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Distal to a chronic coronary artery stenosis, structural remodeling of the microvasculature occurs. The microvascular functional changes distal to the stenosis have not been studied in detail. We tested the hypothesis that microvascular structural remodeling is accompanied by altered regulation of coronary vasomotor tone with increased responsiveness to endothelin-1. Vasomotor tone was studied in coronary microvessels from healthy control swine and from swine 3 to 4 months after implantation of an occluder that causes a progressive coronary narrowing, resulting in regional left ventricular dysfunction and blunted myocardial vasodilator reserve. Arterioles (approximately 200-microm passive inner diameter at 60 mm Hg) were isolated from regions perfused by the stenotic left anterior descending and normal left circumflex coronary arteries and studied in vitro. Passive pressure-diameter curves demonstrated reduced distensibility of subendocardial left anterior descending compared with subendocardial left circumflex or control arterioles, suggestive of structural remodeling. Myogenic responses were blunted in subendocardial left anterior descending compared with left circumflex arterioles, reflecting altered smooth muscle function. However, vasodilator responses to nitroprusside and bradykinin were not different in the endocardium, suggesting preserved endothelium and smooth muscle responsiveness. Finally, vasoconstrictor responses to endothelin-1 were enhanced in left anterior descending arterioles compared with left circumflex or control arterioles. Regional myocardial vascular conductance responses to bradykinin and endothelin in vivo confirmed the in vitro observations. In conclusion, inward remodeling of coronary microvessels distal to a stenosis is accompanied by exaggerated vasoconstrictor responses to endothelin-1. These structural and functional alterations may aggravate flow abnormalities distal to a chronic coronary artery stenosis.

High sodium intake blunts the efficacy of angiotensin (Ang)-converting enzyme (ACE) inhibition (ACEi), but the underlying mechanism is incompletely characterized. High sodium has been reported to increase vascular expression and vascular activity of ACE. To investigate whether high-dietary sodium-induced effects on vascular conversion of Ang I might be involved in the sodium-induced blunting of the response to ACEi, the authors studied the vasoconstrictor responses to Ang I and Ang II of isolated aortic rings from healthy rats on low dietary sodium (LS: 0.05% NaCl) and high dietary sodium (HS: 2.0% NaCl) after 3 weeks of ACEi (lisinopril 75 mg/L) or vehicle (CON). Blood pressure was similar in LS and HS in CON, but HS blunted the blood pressure response to ACEi. Functional conversion of Ang I was assessed as the difference in dose-response curves to Ang I and Ang II in parallel aortic rings. Sodium intake did not affect the dose-response curves to Ang I and Ang II in CON. In the ACEi groups, a significant difference was present between the curves for Ang I and Ang II on LS (deltaEC50, 6.7 nM; range, 2.2-13 nM; P < 0.01) but not on HS (deltaEC50: 1.3 nM; range, 0.0-4.1 nM, median [interquartile range], NS). Thus, HS blunts the ACEi-induced reduction of functional vascular Ang I conversion compared with LS. Whether the blunted functional vascular conversion is causally related to the blunted blood pressure response remains to be elucidated.

Beta-blocker therapy has been shown to be associated with an increase in the plasma concentration of A-type natriuretic peptide (ANP). Whether the plasma concentration of B-type natriuretic peptide (BNP), which is mainly derived from ventricular tissue, is also increased and whether this increase is caused by increased production or decreased metabolism by down-regulation of the natriuretic peptide-clearance receptor remains to be established. In a double-blind crossover study effects of 8 weeks' treatment of bisoprolol,10 mg once daily, and losartan, 50 mg once daily, on plasma concentrations of ANP, BNP, and N-terminal (Nt)-ANP and ambulatory blood pressure (ABP) were measured in 24 hypertensive patients. With bisoprolol plasma concentrations of ANP and BNP increased (P < 0.001) by 93 +/- 88% (mean +/- SD) and 148 +/- 117%, whereas these parameters did not change with losartan. Nt-ANP, which is not metabolized by the NP clearance receptor, increased by 83 +/- 45%, and increments in ANP and Nt-ANP were related (r =0.77, P < 0.001). The decrease in ABP was greater with bisoprolol than with losartan. Monotherapy with bisoprolol, but not with losartan, is associated with substantial increments in plasma concentrations of ANP, Nt-ANP, and BNP. As the magnitude of the increase in ANP and Nt-ANP was comparable, the beta-blocker-induced increase in NPs is not likely to be explained by a decrease in NP clearance receptor density.

