Effect of D-Ala-2-Me-Phe-4-Gly-ol-5 enkephalin on epinephrine-induced arrhythmias in the rat and the interrelationship to the parasympathetic nervous system

The purpose of this study was to evaluate the effects of the millimicrons opioid agonist D-Ala-2-Me-Phe-4-Gly-ol enkephalin (DAGO) on catecholamine-induced arrhythmias. Arrhythmias were produced, in the rat, by continuous infusion of epinephrine until the development of fatal arrhythmias that were usually ventricular fibrillation. Intracerebroventricular (ICV) administration of DAGO, 3 nmol, significantly (p less than 0.05) shifted to the right the relationship between epinephrine and both the onset of ventricular arrhythmias and the development of fatal arrhythmias. Naloxone, 1 mg/kg i.v., prevented these effects of DAGO. Atropine, 1 mg/kg i.v. or 20 micrograms/kg ICV, prevented the shift in these dose response relationships. Antagonism of DAGO's effects on arrhythmias could not be explained by an alteration of the blood pressure response to epinephrine. However, DAGO significantly increased blood pressure and decreased heart rate in separate experiments in animals that did not receive epinephrine and atropine prevent the heart rate and blood pressure effects of DAGO. These data show that 1) the millimicrons opioid receptor agonist DAGO suppresses epinephrine-induced arrhythmias, 2) the site of action can be within the CNS, 3) there is a role for the central parasympathetic nervous system to mediate the effect of DAGO and 4) endogenous opioids could modulate catecholamine-induced cardiac arrhythmias.     

Angiotensin in the brain suppresses epinephrine-induced cardiac arrhythmias through CNS opioid mechanisms.

To test the hypothesis that angiotensin II (Ang II) in the central nervous system modulates catecholamine-induced cardiac arrhythmias and to determine whether endogenous opioids are operative in this action, arrhythmias were produced in male Wistar rats, by continuous infusion of epinephrine at incremental doses until the development of fatal arrhythmias that were usually ventricular fibrillation. Rats were instrumented with catheters in the lateral cerebral ventricle, femoral vein and femoral artery. Ang II, 0.5 microgram, in the lateral cerebral ventricle (ICV) markedly and significantly (p less than 0.05) increased the epinephrine dose, at the occurrence of ventricular premature beats compared to the control group 228 +/- 11 (SEM) vs 116 +/- 7 micrograms epinephrine/kg and at the onset of fatal arrhythmias 225 +/- 13 vs 185 +/- 9 micrograms epinephrine/kg. Ang II, 0.5 microgram i.v., did not affect arrhythmia threshold. The angiotensin converting enzyme inhibitor captopril, 1 mg/kg, decreased arrhythmia threshold as ventricular arrhythmias were first noted at 106 +/- 4 and fatal arrhythmias occurred at 118 +/- 4 micrograms epinephrine/kg. The Ang II receptor antagonist saralasin 150 micrograms/kg ICV, blunted and 300 micrograms/kg ICV reversed the effect of Ang II. The mu opioids antagonist naloxone and the kappa opioid antagonist MR 2266, 50 micrograms/kg ICV, prevented the effect of Ang II on fatal arrhythmias. The action Ang II on arrhythmias could not be explained by the effects of Ang II on blood pressure or heart rate. These data indicate a role for Ang II within the CNS to modulate cardiac arrhythmias and that this is mediated in part, by endogenous opioids.     

The effect of inhibitors of endogenous opioid degradation, bacitracin, bestatin, captopril, and D-phenylalanine, on digoxin-induced arrhythmias in guinea pigs

