Continuous Isoproterenol Infusion Research Articles

Protecting the myocardium: a role for the beta2 adrenergic receptor in the heart.

The sympathetic nervous system enhances cardiac muscle function by activating beta adrenergic receptors (betaARs). Recent studies suggest that chronic betaAR stimulation is detrimental, however, and that it may play a role in the clinical deterioration of patients with congestive heart failure. To examine the impact of chronic beta1AR and beta2AR subtype stimulation individually, we studied the cardiovascular effects of catecholamine infusions in betaAR subtype knockout mice (beta1KO, beta2KO). Prospective, randomized, experimental study. Animal research laboratory. beta1KO and beta2KO mice and wild-type controls. The animals were subjected to 2 wks of continuous infusion of the betaAR agonist isoproterenol. Analyses of cardiac function and structure were performed during and 3 days after completion of the infusions. Functional studies included graded exercise treadmill testing, in vivo assessments of left ventricular function using Mikro-Tip catheter transducers, right ventricular pressure measurements, and analyses of organ weight to body weight ratios. Structural studies included heart weight measurements, assessments of myocyte ultrastructure using electron microscopy, and in situ terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling staining to quantitate myocyte apoptosis. We found that isoproterenol-treated beta2KO mice experienced greater mortality rates (p =.001, chi-square test using Fisher's exact method) and increased myocyte apoptosis at 3- and 7-day time points (p =.04 and p =.0007, respectively, two-way analysis of variance). The results of this study suggest that in vivo beta2AR activation is antiapoptotic and contributes to myocardial protection.

Inducible cAMP early repressor (ICER) is a negative-feedback regulator of cardiac hypertrophy and an important mediator of cardiac myocyte apoptosis in response to beta-adrenergic receptor stimulation.

Although stimulation of the beta-adrenergic receptor increases levels of cAMP and activation of the cAMP response element (CRE) in cardiac myocytes, the role of the signaling mechanism regulated by cAMP in hypertrophy and apoptosis is not well understood. In this study we show that protein expression of inducible cAMP early repressor (ICER), an endogenous inhibitor of CRE-mediated transcription, is induced by stimulation of isoproterenol (ISO), a beta-adrenergic agonist with a peak at approximately 12 hours and persisting for more than 24 hours in neonatal rat cardiac myocytes. ICER is also upregulated by phenylephrine but not by endothelin-1. Continuous infusion of ISO also increased ICER in the rat heart in vivo. Overexpression of ICER significantly attenuated ISO- and phenylephrine-induced cardiac hypertrophy but did not inhibit endothelin-1-induced cardiac hypertrophy. Overexpression of ICER also stimulated cardiac myocyte apoptosis. Antisense inhibition of ICER significantly enhanced beta-adrenergic hypertrophy, whereas it significantly inhibited beta-adrenergic cardiac myocyte apoptosis, suggesting that endogenous ICER works as an important regulator of cardiac hypertrophy and apoptosis. Inhibition of CRE-mediated transcription by dominant-negative CRE binding protein inhibited cardiac hypertrophy, whereas it stimulated cardiac myocyte apoptosis, thereby mimicking the effect of ICER. Both ISO and ICER reduced expression of Bcl-2, an antiapoptotic molecule, whereas antisense ICER prevented ISO-induced downregulation of Bcl-2. These results suggest that ICER is upregulated by cardiac hypertrophic stimuli increasing CRE-mediated transcription in cardiac myocytes and acts as a negative regulator of hypertrophy and a positive mediator of apoptosis, in part through both inhibition of CRE-mediated transcription and downregulation of Bcl-2.

