Chronic administration of moxonidine suppresses sympathetic activation in a rat heart failure model.

Excessive sympathetic activity contributes to cardiovascular abnormalities, which negatively affect the prognosis of heart failure. The present study evaluated the effects of moxonidine, an imidazoline I(1) receptor agonist, on sympathetic activation and myocardial remodelling in a rat heart failure model. Rats were subjected to coronary artery ligation, and treated with moxonidine, 3 or 6 mg/kg/day, from 1 to 21 days after myocardial infarction. After 21 days, heart rate and blood pressure were measured in conscious, chronically instrumented rats. Plasma catecholamine levels were determined by high-performance liquid chromatography. Effects on post-myocardial infarction remodelling were evaluated from the ventricular weight body weight ratio and interstitial collagen deposition, measured morphometrically in the interventricular septum remote from the infarcted area. Moxonidine dose-dependently decreased myocardial infarction induced tachycardia but did not affect myocardial infarction reduced blood pressure. Plasma noradrenaline levels, which were elevated after myocardial infarction, decreased below sham-values with 6 mg/kg/day moxonidine. Ventricular weight-body weight ratio as well as interstitial collagen were significantly elevated in myocardial infarcted rats, and restored to sham values with 6 mg/kg/day moxonidine. These data suggest that moxonidine suppresses myocardial infarction induced sympathetic activation in a dose-dependent way as indicated by reduced heart rate and plasma noradrenaline levels. Furthermore, post-myocardial infarction remodelling may be attenuated at a higher dose-range of moxonidine as shown by normalisation of ventricular weight body weight ratio and interstitial collagen.

Altered cardiac collagen and associated changes in diastolic function of infarcted rat hearts.

OBJECTIVE: Anti-inflammatory drugs have been shown to modulate collagen deposition during myocardial infarction (MI) induced remodeling. Chronic effects of methylprednisolone (5 mg/kg/day) and low-dose aspirin (25 mg/kg/day) on cardiac collagen and left ventricular diastolic function were studied in rat hearts, 21 days after MI. METHODS: Left ventricular function was assessed at baseline and after beta-adrenergic stimulation with isoproterenol in isolated perfused hearts, using an intraventricular balloon. After diastolic arrest, left ventricular pressure-volume curves were obtained. Left ventricular dilation was defined as the corresponding left ventricular volume at 20 mmHg left ventricular diastolic pressure. In histological sections, perivascular and interstitial collagen content were quantified morphometrically as the Sirius Red positive area in the non-infarcted interventricular septum. RESULTS: Impaired baseline left ventricular function of MI-hearts was improved by methylprednisolone but not by low-dose aspirin. Isoprotenerol significantly enhanced systolic function in all hearts, whereas it augmented the decrease in left ventricular diastolic pressure only in methylprednisolone-treated MI-hearts. The rightward shift of the pressure-volume curve after MI was aggravated by methylprednisolone but not with low-dose aspirin treatment. Low-dose aspirin reduced perivascular but not interstitial collagen whereas methylprednisolone decreased both perivascular and interstitial collagen. CONCLUSIONS: Our findings indicate that MI-induced collagen deposition in the spared myocardium can be affected by chronic therapy with low-dose aspirin or methylprednisolone. The effects on interstitial collagen seemed reflected in an altered left ventricular diastolic function.

Sodium nitroprusside enhances in vivo left ventricular function in beta-adrenergically stimulated rabbit hearts.

OBJECTIVE: Sodium nitroprusside (SNP) is an activator of soluble guanylate cyclase, which depresses myocardial contractility. These exclusively negative inotropic effects of SNP were recently challenged by in vitro data.. In isolated rat ventricular myocytes, a moderate increase of cGMP improved the contractile response at baseline and in isoprenaline-stimulated conditions. The present study evaluated in vivo the inotropic effects of SNP at baseline and during administration of low dose dobutamine. METHODS: Anesthetized open-chest rabbits (n = 18) were instrumented with micromanometers, ultrasound crystals and atrial pacing wires. Measurements were obtained during caval occlusion with ventilation suspended at end-expiration. Systolic function was assessed with dP/dtmax and the slope Ees of the end-systolic pressure-volume relation. Diastolic function was assessed with the time constant tau and the stiffness constant Kc of the diastolic pressure-volume relation. SNP (0.02, 0.08, 0.32 microgram x kg-1) was administered at baseline and during low dose dobutamine. RESULTS: At baseline, SNP reduced dP/dtmax from 3750 +/- 88 to 3470+/- 88 mmHg/s (mean +/- s.e.m.) and Ees from 148 +/- 16 to 103 +/- 13 mmHg/ml (P < 0.01) . During dobutamine infusion, SNP increased dP/dtmax from 4340 +/- 125 to 4681 +/- 230 mmHg/s and Ees from 148 +/- 19 to 190 +/- 30 mmHg/ml (P < 0.01). Effects of SNP on dP/dtmax and Ees were different at baseline and during dobutamine (interaction P < 0.01). SNP did not alter Kc at baseline nor during dobutamine. CONCLUSIONS: SNP enhances in vivo systolic function in beta-adrenergically stimulated rabbits.

Continuous total intravenous anesthesia, using propofol and fentanyl in an open-thorax rabbit model: evaluation of cardiac contractile function and biochemical assessment.

Effects are reported of an anesthetic protocol involving use of predetermined intravenous (i.v.)-administered drug doses during acute experimental procedures in vagotomized, New Zealand White rabbits with open thorax (n = 20) in a nonsurvival study. After induction of anesthesia by intramuscular (i.m.) administration of ketamine hydrochloride (25 mg/kg of body weight) and xylazine hydrochloride (15 mg/kg), continuous total intravenous anesthesia (TIVA) with propofol (0.6 mg.kg-1.min-1), fentanyl (0.48 micrograms.kg-1.min-1) and the neuromuscular agent vecuronium bromide (0.003 mg.kg-1.min-1) was maintained. Oxygenation conditions, acid-base balance, biochemical and hemodynamic variables, and cardiac contractile function were assessed. Measurements were made and blood analysis was done at the moment of ear vein catheterization (P1); before (P2) and after (P3) sternotomy; after complete instrumentation (P4); and at the beginning (T1), in the middle (T2), and at the end (T3) of the experimental protocol. From T1 to T3, heart rate was kept constant by use of atrial pacing at a rate of 235 +/- 15 beats/min. During surgical preparation and instrumentation, hemoglobin (Hb) concentration decreased from 12.5 +/- 0.9 g/dl (mean +/- SEM) to 7.7 +/- 0.7 g/dl and remained stable thereafter. Blood gas analysis (PO2, PCO2, pH, HCO3-, base excess, measured SaO2) and measurement of plasma lactate concentration revealed constant, adequate oxygenation. Plasma electrolyte values (Na+, Cl-, K+, Ca2+) remained within physiologic ranges throughout. Blood glucose concentration increased from 229 +/- 30 mg/dl at P1 to 382 +/- 34 mg/dl at P3. At T1, glycemia had returned to normal values and remained stable. Heart rate, blood pressure, ventricular elastance (Ees), and diastolic stiffness constant (Kc) remained stable throughout. Other indices of ventricular function (dP/dtmax, thickening, ejection duration, and maximal left ventricular pressure) remained unaltered as well. Left ventricular relaxation (dP/dtmin, tau) did not change. After anesthesia induction by i.m. administration of ketamine and xylazine, TIVA with predetermined drug dosages of propofol and fentanyl provided stable cardiovascular function for open-thorax long-term experimental observations in a nonsurvival setting.