The purpose of this study was to investigate the effect of inhibition of endogenous opioid degradation on digitalis-induced arrhythmias, utilizing the inhibitors bacitracin, bestatin, captopril, and D-phenylalanine. Guinea pigs, anesthetized with pentobarbital, 50 mg/kg i.p., and breathing spontaneously received intracerebroventricular (i.c.v.) injection of bacitracin (6.8 mg/kg), bestatin (1 mg/kg), captopril (2 mg/kg), D-phenylalanine (1.2 mg/kg) or the diluent, saline. Digitalis arrhythmias were induced by a 50 micrograms/kg i.v. bolus of digoxin followed by 500 micrograms.kg-1.h-1 i.v. Bacitracin and bestatin, but not captopril or D-phenylalanine, significantly (p less than 0.05) altered the relationship between the digoxin dose and the first occurrence of arrhythmias, i.e., digoxin-induced ventricular arrhythmias became manifest at lower digoxin doses. The mean digoxin dose and ED50s, at which arrhythmias first occurred, were significantly (p less than 0.05) reduced by bacitracin and bestatin. The findings were similar for fatal arrhythmias, although D-phenylalanine appeared to decrease the digoxin dose at the development of fatal arrhythmias. The opioid antagonist naloxone, in a 50 micrograms/kg bolus and 50 micrograms.kg-1.h-1 i.c.v., completely prevented these effects of bacitracin and reduced the effect of bestatin. The relationship to arrhythmias could not be ascribed to an effect on blood pressure, as the blood pressure response to digoxin was the same in bestatin, D-phenylalanine, and control groups. To examine whether systemic administration of an inhibitor of opioid degradation had similar effects, a second protocol was selected with systemic administration of bacitracin because it altered the dose effect relationship after i.c.v. administration and systemic concentrations could be readily attained. Bacitracin, in a 13.5 mg/kg i.v. bolus and 135 mg.kg-1.h-1 i.v., was followed by 100 micrograms/kg digoxin i.v. every 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dynorphin A (1-13) in the brain suppresses epinephrine-induced ventricular premature complexes and ventricular tachyarrhythmias.

The objectives of this study were to test the hypothesis that dynorphin in the central nervous system modulates epinephrine-induced cardiac arrhythmias and that central cholinergic mechanisms are operative in this action of dynorphin. Cardiac arrhythmias were produced by continuous intravenous infusion of epinephrine, in Wistar rats, previously instrumented with catheters in the lateral cerebral ventricle, femoral vein and femoral artery. Epinephrine produced ventricular premature complexes and later the development of fatal ventricular fibrillation. Dynorphin A (1-13), 5 or 20 micrograms (3 or 12 nM) administered into the lateral cerebral ventricle (ICV), significantly (P less than 0.05) increased the threshold for development of cardiac arrhythmias. Dynorphin A (1-13), 20 micrograms, increased the epinephrine dose at the occurrence of ventricular premature beats to 171 +/- 8 (mean +/- 1 S.E.M.) compared to 120 +/- 5 micrograms epinephrine/kg in the control group and increased the dose at the onset of fatal arrhythmias to 186 +/- 8 compared to 141 +/- 10 micrograms epinephrine/kg in the control group. The action of dynorphin was significantly (P less than 0.05) antagonized by the kappa opioid antagonist MR2266. Atropine sulfate, administered ICV or intravenously, produced a dose dependent antagonism of this action of dynorphin A (1-13). This was not due to the peripheral effects of atropine, as atropine methylnitrate, which does not cross the blood brain barrier, did not oppose the effects of dynorphin A (1-13). These data indicate (i) dynorphin A (1-13) increases the threshold for or suppresses the manifestations of epinephrine-induced ventricular arrhythmias, (ii) dynorphin's action on cardiac arrhythmias is mediated through central cholinergic rather than peripheral parasympathetic mechanisms (iii) dynorphin may play a role as an endogenous opioid within the brain that modulates cardiac arrhythmias in circumstances of elevated circulating epinephrine concentration.     

Adrenaline causes potassium influx in skeletal muscle and potassium efflux in cardiac muscle in rats: the role of Na/K ATPase

Previous in vitro evidence suggests that adrenaline causes K influx in skeletal muscle by stimulating a ouabain sensitive Na/K ATPase membrane pump. However in rabbits, adrenaline induced hypokalaemia was not significantly altered by pretreatment with digoxin (50 micrograms/kg). Rats were infused with adrenaline or saline after being given a tracer dose of 42KCl. Adrenaline caused a highly significant uptake of 42K in skeletal muscle and a decrease in 42K uptake in ventricle. Rats were also studied after receiving a high dose of digoxin (1.4 mg/kg) which by itself produced a significant increase in plasma K, a decrease in plasma Na and a decreased uptake of 42K in ventricle and lung. These results suggest that adequate widespread Na/K ATPase inhibition had been achieved by this dose of digoxin but despite this, adrenaline still caused hypokalaemia and also still caused significant 42K tissue uptake by skeletal muscle. These results suggest that adrenaline causes K influx by skeletal muscle and K efflux by cardiac tissue. Furthermore, the former mechanism was not inhibited by pretreatment with digoxin.     