Background: Despite effective treatment with anticoagulants, 2% to 7% of patients with pulmonary embolism will die as a result of their disease., Methods and Results: We examined in 110 consecutive patients with pulmonary embolism whether plasma brain natriuretic peptide (BNP), a novel marker of (right) ventricular dysfunction, is a predictor of fatal pulmonary embolism. The relationship between BNP concentration measured at presentation and clinical outcome was assessed by comparing the proportion of outcome events among tertiles. Positive and negative predictive values of BNP levels in the highest and lowest tertiles were calculated. The risk of death related to pulmonary embolism if the BNP level is >21.7 pmol/L is 17% (95% CI, 6% to 33%). The negative predictive value for uneventful outcome of a BNP value <21.7 pmol/L is 99% (95% CI, 93% to 100%)., Conclusions: This is the first study to show that plasma BNP levels seem to predict adverse outcome in patients with acute pulmonary embolism.

Objective: The objective of this study was to investigate ACE- and chymase-dependent angiotensin I-to-II conversion in human coronary arteries (HCAs)., Methods and Results: HCA rings were mounted in organ baths, and concentration-response curves to angiotensin II, angiotensin I, and the chymase-specific substrate Pro(11)-D-Ala(12)-angiotensin I (PA-angiotensin I) were constructed. All angiotensins displayed similar efficacy. For a given vasoconstriction, bath (but not interstitial) angiotensin II during angiotensin I and PA-angiotensin I was lower than during angiotensin II, indicating that interstitial (and not bath) angiotensin II determines vasoconstriction. PA-angiotensin I increased interstitial angiotensin II less efficiently than angiotensin I. Separate inhibition of ACE (with captopril) and chymase (with C41 or chymostatin) shifted the angiotensin I concentration-response curve approximately 5-fold to the right, whereas a 10-fold shift occurred during combined ACE and chymase inhibition. Chymostatin, but not captopril and/or C41, reduced bath angiotensin II and abolished PA-Ang I-induced vasoconstriction. Perfused HCA segments, exposed luminally or adventitially to angiotensin I, released angiotensin II into the luminal and adventitial fluid, respectively, and this release was blocked by chymostatin., Conclusions: Both ACE and chymase contribute to the generation of functionally active angiotensin II in HCAs. However, because angiotensin II loss in the organ bath is chymase-dependent, ACE-mediated conversion occurs more efficiently (ie, closer to AT(1) receptors) than chymase-mediated conversion.

Background: Several studies have suggested that epinephrine augments the release of norepinephrine from sympathetic nerve terminals through stimulation of presynaptic receptors, but evidence pertaining to this mechanism in the heart is scarce and conflicting. Using the microdialysis technique in the porcine heart, we investigated whether epinephrine, taken up by and released from cardiac sympathetic nerves, can increase norepinephrine concentrations in myocardial interstitial fluid (NE(MIF)) under basal conditions and during sympathetic activation., Methods and Results: During intracoronary epinephrine infusion of 10, 50, and 100 ng/kg per minute under basal conditions, large increments in interstitial (from 0.31+/-0.05 up to 140+/-30 nmol/L) and coronary venous (from 0.16+/-0.08 up to 228+/-39 nmol/L) epinephrine concentrations were found, but NE(MIF) did not change. Left stellate ganglion stimulation increased NE(MIF) from 3.4+/-0.5 to 8.2+/-1.5 nmol/L, but again, this increase was not enhanced by concomitant intracoronary epinephrine infusion. Intracoronary infusion of tyramine resulted in a negligible increase in epinephrine concentration in myocardial interstitial fluid (EPI(MIF)), whereas 30 minutes after infusion of epinephrine an increase of 9.5 nmol/L in EPI(MIF) was observed, indicating that epinephrine is taken up by and released from cardiac sympathetic neurons. Although 68% to 78% of infused epinephrine was extracted over the heart, the ratio of interstitial to arterial epinephrine concentrations was only approximately 20%, increasing to 29% with neuronal reuptake inhibition., Conclusions: Our findings demonstrate epinephrine release from cardiac sympathetic neurons, but they do not provide evidence that epinephrine augments cardiac sympathoneural norepinephrine release under basal conditions or during sympathetic activation.

