Are users of sulphonylureas at the time of an acute coronary syndrome at risk of poorer outcomes?

AIMS: Adenosine triphosphate sensitive potassium (K(ATP)) channel activity is cardioprotective during ischaemia. One of the purported mechanisms for sulphonylurea adverse effects is through inhibition of these channels. The purpose of this study is to examine whether patients using K(ATP) channel inhibitors at the time of an acute coronary syndrome are at greater risk of death or heart failure (HF) than those not exposed. METHODS: Using linked administrative databases we identified all adults who had an acute coronary syndrome between April 2002 and October 2006 (n = 21 023). RESULTS: Within 30 days of acute coronary syndrome, 5.3% of our cohort died and 15.6% were diagnosed with HF. Individuals with diabetes exhibited significantly higher risk of death (adjusted OR: 1.20, 95% CI: 1.03-1.40) and death or HF (aOR: 1.73, 95% CI: 1.59-1.89) than individuals without diabetes. However, there was no significantly increased risk of death (aOR: 1.00, 95% CI: 0.76-1.33) or death/HF (aOR: 1.06, 95% CI: 0.89-1.26) in patients exposed to K(ATP) channel inhibitors versus patients not exposed to K(ATP) channel inhibitors prior to their acute coronary syndrome. CONCLUSIONS: Diabetes is associated with an increased risk of death or HF within 30 days of an acute coronary syndrome. However, we did not find any excess risk of death or HF associated with use of K(ATP) channel inhibitors at the time of an acute coronary syndrome, raising doubts about the hypothesis that sulphonylureas inhibit the cardioprotective effects of myocardial K(ATP) channels.

Deletion of p47phox attenuates the progression of diabetic nephropathy and reduces the severity of diabetes in the Akita mouse.

AIMS/HYPOTHESIS: Reactive oxygen species (ROS) contribute to diabetes-induced glomerular injury and endoplasmic reticulum (ER) stress-induced beta cell dysfunction, but the source of ROS has not been fully elucidated. Our aim was to determine whether p47(phox)-dependent activation of NADPH oxidase is responsible for hyperglycaemia-induced glomerular injury in the Akita mouse, a model of type 1 diabetes mellitus resulting from ER stress-induced beta cell dysfunction. METHODS: We examined the effect of deleting p47 (phox) (also known as Ncf1), the gene for the NADPH oxidase subunit, on diabetic nephropathy in the Akita mouse (Ins2 (WT/C96Y)) by studying four groups of mice: (1) non-diabetic mice (Ins2 (WT/WT)/p47 (phox+/+)); (2) non-diabetic p47 (phox)-null mice (Ins2 (WT/WT)/p47 (phox-/-)); (3) diabetic mice: (Ins2 (WT/C96Y)/p47 (phox+/+)); and (4) diabetic p47 (phox)-null mice (Ins2 (WT/C96Y)/p47 (phox-/-)). We measured the urinary albumin excretion rate, oxidative stress, mesangial matrix expansion, and plasma and pancreatic insulin concentrations in 16-week-old mice; we also measured glucose tolerance and insulin sensitivity, islet and glomerular NADPH oxidase activity and subunit expression, and pro-fibrotic gene expression in 8-week-old mice. In addition, we measured NADPH oxidase activity, subunit expression and pro-fibrotic gene expression in high glucose-treated murine mesangial cells. RESULTS: Deletion of p47 (phox) reduced kidney hypertrophy, oxidative stress and mesangial matrix expansion, and also reduced hyperglycaemia by increasing pancreatic and circulating insulin concentrations. p47 (phox-/-) mice exhibited improved glucose tolerance, but modestly decreased insulin sensitivity. Deletion of p47 (phox) attenuated high glucose-induced activation of NADPH oxidase and pro-fibrotic gene expression in glomeruli and mesangial cells. CONCLUSIONS/INTERPRETATION: Deletion of p47 (phox) attenuates diabetes-induced glomerular injury and beta cell dysfunction in the Akita mouse.

Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury.