The lack of involvement of central nervous system in the antiarrhythmic effects of prostaglandins E2, F2 alpha, and I2 in cat

The role of the central nervous system (CNS) in the antiarrhythmic effects of prostaglandins (PGs) E2, F2 alpha, and I2 was studied by administering each agent into the left lateral cerebral ventricle (i.c.v. administration) of chloralose-anaesthetized cats. The cardiac arrhythmias were produced by intravenous (i.v.) infusion of ouabain (1 microgram/kg/min). The PGs E2, F2 alpha and I2 on i.c.v. administration in the dose range of 1 ng to 10 micrograms failed to inhibit ouabain-induced cardiac arrhythmias. However, when infused i.v., PGE2 (1 microgram/kg/min), PGF2 alpha (5 micrograms/kg/min), and PGI2 (2 micrograms/kg/min) effectively suppressed these arrhythmias. The standard antiarrhythmic drug propranolol (0.5-8.0 mg) on i.c.v. administration also significantly reduced the ouabain-induced cardiac arrhythmias. It is suggested that the CNS is not the site of action of PGs E2, F2 alpha, and I2 in antagonising the ouabain-induced cardiotoxicity in cats.     

Central nervous system mediated vasodepressor action of atrial natriuretic factor

Administration of 20, 4 or 2.5 micrograms/kg of atriopeptin III (AT III) into the fourth ventricle of the brain of spontaneously hypertensive rats produced a 13, 14 and 7 mm Hg decrease in MAP respectively, while 1 microgram/kg had no effect on MAP and was significantly different from 20 or 4 micrograms/kg (p less than 0.025). In contrast, injection of AT III 20 micrograms/kg into the lateral ventricle did not produce a change in MAP. To examine an interaction of AT III with the opioidergic system, the opiate antagonist, naloxone HCl, 10 micrograms, was given by ICV injection 10 minutes prior to AT III, and significantly prevented the depressor response to AT III (p less than 0.025 compared with AT III alone). Injection of specific anti-sera to beta-endorphin failed to prevent the AT III-induced depressor response. Our results demonstrate that AT III can act within the central nervous system to decrease the MAP of rats, most likely at a locus in proximity to the fourth ventricle of the brain. Further, an interaction with the central opioidergic nervous system underlies the central effects of AT III.     

Autonomic effects of central injections of D-Ala2-Met-enkephalinamide (DAME) in the conscious monkey

The use of naloxone (NAL), an opioid receptor antagonist, has provided indirect evidence that endogenous opioids contribute to cardiovascular depression during shock. To determine if endogenous opioids act centrally to influence cardiovascular function, injections of D-Ala2-Met-enkephalinamide (DAME), a potent Met-enkephalin analog, were made into the 3rd cerebral ventricle (ICV) of 5 conscious cynomulgus monkeys restrained in primate chairs. Systolic blood pressure (SBP) and heart rate (HR) were determined every 10 min during a 30-60 min control period and for up to 5 hr post-injection. Colonic temperature (Tc) was monitored continuously. SBP declined from baseline values with 50 and 100 micrograms (85.2 and 170.4 nM) doses but was significant (p less than 0.001) for only the 100 micrograms dose between 15-125 min post-injection. HR also decreased but did not exhibit any significant variation with time. However, when averaged across time, HR fell significantly (p less than 0.001) from baseline: -9.1 +/- 2.3 and -15.0 +/- 2.1 b/min for 50 and 100 micrograms DAME, respectively. Tc displayed a nonsignificant, delayed (greater than 2 hr) rise in Tc with the 50 micrograms dose, whereas the 100 micrograms dose caused a significant (p less than 0.001) decline in Tc (from 65-125 min post-injection). NAL injected ICV attenuated the effects of DAME but had no effect on SBP, HR or Tc when injected alone. Systemic injection of DAME (300 micrograms) in one monkey produced a transient decline in SBP (26 mmHg within 2 min) which returned to baseline values 4 min post-injection. HR and Tc were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of hypoxemia and respiratory acidosis on the plasma kinetics and tissue distribution of digoxin in the conscious dog

