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Several studies have indicated an interaction between the renin-angiotensin (ANG II) system and endothelin (ET) in the regulation of vascular tone. Previously, we have shown that both ET and ANG II exert a vasoconstrictor influence on the coronary resistance vessels of awake normal swine. Here, we investigated whether the interaction between ANG II and ET exists in the control of coronary resistance vessel tone at rest and during exercise using single and combined blockade of angiotensin type 1 (A[T.sub.1]) and E[T.sub.A]/E[T.sub.B] receptors. Since both circulating ANG II and ET levels are increased after myocardial infarction (MI), we investigated if the interaction between these systems is altered after MI. In awake healthy swine, coronary vasodilation in response to E[T.sub.A]/E[T.sub.B] receptor blockade in the presence of A[T.sub.1] blockade was similar to vasodilation produced by E[T.sub.A]/E[T.sub.B] blockade under control conditions. In awake swine with a 2- to 3-wk-old MI, coronary vasodilator responses to individual A[T.sub.1] and E[T.sub.A]/E[T.sub.B] receptor blockade were virtually abolished, despite similar coronary arteriolar A[T.sub.1] and A[T.sub.A] receptor expression compared with normal swine. Unexpectedly, in the presence of A[T.sub.1] blockade (which had no effect on circulating ET levels), E[T.sub.A]/E[T.sub.B] receptor blockade elicited a coronary vasodilator response. These findings suggest that in normal healthy swine the two vasoconstrictor systems contribute to coronary resistance vessel control in a linear additive manner, i.e., with negligible cross-talk. In contrast, in the remodeled myocardium, cross-talk between ANG II and ET emerges, resulting in nonlinear redundant control of coronary resistance vessel tone. coronary blood flow; exercise; left ventricular remodeling; neurohormones; receptor

The renin-angiotensin system plays an important role in cardiovascular homeostasis by contributing to the regulation of blood volume, blood pressure, and vascular tone. Because [AT.sub.1] receptors have been described in the coronary microcirculation, we investigated whether ANG II contributes to the regulation of coronary vascular tone and whether its contribution is altered during exercise. Since the renin-angiotensin system is activated after myocardial infarction, resulting in an increase in circulating ANG II, we also investigated whether the contribution of ANG II to the regulation of vasomotor tone is altered after infarction. Twenty-six chronically instrumented swine were studied at rest and while running on a treadmill at 1-4 km/h. In 13 swine, myocardial infarction was induced by ligation of the left circumflex coronary artery. Blockade of [AT.sub.1] receptors (irbesartan, 1 mg/kg iv) had no effect on myocardial [O.sub.2] consumption but resulted in an increase in coronary venous [O.sub.2] tension and saturation both at rest and during exercise, reflecting coronary vasodilation. Despite increased plasma levels of ANG II after infarction and maintained coronary arteriolar [AT.sub.1] receptor levels, the vasodilation evoked by irbesartan was significantly reduced both at rest and during exercise. In conclusion, despite elevated plasma levels, the vasoconstrictor influence of ANG 1I on the coronary circulation in vivo is reduced after myocardial infarction. This reduction in ANG If-induced coronary vasoconstriction may serve to maintain perfusion of the remodeled myocardium. renin-angiotensin system; coronary circulation; remodeling; heart failure; autonomic nervous system