Background: The renin-angiotensin system (RAS) is a key player in the progression of heart failure. Angiotensin-(1-7) is thought to modulate the activity of the RAS. Furthermore, this peptide may play a part in the beneficial effects of angiotensin-converting enzyme inhibitors in cardiovascular disease. We assessed the effects of angiotensin-(1-7) on the progression of heart failure., Methods and Results: Male Sprague-Dawley rats underwent either coronary ligation or sham surgery. Two weeks after induction of myocardial infarction, intravenous infusion of angiotensin-(1-7) (24 microg/kg per hour) or saline was started by minipump. After 8 weeks of treatment, hemodynamic parameters were measured, endothelial function was assessed in isolated aortic rings, and plasma angiotensin-(1-7) levels were determined. Myocardial infarction resulted in a significant deterioration of left ventricular systolic and diastolic pressure, dP/dt, and coronary flow. Raising plasma levels 40-fold, angiotensin-(1-7) infusion attenuated this impairment to a nonsignificant level, markedly illustrated by a 40% reduction in left ventricular end-diastolic pressure. Furthermore, angiotensin-(1-7) completely preserved aortic endothelial function, whereas endothelium-dependent relaxation in aortas of saline-treated infarcted rats was significantly decreased., Conclusions: Angiotensin-(1-7) preserved cardiac function, coronary perfusion, and aortic endothelial function in a rat model for heart failure.

Background: Angiotensin-converting enzyme (ACE) metabolizes many small peptides and plays a key role in blood pressure regulation. Elevated serum ACE is claimed to be associated with an increased risk for cardiovascular disease. Previously, two families with dramatically increased serum ACE were described, but no systematic survey of affected individuals was performed, and the molecular background of this trait is unknown., Methods and Results: Eight families were identified with autosomal dominant inheritance of a dramatic (5-fold) increase of serum ACE activity. Strikingly, no clinical abnormalities were apparent in the affected subjects. Isolated blood cells were used for genetic and biochemical analysis. The level of ACE expression on the blood leukocytes and dendritic cells and total cell-associated ACE of the affected individuals was similar to that in nonaffected relatives; however membrane-bound mutant ACE was much more efficiently clipped from the cell surface compared with its wild-type counterpart. A point mutation causing Pro1199Leu in the stalk region of the ACE molecule cosegregates with the increase in serum ACE (LOD score, 6.63)., Conclusions: A point mutation in the stalk region of the ACE protein causes increased shedding, leading to increased serum ACE, whereas cell-bound ACE is unaltered, and affected individuals exhibit no clinical abnormalities. These findings qualify the importance of serum ACE and establish a new determinant of ACE solubilization.

The deletion (D) allele of the angiotensin-converting enzyme (ACE) is associated with high ACE levels. Subjects homozygous for the D allele should therefore exhibit enhanced angiotensin I-induced vasoconstrictor responses and diminished bradykinin-induced vasodilator responses as compared with subjects homozygous for the insertion (I) allele. In eight II and eight DD normotensive male subjects, angiotensin I, bradykinin, and angiotensin II were infused in the forearm. Changes in forearm blood flow were registered with venous occlusion plethysmography. Blood was sampled to quantify angiotensin I to II conversion. Plasma ACE levels were 60% higher, and DD subjects showed an enhanced response to angiotensin I infusion (p < 0.05). No differences in angiotensin I to II conversion, angiotensin H vasoconstriction, and bradykinin vasorelaxation were found. The ACE-inhibitor enalaprilate inhibited angiotensin I-induced vasoconstriction, but did not significantly affect bradykinin-induced vasodilation. The AT1-receptor antagonist losartan (3,000 ng/kg/min) inhibited angiotensin II-induced vasoconstriction. In conclusion, subjects with the DD genotype display an enhanced vasoconstrictor response to angiotensin I, which cannot be explained on the basis of a similarly enhanced angiotensin I to II conversion rate or a difference in vascular reactivity. Possibly therefore, differences in angiotensin I to II conversion occur within the vascular wall only, at a site that does not readily equilibrate with blood plasma.