The aim of the present study was to investigate the influence of hypoxemia combined with respiratory acidosis on the kinetics of digoxin in conscious dogs. One group of three beagles was exposed to air and 7 days later to 10% O2, 10% CO2, and 80% N2. In a second group of three dogs, the order of exposure to the two atmospheric conditions was reversed. The dogs received 25 micrograms/kg digoxin and blood and urine samples were collected over the next 29 h. At the conclusion of the second treatment, the dogs were sacrificed to determine digoxin concentrations in the left ventricle, liver, renal cortex, and skeletal muscle. Digoxin total body clearance increased from 6.2 +/- 0.9 in control to 9.0 +/- 1.0 mL X min-1 X kg-1 in hypoxemic and hypercapnic dogs (p less than 0.05). The digoxin apparent volume of distribution at steady state (Vss) was increased in the dogs with hypoxemia and hypercapnia (11.63 +/- 1.11 vs. 8.62 +/- 0.41 L/kg in the controls, p less than 0.05). As a consequence the digoxin plasma half-life remained unchanged (18.6 +/- 1.5 h in hypoxemic and hypercapnic dogs versus 20.1 +/- 2.8 h in the controls). In dogs with hypoxemia and hypercapnia, the ratio of tissue to plasma digoxin concentrations tended to increase in the liver, in the renal cortex, and in the left ventricle and remained unchanged in the left hind leg muscle. In vitro studies showed that the digoxin total binding to erythrocyte membranes was slightly increased in the dogs with hypoxemia and hypercapnia, resulting from an increase in the apparent intrinsic association constant for digoxin (p less than 0.003). It is concluded that hypoxemia combined with respiratory acidosis changes digoxin disposition in the conscious dog and is the cause of a digoxin redistribution into the tissues.     

Cardiac sensitivity to hyperkalemia in adrenalectomized dogs.

In dogs with bilateral adrenalectomy loaded with K by infusion of 2 mEq KCI/kg/hr there is a marked increase of cardiac sensitivity to hyperkalemia. Typical ECG changes begin at lower serum K levels (5-6 mEq/l) and the prelethal arrhythmias that signal the imminent onset of fatal when mean serum K is 7.6 mEq/l, 2.9 mEq/l above the average pre-infusion level. In control dogs, ECG changes start above 8 mEq K/liter, and prelethal arrhythmias appear between 9.5 and 10.2 mEq/l, a mean increase of 5.6 mEq/l above the average preinfusion level.     

Neuropathy target esterase in hens after sarin and soman

To estimate the potential of small doses of sarin (types I and II) and soman to cause delayed neuropathic effects, 400, 200, 61, and 0 micrograms/kg of sarin-I, 280, 140, 70, and 0 micrograms/kg of sarin-II, and 14.2, 7.1, 3.5, and 0 micrograms/kg of soman by gavage were compared with 510 mg/kg tri-o-cresyl phosphate (TOCP) in 14- to 18-month-old SPF white leghorn hens (4/dose) protected with atropine (100 mg/kg). The neuropathy target esterase (NTE) activity 24 hr after dosing was determined in brain, spinal cord, and lymphocytes and in plasma and brain for cholinesterase and carboxylesterase. None of the compounds showed statistically significant NTE decreases. Sarin-II showed a dose-related trend in the lymphocyte NTE (to 33% of control at 280 micrograms/kg), suggesting that longer exposure to lower doses might cause a cumulative neurotoxic insult. All of the agents decreased the activity of plasma and brain cholinesterase and carboxylesterase. Using more than 70% inhibition of brain NTE as a biochemical predictor of delayed neuropathy, sarin and soman appear unable to cause delayed neuropathy at nonlethal doses within this protocol.     

