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Biomedical subjects

B A Berkowitz

Publications and source records attributed to B A Berkowitz.

At least 109 records · Page 6Linked to original sources
PubMed1977

Antagonism of general anesthesia by naloxone in the rat.

The effect of naloxone, a narcotic antagonist, on the response of animals to painful stimuli during anesthesia was studied. Rats were anesthetized with cyclopropane, halothane, or enflurane in groups of 12. Following induction, inspired anesthetic concentration was gradually reduced to a point at which 35-60 per cent of animals responded to tail clamping. Thereafter the anesthetic concentration was held constant for 30 minutes. Rats in each group then received saline solution or naloxone, 10mg/kg, given intravenously. The response to tail clamping was retested 5 minutes later. In additional experiments EEG's were recorded from rats anesthesized with one of these anesthetics. After a stable light plane of anesthesia had been attained, each animal was given naloxone, 10 mg/kg, iv, and the EEG recorded for an additional 5 minutes. In the tail-clamping experiments, naloxone approximately doubled the number of rats responding during cyclopropane, halothane, or enflurane anesthesia. The EEG patterns of several animals anesthetized with either cyclopropane or halothane changed to patterns consistent with lighter planes of anesthesia after naloxone administration. That naloxone alters the depth of inhalational anesthesia suggests that anesthetics may release an endogenous morphine-like factor (MLF) in the central nervous system.

Anesthesia, General↗
PubMed1977

Vascular adenylate cyclase: role of age and guanine nucleotide activation.

Particulate adenylate cyclase activity was examined in broken cell preparations of rat aorta and mesenteric artery from 3- to 5- and 9- to 13-week-old rats. While basal adenylate cyclase activity of the mesenteric artery was 4-fold greater than aortic enzyme activity, there was no difference in enzyme activity with age. GTP and the GTP analogue, 5'-guanylylimidodiphosphate [Gpp(NH)p] stimulated adenylate cyclase activity. Stimulation by Gpp(NH)p did not differ with age for either tissue and occurred without a detectable lag. The vasodilators, isoproterenol, 2-chloroadenosine and prostaglandin E1, were ineffective in increasing adenylate cyclase activity, although marked stimulation was demonstrated with both sodium fluoride and Gpp(NH)p. Even in combination with Gpp(NH)p, isoproterenol did not increase particulate adenylate cyclase activity of these blood vessels; however, with intact arteries, isoproterenol (10(-7)M) did increase aortic and mesenteric cyclic AMP levels. Isoproterenol increased cyclic AMP levels in rats of both ages, at a time when isoproterenol was less effective in maximally relaxing aortic strips from 9- to 13-week-old rats. These data indicate that diminished aortic relaxation with age is not associated with a reduced ability of vascular relaxants to increase aortic cyclic AMP levels. Furthermore, as a first step in establishing that guanine nucleotides are regulators of vascular adenylate cyclase, both GTP and Gpp(NH)p were found to be potent activators of adenylate cyclase from blood vessels.

Adenosine↗
PubMed1977

Role of the thyroid gland in the development and maintenance of spontaneous hypertension in rats.

We studied the vascular mechanisms involved in the prevention of the development of hypertension following thyroidectomy. Ablation of the thyroid gland of 4-week-old spontaneously hypertensive (SH) rats inhibited the development of hypertension and reduced the sensitivity of aortic strips to the vasoconstrictors phenylephrine, norepinephrine, and potassium chloride and the vasodilator isoproterenol. Daily injections of a replacement dose of L-thyroxine caused a complete recurrence of hypertension in these rats. This was accompanied by complete recovery of the aortic sensitivity to the vasconstrictors and isoproterenol. In 10-week-old SH rats thyroidectomy prevented a further increase of blood pressure but did not reverse the hypertention. Here, the aortic sensitivity to vasoactive substances also was reduced but to a lesser extent than in the SH rats thyroidectomized at 4 weeks of age. Hypertension was not obviously associated with hyperfunction of the thyroid gland. Furthermore, we found that at 4 weeks of age, during the prehypertensive period, SH rats have a significantly lower (42%) serum thyroxine level than age-matched normotensive Kyoto Wistar, American Wistar, and Sprague-Dawley rats. However, at 6 and 9 weeks, the serum thyroxine levels of SH rats are similar to those of the normotensive rats. In conclusion, we propose that the reduced sensitivity to endogenous vasoconstrictors in arteries of SH rats following juvenile ablation of the thyroid gland may prevent the development of hypertension in these rats. Moreover, the low serum thyroxine level in SH rats during the prehypertensive period may explain why young SH rats do not develop hypertension before 6 weeks of age.