Propofol-Nitrous Oxide Anesthesia Enhances the Heart Rate Response to Intravenous Isoproterenol Infusion

Heart rate (HR) response to IV atropine is attenuated during propofol-nitrous oxide (N2O) anesthesia. We studied the effects of propofol-N2O anesthesia on isoproterenol-induced HR changes. The control group (n = 15) received no propofol and no N2O. Patients in the propofol-N2O group (n = 21) received IV propofol 2.5 mg/kg over 1 min followed by a continuous infusion of propofol 10 mg · kg−1 · h−1. After tracheal intubation, anesthesia was maintained with propofol 5 mg · kg−1 · h−1 and 67% N2O in oxygen. All patients in both groups received IV isoproterenol at incremental infusion rates (2.5, 5, 7.5, 10, 12.5, 15, and 17.5 ng · kg−1 · min−1 for 2 min at each dose) until HR increased more than 20 bpm from baseline values. At the end of each infusion period, hemodynamic data were collected. The HR response to isoproterenol 7.5 ng · kg−1 · min−1 was increased more in the propofol group than in the control group (20 ± 5 versus 14 ± 4 bpm;P < 0.05). During the isoproterenol infusion at 10 ng · kg−1 · min−1, HR increased by more than 20 bpm in all patients in the propofol group but in only 31% of patients in the control group (P < 0.0001). These results suggest that continuous isoproterenol infusion might be useful when a large dose of atropine is ineffective in restoring normal HR during propofol-N2O anesthesia.

Comparison between isoproterenol and nitroglycerin sensitized head-upright tilt in patients with unexplained syncope and negative or positive passive head-up tilt response

It is unknown if the head-upright tilt test in patients who receive isoproterenol and nitroglycerin can identify different populations with vasovagal syncope. The aim of this study was to compare the positive or negative responses to passive tilt between isoproterenol- and nitroglycerin-sensitized upright tilt. Ninety-six patients referred for unexplained recurrent syncope underwent passive tilt (45 minutes at 70° angle), which was then systematically followed, within the same session and in a random order, by a 20-minute tilt at a 70° angle after administration of nitroglycerin (NTG-tilt) and 10-minute tilt at a 70° angle with a continuous infusion of isoproterenol (ISO-tilt). NTG-tilt led to significantly more positive responses than passive tilt or ISO-tilt (55% vs 34% vs 42%, respectively). In the subgroup of patients with a positive response during passive tilt, the percentage of positive responses with NTG-tilt was significantly higher than with ISO-tilt (94% vs 67%). The agreement between NTG-tilt and ISO-tilt was very weak (Kappa coefficient 0.06). In the subgroup of patients with a negative response during passive tilt, the percentage of positive responses between NTG-tilt and ISO-tilt was similar (35% vs 29%). The agreement between NTG-tilt and ISO-tilt was good (Kappa coefficient 0.34). NTG-tilt led to a higher number of positive responses than ISO-tilt, especially when passive tilt outcome was positive. These 2 pharmacologic agents may identify 2 different subpopulations of patients because of their specific pharmacologic actions.

The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization.

With continuous exposure to beta2-adrenergic agonists, vascular tissue becomes desensitized to agonist-mediated vasodilatation. We studied the effects of two common polymorphisms of the beta2-adrenergic receptor, one at codon 16 and one at codon 27, on agonist-mediated vasodilatation and desensitization in the vascular bed. We studied 26 healthy subjects who were selected to represent three genotypes: 7 were homozygous for the alleles encoding Arg16 and Gln27, 8 were homozygous for the alleles encoding Gly16 and Gln27, and 11 were homozygous for the alleles encoding Gly16 and Glu27. Vascular responses were assessed by measuring changes in the diameter of a dorsal hand vein. A dose-response curve of the effect of the beta2-adrenergic-receptor agonist isoproterenol was constructed (dose range, 4 to 480 ng per minute). Desensitization was then induced by a 2-hour continuous infusion of isoproterenol, and venodilatation was measured 30, 60, 90, and 120 minutes after the start of the infusion. Subjects who were homozygous for Arg16 had almost complete desensitization; venodilatation in response to isoproterenol in this group decreased from a mean (+/-SE) of 44+/-11 percent to 8+/-4 percent (P=0.006). In contrast, subjects who were homozygous for Gly16 did not have significant desensitization, irrespective of the amino acid encoded by codon 27. Subjects who were homozygous for Glu27 had higher maximal venodilatation in response to isoproterenol than those who were homozygous for Gln27 (86+/-13 percent vs. 54+/-8 percent, P=0.03). The Arg16 polymorphism of the beta2-adrenergic receptor is associated with enhanced agonist-mediated desensitization in the vasculature, and the Glu27 polymorphism is associated with increased agonist-mediated responsiveness. Therefore, polymorphisms of the beta2-adrenergic receptor are potentially important determinants of the vascular response to stress.