Heme oxygenase-1 and the ischemia-reperfusion injury in the rat heart

Carbon monoxide (CO) is a signaling gas produced intracellularly by heme oxygenase (HO) enzymes using heme as a substrate. During heme breakdown, HO-1 and HO-2 release CO, biliverdin, and Fe(2+). In this study, we investigated the effects of manipulation of the HO-1 system in an in vivo model of focal ischemia-reperfusion (FIR) in the rat heart. Male Wistar albino rats, under general anesthesia and artificial ventilation, underwent thoracotomy, the pericardium was opened, and a silk suture was placed around the left descending coronary artery; ischemia was induced by tightening the suture and was monitored for 30 min. Subsequently, the ligature was released to allow reperfusion lasting for 60 min. The first group of rats was sham operated and injected intraperitoneally (i.p.) with saline. The second group underwent FIR. The third group was treated ip 18 hr before FIR with hemin (4 mg/kg). The fourth group was pretreated ip 24 hr before FIR and 6 hr before hemin with zinc protoporphyrin IX (ZnPP-IX, 50 microg/kg). Specimens of the left ventricle were taken for determination of HO expression and activity, infarct size, malonyldialdehyde (MDA) production, and tissue calcium content. FIR led to a significant increase in the generation of MDA and notably raised tissue calcium levels. Induction of HO-1 by hemin significantly decreased infarct size, incidence of reperfusion arrhythmias, MDA generation, and calcium overload induced by FIR. These effects were prevented by the HO-1 inhibitor ZnPP-IX. The present experiments show that the concerted actions of CO, iron, and biliverdin/bilirubin modulate the FIR-induced myocardial injury.     

Growth hormone response of bull calves to growth hormone-releasing factor

Three experiments were conducted to determine serum growth hormone (GH) response of bull calves (N = 4; 83 kg body wt) to iv injections and infusions of human pancreatic GH-releasing factor 1-40-OH (hpGRF). Peak GH responses to 0, 2.5, 10, and 40 micrograms hpGRF/100 kg body wt were 7 +/- 3, 8 +/- 3, 18 +/- 7, and 107 +/- 55 (mean peak height +/- SEM) ng/ml serum, respectively. Only the response to the 40-microgram dose was greater (P less than 0.05) than the 0-microgram dose. Concentrations of prolactin in serum were not affected by hpGRF treatment. In calves injected with hpGRF (20 micrograms/100 kg body wt) at 6-hr intervals for 48 hr, GH increased from a mean preinjection value of 3.1 ng/ml serum to a mean peak response value of 70 ng/ml serum. Differences in peak GH response between times of injection existed within individual calves (e.g., 10.5 ng/ml vs 184.5 ng/ml serum). Concentrations of GH in calves infused continuously with either 0 or 200 micrograms hpGRF/hr for 6 hr averaged 7.4 +/- 3 and 36.5 +/- 11 ng/ml serum, respectively (P less than 0.05). Concentrations of GH oscillated markedly in hpGRF-infused calves, but oscillations were asynchronous among calves. We conclude that GH response of bull calves to hpGRF is dose dependent and that repeated injections or continuous infusions of hpGRF elicit GH release, although magnitude of response varies considerably. We hypothesize that differences in GH response to hpGRF within and among calves, and pulsatile secretion in the face of hpGRF infusion may be related to the degree of synchrony among exogenous hpGRF and endogenous GRF and somatostatin.     

Influence of 15-keto-metabolites and 13,14-dihydro-15-keto-metabolites of PGE2 and PGF2 alpha as well as of 6-keto-PGF1 alpha as a metabolite of PGI2 on aconitine induced cardiac arrhythmia in rats

The 15-keto-metabolites of PGE2 and PGF2 alpha produced an antiarrhythmic effect on aconitine induced arrhythmias in rats. The ED50 values of these metabolites were approximately 2.0 micrograms/kg. The 13,14-dihydro-15-keto-metabolites of PGE2 and PGF2 alpha had no statistically significant antiarrhythmic effect. PGI2 (0.25-1.00 micrograms/kg) produced an antiarrhythmic effect between 15-54% (ED50 0.75 micrograms/kg), whereas 6-keto-PGF1 alpha, a metabolite of PGI2, showed no significant antiarrhythmic effect. The results suggest a participation of 15-keto-metabolites in the antiarrhythmic effects of PGE2 and PGF2 alpha.     