Despite substantial progress, mortality and morbidity of the acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), remain unacceptably high. There is no effective treatment for ARDS/ALI. The renin-angiotensin system (RAS) through Angiotensin-converting enzyme (ACE)-generated Angiotensin II contributes to lung injury. ACE2, a recently discovered ACE homologue, acts as a negative regulator of the RAS and counterbalances the function of ACE. We hypothesized that ACE2 prevents Bleomycin (BLM)-induced lung injury. Fourteen to 16-week-old ACE2 knockout mice-male (ACE2(-/y)) and female (ACE2(-/-))-and age-matched wild-type (WT) male mice received intratracheal BLM (1.5U/kg). Male ACE2(-/y) BLM injured mice exhibited poorer exercise capacity, worse lung function and exacerbated lung fibrosis and collagen deposition compared with WT. These changes were associated with increased expression of the profibrotic genes α-smooth muscle actin (α-SMA) and Transforming Growth Factor ß1. Compared with ACE2(-/y) exposed to BLM, ACE2(-/-) exhibited better lung function and architecture and decreased collagen deposition. Treatment with intraperitoneal recombinant human (rh) ACE2 (2 mg/kg) for 21 days improved survival, exercise capacity, and lung function and decreased lung inflammation and fibrosis in male BLM-WT mice. Female BLM WT mice had mild fibrosis and displayed a possible compensatory upregulation of the AT2 receptor. We conclude that ACE2 gene deletion worsens BLM-induced lung injury and more so in males than females. Conversely, ACE2 protects against BLM-induced fibrosis. rhACE2 may have therapeutic potential to attenuate respiratory morbidity in ALI/ARDS.

Effects of hypoxia-induced intrauterine growth restriction on cardiac siderosis and oxidative stress.

We have previously shown that adult rat offspring born intrauterine growth restricted (IUGR) as a result of a prenatal hypoxic insult exhibit several cardiovascular characteristics that are compatible with common manifestations of chronic iron toxicity. As hypoxia is one of the major regulators of iron absorption and metabolism, we hypothesized that hypoxia-induced IUGR offspring will have long-term changes in their ability to regulate iron metabolism leading to myocardial iron deposition and induction of myocardial oxidative stress. Pregnant Sprague Dawley rats were randomized to control (n = 8) or maternal hypoxia (11.5% oxygen; n = 8) during the last 6 days of pregnancy. At birth, litters were reduced to eight pups (four male and four female). At 4 or 12 months of age, offspring were euthanatized and samples (blood and myocardium) were collected. In only the male offspring, IUGR and aging were associated with an increase in myocardial markers of oxidative stress such as oxidized/reduced glutathione ratio and malondialdehyde. Aged male IUGR offspring also exhibited interstitial myocardial remodeling characterized by myocyte loss and disrupted extracellular matrix.Contrary to our hypothesis, however, neither IUGR nor aging were associated with changes in any systemic or local markers of iron metabolism. Our results suggest that hypoxic insults leading to IUGR produce long-term effects on the levels of oxidative stress and connective tissue distribution in the myocardium of male but not female offspring.

SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS.

BACKGROUND: Angiotensin converting enzyme 2 (ACE2), a monocarboxylase that degrades angiotensin II to angiotensin 1-7, is also the functional receptor for severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) and is highly expressed in the lungs and heart. Patients with SARS also suffered from cardiac disease including arrhythmias, sudden cardiac death, and systolic and diastolic dysfunction. MATERIALS AND METHODS: We studied mice infected with the human strain of the SARS-CoV and encephalomyocarditis virus and examined ACE2 mRNA and protein expression. Autopsy heart samples from patients who succumbed to the SARS crisis in Toronto (Canada) were used to investigate the impact of SARS on myocardial structure, inflammation and ACE2 protein expression. RESULTS: Pulmonary infection with the human SARS-CoV in mice led to an ACE2-dependent myocardial infection with a marked decrease in ACE2 expression confirming a critical role of ACE2 in mediating SARS-CoV infection in the heart. The SARS-CoV viral RNA was detected in 35% (7/20) of autopsied human heart samples obtained from patients who succumbed to the SARS crisis during the Toronto SARS outbreak. Macrophage-specific staining showed a marked increase in macrophage infiltration with evidence of myocardial damage in patients who had SARS-CoV in their hearts. The presence of SARS-CoV in the heart was also associated with marked reductions in ACE2 protein expression. CONCLUSIONS: Our data show that SARS-CoV can mediate myocardial inflammation and damage associated with down-regulation of myocardial ACE2 system, which may be responsible for the myocardial dysfunction and adverse cardiac outcomes in patients with SARS.

