icatibant and Heart-Failure

Animal models suggest a vasomotor role for the B1 kinin receptor in cardiovascular disease states. In patients with heart failure treated with angiotensin-converting enzyme inhibition (ACEi), or combined B1/B2 receptor antagonism, but not B2 receptor antagonism alone, causes vasoconstriction. However, B1 agonism has no effect on vasomotor or fibrinolytic function. Findings from transgenic animals lacking the B2 receptor suggest that these conflicting data may be explained by cross-talk between B1 and B2 receptors. We hypothesized that B1 stimulation causes vasodilatation and tissue plasminogen activator release in the human forearm when B2 receptor signaling is inhibited. Forearm blood flow was measured in 16 patients with heart failure receiving ACEi. In double-blinded crossover studies, intrabrachial Lys-[Leu8]-des-Arg9-bradykinin (B1 antagonist), lys-des-Arg9-bradykinin (B1 agonist), bradykinin (B2 agonist), and sodium nitroprusside (endothelium-independent vasodilator) were infused alone or with HOE-140 (B2 antagonist). HOE-140 did not affect basal vascular tone or t-PA release, but it abolished bradykinin-induced vasodilatation and t-PA release (P < 0.0001). Blood flow and t-PA release were unaffected by B1 agonism or antagonism in the presence and absence HOE-140. Our findings do not support a role for crosstalk between the B1 and B2 kinin receptors in the human peripheral circulation.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Cross-Over Studies; Double-Blind Method; Female; Heart Failure; Humans; Infusions, Intra-Arterial; Kallidin; Middle Aged; Nitroprusside; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Regional Blood Flow; Tissue Plasminogen Activator; Vasodilation

Bradykinin, an endogenous vasodilator peptide, is metabolized by ACE. The aims of the present study were to determine the doses of B9340, a bradykinin receptor antagonist, that inhibit vasodilatation to exogenous bradykinin and to assess the contribution of bradykinin to the maintenance of basal vascular tone in patients with heart failure receiving chronic ACE inhibitor therapy.. Forearm blood flow was measured using bilateral venous occlusion plethysmography. On three occasions in a double-blind randomized manner, 8 healthy volunteers received intrabrachial infusions of placebo or B9340 (at 4.5 and 13.5 nmol/min). On each occasion, placebo or B9340 was coinfused with bradykinin (30 to 3000 pmol/min) and substance P (4 to 16 pmol/min). B9340 caused no change in basal FBF but produced dose-dependent inhibition of the vasodilatation to bradykinin (P<0.001) but not substance P. The effects of bradykinin antagonism were studied in 17 patients with NYHA grade II through IV heart failure maintained on chronic ACE inhibitor therapy. Incremental doses of B9340, but not HOE-140, produced a dose-dependent vasoconstriction (P=0.01). After withdrawal of ACE inhibitor therapy, B9340 produced no significant change in forearm blood flow. After reinstitution of therapy, B9340 again resulted in vasoconstriction (P<0.03).. B9340 is a potent and selective inhibitor of bradykinin-induced vasodilatation. Bradykinin does not contribute to the maintenance of basal peripheral arteriolar tone in healthy humans or patients with heart failure but contributes to the vasodilatation associated with chronic ACE inhibitor therapy in patients with heart failure via the B(1) receptor.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Flow Velocity; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Drug Synergism; Female; Forearm; Heart Failure; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Plethysmography; Reference Values; Regional Blood Flow; Substance P; Vasodilation

