Blockade In Dogs Research Articles

HEMODYNAMIC EFFECTS OF COMBINED NIFEDIPINE AND SEVOFLURANE IN DOGS WITH AND WITHOUT BLOCKADE OF THE AUTONOMIC NERVOUS SYSTEM

S96 INTRODUCTION: Nifedipine, a dihydropyridine Ca2+ channel antagonist, is a potent vasodilator [1] and is used to treat hypertension, coronary and other vasospasm. It may depress cardiovascular function in particular when combined with inhalation anesthetics. These effects may be masked by improved ventricular filling and increase of sympathetic nervous system tone [2]. Thus, this study investigates the effects of nifedipine on cardiovascular function in sevoflurane anesthetized chronically instrumented dogs with and without blockade of the autonomic nervous system (ANS). METHODS: The protocol was approved by the District Government of Munster. Six dogs were chronically instrumented for measurement of heart rate (HR), left atrial (LAP), aortic (ABP) and left ventricular pressure (LVP), LVdP/dt, blood flow velocity (BFV) in the left anterior descending coronary artery (LAD) and myocardial wall thickening fraction. Two experiments were performed in a cross over fashion on separate days: After baseline-registration (BL), sevoflurane anesthesia was induced by mask (Fi=2.5% sevoflurane). In case of ANS blockade 3 mg/kg atropinemethylnitrate, 2 mg/kg propanolol and 20 mg/kg hexamethonium were adminstered i.v. After steady-state conditions, a continuous infusion of nifedipine at a rate of 1 [micro sign]g/kg/min (dose 1) after a loading dose of 50 [micro sign]g/kg followed by a rate of 2 [micro sign]g/kg/min after a loading dose of 75 [micro sign]g/kg (dose 2) was started. Comparisons were made by ANOVA for repeated measures followed by paired t-test with Bonferroni correction. RESULTS: Induction of sevoflurane-anesthesia led to a decrease of MAP. LVdP/dt and WTF and an increase in HR. Bolus injection of nifedipine resulted in a further reduction of MAP, LVdp/dt and WTF only at dose 2. These changes were not present after 30 minutes of infusion. ANS blockade decreased HR, LVdP/dt and MAP. Infusion of nifedipine with ANS blockade led to a decrease of MAP, LVdP/dt and WTF (Table 1).Table 1DISCUSSION: This study demonstrates that nifedipine increases the negative inotropic effects of sevoflurane during ANS blockade in dogs. Slow Ca2+ channel blockers like nifedipine inhibit flux through voltage-dependent Ca2+-channels and decrease intracellular [Ca2+]. The direct effects of Ca2+ channel blockade are attenuated or even reversed in the presence of an intact ANS. This reversal is also present during sevoflurane anesthesia in chronically instrumented dogs with intact autonomic nervous system.

Edrophonium for the antagonism of neuromuscular blockade in dogs

Neuromuscular, electrocardiographic and autonomic nervous changes were studied when edrophonium and four combinations of edrophonium and atropine were used to antagonise vecuronium-induced neuromuscular blockade in 87 dogs anaesthetised with halothane. Edrophonium (500 micrograms/kg body-weight) was given alone, or with atropine (40 micrograms/kg) or one minute after a dose of 600 micrograms of atropine, and a lower dose of edrophonium (250 micrograms/kg) was used with high (40 micrograms/kg) and low (20 micrograms/kg) doses of atropine. The neuromuscular blockade was antagonised when some recovery was present. The reversal was rapid and complete in 75 cases, but the remaining 12 dogs which received the low dose of edrophonium required a second injection. Trials with the high dose of edrophonium alone were discontinued because cardiac arrest occurred in one dog and bronchosecretion with profuse salivation in another. The heart rate increased with the low dose of edrophonium and the high dose of atropine, and increased and then decreased when edrophonium was followed by 600 micrograms of atropine. The heart rate was stable when the high and low doses of atropine and edrophonium were matched. All the treatments caused atrioventricular blockade. Non-cardiac autonomic changes (salivation and bronchosecretion) occurred in only two of the 87 dogs.