Effect of inhaled nitric oxide on cardiovascular response to catecholamine in heart failure.

We examined the dose responses to continuous infusion of isoproterenol (ISO) and norepinephrine (NE) in normal (control) and procainamide-induced heart failure dogs with or without inhalation of 70 ppm nitric oxide (NO). Inhaled NO affected neither left ventricular (LV) function nor hemodynamics at baseline in both control and heart failure dogs. There were no significant differences in the responses to ISO and NE with or without inhaled NO in the control. The responses of LV dP/dt to ISO and NE were significantly enhanced in heart failure; however, they were not affected by inhaled NO. In contrast, LV pressure and dimension at end diastole were significantly increased, and pulmonary vascular resistance (PVR) was significantly decreased by inhaled NO during infusion of both ISO and NE in heart failure. In conclusion, the positive inotropic response to cathecholamine is not affected by inhaled NO even in heart failure. Inhaled NO decreases PVR, but potentially increases LV preload in the presence of additional stress of cathecholamine in heart failure.

Torsade de Pointes During Orthotopic Liver Transplantation

Torsade de Pointes During Orthotopic Liver Transplantation

Isoproterenol test and head-up tilt test for diagnosis of vasovagal syncope in elderly patients

The elderly can be affected by vasovagal syncope, but they often do not have preceding symptoms. The head-up tilt test (HTT) is successfully used in half of the patients in which the diagnosis is difficult. In young people the association with the isoproterenol test improves the sensitivity of the HTT. In the elderly the effect of such an association is still debated, therefore, the present study was aimed at evaluating the usefulness of the association between the two tests in old subjects to unmask the vasovagal nature of some syncopes of unknown origin. Twenty-four patients with negative HTT (18 males and 6 females; mean age 65 years) 10 with and 14 without organic heart disease were studied. The test protocol consisted of a continuous intravenous infusion of isoproterenol in successive stages starting from a dosage of 1 gamma/min for 5 min in supine position and then for 10 min in passive upright position at 80 (1st stage) up to maximum of 5 gamma/min (5th stage). The results obtained were: 12 patients (50%) had a positive test (reproduction of syncope) with a vasodepressor response in 6 of them and a mixed response in 6 patients. The mean time to syncope was during the 4th min of the 4th stage of treatment. The heart rate increase was 36% between the initial and peak values achieved during the test in patients with a positive test, and 10.5% in patients with negative test (p < 0.05). These results indicate that the isoproterenol test seems to increase the sensitivity of HTT in elderly patients with syncope of unknown origin.

Desensitization and Selective Down-Regulation of Rat Cardiac β1-Adrenoceptors by Prolonged In Vivo Infusion of T-0509, a β1-Adrenoceptor Full Agonist