Physiological roles of angiotensin-converting enzyme 2.

Angiotensin-converting enzyme 2 (ACE2) is a recently discovered homologue of the key enzyme of the renin-angiotensin system, the angiotensin-converting enzyme. The ACE2 enzyme is mainly expressed in cardiac blood vessels and tubular epithelia of the kidneys. Together with ACE2's unique metallocarboxypeptidase activity, the restricted tissue distribution suggests a distinctive physiological function in blood pressure, blood flow and fluid regulation. The ace2 gene was mapped to quantitative trait loci affecting susceptibility to hypertension in rats. Furthermore, ACE2 appears to be a negative regulator of ACE in the heart. ACE2 messenger RNA and protein levels are substantially regulated in the kidney of diabetic and pregnant rats. The mechanism of ACE2 function and its physiologic significance are not yet fully understood; however, as ACE2 differs in its specificity and physiological role from ACE, this opens a new potential venue for drug discovery aimed at cardiovascular disease, hypertension and diabetic complications.

Impaired glucose-stimulated insulin secretion, enhanced intraperitoneal insulin tolerance, and increased beta-cell mass in mice lacking the p110gamma isoform of phosphoinositide 3-kinase.

Phosphoinositide 3-kinase (PI3 kinase) has been implicated in G protein-coupled receptor regulation of pancreatic beta-cell growth and glucose-stimulated insulin secretion. The G protein-activated p110gamma isoform of PI3 kinase was detected in insulinoma cells, mouse islets, and human islets. In 7- to 10-wk-old mice, knockout of p110gamma reduced the plasma insulin response to ip glucose injection and impaired first and second phase glucose-stimulated insulin secretion from pancreata perfused ex vivo. The p110gamma -/- mice responded to preinjection with the glucagon-like peptide-1 receptor agonist exendin 4, such that plasma glucose and insulin responses to ip glucose injection were not different from wild types. Mice lacking p110gamma were not diabetic and were only slightly glucose intolerant (ip glucose injection) compared with wild types, in part due to enhanced responsiveness to insulin as determined by an ip insulin tolerance test. Despite severely reduced insulin secretion in these animals, the p110gamma -/- mice had greater pancreatic insulin content, and an increased beta-cell mass due to beta-cell hypertrophy. These surprising results suggest that the G protein-coupled p110gamma isoform of PI3 kinase is not central to the development or maintenance of sufficient beta-cell mass but positively regulates glucose-stimulated insulin secretion.

Response by the corpuscles of Stannius to hypotensive stimuli in three divergent ray-finned fishes (Amia calva, Anguilla rostrata, and Catastomus commersoni): cardiovascular and morphological changes.

In accordance with their vital role in cardiovascular physiology () corpuscles of Stannius (CS) from two teleosts and an holostean species showed marked and consistent degranulation and exocytotic responses to hypotensive stimuli. In eels (Anguilla rostrata LeSueur) acute blood withdrawal (hypovolemic hypotension) was followed by a prompt decrease in cardiac output (CO) and dorsal aortic pressure (P(DA)), a compensatory tachycardic response and an increase in systemic vascular resistance (R(SYS)). Isovolemic hypotension induced by papaverine i.v., led to a similar, but more prolonged, decrease in P(DA) but the heart rate (HR) continued to accelerate, thereby counterbalancing the severe and persistent decrease in R(SYS). Both hypovolemic and isovolemic hypotension were followed by a significant depletion of cytoplasmic granules from eel CS even though plasma concentrations of Ca, Mg, Na(+), and K(+) were normal. In an ancient holostean fish, the bowfin, Amia calva and a generalized teleost fish, Catastomus commersoni, the number of cytoplasmic granules decreased by 39% and 54%, respectively, 120 min after the acute withdrawal of 8 ml kg bw(-1) of blood. These findings suggest that a primary role of the CS is to release cytoplasmic granules containing renin or isorenin into the blood circulation, in response to hypotension and/or hypovolemia.

The molecular physiology of the cardiac transient outward potassium current (I(to)) in normal and diseased myocardium.

