Search PubMed⌕ Search

Biomedical subjects

L Hittinger

Publications and source records attributed to L Hittinger.

At least 19 recordsLinked to original sources
PubMed2001

Myocardial stunning in exercise-induced ischemia in dogs: lack of late preconditioning.

Late preconditioning (PC) against myocardial stunning develops after coronary artery occlusion (CAO) at rest and subsequent reperfusion. We investigated whether late PC occurs after exercise-induced ischemia (high-flow ischemia) in dogs. A circumflex coronary artery stenosis (by using occluders) was set up before the onset of treadmill exercise in nine chronically instrumented dogs to suppress exercise-induced increase in mean coronary blood flow velocity (CBFV, Doppler) without simultaneously affecting left ventricular (LV) wall thickening (Wth) at rest. Two similar exercises were performed 24 h apart. On day 1, LV Wth was reduced by 84 +/- 5% (P < 0.01), and exercise-induced increases in transmural myocardial blood flow (MBF, fluorescent microspheres) in the ischemic zone were blunted. LV Wth was depressed throughout the first 10 h and returned to its baseline value after 24 h. On day 2, changes in LV Wth and MBF were similar as was the time course for LV Wth recovery, indicating lack of late PC. Also, CBFV responses to acetylcholine, nitroglycerin, and reactive hyperemia (20-s CAO) were not significantly different on days 1 and 2. Similar results were obtained in a subgroup of four additional dogs with more severe stenosis during exercise. Late PC against myocardial stunning was confirmed to occur in a model of 10-min CAO followed by coronary artery reperfusion (CAR) in another four dogs. Thus in contrast with CAO at rest followed by CAR, severe myocardial ischemia in coronary flow-limited exercising dogs does not induce late PC against myocardial stunning.

Acetylcholine↗
PubMed2001

[Left ventricular functional imagery by magnetic resonance. Applications and developments].

Technical developments have considerably reduced the acquisition time and have improved the quality of magnetic resonance imaging. The recent recommendations of the European Society of Cardiology place MRI in the front line of investigations for the diagnosis and evaluation of congenital heart disease, cardiac tumours and pathology of the pericardium and great vessels. With the possibility of obtaining oblique planes in all 3 dimensions, MRI is the reference for the measurement of left ventricular mass, volumes, and ejection fraction, with the major advantage of not depending on hypotheses of left ventricular geometry. In addition to these known applications, the development of functional cardiac MRI has led to significant advances in the study of regional myocardial function and perfusion. The aim of this article is to discuss present indications and the potential developments of functional cardiac MRI, focusing on the quantitative evaluation of myocardial function and perfusion.

Heart Ventricles↗
PubMed2000

Stimulation of bradykinin B(1) receptors induces vasodilation in conductance and resistance coronary vessels in conscious dogs: comparison with B(2) receptor stimulation.

BACKGROUND: Constitutive bradykinin B(1) receptors have been identified in dogs; however, their physiological implications involving the coronary circulation remain to be determined. This study examined, in conscious dogs, the coronary response to des-Arg(9)-bradykinin (a B(1) receptor agonist) and the mechanisms involved. METHODS AND RESULTS: Eleven dogs were instrumented with a left ventricular micromanometer, a circumflex coronary catheter, a cuff occluder, a Doppler flow probe, and ultrasonic crystals to measure coronary blood flow velocity (CBFv) and coronary diameter (CD). Intracoronary des-Arg(9)-bradykinin (3 to 100 ng/kg) and bradykinin (0.1 to 10 ng/kg) did not modify systemic hemodynamics but dose-dependently increased CBFv and CD. Des-Arg(9)-bradykinin was less potent than bradykinin. Hoe 140 (a B(2) antagonist, 10 microg/kg) abolished the effects of bradykinin but did not influence the effects of des-Arg(9)-bradykinin. When CBFv increase was prevented by the cuff occluder, CD responses to bradykinin and des-Arg(9)-bradykinin were maintained. Intracoronary lisinopril (0. 75 mg) increased the CD response to bradykinin, with only minimal effect on CBFv, and extended the duration of the effect. Lisinopril did not alter des-Arg(9)-bradykinin responses. Intracoronary N(omega)-nitro-L-arginine (2 mg/kg) decreased the CD effect of bradykinin and prevented the CBFv and CD effects of des-Arg(9)-bradykinin. The relaxing effect of des-Arg(9)-bradykinin on isolated coronary rings was prevented by des-Arg(9), [Leu(8)]-bradykinin. CONCLUSIONS: In the conscious dog, B(1) receptors are present in coronary vessels, and their stimulation produces vasodilation in conductance and resistance vessels, which is mediated essentially by NO but not modulated by angiotensin-converting enzyme. However, the coronary vasodilation induced by B(1) receptor stimulation is not as great as that produced by B(2) receptor stimulation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Beneficial effects of the T- and L-type calcium channel antagonist, mibefradil, against exercise-induced myocardial stunning in dogs.