We studied the effects of prolonged infusion of a selective β1-adrenoceptor (β1AR) full agonist, T-0509 [( —)-(R)-1-(3,4-dihydroxyphenyI)-2-[(3,4-dimethoxyphenethyl)amino]ethanol hydrochloride], with regard to its inotropic effect in vivo and cardiac βAR density. The results were compared with those for isoproterenol. Continuous infusion of isoproterenol at doses of 2.5-40 μg/kg/hr, s.c. for 6 days shifted the dose-response curves of isoproterenol (i.v.) for LVdP/dtmax to the right and increased the ED50 values up to fourfold. Isoproterenol infusion at 40μg/kg/hr reduced the density of both β1- and β2ARs by 36% and 43% respectively, in left ventricular membranes. Following 6-day infusion of T-0509 at doses sufficient to induce a positive inotropic effect (5-40 μg/kg/hr), the ED50 value of T-0509 (i.v.) for LVdP/dtmax was also increased up to fourfold. In contrast to isoproterenol, infusion of T-0509 caused selective down-regulation of β1/ARs by 30% without changing the number of β2ARs. These results indicate that long-term application of a selective β1AR full agonist causes desensitization to its inotropy in vivo, with subtype-selective down-regulation of β1ARs in cardiac ventricles.

Dexamethasone partially protects the myometrium against β-adrenergic a onist-induced desensitization in vivo in the rat

Our purpose was to determine the ability of dexamethasone to prevent the onset of myometrial desensitization to beta-adrenergic agonists in vivo. On day 5 post partum chronically catheterized rats were randomized to receive either dexamethasone or corn oil (vehicle), followed 12 hours later by a continuous infusion of either isoproterenol or saline solution (vehicle). Uterine contractions were monitored throughout. We measured myometrial glucocorticoid receptor levels in chronically catheterized and sham-operated rats and beta 2-adrenergic receptor densities in the experimental rats before and during the infusions. Surgery did not lead to any decrease in glucocorticoid receptor number. Dexamethasone significantly increased the duration of myometrial responsiveness to isoproterenol compared with vehicle-pretreated rats, although agonist-induced down-regulation of beta-adrenergic receptor number was not prevented. Dexamethasone partially protects the rat myometrium from desensitization induced by the continuous infusion of beta-adrenergic agonists through mechanisms independent of the beta 2-receptor.

Multiple supraventricular tachycardia mechanisms in a single patient treated with radiofrequency catheter ablation

The incidence of atrioventricular (AV) nodal reentrant tachycardia in patients with accessory AV connection is 5 % or 1ess.l The occurrence of either accessory AV pathways or AV nodal reentrant tachycardia with ectopic atria1 tachycardias is even more uncommon.” This article reports the previously undocumented occurrence of sustained ectopic atria1 tachycardia, AV nodal reentry, and AV reciprocating tachycardia in a single patient. The successful treatment of all three tachycardia mechanisms with radiofrequency catheter ablation techniques is described. A 20-year-old man from Turkey was referred for treatment of medically refractory paroxysmal tachycardia. Symptoms of paroxysmal palpitations with dyspnea had been present for 4 years. These episodes occurred almost every evening in the absence of medical therapy. His symptoms were inadequately controlled by digoxin, metoprolol, propafenone, and amiodarone (200 mg/day). Ambulatory ECG monitor tracings suggested a diagnosis of ectopic atria1 tachycardia. Amiodarone therapy was discontinued 10 days before admission to the hospital. His echocardiogram and ECG were normal. According to electrophysiologic testing there was no evidence of antegrade ventricular preexcitation with atria1 pacing. Retrograde AV conduction was eccentric and nondecremental, with the earliest site of atria1 activation in the distal coronary sinus (CS), which was consistent with a concealed left lateral accessory pathway. No tachycardias were induced until after a continuous isoproterenol infusion at 2 pg/min was started. Single atria1 and ventricular extrastimuli induced both sustained orthodromic AV reciprocating tachycardia, utilizing the concealed left lateral accessory pathway, and sustained AV nodal reentrant tachycardia. The AV reciprocating tachycardia had a cycle length of 320 msec with local ventriculoatrial conduction times as follows: distal CS = 90 msec, mid CS = 100 msec, proximal CS = 130 msec, His atrium = 160 msec, and right atria1 appendage = 188 msec (Figs. 1 and 2). With the use of the retrograde transaortic approach, the reciprocating tachycardia

