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Biomedical subjects

J L Caffrey

Publications and source records attributed to J L Caffrey.

At least 37 records · Page 2Linked to original sources
PubMed1993

(+)Naloxone potentiates the inotropic effect of epinephrine in the isolated dog heart.

Naloxone potentiates the inotropic effect of circulating catecholamines in the isolated canine heart. The stereospecificity of this response was evaluated with the aid of the less active (+)enantiomer of naloxone. The more common (-)isomer of naloxone increased the contractile response to epinephrine only at the higher dose tested (4 mg). This effect of naloxone was not observed at a tenfold lower dose (0.4 mg), indicating a very narrow dose-response range. (+)Naloxone was effective at the lower dose and was, therefore, equal to or better than (-)naloxone in potentiating the inotropic effect of epinephrine. When introduced afterward, (-)naloxone did not add to the effect of (+)naloxone. These data suggest that naloxone modifies cellular responsiveness to catecholamines through a nontraditional opiate receptor, through a nonopiate receptor, or through a nonreceptor mechanism.

Animals↗
PubMed1992

Screening for opioids in dog heart.

Dog hearts divided into right and left atria, right and left ventricles and intraventricular septum were homogenized in acid for extraction. Total opioids, and specific peptides (methionine-enkephalin, methionine-enkephalin-arg6-gly7-leu8) were determined by radioreceptor and radioimmunoassay, respectively. Catecholamines were quantitated amperometrically following HPLC. The effects of anesthetic agents (pentobarbital, alpha-chloralose), hemorrhage and ganglionic blockade (hexamethonium and atropine) were evaluated. Total opioids, enkephalins and epinephrine were distributed uniformly throughout the myocardium, while norepinephrine was preferentially concentrated in the atria. Immunoreactive methionine-enkephalin accounted for only 1 to 2% of the total cardiac opioids estimated by radioreceptor assay. Hemorrhage lowered methionine-enkephalin content throughout the myocardium with no significant effect on total opioids or catecholamines. Ganglionic blockade increased total opioid, methionine-enkephalin-arg6-gly7-leu8 and catecholamine content without altering methionine-enkephalin content. HPLC of left ventricular extracts demonstrated that 50% of met-enkephalin-immunoreactivity eluted at retention times equal to synthetic metenkephalin. In summary, there appears to be substantive opioid concentrations within canine myocardium which respond to physiological and pharmacological interventions. These cardiac opioid responses do not parallel changes observed for catecholamines under the same conditions.

Amino Acid Sequence↗
PubMed1992

Dynorphin, naloxone, and overflow of norepinephrine during cardiac nerve stimulation in dogs.

The effects of dynorphin-(1-9) and naloxone on norepinephrine (NE) overflow and myocardial contractility were determined during left cardiac nerve stimulation in the anesthetized dog. Stimulation-induced increases in NE overflow from the left ventricle were monitored during control conditions, during infusion of dynorphin-(1-9), during dynorphin plus naloxone, and after naloxone alone. Four electrical stimulations were applied for 1 min at 20-min intervals. Repeated left cardiac nerve stimulations (control group) reduced stimulated NE overflow 50-60% by 1 h. If stimulations were only conducted at 0 and 1 h, the decline in NE overflow was not observed. Intracoronary dynorphin (2 nmol.min-1.kg-1, 20 min) lowered the stimulation-induced increase in NE overflow further and reduced first time derivative of left ventricular pressure (dP/dt) and myocardial O2 consumption responses. Naloxone (100 micrograms/kg) prevented all of the dynorphin-mediated effects. When given alone, naloxone increased both NE overflow and left ventricular dP/dt during stimulation and prevented or significantly delayed the gradual decline in overflow observed in stimulated controls. A postjunctional effect of dynorphin was evaluated by comparing contractile responses to the intracoronary infusion of NE before and during dynorphin. Dynorphin did not alter contractile function at rest or during NE infusion. In summary, dynorphin-(1-9) depresses nerve stimulation-induced, cardiac NE overflow, and myocardial contractility in a naloxone-reversible fashion. Alone, naloxone appears to regulate stimulated NE overflow through a qualitatively different mechanism. Endogenous opioids may normally moderate myocardial function during cardiac nerve stimulation by regulating junctional NE concentrations through a combination of effects on NE release and/or its subsequent reuptake.