ACE inhibitors have been shown to potentiate the effects of exogenous bradykinin by inhibition of its breakdown. Despite this, there is little evidence that inhibition of endogenous bradykinin breakdown actually contributes to the effects of ACE inhibitors, or indeed, other inhibitors of the renin-angiotensin system, such as angiotensin II type I receptor (AT(1)) antagonists, and no evidence at all that it does so in patients with heart failure.. Twelve patients with heart failure (11 male, 1 female, ages 59 to 81 years) were randomized to double-blind crossover treatment with enalapril 10 mg BID followed by losartan 25 mg BID, or the reverse, each for 5 weeks. At the end of each treatment period, forearm blood flow was measured by venous occlusion plethysmography during an intrabrachial infusion of bradykinin before and after an intrabrachial infusion of Hoe-140 (a potent, selective, and long-acting bradykinin antagonist). Bradykinin caused profound vasodilatation after enalapril (peak, 357+/-67%) and less after losartan (peak, 230+/-46%). Despite this, Hoe-140 had no discernible effects after enalapril or losartan. Similarly, this was despite the finding that Hoe-140 significantly reduced vasodilatation to bradykinin after enalapril (peak, 192+/-35%) and losartan (peak, 66+/-13%).. Inhibition of endogenous bradykinin breakdown does not appear to contribute to the effects of ACE inhibition or AT(1) antagonism in the forearm of patients with heart failure at rest, despite the very obvious effects of ACE inhibition compared with AT(1) antagonism on exogenous bradykinin.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Cross-Over Studies; Double-Blind Method; Drug Interactions; Enalapril; Female; Heart Failure; Humans; Losartan; Male; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Vasodilator Agents

Previous animal and human studies have suggested that a muscle reflex engaged during contraction leads to heightened levels of sympathetic activity in congestive heart failure (CHF). The present experiment was designed to test the role for bradykinin, which is produced within contracting skeletal muscle and contributes to the muscle reflex through its action on kinin B(2) receptors located on the endings of thin fiber muscle afferents. CHF was induced in rats by myocardial infarction (MI) after coronary artery ligation. Echocardiography was performed to determine fractional shortening (FS), an index of the left ventricular function. In the decerebrate rats, we examined renal sympathetic nerve activity (RSNA) during 1 min intermittent (1 to 4 s stimulation to relaxation) contraction of left triceps surae muscles. RSNA responded synchronously as tension was developed, and the response was significantly (P < 0.05) greater in MI rats [+39 +/- 9% s(-1) (integrated RSNA over time); n = 16] with 20 +/- 2% of FS than that in control healthy rats (+19 +/- 2% s(-1); n = 16) with 49 +/- 2% of FS. Tension development did not differ significantly between the two groups of rats. Thirty minutes after intra-arterial injection into the hindlimb circulation of the kinin B(2) receptor antagonist, HOE-140 (2 microg/kg), the RSNA response to contraction was significantly reduced in the MI rats (+26 +/- 7% s(-1)) but not in the control rats (+17 +/- 2% s(-1)). These data suggest that bradykinin within contracting muscle is part of the exaggerated muscle reflex seen in CHF.

Topics: Animals; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Bradykinin Receptor Antagonists; Coronary Vessels; Decerebrate State; Heart Failure; Heart Rate; Hindlimb; In Vitro Techniques; Kidney; Male; Muscle Contraction; Muscle, Skeletal; Myocardial Ischemia; Neurons, Afferent; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Sympathetic Nervous System; Ultrasonography

