Cardiovascular effects of a μ-selective opioid agonist (tyrosine-D-arginine-phenylalanine-lysine-NH2) in fetal sheep: Sites and mechanisms of action☆☆☆★ (original) (raw)
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Central opioid modulation of fetal cardiovascular function: role of mu- and delta-receptors
The American journal of physiology, 1990
To investigate the role of mu- and delta-receptors in opioid modulation of fetal cardiovascular function, we compared the effects on fetal heart rate (FHR) and fetal blood pressure (FBP) of [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAGO, a mu-selective agonist), [D-Pen2,D-Pen5]-enkephalin (DPDPE, delta-selective agonist), and [D-Ala2,D-Leu5]-enkephalin (DADLE, a mixed mu- and delta-agonist) in 24 fetal lambs. All peptides were infused intracerebroventricularly at a constant rate for 1 h. Three to seven animals were studied at each of six dose levels ranging from 1.58 to 476 nmol/h. Saline infusion did not elicit any changes in FBP or FHR. DAGO caused a dose-dependent increase in FHR, with the peak response being 61.6 +/- 9.9% at the highest dose. The effects of DAGO on FBP were small (maximum being 11.1 +/- 3.4%) and did not reach statistical significance. In contrast, DPDPE did not induce any changes in either FHR or FBP over the same dose range, suggesting that delta-receptors do not...
Neonatal Adaptation: Cardiac Adrenergic Effector Mechanisms after Birth in Newborn Sheep
Pediatric Research, 1991
ABSTRACX. At birth, there is a marked increase in cir-occur both in viva and in vitro in response to both endogenous culating plasma catecholamine concentrations. This in-and exogenous receptor ligands (4-2 1). crease is critical to many of the physiologic adjustments to At birth, there is a marked increase in sympathoadrenal activpostnatal life. Because the levels observed are higher than ity reflected by changes in circulating catecholamine concentrathose seen in most other physiologic conditions in adults, tions. Plasma norepinephrine rises 5-to 10-fold and plasma previous investigators have suggested that the newborn is epinephrine 10-to 20-fold over the first several hours of life (22less sensitive to adrenergic stimulation or that desensiti-26). We have previously demonstrated that the majority of zation to adrenergic stimulation occurs rapidly. To inves-circulating norepinephrine arises from increased postganglionic tigate this question, we designed experiments to measure sympathetic nerve activity (24), whereas the increase in plasma myocardial Sadrenergic receptor density and sensitivity epinephrine is derived almost solely from adrenal medullary before and after exposure to the catecholamine surge at secretion (25). These changes are critical to successful postnatal birth in term newborn sheep. We also measured the status physiologic adaptation and survival (25). It is unclear, however, of sympathetic innervation, reflected by myocardial nor-to what extent these changes in circulating catecholamines affect epinephrine content. At birth, plasma catecholamines in-adrenergic receptor mechanisms after birth. Because circulating creased 4-to 6-fold with associated increases in heart rate, catecholamine levels in the early newborn period are higher than blood pressure, and cardiac output. Myocardial B-adrener-those observed in most other physiologic conditions in adults gic receptor at birth (135 fmol/mg protein) did not change (22), previous investigators have suggested that the newborn is significantly by 6 h of life (157 fmol/mg protein). Myocar-less sensitive to adrenergic stimulation or that desensitization to dial adenyl cyclase activity, reflecting receptor sensitivity, adrenergic stimulation occurs rapidly (26). To examine this and myocardial sympathetic innervation also did not question, we designed experiments in newborn fetal sheep to change. These results suggest that, despite exposure to measure cardiac BAR and catecholamine-stimulated adenyl cysustained adrenergic stimulation, myocardial adrenergic clase activity in newborn sheep after exposure to the surge in effector mechanisms do not change in the newborn sheep catecholamines at birth. at birth. (Pediatr Res 29: 98-103, 1991) MATERIALS AND METHODS Abbreviations Sixteen Western mixed breed fetuses from time-dated single-BAR, @-adrenergic receptor ton, twin, or triplet pregnancies were operated on at 139 d (term GTP, guanosine triphosphate is 150 d). The details of delivery and postnatal stabilization were ECS0, half maximal concentration identical to previous reports (25). After overnight fast, the ewes Bmax, maximum binding capacity were premedicated with ketamine (750 mg) and atropine (1.2 'H-DHA, tritiated dehydroalprenolol mg). Maternal jugular venous catheterization