Cardiovascular responses to opioid agonists injected into the nucleus of tractus solitarius of anesthetized cats

It has been proposed that various opiate receptor subtypes mediate different cardiovascular responses to centrally administered opioids. We evaluated this hypothesis in chloralose-urethane anesthetized cats by monitoring the cardiovascular and respiratory responses to relative mu [morphine, morphiceptin, D-Ala2, MePhe4, Gly-ol5 enkephalin (DAGO)] and delta [D-Ala2, D-Leu5enkephalin (DADL)] agonists microinjected (0.5 ul/kg) into the caudal region of the Nucleus of Tractus Solitarius (NTS). Dynorphin (1-13), an endogenous opioid which exhibits selective affinity towards the kappa receptor, was also tested. Dynorphin at a dose of 50 nMol/kg did not alter cardiovascular or respiratory variables. Morphine (10-54 nMol/kg) and DAGO (50 nMol/kg) had no effect on blood pressure, heart rate or respiratory rate; morphiceptin (100-320 nMol/kg) caused tachycardia only at the highest dose. DADL (10-100 nMol/kg) elicited a dose-dependent depression of blood pressure. High doses of DADL depressed heart rate and respiratory rate. The depressor effects of DADL were reversed by low doses of naloxone (0.1 mg/kg). This dose of naloxone also elicited pressor responses in cats treated with the other opioids and reversed the morphiceptin-induced tachycardia. These data indicate that opioid agonists differ with regard to their cardiovascular and respiratory effects following microinjection into the NTS of anesthetized cats, with the delta agonist DADL showing greatest activity.     

Ischemia-induced changes in sarcolemmal (Na+, K+)-ATPase, K+-pNPPase, sialic acid, and phospholipid in the dog and effects of the nisoldipine and chlorpromazine treatment

This work was undertaken to study functional and structural changes of the cardiac sarcolemmal membrane which was isolated from the ischemic lesion in the dog. The sarcolemmal fraction was prepared, by adopting the method devised by Reeves and Sutko , from the right ventricle and the subendocardial and subepicardial layers of the left ventricle. Ischemic lesion was produced by occlusion of a branch of the left anterior descending coronary artery for a period of 1.5 hr in the thoracotomized dog, followed by release of the occlusion for 3 hr. Nisoldipine, 5 micrograms/kg, was given twice intravenously, and chlorpromazine was infused at a rate of 10 micrograms/kg X min, in addition to the administration of twice bolus doses of 400 micrograms/kg each. Nisoldipine significantly decreased the incidence of premature ventricular contractions and microvascular hemorrhage. Sarcolemmal purity was monitored by using enzyme and chemical markers; the results indicated that the membrane preparation was tenfold purified over the homogenate. Although the activities of ouabain-sensitive (Na+, K+)-ATPase and ouabain-sensitive K+-p-nitrophenylphosphatase ( pNPPase ) of the sarcolemmal preparation isolated from the subendocardial layer were similar to those from the subepicardial layer in the nonischemic left ventricle, a significant decrease in these activities was observed only when the sarcolemmal fraction isolated from the subendocardial layer of ischemic area was compared with that from the subendocardial layer of nonischemic area. In contrast, the sialic acid content of the sarcolemma from the ischemic subendocardial layer was significantly increased compared to that of the nonischemic subendocardial layer. No such changes occurred in sarcolemma prepared from the ischemic subepicardial layer. The total phospholipid content as well as phosphatidylcholine and -ethanolamine contents of the sarcolemmal membrane prepared from the subendocardial layer of ischemic area were significantly decreased compared to nonischemic area. Nisoldipine prevented the ischemia-induced alterations in sarcolemmal (Na+, K+)-ATPase, pNPPase , sialic acid and phospholipids of the subendocardial layer. Chlorpromazine showed a less consistent effect than did Nisoldipine under our experimental conditions. Our study thus demonstrates that the lipid component and function of cardiac sarcolemmal membrane are altered in the early ischemic lesion and that these alterations are nonuniform in distribution and are alleviated by some pharmacological intervention.     