Age Factors↗
PubMed1977

Calcium antagonist activity of methadone, l-acetylmethadol and l-pentazocine in the rat aortic strip.

These studies described physiologic evidence that methadone and related compounds can function as calcium antagonists. Methadone (1 X 10(-5)-1 X 10(-4) M) inhibited the contraction of the isolated rat aortic strip preparation produced by potassium chloride, norepinephrine, l-pentazocine or morphine. Methadone was most effective in diminishing aortic contractions which were highly dependent on the concentration of extracellular calcium. The d- and l-isomers of methadone were equipotent inhibitors of aortic contraction. l-Acetylmethadol (1 X 10(-6)-1 X 10(-5) M) was a potent inhibitor of vascular contraction. l-Pentazocine inhibited its own ability to contract the aorta as the dose was raised 3 X 10(-5) M. The inhibition of aortic contraction produced by methadone, l-acetylmethadol and l-pentazocine was overcome by raising the concentration of calcium in the tissue baths. The inhibition of contraction and the apparent calcium-antagonist activity of these drugs best correlates with their lipid solubility. Since calcium is a critical regulator of cellular function, the calcium-antagonist action of methadone and l-acetylmethadol may prove to be important in mediating some of their pharmacologic and toxicologic effects.

Animals↗
PubMed1977

Nitrous oxide analgesia: reversal by naloxone and development of tolerance.

The objective of this study was to characterize further the nature of nitrous oxide analgesia and to establish if tolerance to nitrous oxide occurs. Methods for studying the analgesic action of a gas are described. In mice, nitrous oxide is analgesic in the phenylquinone and acetic acid abdominal constriction tests. Aspirin and very high doses of alcohol are also active in these tests; however, only nitrous oxide-induced analgesia is antagonized by narcotic antagonists. These data indicate the mechanism of action of nitrous oxide analgesia differs from that of the other two drugs. Nitrous oxide produced a dose-related analgesic response in rats (ED50, 67%) as measured by the tail-flick method. Naloxone, 5 to 30 mg/kg, also antagonized nitrous oxide analgesia in rats. Lower doses of the antagonist were not effective. Tolerance developed to the effects of nitrous oxide in both rats and mice after prolonged exposure. These data lend support to the hypothesis that nitrous oxide and opiates have a significant pharmacologic resemblance and may ultimately produce similar molecular events in the brain leading to the relief of pain.

Acetates↗
PubMed1976

Nitrous oxide "analgesia": resemblance to opiate action.

Nitrous oxide produced a dose-related "analgesia" in mice (median effective dose, 55 percent). The analgesia was evaluated by means of a phenylquinone writhing test. Narcotic antagonists or chronic morphinization reduced nitrous oxide analgesia. Either nitrous oxide releases an endogenous analgesic or narcotic antagonists have analgesic antagonist properties heretofore unappreciated.

Analgesia↗
PubMed1976

Pharmacokinetics of naloxone in rats and in man: basis for its potency and short duration of action.

Using a specific and sensitive radioimmunoassay, naloxone concentrations in the brains and sera of rats were measured at intervals for four hours following iv injection (5 mg/kg). Decrement curves of naloxone were compared with those after iv injection of morphine (5 mg/kg). Serum concentration of naloxone at 5 minutes was 1.45 +/- 0.1 mug/ml (mean +/- SE) and that of morphine was 1.0 +/- 0.08 mug/ml. Their serum half-lives from one to four hours were approximately the same, 30-40 minutes. With naloxone, the brain-serum concentration ratios ranged from 2.7 to 4.6. Concentration of naloxone in the brain declined parallel to that in the serum. However, with morphine the initial brain concentration was approximately one tenth that in the serum (0.096 +/- 0.04 mug/ml). The brain morphine concentration was sustained for one hour, while serum morphine concentrations declined from 1.0 to 0.19 mug/ml during this period. Two minutes after iv injection of naloxone HCl (0.4 mg) in nine healthy volunteers, the serum drug concentration was 0.01 +/- .001 mug/ml. At 5 minutes, 97 per cent of the administered dose was no longer found in the serum, the serum concentration being 0.004 +/- .0003 mug/ml. From 20 minutes to two hours after injection, the calculated mean serum half-life of naloxone was 64 minutes. These results suggest that the rapid penetrance of naloxone into the brain and the high brain-serum concentration ratio contribute to its rapid onset of action and potency as a narcotic antagonist. The rapid decline of naloxone concentration in the brain found in the animal model, in contrast to that of morphine, could be the basis for its relatively short duration of action.