Enhanced atrial peptide natriuresis during angiotensin and aldosterone blockade in dogs

The hypothesis that the weak natriuretic effect elicited by modest amounts of atrial peptide is mediated via the inhibition of renin and aldosterone was evaluated in the conscious dog. The formation of angiotensin II (ANG II) and the effects of aldosterone (Aldo) were blocked acutely by enalaprilat and canrenoate, respectively. Infusion of alpha-human atrial natriuretic peptide (alpha-hANP) for 2 h at 25 ng.kg-1.min-1 increased plasma atrial peptide concentration 7- to 10-fold. In control experiments, i.e., experiments without ANG II-Aldo blockade, infusion of atrial peptide doubled urine volume (UV) from 0.21 +/- 0.01 to 0.43 +/- 0.09 ml/min and sodium excretion (UNaV) from 18 +/- 5 to 37 +/- 7 mueq/min; mean arterial blood pressure (AP) and atrial pressures decreased, whereas total peripheral resistance increased. The induction of ANG II-Aldo blockade elevated UNaV and UV 10- and 6-fold, respectively, and decreased AP. The subsequent 2-h infusion of atrial peptide elicited a further increase in UNaV (from 195 +/- 28 to 334 +/- 60 mueq/min); the hemodynamic changes were similar to those seen in the absence of ANG II-Aldo blockade, except that AP did not decrease significantly during the administration of atrial peptide. The data demonstrate that pharmacological inhibition of the effects of converting enzyme and Aldo does not impede the natriuretic response elicited by a 7- to 10-fold increase in circulating atrial peptide; in fact, the magnitude of the natriuresis is markedly enhanced during this blockade.

Effects of selective alpha 1-adrenoceptor blockade in dogs with hypoxic pulmonary vasoconstriction.

The acute effects of the selective alpha 1-blocker, E-643 (Bunazosine), on experimental pulmonary hypertension (PH) caused by hypoxic pulmonary vasoconstriction (HPV) in mongrel dogs were examined. Ninety second ventilation with 5% O2 and 95% N2 was used for hypoxic stimulation. The effects of E-643 were evaluated at doses of 1, 5, 10, 20 and 50 micrograms/kg in this order until the systemic arterial mean pressure (SAm) had decreased by 20 mmHg when compared with the control value during room air ventilation. PaO2 and PaCO2 decreased by 64.6 +/- 11.0 Torr and 2.4 +/- 2.5 Torr, respectively, and the pH increased by 0.031 +/- 0.012 during hypoxic ventilation. These blood gas changes affected during hypoxic stimulation were almost the same before E-643 administration. Progression of arterial blood hypoxemia due to E-643 administration during room air ventilation was not observed. SAm decreased by 8.0 +/- 11.9 mmHg after E-643 administration, while left atrial mean pressure (LAm) and cardiac output (CO) did not change significantly. Prior to E-643 administration, mean pulmonary arterial pressure (PAm) and pulmonary vascular resistance (PVR) increased by 6.4 +/- 3.3 mmHg and 6.2 +/- 3.8 HRU, respectively, during the 90 sec hypoxic ventilation period. After E-643 administration, the increases in PAm and PVR were 3.9 +/- 1.7 mmHg and 3.3 +/- 2.3 HRU, respectively. The suppression of increases in PAm and PVR was significant. The conclusion is that E-643, a selective alpha 1-blocker, is effective at restraining HPV in the dog model.

Morphological and functional stimulation of adrenal reticularis zone by dopaminergic blockade in dogs.

In order to investigate factors affecting adrenal maturation leading to adrenarche, the effect of dopaminergic blockade on the morphology and function of the adrenal reticularis zone was studied in fourteen preadrenarchal dogs. Seven animals of 7 weeks of age (adrenarche at 11 weeks) were treated with domperidone (DOM) 3 times/day p.o. (3 mg/kg) at 09.00 h, 14.00 h, and 21.00 h, plus an additional injection of DOM s.c. (0.6 mg/kg) at 21.00 h for 15 days. Seven control animals received diluent. Twelve hours after the last injection, dogs received 0.25 mg ACTH i.m. and were sacrificed 60 min later. Blood was collected and adrenals removed. After histological evaluation, the percent of the reticularis, fasciculata, and glomerulosa zones with respect to the total cortex was calculated. Plasma androstenedione (A), dehydroepiandrosterone (DHA), 17-OH-progesterone (17P), and cortisol (F) levels in response to ACTH were also assessed. DOM-treated dogs show a significant development of the zona reticularis compared to control animals (19.2 +/- 0.6% vs 8.8 +/- 2.09% respectively, X +/- SE, P less than 0.01). In the same animals, the DHA response to ACTH (9.0 +/- 1.6 ng/dl) was significantly higher than in placebo-treated dogs (3.8 +/- 1.1 ng/dl, P less than 0.05) while no significant differences were found in F, A, and 17P levels between the two groups. Finally the post-ACTH A/DHA ratio of DOM-treated dogs (1.33 +/- 0.28) was significantly decreased in respect to the placebo-treated animals (5.49 +/- 2.54, P less than 0.01). These data demonstrate that the morphological and functional development of zona reticularis may be subject to dopaminergic control and this could represent an important step in the initiation of adrenarche. However, the cellular mechanism responsible remains to be clarified.