Inhibitory effect of endothelin on renin release in dog kidneys

To investigate the effect of endothelin on renin release, experiments were performed in barbiturate-anaesthetized dogs with denervated kidneys. Intrarenal infusion of endothelin (1 ng min-1 kg-1 body wt) reduced renal blood flow (RBF) from 145 +/- 10 ml min-1 to 98 +/- 9 ml min-1 without altering renin release (1 +/- 1 microgram angiotensin I (AI) min-1). Renin release was then increased either by renal arterial constriction or ureteral occlusion. When renal arterial pressure was reduced to 50 mmHg, renin release averaged 79 +/- 20 micrograms AI min-1 in six dogs and fell significantly to 24 +/- 6 micrograms AI min-1 during endothelin infusion. During ureteral occlusion the inhibitory effect of endothelin on renin release either during inhibition of beta-adrenergic activity with propranolol or after inhibiting prostaglandin synthesis by indomethacin during intrarenal infusion of isoproterenol was examined. After propranolol administration ureteral occlusion increased renin release from 5 +/- 2 micrograms AI min-1 to 38 +/- 12 micrograms AI min-1 in six dogs. Subsequent intrarenal endothelin infusion (1 ng min-1 kg-1 body wt) during maintained ureteral occlusion reduced renin release to 10 +/- 3 micrograms AI min-1. In six other dogs prostaglandin synthesis was inhibited by indomethacin. Subsequent infusion of isoproterenol (0.2 microgram min-1 kg-1 body wt) to stimulate beta-adrenoceptor activity increased renin release from 13 +/- 4 micrograms AI min-1 to 68 +/- 8 micrograms AI min-1 during ureteral occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of zatebradine on contractility, relaxation and coronary blood flow

Objectives. The purpose of this study was to compare the effects of zatebradine on heart rate, contractility and relaxation with those of its structural analog verapamil. We used isoproterenol, a potent beta-agonist, to see how these effects were modulated by sympathetic activation. We also compared the effects of zatebradine and verapamil on coronary blood flow and coronary blood flow reserve.Background. Zatebradine, previously called UL-FS 49, is a new bradycardic agent believed to act selectively at the sinoatrial node.Methods. Isolated isovolumetric pig hearts were prepared and left ventricular pressure, its first derivative (dP/dt), tau and heart rate were measured both before and after administration of either 0.975 mg of zatebradine (Group I, n = 8) or 125 μg of verapamil (Group II, n = 8). After the effects of each drug reached a plateau, a continuous infusion of isoproterenol was started and measurements were obtained again and compared with a third group of measurements from control hearts infused with isoproterenol after receiving only saline solution (n = 8). We also assessed the effects of zatebradine and verapamil on coronary vascular tone by measuring flow in the left anterior descending coronary artery in intact anesthetized open chest pigs both before and after the Intracoronary administration of these drugs (n = 8 for each). All preparations were atrially paced to negate any bradycardic effects of the drugs.Results. In the group that received zatebradine, mean (±SE) heart rate decreased from 143 ± 8 to 99 ± 4 beats/min (p < 0.01) and there was no significant change in either peak left veatricular systolic pressure, dP/dt or tau. In contrast, verapamil produced a lesser decrease in heart rate (136 ± 7 to 120 ± 7 beats/min, p < 0.05) but produced substantial decreases in peak left ventricular pressure (100 ± 3 to 45 ± 4 mm Hg, p < 0.01) and dP/dt (68% decrease, p < 0.01) and an increase in tau (+26%, p < 0.05). Isoproterenol restored these variables toward normal values in the hearts treated with verapamil, although left vestricular systolic pressure and dP/dt were restored to control values only at the highest isoproterenol concentrations. In the hearts treated with zatebradine, isoproterenol sagnificantly increased left ventricular pressure and contractility and decreased tau; however, beast rate remained unchanged at peak effect. Zatebradine had no effect on coronary blood flow and there was a 100% increase in flow with reactive heyperemia, Conversely, verapamil increased coromry flow by 100%, with no subsequent further increase by reactive hyperemia compared with control values.Conclusions. Although structurally similar to verapamil, zatebradine is a nighty specific bradycardic agent. It has little direct effect on left ventricular developed pressare, contractility, relaxation and coronary vascular tone. Furthermore, the bradycardic effect of zatebradine unlike that of verapamil, is not overcome by doses of isoproterenol that increase developed pressure and contractility and improve relaxation. Because of its highly specific bradycardic effect, this drug may potentially be useful in treating patients with ischemic heart disease or congestive heart failure.