Animals↗
PubMed1991

Enkephalin lowers vascular resistance in dog hindlimb via a peripheral nonlimb site.

The intravenous administration of methionine enkephalin in anesthetized dogs produces an abrupt decline in mean arterial pressure, left ventricular pressure, and the maximal rate of left ventricular pressure development. All of these changes are prevented by receptor blockade with the opiate antagonist, naloxone. To evaluate peripheral vascular contributions to these responses, experiments were conducted in a constant pressure-isolated perfused hindlimb. In this model, the sharp decline in mean arterial pressure associated with enkephalin injection (5 micrograms/kg iv) coincided with an equally sharp decline in vascular resistance (rise in blood flow) in the hindlimb. Both were blocked by naloxone pretreatment (1 mg/kg). When equal doses of enkephalin were administered directly into the femoral inflow (external iliac artery), both arterial pressure and hindlimb flow responses were all but eliminated. This observation ruled out significant direct vascular interactions in the response and indicated a site of action outside the hindlimb. Additional catheters were placed in the bracheocephalic artery and descending aorta to permit the comparison of arterial injections conducted, respectively, into the cerebral or abdominal circulations. Injections introduced into the descending aorta consistently produced the greatest response, followed by injections (in descending order of effectiveness) into the jugular, the brachiocephalic, and external iliac. The response in the hindlimb vasculature was initiated at a site somewhere between the diaphragm and terminal aorta. The vascular response to enkephalin was subsequently eliminated by blocking ganglionic transmission with the nicotinic antagonist mecamylamine. These observations suggest that the opioids probably interrupt local vasomotor traffic via opiate receptors in regional sympathetic ganglia or in the spinal cord.

Animals↗
PubMed1990

Naloxone enhances cardiac contractile responses to epinephrine without altering epinephrine uptake from plasma.

Naloxone potentiates the inotropic effect of selected beta-agonists in the canine isolated heart. This could be accomplished by elevating circulating catecholamines through a reduction in their disposal or by the facilitation of events at or subsequent to the cardiac beta-receptor. To evaluate the first hypothesis, epinephrine was infused intravenously into a blood-perfused isolated heart-lung preparation. Catecholamines were determined and myocardial and pulmonary epinephrine uptakes were calculated. Naloxone enhanced the inotropic effect (peak +dP/dt) during epinephrine infusion. Coronary blood flow and coronary venous epinephrine concentrations were also elevated after naloxone. Calculated myocardial and pulmonary uptake of epinephrine were, however, unaltered by naloxone. The increased coronary sinus epinephrine after naloxone was evaluated further in experiments redesigned to eliminate the influence of changing coronary blood flow. Epinephrine was infused into the left common coronary and coronary blood flow as maintained constant, 100% above the resting flow rate. Naloxone enhanced the contractile response to epinephrine without altering coronary artery or coronary sinus epinephrine concentrations or myocardial epinephrine uptake. By comparison, corticosterone, an extra-neuronal uptake inhibitor, also potentiated the inotropic effect of infused epinephrine under identical conditions. However, corticosterone was accompanied by a significant increase in coronary sinus epinephrine concentration and a decrease in myocardial epinephrine uptake. We therefore concluded that the ability of naloxone to enhance the inotropic effect of epinephrine is not mediate through an increase in plasma epinephrine concentration secondary to a decrease in the disposal of circulating catecholamines.

Animals↗
PubMed1990

Naloxone potentiates contractile responses to epinephrine in isolated canine arteries.