In the present study, we investigated the effects of basal and intra-arterial infusion of bradykinin on unstressed forearm vascular volume (a measure of venous tone) and blood flow in healthy volunteers (n=20) and in chronic heart failure patients treated with ACEIs [ACE (angiotensin-converting enzyme) inhibitors] (n=16) and ARBs (angiotensin receptor blockers) (n=14). We used radionuclide plethysmography to examine the effects of bradykinin and of the bradykinin antagonists B9340 [B1 (type 1)/B2 (type 2) receptor antagonist] and HOE140 (B2 antagonist). Bradykinin infusion increased unstressed forearm vascular volume in a similar dose-dependent manner in healthy volunteers and ARB-treated CHF patients (healthy volunteers maximum 12.3+/-2.1%, P<0.001 compared with baseline; ARB-treated CHF patients maximum 9.3+/-3.3%, P<0.05 compared with baseline; P=not significant for difference between groups), but the increase in unstressed volume in ACEI-treated CHF patients was higher (maximum 28.8+/-7.8%, P<0.001 compared with baseline; P<0.05 for the difference between groups). In contrast, while the increase in blood flow in healthy volunteers (maximum 362+/-9%, P<0.001) and in ACEI-treated CHF patients (maximum 376+/-12%, P<0.001) was similar (P=not significant for the difference between groups), the increase in ARB-treated CHF patients was less (maximum 335+/-7%, P<0.001; P<0.05 for the difference between groups). Infusion of each receptor antagonist alone similarly reduced basal unstressed volume and blood flow in ACEI-treated CHF patients, but not in healthy volunteers or ARB-treated CHF patients. In conclusion, bradykinin does not contribute to basal venous tone in health, but in ACEI-treated chronic heart failure it does. In ARB-treated heart failure, venous responses to bradykinin are preserved but arterial responses are reduced compared with healthy controls. Bradykinin-mediated vascular responses in both health and heart failure are mediated by the B2, rather than the B1, receptor.

Topics: Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin Receptor Antagonists; Dose-Response Relationship, Drug; Female; Forearm; Heart Failure; Humans; Male; Middle Aged; Receptors, Bradykinin; Regional Blood Flow; Vascular Resistance; Vasodilator Agents

We hypothesized that left ventricular (LV) remodeling and matrix loss in volume overload (VO) are mediated by bradykinin (BK) and exacerbated by chronic angiotensin-converting enzyme (ACE) inhibition.. Chronic ACE inhibition increases anti-fibrotic BK and does not attenuate LV remodeling in pure VO. The relative contribution of changes in extracellular matrix versus cardiomyocyte elongation in acute and chronic LV chamber remodeling during VO is unknown.. Echocardiography, LV collagen content, and isolated cardiomyocytes were studied in rats after aortocaval fistula (ACF) of 12 h, 2 and 5 days, and 4, 8, and 15 weeks. We also studied ACF rats after BK2 receptor (BK2R) blockade (2 days) or ACE inhibition (4 weeks).. At 2 days after ACF, LV end-diastolic dimension (LVEDD)/wall thickness was increased, and LV interstitial collagen was decreased by 50% without cardiomyocyte elongation. The BK2R blockade prevented collagen loss and normalized LVEDD/wall thickness. From 4 to 15 weeks after ACF, interstitial collagen decreased by 30% and left ventricular end-systolic (LVES) dimension increased despite normal LVES pressure and isolated cardiomyocyte function. The ACE inhibition did not decrease LVEDD/wall thickness, further decreased LV interstitial collagen, and did not improve LV fractional shortening despite decreased LVES pressure.. Immediately after ACF induction, eccentric LV remodeling is mediated by interstitial collagen loss without cardiomyocyte elongation. Acute BK2R blockade prevents eccentric LV remodeling and improves function. Chronic ACE inhibition does not prevent eccentric LV remodeling or improve function. These findings suggest that ACE inhibitor-mediated increase in LV BK exacerbates matrix loss and explains why ACE inhibition is ineffective in VO.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Collagen; Diastole; Disease Models, Animal; Heart Failure; Heart Ventricles; Male; Myocytes, Cardiac; Organ Size; Ramipril; Rats; Rats, Sprague-Dawley; Systole; Ventricular Function, Left; Ventricular Remodeling