Withdrawal of the endothelin (ET)-mediated vasoconstrictor influence contributes to metabolic coronary vasodilation during exercise. Because production of nitric oxide (NO) and prostanoids increases with increasing shear stress and because NO and prostanoids are able to modify the release of ET, we hypothesized that the withdrawal of ET-mediated coronary vasoconstriction during exercise is mediated through NO and/or prostanoids. To test this hypothesis, 19 chronically instrumented swine were studied at rest and while running on a treadmill up to 85-90% of maximal heart rate. Blockade of [ET.sub.A]/[ET.sub.B] receptors with tezosentan resulted in an increase in coronary venous [O.sub.2] levels (i.e., in coronary vasodilation) at rest, which waned at increasing levels of exercise intensity. Inhibition of either NO synthase [[N.sup.[omega]]-nitro-L-arginine (L-NNA)] or cyclooxygenase (indomethacin) did not affect the response to tezosentan under resting conditions but unmasked a vasodilator response to tezosentan during exercise. The vasodilator response to tezosentan during exercise increased progressively after combined administration of L-NNA and indomethacin. These findings suggest that NO and prostanoids act synergistically to inhibit the vasoconstrictor influence of ET on the coronary circulation during exercise, thereby facilitating the exercise-induced vasodilation of coronary resistance vessels. coronary circulation; coronary blood flow; myocardial oxygen balance; exercise

Left ventricular dysfunction in swine with a recent myocardial infarction (MI) is associated with neurohumoral activation, including increased catecholamines and endothelin (ET). Although the increase in ET may serve to maintain blood pressure and, hence, perfusion of essential organs such as the heart and brain, it could also compromise myocardial perfusion by evoking coronary vasoconstriction. In the present study, we tested the hypothesis that endogenous ET contributes to perturbations in myocardial [O.sub.2] balance during exercise in remodeled myocardium of swine with a recent MI. For this purpose, 26 chronically instrumented swine (10 with and 16 without MI) were studied at rest and while running on a treadmill at 1-4 km/h. After MI, plasma ET increased from 3.2 [+ or -] 0.4 to 4.9 [+ or -] 0.3 pM (P < 0.05). In normal swine, blockade of ETA (by EMD-122946) or E[T.sub.A]-E[T.sub.B] (by tezosentan) receptors resulted in an increase in coronary venous P[O.sub.2], i.e., coronary vasodilation at rest, which decreased during exercise. In contrast, neither E[T.sub.A] nor E[T.sub.A]-E[T.sub.B] receptor blockade resulted in coronary vasodilation in swine with MI. Coronary vasoconstriction to intravenous ET-1 infusion in awake resting swine was blunted after MI. To investigate whether factors released by cardiac myocytes contributed to decreased vascular responsiveness to ET, we performed ET-1 dose-response curves in isolated coronary arterioles (70-200 [micro]m). Vasoconstriction to ET-1 in isolated arterioles from MI swine was enhanced. In conclusion, the vasoconstrictor influence of endogenous as well as exogenous ET on coronary circulation in vivo is reduced. Because the response of isolated coronary arterioles to ET is increased after MI, the reduced vasoconstrictor influence in vivo suggests modulation of ET receptor sensitivity by cardiac myocytes, which may serve to maintain adequate myocardial perfusion. coronary microcirculation; coronary blood flow; myocardial oxygen balance; left ventricular dysfunction