Abnormalities in calcium homeostasis such as calcium overload have been shown to participate in the pathogenesis of myocardial stunning. The goal of this study was to investigate the effects of mibefradil, a mixed T- and L-type calcium channels antagonist on exercise-induced ischemia (i.e., high-flow ischemia). Nine dogs were permanently instrumented to measure left ventricular wall thickening (Wth) and coronary blood flow (Doppler). Infusion of saline or mibefradil (30 and 40 microg/kg/min, i.v., for 20 min) was started 10 min before exercise (10 min, 14 km/h; slope, 13%) and stopped at its end. Circumflex coronary artery stenosis (pneumatic occluders) was set up 5 min before exercise to suppress exercise-induced increase in mean coronary blood flow without simultaneously affecting Wth at rest. Mibefradil (30 microg/kg/min) was also administered at the beginning of the recovery period in a subset of four dogs. During exercise with saline, Wth was dramatically reduced (-77 +/- 7%; p < 0.05) and recovered only after 24 h. Mibefradil at both doses significantly limited tachycardia during exercise (211 +/- 7 and 210 +/- 5 beats/min vs. 240 +/- 8 beats/min for mibefradil, 30 microg/kg/min, mibefradil, 40 microg/kg/min, and saline, respectively) but exerted no negative inotropic effects. Mibefradil at both doses significantly reduced the intensity of myocardial stunning and the time to recovery in Wth (3 h). Administration of mibefradil at the beginning of the recovery period did not protect against myocardial stunning. Administration of a mixed T- and L-type calcium channel antagonists before ischemia confers cardioprotection against exercise-induced myocardial stunning. This may potentially be related to the limitation of exercise-induced tachycardia and/or the prevention of calcium overload.

Animals↗
PubMed2000

[Role of nitric oxide in heart failure].

The benefit effects of nitric oxide (NO) donors in acute heart failure have led to the development of vasodilators as treatment of chronic heart failure. However, the mechanisms involved in the effects of NO are complex and still discussed. In chronic heart failure, the eNOS downregulation in vascular endothelium explains the alteration of endothelial function. In addition, in the myocardium, cytokines induce the expression of inducible nitric oxide synthase (iNOS) which increase NO production by myocytes and surrounding cells. This excess of NO production, associated with anion superoxide synthesis, limits the inotropic properties of catecholamines and exert proapoptotic effects. The role of NO donors in heart failure treatment is still controversial but by reducing preload they improve patient's symptoms. Beside blockade of the renin-angiotensin system, the angiotensin converting enzyme inhibitors act via the inhibition of bradykinin degradation which increase NO levels. Finally, vascular endothelial NO expression is improved by exercise training and participates in the improvement of exercise capacity in patients with chronic heart failure involved in cardiac readaptation program.

Animals↗
PubMed1999

Reduced subendocardial ryanodine receptors and consequent effects on cardiac function in conscious dogs with left ventricular hypertrophy.