Adult↗
PubMed1976

Vascular contraction: effect of age and extracellular calcium.

Contractile responses to norepinephrine, serotonin and potassium chloride were determined in vitro for aortas from rats 1, 2, 3 and 12 months of age. Responses were measured under conditions of optimum length (3 cm) and resting tension (1 g). Aortic response to a maximum concentration of norepinephrine was greatest for vessels from 3-month-old rats. For all three agonists, aortas from 12-month-old rats contracted less than aortas from 2-month-old rats. The role of calcium in aortic contraction also varied with age. For rats 1-2 months of age, serotonin and potassium chloride-induced contractions were highly dependent on extracellular calcium, while norepinephrine-induced contraction showed only a slight dependence on extracellular calcium. In 12-month-old rats, all agonists were dependent on extracellular calcium for contraction. For serotonin and norepinephrine, the ability of muscle to contract in calcium-free media was decreased with age. Although the mechanism for such an altered dependence of aortic contraction on calcium has not been established, it is proposed that the utilization of extracellular calcium for contraction is not only agonist- but also age-dependent.

Aging↗
PubMed1976

The relationship of pharmacokinetics to pharmacological activity: morphine, methadone and naloxone.

This review illustrates current approaches to the study of the disposition in man of the strong analagesics morphine and methadone and the narcotic antagonist naloxone. Morphine administered orally is rapidly absorbed but equally rapidly metabolised to morphine glucuronide. This contributes to the diminished oral efficacy of morphine. Following intramuscular administration morphine is very rapidly absorbed. After intravenous injection, the serum levels of morphine during the first 10 minutes are higher and more variable in older patients. The half-life of morphine between 20 minutes and 6 hours is 2 to 3 hours and this value does not appear to be influenced by the age of the patient. Similar half-lives for morphine have been reported to normal volunteers and in anaethetised patients who received morphine. Thus, surgical anaesthesia may not markedly influence morphine half-life and disposition. Based on urinary excretion data in man, accelerated morphine metabolism and excretion do not contribute to morphine tolerance. Methadone is now widely used in the treatment of narcotic abuse. The half-life of methadone averages 25 hours. The prolonged retention of methadone in the plasma may be related to its extensive binding to plasma proteins. With chronic dosing, studies in both animals and man indicate an increase in the metabolism of methadone. Unlike morphine, the urinary excretion of methadone increases with acidification of the urine. Women may metabolise methadone to a greater extent than do men. With the exception of pupillary effects, the plasma levels of methadone correlate poorly with its pharmacological activity. There is a marked variation in methadone plasma levels between patients and within the same patient. Naloxone rapidly disappears from the serum in man and the initial distribution phase has a half-life of 4 minutes. The half-life of naloxone in serum following distribution is 64 minutes. Based on animal studies, the rapid onset of the narcotic antagonist action of naloxone can be related to its rapid entry into the brain, whereas its potency stems in part from its high lipid solubility which allows a high brain concentration to be achieved. The short duration of action of naloxone may result from its rapid egress from the brain.

Absorption↗
PubMed1976

Decreased vascular relaxation in hypertension.

Relaxation of spirally cut aortic strips was diminished in vessels from both spontaneously hypertensive rats and renal hypertensive rats. Aortic relaxation was decreased in response to the cyclic nucleotides and the beta adrenergic stimulant, isoproterenol, in both models, of hypertension. Defective aortic relaxation also occurred with two other vasodilators, nitroglycerin and adenosine. Further evidence for a reduced relaxant ability of blood vessels from hypertensive rats was obtained by measuring aortic relaxation after exposure and subsequent removal of vascular contractile agonists. The time for aortic preparations from spontaneously hypertensive rats to relax to base-line tension after maximum contraction with norepinephrine, serotonin and potassium chloride was significantly prolonged compared to recovery time for vessels from Kyoto Wistar normotensive rats. Treatment of the spontaneously hypertensive rat with reserpine, but not hydralazine, resulted in an improved ability of aortic preparations to relax. Based on these data, we propose that defects in vascular relaxation may contribute to hypertension and that some antihypertensive drugs may improve or facilitate vascular relaxation.