The production of endogenous nitric oxide, which regulates myocardial oxygen consumption, is decreased in heart failure. As with angiotensin-converting enzyme (ACE) inhibitors, amlodipine, a calcium antagonist, increases kinin-mediated nitric oxide production in coronary microvessels. We investigated the possibility of synergy between ACE inhibitors and amlodipine in regulating myocardial oxygen consumption. Left ventricular myocardium was isolated from 6 healthy dog hearts and 5 human hearts with end-stage heart failure at the time of orthotopic heart transplantation. Myocardial oxygen consumption was measured before and after administration of bradykinin, S-nitroso N-acetyl penicillamine (SNAP, a nitric oxide donor), ramiprilat (an ACE inhibitor), amlodipine, and the combination of a sub-threshold dose of ramiprilat (10(-8) md/L) + amlodipine. These experiments were repeated with L-nitro-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthesis), dichloroisocoumarin (an inhibitor of kinin synthesis), and HOE 140 (a B2 kinin-receptor antagonist). Baseline myocardial oxygen consumption in canine hearts was 182 +/- 21 nmol/g/min. Bradykinin and SNAP caused dose-dependent reductions in myocardial oxygen consumption (p <0.05). Ramiprilat and amlodipine caused a 10 +/- 3.2% and 11 +/- 0.8% reduction in myocardial oxygen consumption, respectively, when used alone (p <0.05). In the presence of a subthreshold dose of ramiprilat, amlodipine caused a larger (15 +/- 1.7%) reduction in myocardial oxygen consumption compared with either drug used alone (p <0.05). In human hearts, baseline myocardial oxygen consumption was 248 +/- 57 nmol/g/min. Amlodipine caused a larger reduction in myocardial oxygen consumption when used with ramiprilat (22 +/- 3.2%) as compared with amlodipine alone (15 +/- 2.6%). The effect of both drugs was attenuated by L-NAME, dichloroisocoumarin, and HOE 140 (p <0.05). In conclusion, ACE inhibitors and amlodipine act synergistically to regulate myocardial oxygen consumption by modulating kinin-mediated nitric oxide release, and this combination of drugs may be useful in the treatment of heart failure.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Calcium Channel Blockers; Child; Coumarins; Dogs; Drug Synergism; Drug Therapy, Combination; Female; Heart Failure; Humans; Isocoumarins; Male; Middle Aged; Myocardial Contraction; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oxygen Consumption; Penicillamine; Ramipril; Serine Proteinase Inhibitors

The purpose of this study was to determine the level and functional effects of endogenous bradykinin in congestive heart failure (CHF).. There is experimental evidence that bradykinin is increased in several cardiac disease states. However, it is unknown whether plasma levels of bradykinin are elevated in CHF. Further, the cardiac and vascular responses to bradykinin in CHF are unclear.. The circulating levels of bradykinin and the effects of endogenous bradykinin were assessed in eight instrumented, conscious dogs both before and after pacing-induced CHF.. Before CHF, the plasma bradykinin level was 53.1 +/- 12.4 pg/ml. Blocking endogenous bradykinin with HOE-140 (0.3 mg/kg), a specific bradykinin B2-receptor antagonist, produced no significant alterations in heart rate, left ventricular (LV) end-systolic pressure (Pes), total systemic resistance (TSR), the time constant of LV relaxation (tau) or the maximal rate of LV filling (dV/dt(max)). However, coronary blood flow was significantly reduced (p < 0.05). LV contractile performance measured by the slopes of pressure-volume relations was unaffected. After induction of CHF, the plasma bradykinin level increased to 234.2 +/- 19.4 pg/ml (p < 0.05). Blocking endogenous bradykinin with HOE-140 reduced coronary blood flow and produced significant increases in Pes and TSR, prolonged tau, decreased dV/dt(max) and elevated minimal LV pressure and mean left atrial pressure. Furthermore, the slopes of pressure-volume relations (p < 0.05) were decreased, indicating depressed contractility with HOE-140 after CHF.. Before CHF, endogenous bradykinin results in coronary dilation but has no effect on systemic arterial vasodilation or cardiac performance. After CHF, endogenous bradykinin is significantly increased and, acting through B2-receptors, produces coronary and arterial vasodilation and improves LV relaxation and contractile performance. Thus, endogenous bradykinin may play an important role in preserving cardiovascular function in CHF.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Dogs; Heart Failure; Hemodynamics; Models, Cardiovascular; Vasodilation; Ventricular Function, Left

Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT1-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT1-ant may block the RAS at the level of the AT1 receptor and activate the angiotensin II type 2 (AT2) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT1-ant has a similar effect and whether these effects are partly due to activation of the AT2 receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B2 receptor antagonist icatibant (B2-ant); or (c) an AT1-ant with and without an AT2-antagonist (AT2-ant) or B2-ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT1-ant. The B2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT1-ant was blocked by the AT2-ant. The decreases in LVEDV and LVESV caused by the AT1-ant were also partially blocked by the B2-ant. We concluded that (a) in HF both ACEi and AT1-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT1-ant is triggered by activation of the AT2 receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT1 receptors increases both renin and angiotensins; these angiotensins stimulate the AT2 receptor, which in turn may play an important role in the therapeutic effect of the AT1-ant via kinins and other autacoids.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Cardiovascular System; Disease Models, Animal; Drug Interactions; Heart Failure; Imidazoles; Kinins; Male; Models, Cardiovascular; Myocardial Infarction; Myocardium; Pyridines; Ramipril; Rats; Rats, Inbred Lew; Receptor, Angiotensin, Type 1; Tetrazoles

Neutral endopeptidase inhibition (NEP-I) and angiotensin converting enzyme inhibition (ACE-I) act synergistically to produce acute beneficial hemodynamic effects in models of heart failure. Blockade of the formation of angiotensin II (Ang II) acting together with potentiation of the natriuretic peptides, bradykinin and other vasoactive peptides may mediate the interaction of dual enzyme inhibition. In this study, the potential roles of Ang II repression and bradykinin potentiation were evaluated in conscious cardiomyopathic hamsters with compensated heart failure. The Ang II AT1 receptor antagonist, SR 47436 (BMS-186295), was administered at 30 mumol/kg, i.v. followed by i.v. infusion at 1 mumol/kg/min in combination with NEP-I (SQ-28603 at 30 mumol/kg i.v.). Cardiac preload (left ventricular end diastolic pressure) and afterload (left ventricular systolic pressure) decreased significantly more after the combination of Ang II blockade and NEP-I than after either treatment alone. This indicated that repression of Ang II contributes importantly to the NEP-I/ACE-I interaction. Bradykinin B2 receptor antagonism by Hoe 140 at 100 micrograms/kg, i.v. significantly blunted the decrease in left ventricular end diastolic pressure but not the decrease in left ventricular systolic pressure after dual NEP-I/ACE-I (SQ-28603 and enalaprilat each at 30 mumol/kg, i.v.). This suggests that bradykinin potentiation contributes to the preload-reducing, but not the afterload-reducing, acute effects of NEP-I/ACE-I. Hence, both Ang II repression and bradykinin potentiation are factors contributing to the synergistic hemodynamic effects of combined NEP-I and ACE-I in hamsters with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alanine; Angiotensin II; Animals; Biphenyl Compounds; Blood Pressure; Blood Volume; Bradykinin; Cricetinae; Drug Synergism; Enalaprilat; Heart Failure; Irbesartan; Male; Neprilysin; Tetrazoles; Vasodilation; Ventricular Function, Left

The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in the prevention of heart failure following myocardial infarction are widely accepted. However, the underlying mechanisms are still a matter of discussion. We therefore investigated the relative contribution of the breakdown of bradykinin and of the inhibition of angiotensin-II synthesis to the beneficial actions of ACE inhibitors in chronic heart failure following myocardial infarction.. We compared the effects pretreatment with the ACE inhibitor moexipril with those of the type 1 angiotensin (AT1)-receptor antagonist losartan on structural and functional cardiac parameters after myocardial infarction in rats. In addition, the bradykinin B2-receptor antagonist icatabant was used to investigate the role of bradykinin in the cardioprotective effects of ACE inhibition. Rats underwent a sham operation or surgery to induce myocardial infarction. Treatment was started 1 week before myocardial infarction and continued for another 6 weeks after the procedure.. Moexipril reduced infarct size (100 +/- 9mm2 compared with 165 +/- 8mm2), the ratio of total heart weight to body weight (2.6 +/- 0.1 g/kg compared with 2.9 +/- 0.1 g/kg) and end-diastolic pressure (8.2 +/- 1.5 mmHg compared with 14.0 +/- 1.7 mmHg). All of these effects of the ACE inhibitor were blocked by concomitant treatment with icatibant. Losartan did not affect any of these cardiac parameters.. The cardioprotective effects of the ACE inhibitor moexipril administered before myocardial infarction in the present study were a result of the reduced breakdown of kinins rather than of the reduced synthesis of angiotensin II.