The goal of this study was to examine the transmural distribution of ryanodine receptors in left ventricular (LV) hypertrophy (LVH) and its in vivo consequences. Dogs were chronically instrumented with an LV pressure gauge, ultrasonic crystals for measurement of LV internal diameter and wall thickness, and a left circumflex coronary blood flow velocity transducer. Severe LVH was induced by chronic banding of the aorta (12+/-1 months), which resulted in a 78% increase in LV/body weight. When ryanodine was infused directly into the circumflex coronary artery, it did not affect LV global function or systemic hemodynamics; however, it reduced LV wall thickening and delayed relaxation in the posterior wall in control dogs but was relatively ineffective in dogs with LVH. In LV sarcolemmal preparations, [3H]ryanodine ligand binding revealed a subendocardial/subepicardial gradient in normal dogs. In LVH there was a 45% decrease in ryanodine receptor binding and a loss in the natural subendocardial/subepicardial gradient, which roughly correlated inversely with the extent of LVH and directly with regional wall motion. Both mRNA and Western analyses revealed similar findings, with a reduction of the transmural mRNA levels and a loss in the natural gradient between subendocardial and subepicardial layers in LVH. Thus, ryanodine receptor message and binding in LVH is reduced preferentially in the subendocardium with consequent attenuation of the action of ryanodine in vivo. The selectively altered ryanodine regulation subendocardially in LVH could reconcile some of the controversy in this field and may play a role in mediating decompensation from stable LVH.

Animals↗
PubMed1999

Comparison between angiotensin receptor antagonism and converting enzyme inhibition in heart failure. Differential acute effects according to the renin-angiotensin system activation.

This study was designed to assess the influence of the activation status of the renin angiotensin system (RAS) on the hemodynamic effects of EXP 3174 (an angiotensin AT1 receptor antagonist) and enalaprilat (an angiotensin converting enzyme inhibitor) in tachycardia-induced heart failure. Thirteen dogs were chronically instrumented to measure left ventricular (LV) pressure, its first time derivative (LV dP/dt), atrial and aortic pressures, and cardiac output. EXP 3174 (0.1 mg/kg, i.v.) or enalaprilat (1 mg/kg, i.v.) were administered in conscious dogs with heart failure induced by right ventricular pacing (250 beats/min, 3 weeks). EXP 3174 and enalaprilat produced significant vasodilation but the effects of EXP 3174 on mean aortic pressure (MAP), cardiac output, and total peripheral resistance (TPR) were only 50% of those produced by enalaprilat. When dogs were grouped according to their baseline plasma renin activity (PRA) values, in dogs with normal PRA (0.5 +/- 0.1 ng/ml/h) EXP 3174 did not produce significant change in MAP and TPR, while enalaprilat decreased significantly MAP and TPR. In contrast, in dogs with high PRA (6.7 +/- 3.2 ng/ml/h), EXP 3174 produced significant reductions in MAP and TPR, which were similar to those produced by enalaprilat. Thus, in conscious dogs with heart failure, enalaprilat is effective whether the RAS is activated or not. In contrast, EXP 3174 is effective only when the RAS is activated. These results may help in the choice of inhibitors of the RAS in heart failure.

Angiotensin II↗
PubMed1999

Influence of the endothelium, nitric oxide and serotonergic receptors on coronary vasomotor responses evoked by ergonovine in conscious dogs.

1. The respective contributions of coronary vascular endothelium, nitric oxide (NO) and serotonergic receptors to the effects of ergonovine on large and small coronary arteries were investigated in conscious dogs. 2. In seven dogs with an endothelium intact, ergonovine (30 - 1000 microg, i.v.) induced a biphasic response on large coronary artery with an early and transient vasodilatation (up to +2.9+/-0.5% from 3310+/-160 microm, P<0.01) followed by a sustained vasoconstriction (down to -4.9+/-0.5%, P<0.001) which occurred simultaneously with a sustained increase in coronary blood flow (CBF) (up to +100+/-26% from 28+/-4 ml min(-1), P<0.001). After endothelium removal (balloon angioplasty), the ergonovine-induced vasodilatation was abolished and vasoconstriction potentiated (-6.4+/-0.9% after vs -4.9+/-0.5% before endothelium removal, P<0.01). 3. After blockade of NO synthesis by Nomega-nitro-L-arginine (30 mg kg(-1)) in four other dogs, the early vasodilatation induced by ergonovine was abolished but the delayed vasoconstriction as well as the increase in CBF remained unchanged. 4. Both ketanserin and methiothepin (0.3 mg kg(-1)) abolished the early vasodilatation and reduced the delayed vasoconstriction induced by ergonovine. Ketanserin decreased and methiothepin abolished the reduction in coronary resistance induced by ergonovine. 5. Thus, the complex interactions between vascular endothelium and serotonergic receptors to ergonovine-induced constriction of large coronary arteries might explain the induction of coronary spasms in patients with endothelial dysfunction.

