The effect of propranolol on exercise induced tachycardia is determined by plasma concentration and the density of adrenergic receptors on leukocytes

Summary The chronotropic response to a single oral dose of propranolol in 23 healthy subjects has been related to the plasma propranolol concentration and the density of -adrenoceptors on peripheral polymorphonuclear leucocytes. The percentage reduction in exercise-induced tachycardia was significantly correlated with the log plasma propranolol concentration within subjects but not between subjects. Taking the concentration of the active metabolite 4-hydroxypropranolol into account did not improve the interindividual correlation. The reduction in exercise-induced tachycardia was significantly correlated with the maximum binding density of (¹²⁵I)-hydroxybenzylpindolol on polymorphonuclear leucocyte membrane fragments measured before medication. A response index (% reduction in exercise-induced tachycardia/plasma propranolol concentration) was correlated with the maximum binding density of (¹²⁵I)-hydroxybenzylpindolol (predrug) at 2 h (r_s=0.72), 4 h (r_s=0.84) and 6 h (r_s=0.73) after dosing. The data suggest that interindividual variation in the response to propranolol after a single oral dose is determined by interindividual differences both in plasma propranolol and adrenoceptor density.     

Noradrenergic responses in rat hippocampus: evidence for medication by alpha and beta receptors in the in vitro slice

The effect of perfused norepinephrine (NE) on evoked potentials in CA1 of the in vitro rat hippocampus was examined. Weak and variable effects on population spike amplitude were observed, with lower doses of NE generally producing excitations and higher doses more often producing inhibitions. Clonidine, an alpha-receptor agonist, produced a dose-dependent inhibition of population spike amplitude; this inhibition was effectively antagonized by the alpha-antagonist, phentolamine. Isoproterenol (ISO), a beta-agonist, produced marked increases in population spike amplitude which could be antagonized by timolol, a beta-receptor antagonist. Phentolamine did not antagonize the excitations produced by ISO, and timolol had no effect on the inhibitions seen with clonidine. After pretreatment with either phentolamine or timolol, NE perfusion elicited robust and consistent elevations or reductions in the population spike, respectively. A potent cyclic AMP derivative, 8-p-chlorophenylthio cyclic AMP, produced large increases in population spike amplitude which appeared similar to the responses seen with beta-agonists. No changes in field EPSP amplitudes were observed with any of the drugs tested. Taken together, these results suggest that NE may interact with alpha-adrenergic receptors to decrease pyramidal cell excitability, and the beta-adrenergic receptors to increase pyramidal cell excitability; the beta-effect may involve cAMP.     

Noradrenergic responses in rat hippocampus: Evidence for mediation by α and β receptors in the in vitro slice

The effect of perfused norepinephrine (NE) on evoked potentials in CA1 of the in vitro rat hippocampus was examined. Weak and variable effects on population spike amplitude were observed, with lower doses of NE generally producing excitations and higher doses more often producing inhibitions. Clonidine, an α-receptor agonist, produced a dose-dependent inhibition of population spike amplitude; this inhibition was effectively antagonized by the α-antagonist, phentolamine. Isoproterenol (ISO), a β-agonist, produced marked increases in population spike amplitude which could be antagonized by timolol, a β-receptor antagonist. Phentolamine did not antagonize the excitations produced by ISO, and timolol had no effect on the inhibitions seen with clonidine. After pretreatment with either phentolamine or timolol, NE perfusion elicited robust and consistent elevations or reductions in the population spike, respectively. A potent cyclic AMP derivative, 8-p-chlorophenylthio cyclic AMP, produced large increases in population spike amplitude which appeared similar to the responses seen with β-agonists. No changes in field EPSP amplitudes were observed with any of the drugs tested. Taken together, these results suggest that NE may interact with α-adrenergic receptors to decrease pyramidal cell excitability, and with β-adrenergic receptors to increase pyramidal cell excitability; the β-effect may involve cAMP.     