Adenosine↗
PubMed1976

Stereoselective and calcium-dependent contractile effects of narcotic antagonist analgesics in the vascular smooth muscle of the rat.

In patients, pentazocine administered i.v. can have an unusual action for a strong analgesic-an elevation of blood pressure. The objective of this study in rats was to better quantify and explain the molecular mechanism for the vascular action of l-pentazocine and compare it with other analgesics and narcotic antagonists. In anesthetized rats, l-pentazocine (0.3-3 mg/kg i.v.) elevated blood pressure and this effect was potentiated in pithed rats. The contraction appeared to be nonadrenergic as it was not blocked by the alpha blocker, phenoxybenzamine. In vitro, morphine (ED50 = 4 X 10(-5) M) and the l-isomers of pentazocine (ED50 = 8 X 10(-6) M) contracted the spirally cut aortic strip. The l-isomers were approximately 5 times more potent than their d-enantiomers. Contraction of the aorta by l-pentazocine was not inhibited by dibenamine, atropine, diphenhydramine, pyrilamine or indomethacin nor potentiated by propranolol. On the other hand, not only was the contraction highly dependent on the concentration of calcium in the bath but it was also blocked by verapamil and SKF-525A, drugs known to inhibit transmembrane calcium influx. Naloxone (3 X 10(-4) to 1 X 10(-3) M), which produced no contractile effect by itself, reduced aortic contraction of l-pentazocine to the greatest extent, that of potassium moderately and that of norepinephrine only slightly. The naloxone blockade of l-pentazocine vascular contraction was reversed by increasing Ca++ concentration in the media, suggesting the action of naloxone may resemble a calcium blocker. It is proposed that a direct, stereoselective and calcium dependent vascular action of l-pentazocine contributes to its ability to raise blood pressure. The possibility that in high doses narcotic antagonists may decrease calcium influx should also be considered.

Analgesics, Opioid↗
PubMed1975

The diposi tion of morphine in surgical patients.

The disposition of serum morphine following administration of 10 mg/70 kg was determined by a sensitive and specific radioimmunoassay in 31 anethetized surgical patients ranging in age from 23 to 75 yr. Following iv injection, 93 per cent of the morphine disappeared from the serum within 5 min. The early serum levels of the drug (2 min) correlated directly with the patients' ages (r equal to 0.63, p smaller than 0.01). Patient 23 to 50 yr of age averaged 0.29 mug/ml, whereas patients 51 to 75 ur of age averaged 70 percent higher, 0.49 mug/ml. The serum half-life between 10 and 240 min was independent of age and averaged about 2 hr after either iv or im administration. Following im admininstration, morphine was rapidly absorbed, with peak levels occurring within 10 to 20 min. The decline in morphine serum levels paralleled the decline in morphine analgesia and was coincident with the apperance of morphine glucuronide in the serum. These studies demonstrate the applicability and specificity of the radioimmunoassay for morphine and suggest that serum levels of morphine may be a useful and objective indicator of its pharmacologic activity.

Adult↗
PubMed1975

Differences between the effects of dopamine and apomorphine on rat aortic strips.

Dopamine and apomorphine have been compared with regard to contraction and relaxation of aortic strips prepared from rats of different ages. Both dopamine and apomorphine contracted aortic strips from older (9-12 weeks) rats to greater maximal tension than preparations from younger (3--5 weeks) animals. Contraction in response to both agonists could be blocked by the alpha-blocker, Dibenamine. In contrast to dopamine contraction by apomorphine was associated with the development of tachyphylaxis. Both apomorphine and dopamine relaxed the aorta after alpha blockade, however, the relaxation produced by these drugs differed in two major aspects. First, dopamine-induced relaxation was greatest in aortic strips from young rats compared to older rats whereas relaxation with apomorphine was not age dependent. Second, dopamine-induced relaxation was abolished by propranolol but not haloperidol whereas apomorphine relaxation was only blocked by haloperidol. These data establish that the aortic relaxation caused by dopamine is most likely a beta-adrenergically mediated response whereas that produced by apomorphine is not. Moreover, only dopamine was able to increase the concentration of rat aortic cyclic AMP. Should these data be applicable to other vascular beds or species, it is possible that the vascular effects of dopamine will be influenced by age and drugs which impinge on cyclic nucleotide disposition.