Animals↗
PubMed1999

Increased bradykinin levels accompany the hemodynamic response to acute inhibition of angiotensin-converting enzyme in dogs with heart failure.

To determine the short-term effects of angiotensin-converting enzyme (ACE) inhibition on hemodynamics and circulating levels of norepinephrine, angiotensin, and bradykinin, responses to enalaprilat and perindoprilat were examined at doses of 0.03, 0.3, and 1 mg/kg in permanently instrumented conscious dogs with pacing-induced heart failure (right ventricular pacing, 240-250 beats/min, 3 weeks). All doses of the two inhibitors produced similar decrease in mean aortic pressure and increase in cardiac output. Neither inhibitor affected plasma norepinephrine level. Both compounds induced a similar 60-80% decrease in blood angiotensin II level, a similar two- to eightfold increase in blood angiotensin I level, and a 80-95% decrease in the angiotensin II/angiotensin I ratio. There were also a fourfold to 10-fold increase in blood bradykinin-(1-9) level, a twofold increase in blood bradykinin-(1-7) level, and a 70-85% decrease in bradykinin-(1-7)/bradykinin-(1-9) ratio. In addition, the changes in total peripheral resistance induced by the two ACE inhibitors were weakly but significantly correlated with the changes in blood angiotensin II or blood bradykinin-(1-9). Thus whatever the specificity of enalaprilat and perindoprilat, both inhibitors produced similar acute hemodynamic effects in dogs with heart failure, which was associated with marked decrease in circulating angiotensin II level and increase in bradykinin-(1-9) level. This study, which measures for the first time in heart failure the blood bradykinin level after ACE inhibitors, indicates, in concert with angiotensin II reduction, a role for increased bradykinin-(1-9) level in mediating short-term hemodynamic effects of ACE inhibition in this model of heart failure.

Angiotensin I↗
PubMed1999

[Coronary microcirculation. Physiologic and pathologic aspects].

The coronary circulation has a protective regulation system which, in extreme haemodynamic conditions, compensates increased myocardial oxygen demand. The coronary reserve, based on this concept defines the capacity of the system to increase flow temporally, and, thereby, myocardial oxygen supply. The introduction of new methods of investigating the coronary microcirculation has enabled the study of this phenomenon in several cardiovascular pathologies. Two types of investigation are used currently for studying the coronary microcirculation: 1) invasive methods, especially the recently developed intracoronary Doppler and pressure guide, 2) non-invasive methods, and, in particular, contrast echocardiography, position emission tomography and magnetic nuclear resonance. These investigations allow measurement of the coronary reserve or the assessment of the myocardial consequences of abnormalities of the microcirculation. Some workers use these methods to investigate pathological coronary microcirculation in different cardiomyopathies, in the presence of different cardiovascular risk factors (hypertension, diabetes, smoking, hypercholesterolaemia) and after cardiac transplantation.

Coronary Circulation↗
PubMed1999

Coronary microcirculation and cardiovascular pathology.

The recent arrival of new techniques for exploring the coronary microcirculation has facilitated assessment of both the incidence and consequences of disorders of this network in a large number of cardiovascular diseases. The microcirculation is affected in numerous cardiomyopathies in the presence of different cardiovascular risk factors and also following cardiac transplantation. Dysfunction of the microcirculation may correspond to a reduction in the surface of the maximum section of coronary arterioles, which involves multiple mechanisms, although this phenomenon does not appear to play a role in ischaemic heart disease. Reduced coronary flow is most frequently related to vascular rarefaction of multifactorial origin, including greater or lesser degrees of intimal proliferation, perivascular fibrosis, hypertrophy of the media and extrinsic compression.

Cardiovascular Diseases↗
PubMed1999

Coronary microcirculation and cardiovascular pathology.