Prolonged beta-agonist infusion does not induce desensitization or down-regulation of beta-adrenergic receptors in newborn sheep.

In adult animals, prolonged beta-agonist exposure leads to down-regulation of beta-adrenergic receptors and desensitization. Prior evidence from our lab suggests that this may not occur in developing animals. To study this, we measured the response to graded epinephrine infusion [2.7, 5.5, 13.6, 27.3 mumol/(kg.min), (0.5, 1.0, 2.5, 5.0 micrograms/(kg.min)], myocardial beta-agonist receptor density, and components of the receptor-cyclase system in newborn lambs before (n = 6) and after (n = 5) 3 d of continuous isoproterenol administration (2 micrograms/kg/min). beta-Adrenergic receptors were measured by radioligand binding. Epinephrine dose-response curves were analyzed for the threshold and slope for changes in mean blood pressure, systolic blood pressure, and heart rate versus plasma epinephrine levels. Despite 3 d of continuous isoproterenol infusion, we observed no desensitization of the hemodynamic response to epinephrine. There was a reduction in receptor density when expressed per membrane protein [155.3 +/- 19.5 (controls) versus 73.2 +/- 3.8 fmol/mg protein (agonist exposed), p less than 0.05], but no alteration in receptor density when expressed per g cardiac wet weight [258.8 +/- 39.9 (controls) versus 406.8 +/- 74.0 fmol/g wet weight (agonist exposed)]. There was no alteration in agonist affinity or in adenylyl cyclase activity after adjustment for membrane protein recovery. Prolonged beta-agonist infusion in newborn lambs does not desensitize hemodynamic responses to infused epinephrine. We propose that receptor regulation in developing animals is fundamentally different than in adult animals.

Intoxication médicamenteuse par diltiazem : aspects hémodynamiques

A case is reported of a 50-year-old man who took a massive overdose of diltiazem (5 400 mg), together with 1 350 mg potassium clorazepate and 390 mg nordazepate, five months after having experienced a myocardial infarction (MI). On admission, systolic blood pressure was 80 mmHg, with an irregular heart rate of 60 b · min −1. There was superficial polypnoea (40 c · min −1) with hypoxia (PaO 2 : 63.5 mmHg). The ECG revealed, besides the MI scar, complete sinus arrest. Endotracheal intubation and mechanical ventilation were rapidly required. The patient then had gastric lavage, and was given activated charcoal. Treatment with 1.5 mg atropine and 2 g intravenous calcium chloride were unable to amend the cardiac dysrhythmia. A continuous isoproterenol infusion restored a sinus rhythm, but this was not maintained because of the risk of side-effects. Cardiovascular collapse was treated with dobutamine (10 μg · kg −1 · min −1). As the peripheral and pulmonary vascular resistances were greatly diminished (464 dyn · s · cm −5 and 86 dyn · s · cm −5 respectively), α and β mimetics were used : 1 μg · kg −1 · min −1 noradrenaline and 15 μg · kg −1 · min −1 dobutamine. After 7 h of this treatment, spontaneous sinus rhythm returned abruptly. Noradrenaline and dobutamine were replaced thereafter with adrenaline (0.25 μg · kg −1 · min −1), which was stopped 24 h later. There was a marked respiratory and haemodynamic improvement, the patient leaving the intensive care unit on the fourth day and returning home one week after the overdose. The relationships between cellular calcium movements and the adrenergic system are discussed, as well as the possible mechanism of cardiac failure.