The beneficial pressor effects of naloxone in shock have been associated with existing adrenergic systems and in particular with circulating epinephrine. Vascular interactions among alpha adrenergic receptor agents, naloxone, and selected opioids were investigated. The addition of pharmacologic concentrations of the opiate antagonist naloxone enhanced contractile responses to lower doses of epinephrine by more than 100% in isolated renal interlobar arteries. Naloxone lowered the EC50 for both epinephrine and norepinephrine but the magnitude of enhanced responses were much greater for epinephrine. Responses in the presence of naloxone to more selective alpha agonists, phenylephrine and clonidine, were also much less. The enhanced contraction cannot be demonstrated in the absence of added catecholamine and is eliminated by alpha but not by beta adrenergic blockade. Dose responses for naloxone provided an EC50 (micromolar) above those reported for known opiate receptors. Representative mu (morphiceptin), delta (DADL), and kappa (dynorphin 1-9) receptor agonists were ineffective in altering the EC50 for naloxone. Responses opposite to naloxone could be generated with pharmacological additions of another kappa opioid, dynorphin 1-8. This effect was also accomplished without shifting the EC50 for naloxone to the right, suggesting dynorphin and naloxone operate via separate mechanisms. The (+) stereoisomer of naloxone was as or more effective than (-) naloxone, adding support for a nontraditional or nonopiate receptor mechanism. Corticosterone produced responses indistinguishable from naloxone. These pharmacological steroid-like responses to naloxone are used to suggest a hypothesis based upon modulation of extra-neuronal uptake and/or adrenergic receptor desensitization mechanisms.

Animals↗
PubMed1989

Enkephalin metabolism: effect of acute exercise stress and cardiovascular fitness.

Inhibition of enkephalin hydrolysis by catecholamines in vitro suggested that local and/or humoral factors released during exercise might facilitate opiate responses by reducing the rate of opiate peptide inactivation. Several measures of enkephalin hydrolysis were determined in blood samples obtained from subjects designated as trained (VO2max, 64.3 +/- 1.6 ml.min-1.kg-1) and un-trained (VO2max, 37.4 +/- ml.min-1.kg-1) both at rest and after maximal exercise stress tests. Enkephalin hydrolyzing activity assessed under optimal conditions was equally distributed between plasma and intact red cells; however, hydrolysis by red cells increased dramatically following osmotic release of red cell contents. There were no apparent differences in enzyme concentration or its distribution between cells and plasma when comparing trained and untrained subjects; P greater than 0.05. There was also no statistical effect of maximal exercise on these measures in either group. However, when the sequential disappearance of enkephalin added to whole blood in vitro was evaluated, blood from trained subjects degraded the enkephalin more slowly than blood from untrained subjects and had half-lives in vitro 30-50% longer both before and after the exercise test; P less than 0.05. Since enzyme concentrations between the groups were similar, the longer half-lives suggest that circulating factors were responsible for moderating the rate of enkephalin metabolism in vivo and that these factors were more concentrated in trained subjects. This would facilitate opiate responses in trained subjects and perhaps provide them with added tolerance for the effort associated with elite performance levels.

Adult↗
PubMed1987

Mechanism of attenuated pressure-flow autoregulation in right coronary circulation of dogs.

Right coronary autoregulation was assessed in 14 open-chest, anesthetized dogs. In Group 1 (n = 5), the left common and right coronary arteries were cannulated and perfused independently. As coronary perfusion pressures varied simultaneously between 70 and 120 mm Hg, right coronary blood flow changed by 48%, whereas left coronary flow changed by 13%. In this pressure range, the autoregulatory closed-loop gain of the right coronary circulation averaged 0.37 +/- 0.01, reflecting a modest autoregulatory capability but significantly less than that of the left coronary circulation, 0.78 +/- 0.08. In Group 2 (n = 9), only the right coronary artery was perfused, and right coronary venous blood was collected for determining arteriovenous oxygen extraction. Autoregulatory gain was similar to that of Group 1, indicating that collateral flow associated with intercoronary pressure gradients does not mask right coronary autoregulation. Right ventricular myocardial oxygen consumption varied directly with perfusion pressure, ranging from 7.1 +/- 1.0 to 2.9 +/- 0.8 ml O2/min/100 g as pressure was reduced from 160 to 40 mm Hg. Thus, right coronary autoregulation is masked by an opposing change in oxygen demand. When right ventricular oxygen consumption was altered by pacing, a linear flow-oxygen consumption relationship was observed (8.2 +/- 0.4 ml/min/100 g per ml O2/min/100 g). Subtraction of flows associated with pressure-induced changes in metabolism revealed a potential autoregulatory capability of the right coronary circulation similar to that manifested by the left coronary circulation.