was performed and Pa02, partial pressure of arterial oxygen anesthesia was maintained by continuous infusion of ketamine at 5 mg/min during surgery. Fetuses were randomly assigned to death immediately at birth or after 6 h of ventilation. The fetal head and neck were delivered through the uterine incision and fetal breathing was prevented by immediately placing a warm Classical receptor theory holds that ~rolonged receptor occutowel over the head and around the mouth. After local anesthetic P a w leads to decreased responsiveness. This phenomenon, infiltration, a tracheotomy was performed through a midline variously referred to as t a c h~~h~l a x i s or down-regulation, has longitudinal neck incision and an appropriately sized endotrabeen demonstrated to occur in response to endogenous hercheal tube was secured in place. A 5.0 F catheter was inserted manes, neurotransmitters, growth factors, or exogenous agents via the right common carotid artery into the left ventricle under with specific affinity for a single class of receptors (1-3). Altersdirect oscilloscopic pressure monitoring. Time zero animals were tions in receptor number alone are referred to as homologous delivered and killed immediately with a lethal dose of sodium regulation and changes in sensitivity due to alteration in receptor pentathol. ~1 1 6-h animals were delivered onto the maternal coupling to second messenger Systems are referred to as heterolabdomen, covered with a heating pad and warm towels, and ogous regulation (2, 3). This Process has been demonstrated to allowed to stabilize for 10 to 15 min. Arterial blood for blood
Modulation of systemic and renal haemodynamics by -opioids in conscious lambs
Experimental Physiology, 2006
The purpose of the present study was to determine the cardiovascular effects of the κopioid receptor agonist U-50488H at two stages of postnatal maturation under physiological conditions. Experiments were carried out firstly to define systemic and renal haemodynamic responses to κ-opioid receptor activation and, secondly, to determine whether these effects are altered during postnatal maturation. To investigate whether the responses to U-50488H resulted from receptor-dependent effects, responses to U-50488H were also tested in the presence of the specific κ-opioid receptor antagonist 5 -guanidinonaltrindole (GNTI). Experiments were carried out in two groups of conscious, chronically instrumented lambs aged ∼1 and ∼6 weeks. Mean arterial pressure, mean venous pressure and renal blood flow (RBF) were measured for 30 min before and 90 min after i.v. injection of U-50488H or vehicle. Heart rate increased in both age groups of lambs within 10 min of U-50488H administration. Mean arterial pressure decreased for 50 min following U-50488H administration at 1 week but, in contrast, increased transiently at 10 min in 6-week-old lambs, returning to control levels by 20 min. In both age groups, there was a sustained decrease in RBF following U-50488H. The aforementioned responses to U-50488H were abolished by pretreatment with GNTI. These data provide the first measurements of systemic and renal haemodynamic responses to κ-opioid receptor activation during postnatal maturation.
European Journal of Pharmacology, 1991
Pregnant sheep and their fetuses were instrumented between 110 to 120 days of gestation (term, 145 days) for monitoring maternal and fetal arterial blood pressure, heart rate and blood flow in the maternal uterine and fetal intra-abdominal umbilicaf arteries. The administration of 2,5-dimethoxy-4-methylamphetamine (DOM, a 5-HT, agonist) i.v. to the ewe in doses ranging from 1 to 20 &g/kg of ewe body weight produced don-dependent decreases in the blood flow of the uterine and umbili~ai arteries. This was accompanied by an increase in the arterial blood pressure of the mother and fetus and a decrease in the fetal heart rate. DOM significantly increased the vascular resistance to blood flow in the uterine and umbilical arteries. The maximal increase lin the vascular resistance of the uterine and umbilical arteries was 19.6 and 2.6fold, respectively. Ketanserin, a 5-HT, antagonist (1 mg/kg), administrated 30 min prior to DOM significantly inhibited the reduction in blood flow in the uterine and umbilical arteries to DOM and blocked the increased vascular resistance in these vessels. The inhibitory effects of ketanserin on the responses to DON in the uterine and umbilical arteries were surmountable. Our results indicate that DOM is a potent constrictor of the uterine and umbilical vasculature which may lead to fetal distress as evidenced by a decrease in fetal heart rate and arterial blood POz. S-HT2 receptor stimulation by DOM may be involved in these effects since they were biocked by ketanserin.