Distinctive Response of Arrhythmogenic Right Ventricular Disease to High Dose Isoproterenol

Arrhythmogenic right ventricular disease is a potential cause of ventricular arrhythmias. Diagnosis is important due to the risk of sudden death, particularly as first symptom. Diagnosis is based on the angiographic demonstration of abnormal right ventricular morphology and function, while the sensitivity of noninvasive tests is relatively low. Following a particular observation studied in 1984, we prospectively assessed the diagnostic value of high dose isoproterenol infusion in 44 patients with an angiographically determined arrhythmogenic right ventricle. A continuous infusion of isoproterenol (8-30 micrograms/min) was administered during a 3-minute period, regardless of the obtained heart rate. In a control group of 50 patients without structural heart disease, isoproterenol induced a monomorphic ventricular tachycardia salvo in only one patient (2%). In patients with an arrhythmogenic right ventricle, isoproterenol induced one or more ventricular tachycardia runs in 39/44 cases (88%): one triplet in three patients, several runs in 23 patients and a sustained ventricular tachycardia in 13 patients. Arrhythmia was polymorphous in 85% of cases, but left bundle branch block morphology was the predominant pattern. In conclusion, high dose isoproterenol is a highly sensitive test for the diagnosis of arrhythmogenic right ventricular disease.

Alterations in dietary sodium affect isoproterenol-induced cardiac hypertrophy

To assess the role of dietary sodium in the regional development and pathogenesis of isoproterenol (ISO)-induced cardiac hypertrophy, male Fischer rats (150–175g n = 65) were divided into control (C) and ISO-treated (I) and three dietary sodium subgroups; low (8.7–13 mEq/kg) (LS), normal (173.9 mEq/kg) (NS) and high (1378 mEq/kg) (HS). Diets began 2 weeks prior to a 7 day continuous infusion of ISO (Alzet miniosmotic pump; 3 mg/kg/day). Mean total heart weight of all I rat groups was larger than in C rats (p < 0.05). However, low sodium diet ameliorated the percent increase, compared to respective controls, in total heart weight (LSI, 20 ± 3%; NSI, 26 ± 6; HSI, 24 ± 2 (p < 0.05)). Regionally, dietary sodium level did not alter the degree of hypertrophy in the left ventricle plus septum (LVS), but sodium restriction sharply reduced the severe right ventricular (RV) and atrial hypertrophy present in the NSI and HSI rats (LVS: LSI, 18 ± 2%; NSI, 20 ± 2; HSI, 15 ± 2; RV: LSI, 21 ± 7%; NSI, 45 ± 9, HSI, 40 ± 2; atria: LSI, 46 ± 17; NSI, 73 ± 23; HSI, 78 ± 9). Isoproterenol produced diffuse and focal myocardial fibrosis in the subepimyocardium of the LVS with occasional foci of fibrosis in the RV and the subepimyocardium of the LVS. Quantitative analysis demonstrated an increased volume percent of connective tissue limited to the LVS subendomyocardium in all three ISO-treated groups compared to controls (p < 0.05). These data shows that isoproterenol produces greater hypertrophy of the RV and the atria than the LVS and that dietary sodium restriction selectively decreases the degree of hypertrophy of the RV and the atria produced by ISO. The findings also indicate that the myocardial hypertrophy due to ISO is independent of myocardial injury and is thus, not merely a compensatory response to myocyte loss but rather a direct result of beta-adrenergic stimulation.