Metabolic effects of low and high doses of insulin during beta-receptor blockade in dogs.

Metabolic effects of low and high doses of insulin during beta-receptor blockade were studied in eight dogs. Beta-receptor blockade was induced by 0.5 mg/kg propranolol which caused depression of heart performance. This was accompanied by a significant reduction in myocardial blood-flow and oxygen consumption. There was also a significant reduction in arterial concentrations and myocardial uptake of free fatty acids, while arterial concentrations and myocardial uptake of glucose and lactate were not significantly changed. Fifteen minutes after beta receptor blockade, an intravenous (i.v.) bolus injection of 0.5 IU/kg, of insulin, free of glucagon and calcium, was given followed by a continuous infusion of 0.5 IU/kg/h. Glucose and potassium were given to maintain constant levels of these factors. After 30 min another bolus dose of 300 IU insulin was injected. Thirty minutes after a low dose of insulin, a significant increase in heart performance was recorded at unaltered myocardial oxygen consumption. Arterial concentrations of free fatty acids were significantly reduced while levels of glucose and lactate were unchanged. Myocardial uptake of glucose increased significantly while uptake of lactate and free fatty acids was unchanged. After a high dose of insulin there was a considerable improvement in heart performance. Myocardial blood-flow and oxygen consumption were not changed, nor were there alterations in arterial concentrations and myocardial uptake of glucose, lactate and free fatty acids. It is concluded that, during beta-receptor blockade high doses of insulin improve the mechanical performance of the heart through mechanisms that are independent of insulin's effects on substrate metabolism.

Haemodynamic effects of low and high doses of insulin during beta receptor blockade in dogs.

Haemodynamic effects of small and high doses of insulin during beta receptor blockade were studied in nine dogs. Beta receptor blockade was induced by 0.5 mg/kg propranolol and caused depression of cardiac performance with a significant increase in left ventricular end-diastolic pressure (LVEDP) and a significant decrease in heart rate; maximum rate of left ventricular (LV) pressure rise (LVdP/dtmax), stroke volume and cardiac output. At 15 min, after beta receptor blockade, a bolus injection of 0.5 IU/kg of insulin, free of glucagon and calcium, was given followed by a continuous infusion of 0.5 IU/kg/h. After 30 min another bolus dose of 300 IU insulin was injected. Glucose and potassium were given to maintain physiological levels of these factors. Five minutes after a low dose of insulin there was a significant decrease in LVEDP (P less than 0.01), and a significant increase in LVdP/dtmax (P less than 0.01), in stroke volume (P less than 0.01) and in cardiac output (P less than 0.01). The other haemodynamic variables were not significantly changed. Administration of a high dose of insulin further, significantly, improved performance of the beta receptor blocked heart and caused a significant reduction in total peripheral resistance. In conclusion, insulin exerts inotropic and vasodilator effects which are dose-dependent and not related to adrenergic mechanisms.

Role of vasopressin in blood pressure regulation during adrenal insufficiency.

The effect of adrenal insufficiency on the plasma concentrations of two vasoactive hormones, vasopressin and angiotensin II, was studied in conscious dogs. In addition the role of vasopressin in the maintenance of blood pressure during adrenal insufficiency was studied using [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid),2-(O-methyl)tyrosine]arginine vasopressin, a specific antagonist of the vasoconstrictor action of vasopressin. Dogs were bilaterally adrenalectomized and maintained on daily cortisol and deoxycorticosterone acetate injections. Withdrawal of steroids for 4 days resulted in a 4-fold increase in plasma vasopressin concentration (P less than 0.05) and a 3-fold increase in plasma angiotensin II concentration (P less than 0.001); mean arterial pressure did not change significantly. Administration of the vasopressin antagonist in adrenalectomized dogs maintained on steroids had no effect on blood pressure. In marked contrast, vasopressin blockade in dogs with adrenal insufficiency decreased mean arterial pressure by 22 +/- 5 mm Hg (P less than 0.001). These results demonstrate the plasma angiotensin II and vasopressin concentrations increase during adrenal insufficiency in conscious dogs, and that vasopressin plays an important role in blood pressure regulation in this hypovolemic state.