Animals↗
PubMed1986

Naloxone enhances myocardial responses to isoproterenol in dog isolated heart-lung.

Intracoronary injection of naloxone produces rapid local increases in myocardial performance. The role of beta-adrenergic activation in this response was investigated. Naloxone was injected into the left anterior descending artery (LAD) of anesthetized dogs with the adjacent circumflex territory serving as control. Naloxone increased the contractile state locally in the LAD region. Pretreatment with propranolol eliminated the regional inotropic response. An isolated heart-lung model was set up, and isoproterenol dose responses were determined. When repeated after naloxone, contractile (dP/dt) responses to isoproterenol were both augmented and prolonged. In a third study imipramine was used to determine whether naloxone might act by reducing neuronal uptake of the isoproterenol. Imipramine extended the effect of isoproterenol temporally but did not alter the peak response. Adding naloxone increased the peak response to isoproterenol and maintained it above the extended imipramine response. The data support the concept that the blockade of opiate receptors facilitates adrenergic activity mediated by myocardial beta 1-receptors 1) directly through postsynaptic mechanisms, 2) indirectly through beta 2-mediated release of norepinephrine, or 3) via interference with nonneuronal disposal mechanisms.

Animals↗
PubMed1985

Local endogenous opiate activity in dog myocardium: receptor blockade with naloxone.

The participation of endogenous opiates in myocardial performance and coronary blood flow was investigated. Heart rate, left ventricular contractile force (LVCF), left coronary blood flow (LCBF), and left ventricular oxygen extraction were monitored in anesthetized dogs before and after intracoronary opiate receptor blockade with naloxone. LVCF consistently increased in a dose-dependent fashion following intracoronary naloxone. The increasing LVCF was accompanied by significant increases in LCBF and myocardial oxygen consumption, without changes in heart rate. Rapid onset of responses suggested the presence of endogenous opiates operating locally within the myocardium. Similar effects did not follow right atrial injection of naloxone, ruling out a systemic mechanism. Furthermore, naloxone injected into the isolated left anterior descending artery selectively increased contractile force in that perfusion territory while the adjacent untreated circumflex territory showed no change. The administration of dynorphin into the coronaries produced a depression of LVCF qualitatively consistent with these effects. The effect of dynorphin was subsequently reversed with naloxone. These results support the concept that endogenous opiates participate in the regulation of myocardial function through local mechanisms at the myocardial level.

Animals↗
PubMed1985

The interaction of endogenous opiates with autonomic circulatory control in the dog.

The intravenous injection of either methionine or leucine enkephalin sharply reduces blood pressure, peak left ventricular pressure, and peak LV dP/dt in anesthetized dogs. The magnitude of the hypotensive response increases in proportion to the severity of the preceding surgical stress. The peptides are relatively ineffective after only simple surgical procedures but become highly effective when the autonomic balance is shifted toward sympathetic dependence after more complicated procedures or following bilateral carotid occlusion. The greater the animal's dependence upon sympathetic outflow to maintain blood pressure, the more effective is the opiate peptide. This suggests that the peripherally administered opiates may act by opposing existing adrenergic tone. Such antagonism of adrenergic tone during circulatory shock may help to explain some of the benefit of opiate receptor blockade in this condition. The rapid decline in blood pressure can be demonstrated in response to a variety of the proenkephalin-A derived peptides expected to circulate during physiological stresses. Based on a comparison of the responses to a series of peptides, the hypotensive effect is most likely mediated through activating opiate receptors of the delta subtype.