G. Y. Oudit, Z. Kassiri, R. Sah, R. J. Ramirez, C. Zobel and P. H. Backx. The Molecular Physiology of the Cardiac Transient Outward Potassium Current (I(to)) in Normal and Diseased Myocardium. Journal of Molecular and Cellular Cardiology (2001) 33, 851-872. The Ca(2+)-independent transient outward potassium current (I(to)) plays an important role in early repolarization of the cardiac action potential. I(to)has been clearly demonstrated in myocytes from different cardiac regions and species. Two kinetic variants of cardiac I(to)have been identified: fast I(to), called I(to,f), and slow I(to), called I(to,s). Recent findings suggest that I(to,f)is formed by assembly of K(v4.2)and/or K(v4.3)alpha pore-forming voltage-gated subunits while I(to,s)is comprised of K(v1.4)and possibly K(v1.7)subunits. In addition, several regulatory subunits and pathways modulating the level and biophysical properties of cardiac I(to)have been identified. Experimental findings and data from computer modeling of cardiac action potentials have conclusively established an important physiological role of I(to)in rodents, with its role in large mammals being less well defined due to complex interplay between a multitude of cardiac ionic currents. A central and consistent electrophysiological change in cardiac disease is the reduction in I(to)density with a loss of heterogeneity of I(to)expression and associated action potential prolongation. Alterations of I(to)in rodent cardiac disease have been linked to repolarization abnormalities and alterations in intracellular Ca(2+)homeostasis, while in larger mammals the link with functional changes is far less certain. We review the current literature on the molecular basis for cardiac I(to)and the functional consequences of changes in I(to)that occur in cardiovascular disease.

Homocysteine, vitamins, and coronary artery disease. Comprehensive review of the literature.

OBJECTIVE: To summarize results of clinical trials investigating the role of homocysteine (tHcy) as a risk factor for coronary artery disease (CAD) and the role of vitamin therapy (folic acid and vitamins B6 and B12) in primary and secondary prevention of CAD. QUALITY OF EVIDENCE: MEDLINE was searched from January 1976 to January 1999 to locate cross-sectional, retrospective and prospective cohort studies and meta-analyses on CAD using the MeSH words homocysteine, folic acid, vitamins B6 and B12, and coronary artery or heart disease. MAIN MESSAGE: Elevated tHcy levels are prevalent; most retrospective and cross-sectional studies show an association with increased risk of CAD. Results from recent prospective studies are less consistent. Folic acid, alone or with vitamins B6 and B12, reduces tHcy concentrations in the blood. Results from ongoing randomized controlled trials could determine the effect of vitamins B6 and B12 and folic acid supplementation on CAD-related morbidity and mortality and could indicate whether routine supplementation with these vitamins should be advocated. Before mass screening for tHcy can be done, the tHcy assay must be standardized. CONCLUSION: The role of homocysteine and vitamins B6 and B12 in managing CAD is unclear. Routine screening is not recommended.

Modulation of iron uptake in heart by L-type Ca2+ channel modifiers: possible implications in iron overload.

Heart failure is the leading cause of mortality in patients with transfusional iron (Fe) overload in which myocardial iron uptake ensues via a transferrin-independent process. We examined the ability of L-type Ca2+ channel modifiers to alter Fe2+ uptake by isolated rat hearts and ventricular myocytes. Perfusion of rat hearts with 100 nmol/L 59Fe2+ and 5 mmol/L ascorbate resulted in specific 59Fe2+ uptake of 20.4+/-1.9 ng of Fe per gram dry wt. Abolishing myocardial electrical excitability with 20 mmol/L KCl reduced specific 59Fe2+ uptake by 60+/-7% (P<0.01), which suggested that a component of myocardial Fe2+ uptake depends on membrane voltage. Accordingly, 59Fe2+ uptake was inhibited by 10 micromol/L nifedipine (45+/-12%, P<0.02) and 100 micromol/L Cd2+ (86+/-3%; P<0. 001) while being augmented by 100 nmol/L Bay K 8644 (61+/-18%, P<0. 01) or 100 nmol/L isoproterenol (40+/-12%, P<0.05). By contrast, uptake of 100 nmol/L ferric iron (59Fe3+) was significantly lower (1. 4+/-0.3 ng Fe per gram dry wt; P<0.001) compared with divalent iron. These data suggest that a component of Fe2+ uptake into heart occurs via the L-type Ca2+ channel in myocytes. To investigate this further, the effects of Fe2+ on cardiac myocyte L-type Ca2+ currents were measured. In the absence of Ca2+, noninactivating nitrendipine-sensitive Fe2+ currents were recorded with 15 mmol/L [Fe2+]o. Low concentrations of Fe2+ enhanced Ca2+ current amplitude and slowed inactivation rates, which was consistent with Fe2+ entry into the cell, whereas higher Fe2+ levels caused dose-dependent decreases in peak current. Fe3+ had no effect on current amplitude or decay. Combined, our data suggest that myocardial Fe2+ uptake occurs via L-type Ca2+ channels and that blockade of these channels might be useful in the treatment of patients with excessive serum iron levels.