Effect of Drugs on Chemoreceptor Responsiveness in Fetal Sheep
Pediatric Research, 1995
This study was designed to examine the effects of the drugs ketamine, morphine, pentobarbital, and propranolol on fetal chemoreceptor responsiveness. Eleven fetal lambs (gestational age 125-133 d) were chronically instrumented with a catheter in a hindlimb artery and vein and a forelimb artery; a carotid arterial oximeter catheter was placed in six of these fetuses. An inflatable cuff occluder was placed around the maternal hypogastric artery. Acute fetal hypoxemia was induced repeatedly by reducing uterine blood flow. Fetal heart rate, arterial pressure, and carotid arterial oxygen saturation were monitored continuously before and after administering ketamine, morphine, pentobarbital, or propranolol to the fetus. The ratio Aheart rate/AO, saturation has been shown previously to be a reproducible index of chemoreflex response. The differences in baseline values and changes with drugs were compared by multiple regression analysis coded by effects. Chemoreflex response was markedly attenuated by ketamine and morphine but not by pentobarbital or propranolol. Because the cardiovascular response to hypoxemia is blunted by some drugs, caution should be exercised in interpreting heart rate responses to hypoxemia in the fetus when these drugs have been administered to the mother. (Pediatr Res 38: 938-943, 1995) Abbreviation AHRIAsat = ratio of the decrease in heart rate to the decrease in 0, saturation Acute fetal hypoxemia causes a bradycardic response (I), sponse to acute hypoxemia that is quantitative and reproducible which we have previously shown is due to stimulation of (2). peripheral chemoreceptors. The sensitivity of fetal chemoreceptors determines the severity of the bradycardic response. Chemoreceptor sensitivity depends on baseline oxygenation;
Review Cardiorenal Effects of Kappa Opioid Peptides During Ontogeny
2011
This review focuses on the physiological roles for kappa opioid receptors (KORs) in adult animals and humans, as well as in the developing newborn animal. Our recent findings have provided new information that under physiological conditions in conscious newborn animals, activation of KORs with the selective agonist, U-50488H, results in an aquaresis, as previously observed in adult animals and humans. In addition, we have shown in conscious lambs that KORs modulate systemic and renal haemodynamics as well as the arterial baroreflex control of heart rate, providing a previously unidentified role for KORs.
Neonatal Adaptation: Naloxone Increases the Catecholamine Surge at Birth
Pediatric Research, 1987
A marked increase in plasma catecholamines at birth has been described in animals and man. Because the factors that regulate catecholamine secretion are incompletely understood and because it has recently been suggested-that endogenous opiates are important in the regulation of catecholamine secretion, we designed studies to2etermine the influence of opiate receptor blockade prior to delivery on the increase in plasma catecholamines at birth. Term fetal sheep were delivered by cesarean section and randomly assigned to receive naloxone or vehicle. Naloxone was given just prior to umbilical cord cutting as a 2 mg/kg bolus followed by 2 mg/kg/h. Naloxone administration resulted in significantly greater peak levels of plasma norepinephrine (peak levels of 1.5 f 0.4 versus 0.9 f 0.1 ng/ml) and epinephrine (peak levels of 1.4 f 0.7 versus 0.9 f 0.3 ng/ml) and higher norepinephrine values throughout the study period. Naloxone administration was associated with significantly elevated heart rate (peak 184 f 12 versus 207 f 13 beats per min) and blood pressure (peak 95 f 6 versus 88 f 2 mm Hg). These studies demonstrate that opiate receptor blockade from birth markedly augments the neonatal sympathoadrenal response in the term newborn lamb.