Age Factors↗
PubMed1975

Sex hormones and tyrosine hydroxylase activity in vascular and adrenal tissue.

Vascular tyrosine hydroxylase (TH) activity did not appear to be affected by the sex hormones. There were no differences in enzyme activity in the mesenteric artery or vein taken from male and female normotensive or spontaneously hypertensive rats. Castration of either male or female rats did not alter mesenteric artery or vein TH activity, and the administration of estradiol, progesterone, or testosterone also had no effect on vascular TH activity. However, the sex hormones did alter activity in other tissues. Estradiol and progesterone administration to intact female rats increased adrenal TH activity, whereas castration of the male rat decreased it. Although the sex hormones were not important regulators of TH in blood vessels, vascular TH activity did appear to be under some hormonal regulation since hypophysectomy decreased mesenteric artery enzyme activity. Hypophysectomy studies also indicated that adrenal TH activity was under some hormonal regulation.

Adrenal Glands↗
PubMed1975

Disposition of naloxone: use of a new radioimmunoassay.

Understanding of the pharmacology of the narcotic antagonist naloxone has been limited by the lack of a convenient and sensitive method of assay. A radioimmunoassay for naloxone has been developed and is described. It is applicable for drug analysis in either serum or brain. The limit of sensitivity of the assay was 0.1 ng. Naloxone glucuronide, noroxymorphone (nor-naloxone) and morphine were not recognized by the antibody whereas naltrexone and 6-hydroxynaloxone were able to displace naloxone-3H from the antibody. The assay was of sufficient sensitivity to follow the serum levels of naloxone in man for up to 2 hours after an i.v. injection of 0.4 mg. In animal studies, the biologic half-lives of naloxone or morphine (5 mg/kg) were compared after s.c. injection in rats. The peak serum levels A (1 mu/mo), time to peak serum levels (less than 1/2 hour), and serum half-life (40 minutes) were comparable. However, the brain entry and egress of the two compounds differed markedly. Peak brain levels of naloxone occurred within 15 minutes and had declined by 50% within 1 hour, whereas the peak brain levels of morphine were sustained for up to 2 hours. At peak serum levels, the brain/serum ratio for morphine was 0.1 whereas for naloxone it was 15 times greater. We suggest the high brain/serum ratio of naloxone contributes to its potency whereas the rapid egress from the brain is important in the short duration of action of naloxone.

Animals↗
PubMed1975

Antihypertensive drugs and catecholamine metabolism: effects of reserpine and hydralazine on tyrosine hydroxylase activity and norepinephrine concentrations in the spontaneously hypertensive rat.

The antihypertensive drugs, reserpine and hydralazine, produce different effects on tyrosine hydroxylase activity and norepinephrine levels in blood vessels and other tissues of the spontaneously hypertensive rat at doses which cause an equivalent reduction in blood pressure. Reserpine administration is associated with increased tyrosine hydroxylase activity in the mesenteric artery, mesenteric vein and adrenal, but the vasculature appears more sensitive to the effects of reserpine than the adrenal. This increase in tyrosine hydroxylase activity can be related to catecholamine depletion in the mesenteric artery, mesenteric vein and adrenal. Since chlorisondamine, a ganglionic blocking agent, diminished the ability of reserpine to increase tyrosine hydroxylase activity in the mesenteric artery and adrenal, it is likely that increased nerve activity is involved in regulation of the enzyme in both tissues. Hydralazine neither alters tyrosine hydroxylase activity in arteries or veins, nor depletes catecholamine levels in these tissues. In the adrenal, hydralazine increases tyrosine hydroxylase activity independently of any change in catecholamine levels. It would appear that changes in tyrosine hydroxylase activity produced by antihypertensive drugs are organ dependent and may involve both neuronal activity and amine depletion.

Adrenal Glands↗