Clinical and pathophysiological effects of active and passive smoking on the cardiovascular system.

Both passive and active cigarette smoking increase the risk of cardiovascular disease, the leading cause of death in Western industrialized nations. The prevalence of smoking as a major cardiovascular risk factor has been well characterized over the past 30 years. The two demographic groups of particular concern are women and the young. The relationship between active tobacco smoking and increased risk of coronary artery disease (stable and unstable angina, acute myocardial infarction or sudden death), cerebrovascular disease (cerebral infarction, and cerebral and subarachnoid hemorrhage), peripheral arterial disease (large and small vessel) and aortic aneurysm has been well established in numerous longitudinal and cross-sectional epidemiological and basic science studies. More recently, passive smoking has been shown to represent an important risk factor for coronary artery disease. Smoking can elicit both acute and chronic cardiac and vascular events due to the multiplicity of mechanisms involved: hematological, neurohormonal, metabolic, hemodynamic, molecular genetic and biochemical pathways. Smoking cessation can result in both the inhibition of progression and the regression of pathophysiological changes, improving morbidity and mortality among chronic smokers. The incidence of coronary artery and cerebrovascular diseases in former smokers decreases by 50% two to three years following cessation, but a small long term excess risk persists. Smoking as a cardiovascular risk factor and the clinical cardiovascular features associated with active and passive smoking are discussed, and a pathophysiological framework to explain the association between cigarette smoking and cardiovascular disease is provided.

Corpuscles of Stannius and stanniocalcin-like immunoreactivity in the white sucker (Catostomus commersoni): evidence for a new cell-type.

The distribution of stanniocalcin immunoreactivity was examined in the corpuscles of Stannius of the white sucker (Catostomus commersoni) by using a chum salmon stanniocalcin antiserum, Western blotting, and light and electron microscopy. The white sucker possesses at least two stanniocalcin-immunoreactive corpuscles in the most posterior portions of the kidneys. Immunocytochemistry and ultrastructure revealed two cell-types in the corpuscle parenchyma, only one of which was immunoreactive. The nonimmunoreactive cells contained dense-cored vesicles and long processes that extended between the immunoreactive cells and terminated at perivascular spaces. When corpuscle extracts were subjected to electrophoresis and Western blotting, three nonreduced stanniocalcin-like immunoreactive bands (approximately 56, 61, and 64 kDa) were observed. However, in the presence of a reductant, a diffuse band migrating in the range of 28 to 32 kDa was noted. The results of this study on the white sucker demonstrate the presence of a dimeric stanniocalcin-like molecule and present evidence of a previously uncharacterized cell-type in the corpuscles of Stannius.

Tetrapod-type [Asp1] angiotensin is present in a holostean fish, Amia calva.

The renin-angiotensin system has been identified in various vertebrates, from elasmobranchs to mammals. Tetrapod (amphibians to mammals) angiotensin (ANG) has Asp at the N-terminus, but Asp is replaced by Asn in elasmobranch and teleost fish. ANG I has been isolated from incubates of plasma and kidney extracts of the bowfin Amia calva, a holostean fish, using the eel vasopressor activity as an assay system; its sequence was found to be H-Asp-Arg-Val-Tyr-Val-His-Pro-Phe-Asn-Leu-OH after sequence analysis, mass spectrometry, and comparison with the synthetic peptide. This sequence is identical to bullfrog ANG I. [Asn1] ANG I was not detected. Thus the bowfin is the first fish species which contains only [Asp1] ANG I. The bowfin ANG I and II were no more vasopressor than eel peptides in the bowfin, indicating that bowfin ANG II receptors do not distinguish between [Asp1] and [Asn1] peptides. In the rat, bowfin ANG I and rat [Ile5, His9] ANG I have equipressor activities when examined in different animals, but the vasopressor activity of bowfin ANG I decreased following rat ANG I in the same animals, although the activity of rat ANG I was unaffected after bowfin ANG I. The present study directly demonstrates the presence of the renin-angiotensin system in a holostean fish and showed that its ANG II receptors have not yet fully coevolved with the homologous [Asp1] peptide.