Gastric acid response to topical or intravenous histamine and topical H2-receptor blockade in dogs.

This study was undertaken to determine gastric acid surface and to examine the local effect f ranitidine, a histamine H2-receptor antagonist, on the gastric acid response to histamine. Histamine applied to the Heidenhain pouch (HP) mucosa resulted in a slight and dose-dependent stimulation of acid secretion without affecting acid secretion from the main stomach. Ranitidine given into the HP caused dose-dependent inhibition of the HP response to topical or intravenous histamine without affecting the acid response of the main stomach and without any significant change in the serum ranitidine level. Ranitidine applied to the main stomach with the pylorus occluded inhibited histamine-induced acid secretion also without any increase in the serum ranitidine level. This inhibition was about 30% of that obtained with the same dose of ranitidine given into the stomach with the pylorus left open during the experiment. This study provides evidence that topical histamine is a weak stimulant of gastric secretion and that topical ranitidine is capable of local inhibition of the acid response to both topical and intravenous histamine.

Pharmacologic antagonism of beta adrenergic blockade in dogs. II. Hemodynamic effects of simultaneous intravenous infusion of isoproterenol and dopamine during chronic propranolol administration: Spotnitz HM, et al, J Thorac Cardiovasc Surg79:103–108, (Jan) 1980

Pharmacologic antagonism of beta adrenergic blockade in dogs. II. Hemodynamic effects of simultaneous intravenous infusion of isoproterenol and dopamine during chronic propranolol administration: Spotnitz HM, et al, J Thorac Cardiovasc Surg79:103–108, (Jan) 1980

Alteration in myocardial oxygen balance during exercise after beta-adrenergic blockade in dogs.

The effects of beta-adrenergic blockade upon myocardial blood flow and oxygen balance during exercise were evaluated in eight conscious dogs, instrumented for chronic measurements of coronary blood flow, left ventricular pressure, aortic blood pressure, heart rate, and sampling of arterial and coronary sinus venous blood. The administration of propranolol (1.5 mg/kg iv) produced a decrease in heart rate, peak left ventricular (LV) dP/dt, LV (dP/dt/P, and an increase in LV end-diastolic pressure during exercise. Mean coronary blood flow and myocardial oxygen consumption were lower after propranolol than at the same exercise intensity in control conditions. The oxygen delivery-to-oxygen consumption ratio and the coronary sinus oxygen content were also significantly lower. It is concluded that the relationship between myocardial oxygen supply and demand is modified during exercise after propranolol, so that a given level of myocardial oxygen consumption is achieved with a proportionally lower myocardial blood flow and a higher oxygen extraction.

Pharmacologic antagonism of beta adrenergic blockade in dogs: II. Hemodynamic effects of simultaneous intravenous infusion of isoproterenol and dopamine during chronic propranolol administration

Chronic beta adrenergic blockade was induced in eight dogs with 240 to 360 mg of oral propranolol dailty for 2 to 6 weeks. Beta blockade was confirmed by a minimal heart rate response to isoproterenol, 0.06 micrograms/kg/min, in a pentobarbital-anesthetized, open-chest preparation. Subsequent to confirmation of beta blockade, hemodynamic effects of isoproterenol and dopamine were examined individually and in combination. A desirable balance of arterial pressure and cardiac output was achieved by combining isoproterenol, 0.2 to 2.0 micrograms/kg/min, with dopamine, 5 to 20 micrograms/kg/min. This combination increased mean arterial pressure (109 +/- 9 versus 81 +/- 7), cardiac output (4.3 +/- .5 versus 2.8 +/- .3 L/min) and heart rate 156 +/- 4 versus 120 +/- 7) (p less than 0.05). The hemodynamic effects of combined isoproterenol-dopamine were superior to the effects of either drug alone and suggest a method for effective circulatory support of man during chronic beta adrenergic blockade.

