Christopher Hillier

Is the Pregnancy Hormone Relaxin Also a Vasodilator Peptide Secreted by the Heart

Background—It has been shown recently that the pregnancy and parturition hormone, relaxin, is secreted by the heart. This study examined the effects of relaxin in small human resistance arteries from the systemic and pulmonary circulations. Methods and Results—Arteries were obtained from gluteal biopsies and resected lung tissue and studied with the use of wire myography. Cumulative concentration relaxation curves were constructed in systemic arteries with substance P, epoprostenol, atrial natriuretic peptide, and relaxin (concentration range 10−13 -10−7M). The maximal responses were 88(±5)%, 67(±10)%, 52(±16)% and 66(±16)%, respectively. Endothelium removal virtually abolished the action of relaxin. Relaxin had no vasodilator effect in pulmonary arteries. Conclusions—Relaxin is a powerful dilator of systemic resistance arteries secreted by the heart that may contribute to cardiovascular regulation.

Endothelium-dependent relaxation in resistance arteries from spontaneously hypertensive rats: effect of long-term treatment with perindopril, quinapril, hydralazine or amlodipine

Objective To examine the effects of different types of anti hypertensive treatment on endothelium-dependent relaxation in resistance arteries from spontaneously hypertensive rats (SHRs). Design and methods Three-week-old SHRs were treated with the angiotensin converting enzyme (ACE) inhibitor perindopril (1 mg/kg/day) or quinapril (3 mg/kg/day) or the vasodilator hydralazine (50 mg/kg/day) or the calcium antagonist amlodipine (10mg/kg/day). Control SHRs and Wistar-Kyoto (WKY) rats were treated with water. After 21 weeks rats were culled and mesenteric resistance arteries were mounted in a myograph. Relaxation responses to the endothelium-dependent vasodilators acetylcholine (ACh) and bradykinin were recorded before and after incubation with the nitric oxide synthase inhibitor A/G-nitro-L-arginine (L-NOARG), as was the relaxation response to the nitric oxide donor sodium nitroprusside (SNP). Results All drugs prevented the rise in blood pressure found in the untreated SHRs. ACh-induced relaxation was significantly impaired in the untreated SHRs compared with the WKY rats. Treatment with either ACE inhibitor prevented the development of this impaired response. ACE inhibitor treatment significantly increased the relaxation response to bradykinin. Despite lowering blood pressure, hydralazine or amlodipine had no effect on ACh- or bradykinin-induced relaxation. Responses to SNP were not different between untreated SHRs and WKY rats and were not affected by drug treatment. Conclusion Specific properties of certain antihypertensive drugs may play an important role in restoring endothelium-dependent relaxation in the small arteries that regulate peripheral resistance in the SHR.

Adrenomedullin selectively inhibits angiotensin II-induced aldosterone secretion in humans

Objective Adrenomedullin inhibits angiotensin II stimulated aldosterone production in vitro and in vivo in experimental animals. The aim of this study was to investigate the effect of adrenomedullin on angiotensin II and adrenocorticotrophic hormone-stimulated aldosterone production in vivo in healthy humans. Design and Methods Seven volunteers were studied in a quiet, temperature-controlled laboratory. After 35 min of rest, an infusion of placebo or adrenomedullin (3 pmol/kg per min) was given over 60 min; 15 min after starting this first infusion, a second infusion of angiotensin II (0.96 fmol/kg per min) or adrenocorticotrophic hormone (0.1 mIU/kg per min) was co-infused and continued for 45 min. Results Adrenomedullin significantly inhibited angiotensin II stimulated aldosterone production: the increment in aldosterone on the placebo day was 691 pmol/l compared with 552 pmol/l on the adrenomedullin day (P < 0.004). Adrenomedullin did not inhibit adrenocorticotrophic hormone-stimulated aldosterone or cortisol release. Conclusion Adrenomedullin selectively inhibits angiotensin II-stimulated aldosterone production.

Non-esterified fatty acids impair endothelium-dependent vasodilation in rat mesenteric resistance vessels.