Animals↗
PubMed1983

Fluoride-induced changes in renal papillary cyclic-AMP.

Studies were conducted which examined urinary excretion and papillary production of cyclic-AMP in the rat following vasopressin (ADH) stimulation in the presence or absence of inorganic fluoride ion (F). In one set of experiments, six anesthetized Fischer 344 rats were administered 5 munits arginine vasopressin during iv saline and sodium fluoride (NaF) infusions. Urinary cyclic-AMP concentration was unchanged by ADH but declined during NaF infusion, while urinary cyclic-AMP excretion rate was unchanged by ADH or ADH/NaF. In a second set of experiments, 30 rats were divided into six groups of 5 each, and renal papilla and cortex were analyzed for cyclic-AMP. Group I was decapitated and not otherwise surgically manipulated. A second group had iv saline for 90 min while a third group had iv saline and ADH. A fourth group had isotonic NaF iv for 90 min and a fifth group had NaF and ADH. The results indicate that papillary cyclic-AMP is significantly increased by both ADH and NaF doses which did not cause changes in urinary cyclic-AMP excretion rates. We conclude from these experiments that determination of urinary cyclic-AMP concentration is not the best measure of vasopressin action and that tubular sensitivity to the hormone in the presence of F was better demonstrated by changes in papillary cyclic-AMP concentration. Further, it appears that the site of the biochemical renal lesion caused by F is at a site beyond the generation of cyclic-AMP.

Animals↗
PubMed1983

Role of calcium and prostaglandins in the antidiuretic hormone response. Effect of ionophore A23187.

The calcium ionophore A23187 (IP) inhibited the antidiuretic hormone (ADH)-stimulated hydro-osmotic response in toad urinary bladder but had no effect on the osmotic transfer of water in the absence of hormone. Extracellular calcium was necessary for this effect at lower but not at higher IP concentrations. The hydro-osmotic response to exogenous cyclic AMP was unaltered by IP, but the same response produced by inhibition of phosphodiesterase was reduced significantly. Cyclic AMP concentrations in isolated toad bladder epithelial cells were reduced by 50% with IP or exogenous prostaglandin E2 (PGE2). Indomethacin, a prostaglandin synthesis inhibitor, prevented the inhibitory actions of the IP on the ADH-mediated response. Collectively, these observations suggest a key role for cellular calcium in modulating the actions of antidiuretic hormone and are consistent with the hypothesis that the ionophore, through increasing intracellular calcium, stimulates the synthesis of prostaglandins which have a negative feedback on adenylcyclase. This effect would terminate the action of the hormone.

Animals↗
PubMed1982

The assay of Met-enkephalin aminopeptidase with [125I]Met-enkephalin.

Presented here are procedural modifications which permit the utilization of 125I-labeled Met-enkephalin as substrate in the assay of rat brain enkephalin aminopeptidase. Th hydrolysis of enkephalin is monitored by the release of [125I]tyrosine separated on Porapak Q. The release of tyrosine is proportionate with both increasing time and tissue concentration. The estimated Km is near 10(-4) M and the enzyme activity can be inhibited more than 95% with puromycin. The majority of the enzyme activity remains in the 100,000 x g supernatant following differential centrifugation.

Aminopeptidases↗
PubMed1982

Inhibition of the enzymatic degradation of Met-enkephalin by catecholamines.

The influence of the catecholamine hormones and some of their metabolites on the enzymatic degradation of met-enkephalin by rat brain homogenates has been evaluated. The enzyme activity was determined by the release of [125I]-tyrosine from radioiodinated met-enkephalin following Porapak Q column chromatography. Each of the biologically active catecholamines inhibited the measured enzyme activity, and dose-response curves indicated that dopamine was most effective and epinephrine least effective. At 5 x 10(-5)M the O-methylated metabolite of each hormone failed to inhibit the enzyme activity. An enzyme activity similar to that found in brain was also found in adrenal and ileal homogenates. This enzyme activity was strongly inhibited by dopamine as well as by puromycin.

Adrenal Glands↗