Effects of ANG II and III and angiotensin receptor blockers on nasal salt gland secretion and arterial blood pressure in conscious Pekin ducks (Anas platyrhynchos).

The vertebrate renin-angiotensin system controls cardiovascular, renal and osmoregulatory functions. Angiotensin II (ANG II) is the most potent hormone of the RAS but in some vertebrate animals angiotensin III (Val4-ANG III) may be a hormone. We studied the effects of some angiotensins and mammalian ANG II receptor antagonists on nasal salt gland function and arterial blood pressure in conscious white Pekin ducks. Nasal salt gland fluid secretion (NFS) was induced by a 10 ml.kg-1 bw i.v. injection of a NaCl solution (1000 mosmol.kg-1 H2O) and maintained by a continuous i.v. infusion of the same solution at a rate of 0.97 ml.min-1. There was a positive linear correlation between nasal fluid [Na+] and osmolality, between [Na+] and [K+], and also between the rate of NFS and [Na+] and [K+]. [Asp1, Val5]-ANG II (1 nmol.kg-1 i.v.) inhibited NFS but did not change ionic concentrations. Val4-ANG III (1 or 5 nmol.kg-1) and ANG I (1-7) (20 nmol.kg-1) had no effect on NFS. [Sar1, Ile8]-ANG II (SARILE) acted as an ANG II receptor agonist and resulted in a prolonged and complete inhibition of NFS. The AT1 receptor antagonist, losartan (DuP 753) and the AT2 receptor antagonist, PD 123319 both failed to block the inhibitory effect of [Asp1, Val5]-ANG II on the nasal salt glands. [Asp1, Val5]-ANG II (2 nmol.kg-1 i.v.) increased mean arterial blood pressure (MABP), whereas the same dose of [Asn1, Val5]-ANG II (teleost) had only 30% of the pressor potency of the avian ANG II. Neither 1 nor 5 nmol.kg-1 of Val4-ANG III i.v. nor 20 nmol.kg-1 of ANG I (1-7) had any measurable effect on MABP. SARILE blocked completely the pressor response to [Asp1, Val5]-ANG II but the AT1 antagonists losartan and CGP 48933 and the AT2 antagonist PD 123319 all failed to block the pressor response to [Asp1, Val5]-ANG II. These results have substantiated an important role of the nasal salt gland in potassium regulation and highlighted a pharmacological dimorphism of saralasin, namely agonist and antagonist to angiotensin II-mediated inhibition of nasal salt gland function and pressor response, respectively. Using specific nonpeptidergic angiotensin II receptor antagonists, we have confirmed the distinct pharmacology of the avian angiotensin II receptors in a nongallinaceous species and the absence of significant angiotensin I (1-7) and angiotensin II effects on the cardiovascular system and nasal salt gland.

Angiotensin II and cardiovascular regulation in a freshwater teleost, Anguilla rostrata LeSueur.

Cardiac output (CO), dorsal aortic blood flow (BFDA) and blood pressure (PDA), and heart rate (HR) were recorded simultaneously in conscious freshwater eels. Physiological doses of [Asn1,Val5]angiotensin II (ANG II; 25-150 ng/kg iv) were used to investigate its effects on the blood flow [CO, BFDA, and estimated branchial shunting (BS)] and systemic vascular resistance (RSys) components of the pressor response and possible mechanism(s) of action. CO was increased mainly by an elevated stroke volume (SV) due to positive inotropy and/or Frank-Starling principle in a dose-related manner. An intact baroreceptor reflex attenuated the blood flow increase by 25% via the inhibitory cardiac vagal innervation. The elevation in estimated BS was a passive response to the increased CO, since the proportion of CO perfusing the pathway remained constant. PDA showed a similar dose-dependent increase in response to ANG II but the peak PDA preceded the peak CO responses at all doses; RSys was only transiently elevated at peak PDA. The increase in blood flow was an important contributor to the vasopressor responses. Alpha-Adrenergic blockade partially inhibited the pressor effect of ANG II (100 ng/kg) primarily by attenuating the increase in blood flow (50-70%). The data provide evidence for an ANG II-mediated cardiovascular control in teleosts directly and indirectly via catecholamine release.