Pharmacologic antagonism of beta-adrenergic blockade in dogs

Hemodynamic effects of isoproterenol, dopamine, and epinephrine were studied before and after acute beta-adrenergic blockade in 16 open-chest, anesthetized mongrel dogs. Beta blockade was induced with 1 mg. per kilogram of intravenous propranolol. Cardiac output measurements were obtained by thermal dilution, and pressure recordings were obtained in the right ventricle, pulmonary artery, left atrium, left ventricle, and aorta. Derived parameters included stroke volume, pulmonary and systemic vascular resistances, and peak left ventricular dP/dt. In the presence of propranolol, epinephrine became a lethal drug in large doses and did not increase cardiac output in standard doses. Dopamine, in 25 to 50 mcg. per kilogram per minute doses, increased arterial pressure and systemic resistance; cardiac output was diminished compared with dopamine, 10 mcg. per kilogram per minute, prior to propranolol, as a result of increased resistance and decreased LV contractility. Isoproterenol, 0.6 to 0.9 mcg. per kilogram per minute, 15 to 20 times standard dosages, had moderately positive inotropic effects and increased cardiac output. Left ventricular systolic pressure with isoproterenol after propranolol was reduced when compared with effects of smaller doses prior to propranolol. These observations suggest that none of the catecholamines studied would be optimal for circulatory support in heart failure in the presence of propranolol. The present results define a pharmacologic basis for design of appropriate drug combinations for circulatory support in beta-blocked animals.

Coronary vasomotor responses to cardiac sympathetic nerve stimulation after adrenergic beta-receptor in dogs.

Experiments were performed in anesthetized open-chest dogs pretreated with beta adrenoceptor blocking agent. Electrical stimulation of the left cardiac sympathetic nerve resulted in an initial decrease in coronary blood flow followed by a considerable increase after cessation of the stimulation. Atropine and hemicholinium inhibited the poststimulatory rebound phenomenon and corresponding fall in coronary vascular resistance without affecting cardiac activities. Physostigmine potentiated the poststimulatory increase in coronary blood flow and associated bradycardia. Changes after atropine and physostigmine of the initial decrease were slight and statistically not significant. Both phentolamine and 6-hydroxydopamine abolished not only the initial decrease but also the poststimulatory increase in coronary blood flow. Dipyridamole significantly enhanced the poststimulatory increase, while aminophylline suppressed it. It was concluded that the poststimulatory increase in coronary blood flow may consist of reactive hyperemia resulting from the initial decrease and in addition of cholinergic overshoot caused by a withdrawal of the inhibition of acetylcholine release through alpha adrenoceptor activity.

Mechanism of impaired capacity for prolonged muscular work following beta-adrenergic blockade in dogs

Effect of glucose infusion on running ability was studied in dogs after beta-adrenergic blockade. Dogs pretreated with Inderal performed treadmill exercise of moderate intensity until exhaustion. The amount of work performed until exhaustion was 47.7% smaller than in control experiments without blockade. During exercise a significant decrease was found in plasma FFA, blood glucose and muscle glycogen concentration. In order to explain whether the impairment of working capacity is related to hypoglycaemia and a subsequent reduction of glucose supply to the central nervous system, intracarotid glucose infusion at a rate of 70 mg/min was given at the point of exhaustion. This infusion did not restore the working ability. The intravenous glucose infusion at a rate 45 mg/kg per min enabled the previously exhausted dogs to continue the run within 5–7 min. Subsequently they were able to run with glucose infusion at a rate 20 mg/kg per min for a long period of time until they became again exhausted. It was concluded that the impairment of working capacity is directly related to a deficiency of energy substrates available for working muscles. Although the drop in blood glucose level could be a factor forcing the dogs to stop running, the increase of glucose supply to the brain only did not restore the running ability.

Hemodynamic responses to beta-adrenergic blockade in dogs

Rapid intravenous injection of propranolol resulted in a decrease in heart rate and cardiac output and an increase in left atrial pressure in each of 5 dogs. Fluoroscopically, heart size increased and myocardial contractility decreased. Although the administration of propranolol decreases myocardial oxygen requirements, it also results in a mechanical disadvantage by increasing heart size. It is suggested that beta-adrenergic blockade may be hazardous in patients with low cardiac reserve.

Effects of Diethyl Ether on Ventilation with or without Vagal, Somatic and Sympathetic Blockade in Dogs

Effects of Diethyl Ether on Ventilation with or without Vagal, Somatic and Sympathetic Blockade in Dogs