Elevated circulating levels of NEFAs (non-esterified fatty acids) are associated with states of insulin resistance and increased risk of vascular disease. Previous animal and human studies have demonstrated NEFA-induced endothelial dysfunction of large conduit arteries, reversible by the antioxidant ascorbic acid. We therefore investigated the effect of NEFAs on carbachol-induced endothelium-dependent vasodilation of rat resistance arteries in vitro using the technique of wire myography. In addition, we investigated the effect of co-incubation of NEFAs and ascorbic acid. Cumulative concentration-response curves to carbachol (endothelium-dependent vasodilation) and SNAP (S-nitroso-N-acetyl-DL-penicillamine; endothelium-independent vasodilation) were constructed. Those to carbachol were repeated following a 30 min incubation with either oleic acid (10(-4) M) or palmitic acid (10(-4) M), demonstrating significant impairment of endothelium-dependent vasodilation with both [P<0.05, comparison of pD2 values (the negative log concentration of agonist required to effect a 50% response)]. A cumulative concentration-response curve to carbachol was repeated following co-incubation with palmitic acid (10(-4) M) and the antioxidant ascorbic acid (10(-5) M), demonstrating an abolition of the previously observed endothelial dysfunction induced by palmitic acid. There was no impairment of vasodilation to SNAP following NEFA incubation. We conclude that NEFAs directly impair endothelial function in rat resistance arteries via an increase in oxidative stress at the vascular endothelium.

Effects of Neutral Endopeptidase (Neprilysin) Inhibition on the Response to Other Vasoactive Peptides in Small Human Resistance Arteries: Studies with Thiorphan and Omapatrilat

PURPOSEnNew compounds with neprilysin or neutral endopeptidase (NEP) inhibiting activity are under clinical investigation in heart failure and hypertension. We investigated the effect of NEP inhibition on the functional vasomotor responses to a range of vasoactive peptides in human blood vessels.nnnMETHODSnSmall human resistance arteries from patients with coronary artery disease and preserved left ventricular systolic function were studied. Thiorphan (a NEP inhibitor) was compared with captopril (an ACE inhibitor) and omapatrilat (a dual NEP-ACE inhibitor) with regard to their effects on the response of human arteries to key vasoactive peptides.nnnRESULTSnAs expected, both captopril and omapatrilat (but not thiorphan) inhibited the vasoconstrictor effect of angiotensin I (maximal response [SEM]: 27xa0±xa08% vehicle, 6xa0±xa02% captopril, 39xa0±xa010% thiorphan, 8xa0±xa07% omapatrilat, Pxa0<xa00.05). Thiorphan, captopril, and omapatrilat all enhanced the vasodilator response to bradykinin (all Pxa0<xa00.01). Omapatrilat markedly augmented the vasodilator action of adrenomedullin (Pxa0<xa00.05), whilst thiorphan and captopril did not. None of the three inhibitors studied affected the vasodilator action of c-type natriuretic peptide, calcitonin gene-related peptide, vasoactive intestinal polypeptide or substance P.nnnCONCLUSIONSnNEP inhibition with thiorphan modestly augmented the vasodilator action of bradykinin, but did not potentiate the response to adrenomedullin; dual ACE and NEP inhibition with omapatrilat, as expected, markedly augmented the response to bradykinin and also potentiated the effect of adrenomedullin. Thiorphan weakly enhanced the vasoconstrictor response to angiotensin I. Neither omapatrilat nor thiorphan had any effect on the action of a range of other vasoactive peptides including CNP.

The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans.

AIMSnInhibition of neutral endopeptidases (NEP) results in a beneficial increase in plasma concentrations of natriuretic peptides such as ANP. However NEP inhibitors were ineffective anti-hypertensives, probably because NEP also degrades vasoconstrictor peptides, including endothelin-1 (ET-1). Dual NEP and endothelin converting enzyme (ECE) inhibition may be more useful. The aim of the study was to determine whether SLV-306 (daglutril), a combined ECE/NEP inhibitor, reduced the systemic conversion of big ET-1 to the mature peptide. Secondly, to determine whether plasma ANP levels were increased.nnnMAIN METHODSnFollowing oral administration of three increasing doses of SLV-306 (to reach an average target concentration of 75, 300, 1200 ng ml(-1) of the active metabolite KC-12615), in a randomised, double blinded regime, big ET-1 was infused into thirteen healthy male volunteers. Big ET-1 was administered at a rate of 8 and 12 pmol kg(-1)min(-1) (20 min each). Plasma samples were collected pre, during and post big ET-1 infusion. ET-1, C-terminal fragment (CTF), big ET-1, and atrial natriuretic peptide (ANP) were measured.nnnKEY FINDINGSnAt the two highest concentrations tested, SLV-306 dose dependently attenuated the rise in blood pressure after big ET-1 infusion. There was a significant increase in circulating big ET-1 levels, compared with placebo, indicating that SLV-306 was inhibiting an increasing proportion of endogenous ECE activity. Plasma ANP concentrations also significantly increased, consistent with systemic NEP inhibition.nnnSIGNIFICANCEnSLV-306 leads to inhibition of both NEP and ECE in humans. Simultaneous augmentation of ANP and inhibition of ET-1 production is of potential therapeutic benefit in cardiovascular disease.