Variations in left ventricular volume alter myocardial oxygen consumption more at low than at high inotropy

Variations in left ventricular (LV) wall tension during changes in LV end-diastolic volume significantly affect myocardial oxygen consumption (MVO2). In the present study we examined if the reduction in MVO2 per beat accompanying a decline in LV end-diastolic volume at constant LV systolic pressure (LVSP) is dependent on the level of myocardial inotropy. In six anaesthetized open-chest pigs, the blood volume was expanded by i.v. infusion of a Ringer solution. At constant heart rate (by atrial pacing) and LVSP (by adjustments of a proximal aortic snare), LV end-diastolic volume was reduced in steps by withdrawals of blood. This procedure was performed at high inotropy (during a continuous intracoronary infusion of isoproterenol, 0.40 +/- 0.08 micrograms min-1), and at low inotropy (after i.v. injection of 3.4 +/- 0.2 mg propranolol). LVSP was about 25 mmHg higher at high than at low inotropy. The fall in LV tension was therefore greater during blood volume reductions at high than at low inotropy because the fall in LV end-diastolic volume was almost identical and was initiated from the same level at both high and low inotropy. Nevertheless, the slope of the MVO2/LV end-diastolic volume relationship was significantly (P less than 0.05) less steep at high (1.26 +/- 0.30 mumol 100 g-1 mm-1) than at low inotropy (2.06 +/- 0.48 mumol 100 g-1 mm-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Vasculature of various locations of canine gastrointestinal tract responds differently to intravenous isoproterenol.

In this study we investigated the relative vascular response of different locations of the gastrointestinal tract to continuous intravenous infusion of isoproterenol (0.1 microgram kg-1 min-1 for 10 min). The vascular response of some nonsplanchnic organs was also examined. Blood flow of the arteries was measured by electromagnetic flowmetry and that of the tissues by 15-micron microspheres. Isoproterenol increased (P less than 0.05) blood flow of the axillary artery (+52%), and the superior mesenteric artery (+45%), but not that of the inferior mesenteric artery. In the nongastrointestinal tissues, isoproterenol increased (P less than 0.05) the blood flow of the left (+46%), and right ventricle (+85%), and the skeletal muscle (+100%). In the gastrointestinal tract, isoproterenol increased (P less than 0.05) blood flow in the esophagogastric junction (+505%) and antrum (+1511%) only, but not in the gastric body or in any location of the small or large intestine. The drug also caused a large fall in resistance in the esophagogastric junction (-74%) and antrum (-94%), and a small, but significant fall in the duodenum, jejunum, and in the mid-small intestine. It had no significant effect on vascular resistance in the gastric body, ileum, or colon. In those locations of the gastrointestinal tract where isoproterenol caused an increase in blood flow, this effect was confined to the combined mucosal plus submucosal layer, and the drug had no effect on the muscularis. These data suggest that different locations of the gastrointestinal tract respond differently to the same circulating concentration of isoproterenol. The mechanism of this difference in response merits further investigation.(ABSTRACT TRUNCATED AT 250 WORDS)

A no-flush, core-cooling technique for successful cardiopulmonary preservation in heart-lung transplantation

In order to determine whether a no-flush, core-cooling technique could provide extended heart-lung preservation, we placed donor calves on cardiopulmonary bypass and instituted rapid cooling to 15 degrees C during the continuous infusion of isoproterenol. The heart and lungs were harvested after the administration of a cardioplegic solution through the aortic root. In the control group (N = 5), heart and lungs were orthotopically allotransplanted immediately. In the preserved group (N = 5), heart and lungs were similarly excised but were stored in a normal saline bath at 4 degrees C for approximately 4 hours and then transplanted. Both groups received isoproterenol during reperfusion and were studied for 6 hours after implantation. A load independent analysis of myocardial function was done by determining with a sonomicrometer the ratio of the end-systolic pressure to the end-systolic dimension. Pulmonary preservation was evaluated by measurement of extravascular lung water with a double-indicator dilution method, arterial oxygenation on 100% inspired oxygen, and serial lung biopsies. Myocardial and pulmonary function after 4 hours of static preservation was found to be similar to controls. No-flush, core-cooling with cardiopulmonary bypass provides adequate cardiorespiratory function after acute bovine heart-lung allotransplantation. With the use of this technique, successful extended cold ischemic cardiopulmonary preservation for heart-lung transplantation may be achieved.