Byline: Rudolf A. Boer (1), Saraswati Pokharel (2), Markus Flesch (3), Derk A. Kampen (1), Albert J. H. Suurmeijer (1), Frans Boomsma (4), Wiek H. Gilst (1), Dirk J. Veldhuisen (1), Yigal M. Pinto (2) Keywords: Angiotensin II; Signal transduction; Fibrosis; Transforming growth factors; Transgenic animals Abstract: Angiotensin (Ang) II is a key player in left ventricular (LV) remodeling and cardiac fibrosis. Its effects are thought to be transferred at least in part by mitogen-activated protein kinases (MAPK), transforming growth factor (TGF) [beta].sub.1, and the Smad pathway. In this study we sought to elucidate whether Ang II related effects on LV dysfunction and fibrosis in vivo are mediated via MAPK or rather via Smad stimulation. We treated homozygous REN2 rats (7--11 weeks) with placebo, Ang II type 1 (AT.sub.1) receptor blocker or tyrphostin A46 (TYR), an inhibitor of epidermal growth factor receptor tyrosine kinase that blocks extracellular signal-regulated kinase (ERK) activity. REN2 rats had LV hypertrophy (LVH) and LV dysfunction that progressed to heart failure between 10 and 13 weeks. Blood pressure normalized over time. Renin, N-terminal atrial natriuretic peptide (N-ANP), and ERK were activated while p38 MAPK was not. Treatment with AT.sub.1 receptor blockade prevented LVH and right ventricular hypertrophy, normalized systolic and diastolic dP/dt, N-ANP levels, and reduced collagen apposition. Similarly, TYR reduced LVH, N-ANP levels, and collagen apposition. Myocardial ERK activation did not depend on AT.sub.1 receptor signaling as it was not affected by AT.sub.1 receptor blockade. TYR abolished myocardial ERK activity. Smad2 activation was inhibited by AT.sub.1 receptor blockade but was unaltered by TYR. Ang II induced LV remodeling and fibrosis are dependent on both ERK and Smad2 activation. This process is prevented by both AT.sub.1 receptor blockade and TYR, and therefore inhibition of either pathway is equally efficacious in restoring LV function and architecture. Author Affiliation: (1) Thoraxcenter, Department of Cardiology, University Hospital Groningen, P.O. Box 30001, 9700 RB, Groningen, The Netherlands (2) Experimental and Molecular Cardiology Laboratory, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands (3) Klinik fur Innere Medizin III, University of Cologne, Cologne, Germany (4) Department of Internal Medicine/COEUR, Erasmus Medical Center, Rotterdam, The Netherlands Article History: Registration Date: 08/07/2004 Received Date: 14/03/2004 Accepted Date: 15/06/2004 Online Date: 20/08/2004 Article note: R.A.D.B. and S.P. contributed equally to this work

'New pressor protein' (NPP) derived from normal human plasma is an extra renal enzyme that shares strong sequence homology with human coagulation [beta]-FXIIa. Under our bioassay conditions, human NPP (10-20 [micro]l plasma equivalent/~300 g rat iv) can raise the systolic blood pressure (SBP) by 40-50 mmHg, the diastolic blood pressure (DBP) by 15-20 mmHg, and the heart rate (HR) by 70-90 beats/min. Plasma epinephrine (of adrenal medullary origin) and norepinephrine rise by about 50- and 10-fold, respectively. Because [beta]-FXII a is not normally associated with pressor properties, we endeavored to substantiate that the hypertensive effects of impure NPP preparations used in our experiments are attributable to their content of [beta]-FXIIa. We carried out comparisons with highly purified (>90%) commercial human [beta]-FXIIa and found that by gel filtration (Sephadex G-100 and G-75), NPP bioactivity appeared in the ~30-kDa elution zone, consistent with the molecular mass of [beta]-FXIIa. Retention time using fast-protein liquid chromatography anion exchange chromatography was identical. Molecular mass and comigration were confirmed by SDS-PAGE gel electrophoresis, and the recovered ~30-kDa protein bands yielded [beta]-FXIIa fragments identified by mass spectrometry. Matched doses of the NPP preparations produced dose-response curves very similar to those elicited by [beta]-FXIIa with respect to increments of SBP, DBP, and HR, whereas plasma catecholamine increments were generally comparable. We propose that [beta]-FXIIa is substantially, if not exclusively, responsible for the observed effects of our NPP preparations and that this points to a novel axis connecting the FXII coagulation cascade and the sympathoadrenal gland to other cardiovascular regulatory mechanisms. Hageman fragment factor; hypertension; catecholamines

ACE inhibitors may lower the risk of heart disease in patients with kidney failure by reducing the activity of the sympathetic nervous system. Increased sympathetic nerve activity can cause high blood pressure. Researchers directly measured sympathetic nerve activity in the muscles of 14 patients with hypertension, kidney failure and increased sympathetic nerve activity before and after they received the ACE inhibitor enalapril. Enalapril lowered blood pressure and also reduced sympathetic nerve activity.