Background: The systemic hypotension during human sepsis has been ascribed to increased production of nitric oxide (NO). Therefore, inhibitors of NO synthesis have been used in the treatment of hypotension in patients with septic shock. In addition, NO production may inhibit the synthesis and vasoconstrictor effects of endothelin-1 (ET-1). In this study, we tested whether ET-1 contributed to the vasopressor action of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in patients with severe septic shock., Methods and Results: Compared with healthy volunteers, patients with septic shock had increased plasma levels of nitrite/nitrate (37+/-5 [SEM] versus 12+/-5 mmol/L, P<0.01), the stable end products of NO metabolism, and ET-1 (45+/-7 versus 3+/-2 pg/mL, P<0.001). Plasma ET-1 concentration was not related to plasma nitrite/nitrate concentration or blood pressure. Continuous infusion of L-NAME (1 mg. kg-1. h-1 IV) for 12 hours increased mean arterial pressure by 43+/-5% and systemic vascular resistance by 64+/-10% (both P<0.01). The increase in blood pressure and systemic vascular resistance correlated positively with the level of ET-1 (both P<0. 005) but not with plasma nitrite/nitrate level. L-NAME infusion did not result in significant changes in the plasma concentrations of ET-1 or nitrite/nitrate., Conclusions: NO and ET-1 may both play a role in the cardiovascular derangements of human sepsis. Although L-NAME does not increase ET-1 concentration in patients with septic shock, the vasopressor response induced by L-NAME depends on the plasma level of ET-1. These findings may indicate that inhibitors of NO synthesis unmask a tonic pressor response of ET-1 in human septic shock.

We studied hemodynamic changes, catecholamine responses, and the occurrence of improved wall thickening by echocardiography during two different dobutamine-infusion protocols. Forty-three patients were studied by using a stepwise incremental dobutamine dose-infusion protocol (10-40 microg/kg/min, 3-min intervals); a subgroup of 11 patients also underwent a continuous dobutamine-infusion protocol (10 microg/kg/min for 12 min) in random order. No patient used beta-blockers. At 3-min intervals, blood pressure, heart rate, and plasma concentrations of dobutamine, epinephrine, and norepinephrine were measured. The echocardiographic improvement of wall thickening was analyzed only in paired protocols by visual assessment in left ventricular regions with normal wall motion at rest. The mean heart rate increased in the continuous and stepwise protocols from 73 to 99 and 74 to 132 beats/min. There was no significant change in blood pressure response between the two protocols. The mean plasma dobutamine concentrations during the continuous and stepwise protocols at 0, 3, 6, 9, and 12 min were 0/0; 31/38; 80/203; 106/448; and 120/692 ng/ml, respectively. In each patient, a response curve was constructed for the plasma dobutamine concentration versus heart rate. The heart rate increment and dobutamine concentration at which wall thickening was detected were similar with both protocols (14 +/- 5 vs. 12 +/- 7 beats/min) and (80 +/- 40 vs. 92 +/- 48 ng/ml; mean +/- SD). Wall thickening was noted in two of 11 patients between 0 and 3 min and 11 of 11 patients between 3 and 6 min in both protocols. Catecholamine responses during the continuous and stepwise protocols were epinephrine, 23 versus 28/28 versus 36, and norepinephrine 301 versus 323/347 versus 519. Only norepinephrine plasma concentrations increased significantly during the stepwise protocol. A 6-min dobutamine infusion was sufficient during both protocols to reach an adequate plasma dobutamine concentration, which induced a detectable increase of wall thickening in all patients. There is a significant differences between the two protocols with regard to the plasma catecholamine changes, so some of the hemodynamic effects during the stepwise dobutamine-infusion protocol may be mediated through release of endogenous catecholamines.