Angiotensin I- and II- and norepinephrine-mediated pressor responses in an ancient holostean fish, the bowfin (Amia calva).

Dorsal aortic blood pressure (PSYS, systolic; PDIAS, diastolic; and PDA, mean) and heart rate (HR) were measured in resting freshwater bowfins (n = 6), Amia calva L., before and after i.v. injections of 50, 100, 200, 500, and 1000 ng.kg-1 of synthetic [Asn1, Val5]-angiotensin II (ANG II). Baseline PSYS, PDIAS, and PDA were 27.7 +/- 2.8, 22.4 +/- 1.8, and 24.5 +/- 2 mm Hg, respectively. Bowfins were only moderately responsive to ANG II in a stepwise manner and the increase in blood pressure became significant only at the two highest doses; lower doses tended only to increase arterial pressure. Pressor responses due to 200 and 500 ng.kg-1 decayed over a greater time period compared with other doses. alpha-Adrenergic blockade abolished 70% of the ANG II-mediated pressor responses. Eel, salmon, and goosefish angiotensin I (ANG I; 500 ng.kg-1) elicited similar vasopressor responses (magnitude and time course) which were eliminated by prior angiotensin converting enzyme inhibition (captopril; 2-10 mg.kg-1). Bullfrog ANG I evoked a pressor effect, only at a higher dose (5000 ng.kg-1). Consecutive norepinephrine (NE) injections (100, 200, 500, and 1000 ng.kg-1) increased PSYS, PDIAS, and PDA in a dose-dependent manner which was dependent on alpha-adrenoceptors since phentolamine (1-3 mg.kg-1) abolished 80% of the pressor action of NE. PSYS was elevated by 100 ng.kg-1 of NE but PDIAS and PDA were significantly increased only at 200 ng.kg-1 ANG II and NE had no measurable chronotropic effect and resting HR (27.2 +/- 0.8 beats.min-1) was unchanged. Captopril and phentolamine treatments produced rapid hypotension and bradycardia (25-30%) which lasted from 15 to 30 and 20 to 40 min, respectively. The rising and decreasing phases of the NE-mediated pressor responses had shorter durations than ANG II effects. Tachyphylaxis occurred with the high doses of ANG II and NE. The data show that in the ancient bowfin, which evidently lacks renal juxtaglomerular cells, the cardiovascular system can be regulated by the renin-angiotensin system and NE.

Cardiovascular effects of arginine vasotocin, atrial natriuretic peptide, and epinephrine in freshwater eels.

The effects of 150 ng/kg iv injections of arginine vasotocin (AVT), eel atrial natriuretic peptide (ANP), and epinephrine (Epi) on the cardiovascular dynamics of resting freshwater eels, Anguilla rostrata were studied. Injection of AVT into the caudal vein significantly increased cardiac output (CO) from 15.3 to 23.6 ml.min-1.kg-1 primarily by increasing stroke volume. Mean dorsal aortic pressure (PDA) also increased. Estimated branchial shunting (2.54 ml.min-1.kg-1) was elevated by 130% because of an increased proportion of CO, indicating a vasoconstriction of the branchial arterioarterial pathway. In contrast, Epi reduced the fraction of CO perfusing the arteriovenous pathway. Epi also produced a positive chronotropic effect, increased CO and systemic vasoconstriction, resulting in a vasopressor response. These changes occurred earlier than those of AVT and ANP. Pressor responses triggered by AVT and Epi preceded the increases in CO. Injections of 150 and 200 ng/kg ANP caused a reduction in PDA due to a decrease in CO (and SV) but failed to modulate systemic resistance. The change in CO was the primary contributor to the pressor (and depressor) responses elicited by the three hormones.