response (5-50mmHg) of Ang II was both delayed and attenuated (p<0.001) by AM2 which also stimulated heart rate (p<0.001) and cardiac output (p<0.001). AM2 prevented Ang II-induced increases in peripheral resistance (p<0.001). In contrast, plasma aldosterone responses to Ang II were not significantly altered by concomitant AM2 infusion. In conclusion, low dose infusion of AM2 administered to conscious sheep on a low salt diet clearly antagonized the vasopressor action of administered Ang II while stimulating cardiac output and heart rate. In contrast to AM, AM2 had no restraining influence on the aldosterone response to Ang II. The data suggest a possible role for AM2 in cardiovascular homeostasis in part through antagonism of the vasopressor action of Ang II., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Unlike the cardiac circulating hormones, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP) appears to be largely tissue-based and circulates at concentrations considered insufficient to affect organ function. Consistent with CNP's crucial role in regulating skeletal growth, serial studies in juveniles show that both plasma CNP and aminoterminal proCNP (NTproCNP) are highly correlated with growth velocity raising the possibility that skeletal tissues contribute to circulating concentrations of CNP forms during the growing period. Hypothesizing that venous blood draining from bone dense regions is relatively enriched in CNP, we have performed trans-organ regional blood sampling for measurement of CNP forms in 4-week-old lambs and compared the findings to simultaneous levels of ANP and BNP. Because bone growth and CNP synthesis are inhibited by glucocorticoids, identical studies were also undertaken in lambs pretreated with dexamethasone. Highly significant positive arterio-venous gradients of CNP were found across the head, heart, leg and foot. Dexamethasone significantly reduced the CNP arterio-venous gradient across the head and leg but not heart, liver or kidney. In contrast, there was no evidence of tissue secretion of ANP or BNP except across the heart, and no effect on these gradients from dexamethasone. These findings of CNP enrichment in samples from bone dense regions in growing lambs, and their selective reduction by dexamethasone, provide in vivo evidence linking plasma and skeletal tissue concentrations of CNP and further support the use of plasma CNP forms as markers of bone growth.

Although urocortin 1 (Ucn-1) has been reported to circulate in human plasma and be raised in heart failure, little, if any, information is available regarding the source of circulating Ucn-1. Accordingly, we have performed trans-organ arteriovenous sampling for measurement of Ucn-1 concentration in anesthetized sheep before and after development of pacing-induced heart failure. Arterial plasma Ucn-1 levels measured 15.2 +/- 0.5 pmol/L in normal sheep and increased significantly following development of heart failure to 19.1 +/- 1.6 (p < 0.05). Small but significant positive arteriovenous gradients were observed across the hepatic and renal tissue beds in both states, with rises across the hind limb significant in normal animals and across the head in heart failure. This is the first report identifying sources of circulating Ucn-1.

While regional plasma concentrations of the endocrine hormones atrial and brain natriuretic peptide (ANP and BNP) have been studied, there are few reports of regional changes in the largely paracrine C-type natriuretic peptide (CNP) and its amino terminal fragment NT-CNP. Accordingly, we have performed trans-organ arteriovenous sampling for measurement of plasma ANP, BNP, CNP and NT-CNP in anesthetized sheep before and after induction of experimental heart failure. ANP and BNP plasma concentrations are sourced from a single organ (the heart) and are subject to substantial extraction across most tissue beds. In contrast, our data demonstrate that multiple tissues including liver, heart, hind limb and kidney contribute to circulating CNP. Given that arteriovenous gradients for NT-CNP were similar, this is likely to represent de novo secretion. Circulating levels of CNP and NT-CNP were raised in heart failure but to a much lesser degree than ANP and BNP. There was no evidence of net extraction of CNP or NT-CNP across any tissue bed.

Although urotensin II (UII) has been reported to circulate in human plasma and be raised in cardiovascular disorders, little, if any, information is available regarding the source of plasma UII. Accordingly, we have performed trans-organ arteriovenous sampling for measurement of UII concentration in anesthetized sheep. Plasma UII levels were measured in the low picomolar range in normal sheep and arterial plasma levels rose steadily with increasing time of anesthesia. Significant arteriovenous gradients were observed across the heart (36%), liver (40%) and kidney (44%). This is the first report to identify the heart, liver and kidney as sources of UII in the circulation.

The effect of intracerebroventricular infusions of C-type natriuretic peptide (CNP-22, 5 micrograms/h for 3 h) or vehicle on the neurohumoral response of conscious sheep (n = 7) to acute moderate hemorrhage (15 ml/kg in 15 min performed 1 h after start of CNP) was studied. CNP alone (prehemorrhage) induced a transient rise (after 30 min) in heart rate (p = 0.0005), plasma aldosterone (p = 0.007), ACTH (p = 0.049), and cortisol (p = 0.049), with values returning to control levels immediately prehemorrhage. Hemorrhage caused arterial pressure to fall (15 mmHg) and heart rate to rise similarly on both study days. Compared with vehicle, posthemorrhage responses of AVP (p = 0.05) and cortisol (p = 0.004) were greater during CNP. Thus, central CNP-22 augmented the hypothalamic-pituitary-adrenal axis at baseline and in response to hemorrhage in conscious sheep.