The recent arrival of new techniques for exploring the coronary microcirculation has facilitated assessment of both the incidence and consequences of disorders of this network in a large number of cardiovascular diseases. The microcirculation is affected in numerous cardiomyopathies in the presence of different cardiovascular risk factors and also following cardiac transplantation. Dysfunction of the microcirculation may correspond to a reduction in the surface of the maximum section of coronary arterioles, which involves multiple mechanisms, although this phenomenon does not appear to play a role in ischaemic heart disease. Reduced coronary flow is most frequently related to vascular rarefaction of multifactorial origin, including greater or lesser degrees of intimal proliferation, perivascular fibrosis, hypertrophy of the media and extrinsic compression.

Cardiovascular Diseases↗
PubMed1998

Acute effects of an endothelin-1 receptor antagonist bosentan at different stages of heart failure in conscious dogs.

OBJECTIVE: Inhibition by endothelin antagonist is a potential therapy in heart failure. However, the effect of endothelin inhibition during the development of heart failure has not been evaluated. The goal of our study was to examine the acute hemodynamic effects of the mixed endothelin receptor antagonist bosentan in the control state and at different stages of heart failure induced by right ventricular pacing (250 bpm) in conscious dogs. METHODS: Nine dogs were chronically instrumented for the measurements of left ventricular pressure and its first derivative (dP/dt), cardiac output, left ventricular regional wall thickness and aortic pressure. Bosentan (3 mg/kg, i.v. bolus) and placebo were given at control, at 1 week of pacing (stage of left ventricular dysfunction with perserved cardiac output) and at 3 weeks of pacing (phase of heart failure with low cardiac output). RESULTS: With the development of heart failure, baseline plasma endothelin level increased progressively. Placebo did not induce hemodynamic and plasma endothelin changes during the 30 min recording at any stage. At control, bosentan did not change hemodynamics. At 1 and 3 weeks of pacing, bosentan did not modify left ventricular myocardial function indices but reduced mean arterial pressure (by 7 +/- 2 and 8 +/- 1 mm Hg respectively, p < 0.005). Bosentan increased stroke volume at 3 weeks of pacing only. CONCLUSIONS: Endothelin inhibition by endothelin antagonist bosentan, decreases aortic pressure in both early left ventricular dysfunction and in heart failure in contrast with the control state. In the phase of heart failure with low cardiac output, bosentan increases stroke volume. In the early left ventricular dysfunction, bosentan, by reducing arterial pressure, may limit the deterioration of cardiac function through a reduction of the workload imposed on the heart.

Animals↗
PubMed1998

Selective large coronary endothelial dysfunction in conscious dogs with chronic coronary pressure overload.

Coronary vascular responses to acetylcholine (ACh, 3 micrograms/kg i.v.), nitroglycerin (NTG, 25 micrograms/kg i.v.), and a 20-s coronary artery occlusion (reactive hyperemia, RH) were investigated in seven conscious dogs with severe left ventricular (LV) hypertrophy and chronic coronary pressure overload (CCPO) due to supravalvular aortic banding and in seven control dogs. All dogs were instrumented for measurement of ultrasonic coronary diameter (CD) and Doppler coronary blood flow (CBF). LV-to-body weight ratio was increased by 82% in CCPO dogs. In control dogs, ACh increased CD (+ 5.9 +/- 1.7%). This response was reduced (P < 0.05) in CCPO dogs (+ 1.9 +/- 0.9%). Similarly, flow-mediated increases in CD after RH were blunted (P < 0.01) in CCPO (+ 2.1 +/- 0.8) vs. control dogs (+ 6.8 +/- 1.8%). In contrast, ACh and RH increased CBF similarly in both groups. Increases in both CD and CBF to NTG were not different between control dogs and CCPO. Peak systolic CBF velocity was greater, P < 0.01, in CCPO (94 +/- 17 cm/s) compared with control (35 +/- 7 cm/s) dogs, most likely secondary to the increased systolic coronary perfusion pressure (215 vs. 130 mmHg). Histological analyses of large coronary arteries in CCPO revealed medial thickening, intimal thickening, and disruption of the internal elastic lamina and endothelium. In contrast, small intramyocardial arterioles failed to show the intimal and endothelial lesions. Thus, in CCPO selective to the coronary arteries, i.e., a model independent from systemic hypertension and enhanced levels of plasma renin activity, endothelial control was impaired for both flow-mediated and receptor-mediated large coronary artery function, which could be accounted for by the major morphological changes in the large coronary arteries sparing the resistance vessels. The mechanism may involve chronically elevated systolic coronary perfusion pressure, CBF velocity, and potential disruption of laminar flow patterns.