Effect of long-term administration of an analog of growth hormone-releasing factor on the GH response in rats

The effect of the repeated or continuous administration of an analog of GH releasing factor (GH-RF), D-Tyr-1, D-Ala-2, Nle-27, GH-RF(1-29)-NH2 (DBO-29), on the subsequent response to this peptide was investigated in pentobarbital-anesthetized male rats. A sc administration of this analog induced a greater and more prolonged GH release than doses 10 times larger of GH-RF(1-29). The GH increase after sc injection of 10 micrograms/kg bw of the analog was greater than that induced by iv administration of 2 micrograms/kg bw of GH-RF(1-44). Pretreatment with 10 micrograms/kg bw of the analog did not affect the pituitary response to a strong stimulus (20 micrograms/kg bw) of GH-RF(1-44), 24 h later. Pretreatment with the analog in doses of 10 micrograms/kg bw, sc twice a day, 5 days per week for 4 weeks, significantly diminished the GH release in response to a sc injection of the analog (10 micrograms/kg bw), as compared to vehicle-pretreated controls (P less than 0.01). On the other hand, a continuous sc administration of 0.4 micrograms/h of the analog to intact rats for 7 days did not result in a decrease in GH response to a sc injection of the analog (10 micrograms/kg bw). Since the rats injected repeatedly with the analog for 4 weeks still showed a marked, although somewhat reduced response, analogs of this type may be useful clinically.     

Interactions of nimodipine and cocaine on endogenous catecholamines in the squirrel monkey

The effects of nimodipine on the cocaine-induced alterations in blood pressure, heart rate, and plasma catecholamines were studied in the squirrel monkey. Cocaine in intravenously administered doses of 0.5, 1, and 2 mg/kg produced significant increases in blood pressure and significant decreases in heart rate. These cardiovascular changes were associated with transient episodes of arrhythmias and with significant increases in plasma concentrations of dopamine, epinephrine, and norepinephrine. Nimodipine, 1 micrograms/kg/min for 5 min administered intravenously 5 min after cocaine, corrects the cardiovascular and plasma catecholamine concentration changes induced by this alkaloid. The same dose of nimodipine administered 5 min before cocaine prevents elevations of blood pressure. Plasma catecholamine increments are also prevented except for the highest dose of cocaine. Cardiovascular changes induced by cocaine administration in the squirrel monkey are temporally associated with significant increments in plasma catecholamines. Administration of nimodipine prevents or minimizes these endocrine and physiologic changes.     

The synthesis of N-acetyl-leukotriene E4 and its effects on cardiovascular and respiratory function of the anesthetized pig

The effects of the putative bilary metabolite of the peptidoleukotrienes, N-acetyl-leukotriene (LT) E₄ has been investigated in the anesthetized pig. Intravenous bolus doses of synthetic N-acetyl-LTE₄ produced minimal respiratory and cardiovascular actions in the pig. N-acetyl-LTE₄ was approximately 100-fold less active than LTC₄. The actions of N-acetyl-LTE₄ were not blocked by pretreatment of the animals with indomethacin (5 mg/kg iv) or with a selective LTD₄ antagonist L-649,923 (5 mg/kg plus 2 mg/kg/hr iv). In summary, N-acetyl-LTE₄ exerts weak actions in the pig which is consistent with the acetylation process being a mechanism of detoxification.     

Reduction of chronic hypoxic pulmonary hypertension in the rat by beta-aminopropionitrile

We administered antifibrotic agent beta-aminopropionitrile (BAPN) to rats exposed to 10% O2-90% N2 for 3 wk to prevent excess vascular collagen accumulation. Groups of Sprague-Dawley rats studied were air breathing, hypoxic, and hypoxic treated with BAPN, 150 mg/kg twice daily intraperitoneally. After the 3-wk period, we measured mean right ventricular pressure (RVP), the ratio of weight of right ventricle to left ventricle plus septum (RV/LV + S), and hydroxyproline content of the main pulmonary artery (PA) trunk. Hypoxia increased RVP from 14 to 29 mmHg; RVP was 21 mmHg in hypoxic BAPN-treated animals. Hypoxia increased the RV/LV + S ratio from 0.28 to 0.41; the ratio was 0.32 in hypoxic BAPN-treated animals. Hypoxia increased PA hydroxyproline from 20 to 239 micrograms/artery; hydroxyproline was 179 micrograms/artery in hypoxic BAPN-treated animals. Thus BAPN prevented pulmonary hypertension, right ventricular hypertrophy, and excess vascular collagen produced by hypoxia. We conclude that vascular collagen contributes to the maintenance of chronic hypoxic pulmonary hypertension.