Topics: Adrenergic beta-Antagonists; Analysis of Variance; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Bradykinin; Disease Models, Animal; Heart; Heart Failure; Hemodynamics; Imidazoles; Isoquinolines; Losartan; Male; Myocardial Contraction; Myocardial Infarction; Myocardium; Organ Size; Rats; Rats, Wistar; Tetrahydroisoquinolines; Tetrazoles

It is known that angiotensin converting enzyme (ACE) inhibitors not only prevent the formation of angiotensin II, but also potentiate the activity of bradykinin. We investigated the effects of the ACE-inhibitor ramipril in two models of cardiac ischemia. In anesthetized dogs with a coronary occlusion of 6-h duration, both ramiprilat and bradykinin significantly reduced infarct-size. This effect was prevented by the co-administration of the bradykinin antagonist HOE 140. In rats with a coronary occlusion of 6-weeks duration, ramipril administration significantly reduced infarct-size and prevented the development of left ventricular hypertrophy. Thus, ramipril showed a cardioprotective activity in models of acute as well as of chronic myocardial ischemia. These effects are probably mediated by the potentiation of bradykinin.

Topics: Animals; Bradykinin; Dogs; Dose-Response Relationship, Drug; Drug Therapy, Combination; Heart Failure; Myocardial Infarction; Myocardium; Ramipril; Rats

Rats with aortocaval fistula, an experimental model of congestive heart failure (CHF), display two distinct patterns of sodium excretion: some rats develop marked sodium retention and worsening edema with urinary excretion of sodium (UNaV) < 200 microEq per 24 hours, i.e., uncompensated CHF, whereas in others sodium balance rapidly returns to normal (UNaV > 1,400 microEq per 24 hours), i.e., compensated CHF. Similar patterns of sodium excretion are found in patients with CHF. The mechanisms underlying these responses are not fully understood. The present study was designed to assess whether bradykinin plays a role in the compensatory response to CHF. Infusions of either 10 or 50 micrograms/kg per minute of synthetic atrial natriuretic factor (ANF)8-33 into sham-operated control animals produced significant increases in urine flow and fractional excretion of sodium (FENa). Infusions of ANF at the same doses into rats with compensated CHF increased FENa from 0.11 +/- 0.03% to a maximum of 6.10 +/- 1.30%, whereas the rise in FENa in animals with uncompensated CHF was significantly reduced (0.05 +/- 0.01% to 0.59 +/- 0.18%) compared with sham-operated controls (0.23 +/- 0.05% to 8.32 +/- 1.0%) or the group with compensated CHF. Treatment of the compensated rats with the bradykinin antagonist HOE-140 (D-Arg,[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) given at a rate of 100 nmol/kg per hour did not affect their renal response to the ANF. In addition, infusion of the bradykinin antagonist alone into compensated rats with aortocaval fistula had no significant effect on their basal urinary flow rate or sodium excretion during the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adaptation, Physiological; Animals; Aorta; Arteriovenous Shunt, Surgical; Atrial Natriuretic Factor; Bradykinin; Diuresis; Dose-Response Relationship, Drug; Heart Failure; Male; Natriuresis; Potassium; Rats; Rats, Inbred Strains; Sodium; Venae Cavae