Acetylcholine↗
PubMed1998

[Effects of high sodium intake on ventricular remodeling in mice].

BACKGROUND: Despite extensive research, controversy still exists regarding the role of dietary sodium intake on hypertension and left ventricular (LV) hypertrophy. Echocardiography is a powerful tool to assess LV hypertrophy and recent technical developments allow now its use in small animals. METHODS: We examined the effect of high sodium intake on LV geometry using echocardiography in mice. Three groups of Swiss mice were submitted, for 8 weeks, to different salt diets (0.6, 2 and 4% NaCl; n = 12, n = 8 and n = 12 respectively). LV end-diastolic (ED) septal and posterior wall thicknesses, LV ED diameter were measured at baseline, 4 and 8 weeks. RESULTS: At baseline, heart rate, LV ED septal and posterior wall thicknesses and LV ED diameter were similar between groups. At 8 weeks, for similar heart rate, LV ED posterior wall thickness were not different (0.6%: 0.64 +/- 0.01, 2%: 0.62 +/- 0.08 and 4%: 0.67 +/- 0.03 mm respectively) but LV septal wall thickness ass increased in a salt diet dependent manner (0.6%: 0.63 +/- 0.01, 2%: 0.75 +/- 0.01, 4%: 0.80 +/- 0.02 mm, p < 0.01). This increase was correlated with urinary sodium excretion (r = 0.84, p < 0.01) but occurred in the absence of change in arterial pressure (tail-cuff plethysmography; 0.6%: 135 +/- 6.2%: 127 +/- 4 and 4%: 139 +/- 9 mmHg respectively). The in-vivo interventricular septal remodeling was confirmed in perfused fixed preparations of hearts. CONCLUSION: Echocardiography allows precise measurements of regional LV wall dimensions in mice, and high sodium intake, in the absence of hypertension, induces interventricular septal remodeling.

Animals↗
PubMed1998

[Physiopathological basis of the treatment of heart failure].

Therapeutic advances have changed the mode of presentation of cardiac failure over the last decades: the main cause, nowadays, is myocardial ischaemia. The modern treatment of cardiac failure is based on relatively simple physiopathological mechanisms which take into account the different aspects of cardiac physiology: a pump, a muscle, a coronary circulation supplying oxygen to the myocardium, an automatic contraction. The concept of vasodilatation and the blocking of vasoconstrictive systems introduced during the 70s is the basis of modern treatment of cardiac failure which involves angiotensin converting enzyme inhibitors and, increasingly, betablockers. In the near future, with earlier treatment of cardiac failure, the stimulation of vasodilator systems could become a new therapeutic strategy. Early detection of ischaemia and its complications with the aim of limiting the loss of cardiac myocytes is a priority for slowing the progression of cardiac failure. The prevention of cardiac failure also depends on educating cardiologists to treat rapidly the factors predisposing to or prolonging episodes of even mild cardiac failure.

Cardiology↗
PubMed1997

Regional myocardial effects of intracoronary bradykinin in conscious dogs.

This study examined in conscious dogs, the coronary and regional myocardial effects of bradykinin (BK) administered by intracoronary route and their modulation by an angiotensin-converting enzyme inhibitor. Eleven dogs were chronically instrumented with a left ventricular (LV) micromanometer, a circumflex coronary catheter, a flow probe, and ultrasonic crystals in the LV posterior wall. In the absence of systemic hemodynamic changes, BK (0.1-10 ng/kg i.c.) produced dose-dependent increases in coronary blood flow velocity (CBFV) and in LV posterior end-diastolic wall thickness (EDWT) but produced no change in LV regional myocardial function as assessed by LV posterior systolic wall thickening. The increases in LV EDWT and CBFV were linearly correlated. The BK B2 antagonist (HOE 140) abolished the effects of BK. Intracoronary enalaprilat (0.75 mg) extended the duration of the effect of BK on CBFV without modification of peak responses and induced a further increase in LV posterior EDWT but no change in LV regional myocardial function. Thus, in conscious dogs, the vasodilator effect of intracoronary BK alone or modulated by enalaprilat is not associated with changes in LV regional myocardial function.

Animals↗