Background: Control of renal hemodynamics by the arterial baroreflex has never been proved in humans. Apart from the physiological viewpoint, this issue is relevant because altered baroreflex function has been implicated in the pathogenesis of human hypertension., Methods and Results: Renal function studies were performed in seated healthy volunteers (n = 12; age range, 20 to 34 years) during sustained neck suction at -60 mm Hg, aiming to selectively activate the carotid sinus arterial baroreceptors. Two protocols were followed. One group of 6 volunteers taking a 20 mmol/d sodium diet underwent 90 minutes of neck suction. Compared with a time-control study, neck suction decreased arterial pressure and heart rate; increased glomerular filtration rate (inulin clearance) from 104 +/- 6 to 114 +/- 8 mL/min (P < .01), renal plasma flow (para-aminohippurate clearance) from 616 +/- 52 to 665 +/- 42 mL/min (P < .01), and renal blood flow (from 1120 +/- 95 to 1209 +/- 77 mL/min, P < .01); and decreased renal vascular resistance (from 86 +/- 8 to 76 +/- 6 mm Hg.min.L-1, P < .01). Neck suction had no effect on plasma renin activity, aldosterone, atrial natriuretic peptide, catecholamines, and renal sodium excretion. The other 6 volunteers took a normal sodium diet and underwent sustained neck suction for 60 minutes. In this group, no effects on renal hemodynamics could be discerned, despite a modest decrease in blood pressure and heart rate., Conclusions: These data show, for the first time, that the arterial baroreflex is involved in the control of renal hemodynamics in humans. However, basal arterial baroreflex control of renal hemodynamics is probably low, and arterial baroreflex activation with subsequent renal vasorelaxation may be found only in conditions in which basal arterial baroreflex control of kidney function is significant, as is presumably the case in seated sodium-restricted subjects.

We noted rapid breakdown at 4 degrees and 20 degrees C of dopamine (DA) (but not of (nor)epinephrine and epinine) in pig plasma, but not in human plasma. The enzyme responsible appears to be a semicarbazide-sensitive amine oxidase (SSAO) because the breakdown can be inhibited by semicarbazide, but not by pargyline, clorgyline, EDTA, or (extra) glutathione. Among catecholamines tested, only DA and 3,4-dihydroxybenzylamine (DHBA, the internal standard of most catecholamine assays using high-performance liquid chromatography (HPLC) with electrochemical detection) were good substrates for the pig plasma SSAO. At 37 degrees C, especially after prolonged storage, all catecholamines break down. This breakdown results from autoxidation since it can be prevented by addition of extra glutathione (but not by semicarbazide) for all catecholamines except DA and DHBA. Breakdown at 37 degrees C of these two compounds cannot be prevented by addition of extra glutathione or semicarbazide, but only by addition of both. For reliable measurements of DA concentrations in pig plasma, blood should be collected in tubes containing not only glutathione, but also semicarbazide. The possibility of similarly high plasma SSAO activity in other species should be investigated further.

Intravenous (i.v.) infusions (1, 2.5, 5, and 10 micrograms/kg/min for 10 min) were used to evaluate the cardiovascular effects of epinine (N-methyl-dopamine) in 8 conscious pigs. Epinine is a nonselective and nonspecific dopamine (DA) agonist, that also stimulates alpha- and beta-adrenoceptors. Epinine (1-5 microgram/kg/min) increased cardiac output (CO) by up to 15 +/- 5% (p less than 0.05), owing to an increase in heart rate (HR, 24 +/- 6%), but an increase in stroke volume (SV, 16 +/- 4%) caused the further increase in CO at 10 micrograms/kg/min. Mean arterial blood pressure decreased gradually from 100 +/- 5 mm Hg to 84 +/- 4 mm Hg during infusions up to 5 microgram/kg/min, but increased to 89 +/- 4 mm Hg during infusion of 10 micrograms/kg/min (p less than 0.05). Systemic vascular resistance had decreased from 36.5 +/- 2.8 to 27.5 +/- 3.0 mm Hg/L/min after infusion of 5 micrograms/kg/min but did not change further during infusion of 10 micrograms/kg/min. LV dP/dtmax increased only at 10 micrograms/kg/min. Myocardial blood flow did not change at any dose, owing to metabolically regulated coronary vasodilatation (myocardial work did not change). Flow to the adrenals (up to 110 +/- 37%) and the spleen (up to 95 +/- 13%) increased dose dependently. Cerebral blood flow increased only at the highest dose (15 +/- 5%, p less than 0.05); flow to the kidneys, liver, small intestine, and skeletal muscle did not change. Flow decreased to the stomach (21 +/- 5%) and skin (for doses less than 2.5 micrograms/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)