Continuous light paradoxically reduces catecholamine-induced melatonin production

Exposure of rats to continuous light for 14 days reduced the stimulation of melatonin content in the pineal gland produced by either isoproterenol administration or exposure to darkness. Since continuous light has been reported to enhance many intermediate biochemical events leading to the synthesis of melatonin, these results demonstrate the importance of examining the end-product of an organ when evaluating the physiological significance of biochemical changes in model biological systems.     

Induction of c-fos and TIS genes in cultured rat astrocytes by neurotransmitters

The interaction of neurotransmitters with their specific receptors initiates a cascade of intracellular biochemical events which lead to induction of specific genes. Included in this cascade is the rapid and transient induction of a family of primary early response genes we term TIS genes (Lim et al.: Oncogene 1: 263-270, 1987). Expression of six TIS gene, including c-fos, was examined in secondary cultures of rat neocortical astrocytes exposed to muscarinic and adrenergic agonists and antagonists to study the early genomic responses which accompany neurotransmitter-induced alteration of glial morphology and physiology. Carbachol induced accumulation of mRNA for c-fos and the other TIS genes. Carbachol-mediated induction of TIS mRNA expression was sensitive to atropine blockade and was potentiated by lithium. Norepinephrine (NE), isoproterenol, or phenylephrine also induced TIS mRNA accumulation. In order to determine which second-messenger pathways mediate NE induction of TIS gene expression, the influences of the beta(B) antagonist propranolol (PR), the alpha I(AI) antagonist prazosin (PZ), and the alpha 2(A2) antagonist yohimbine (YB) were examined. The induction of TIS1 mRNA by NE was partially blocked by PR or PZ alone, and completely abolished by both antagonists in combination. YB had no effect on TIS1 mRNA expression. These results suggest that NE induces TIS1 mRNA through both B- and A 1-adrenergic, but not A2, pathways. The lack of effect of inhibitors of phospholipase A2 and cyclooxygenase suggests that the A1 component is mediated through a protein kinase C pathway. The induction of transient gene expression by neurotransmitters may mediate the secondary genomic responses and phenotypic changes occurring in astrocytes in response to alterations in neuronal neurotransmitter release.     

Immediate haemodynamic effects of prenalterol,a new adrenergic beta-1-receptor agonist,in healthy volunteers

Summary The acute haemodynamic effects of prenalterol, a selective adrenergic beta-1-receptor agonist, were studied in eight healthy male volunteers. Prenalterol was administered i.v. in five increasing doses to a cumulative dose of 5.55 mg. After the last dose of prenalterol, three doses of the selective adrenergic beta-1-receptor antagonist metoprolol were administered i.v. to a cumulative dose of 17.5 mg. After each dose, cardiac output (CO), stroke volume (SV), blood pressure (BP), heart rate (HR), systolic time intervals (STI) and forearm blood flow (FBF) were determined.Prenalterol had the following effects: CO was significantly increased by 21.0% after the fourth dose, but the fifth dose did not further change CO. SV was unchanged after the first four doses, but after the fifth dose a significant decrease in SV of 7.0% was seen. Mean BP was increased significantly by 7.7%, but diastolic BP remained unchanged. HR was increased by 28.4%. Total peripheral resistance was reduced by 8.8%. STI were reduced significantly after the second dose, which indicates that prenalterol has a positive inotropic action. FBF was increased significantly after the fourth dose. After the third dose of metoprolol, the CO, SV, mean BP, HR, STI and FBF had returned to their control values. It is concluded that prenalterol has positive inotropic and chronotropic effects on the myocardium, and that metoprolol is a specific antidote.     

不同的机制介导β肾上腺素受体激动产生的冠状动脉和股动脉血管舒张(英文)

目的:研究β肾上腺素受体激动产生的猪冠状动脉和股动脉血管扩张是否通过不同的机制介导。方法:利用器官组织浴血管环法观察冠状动脉和股动脉在给予不同浓度的异丙肾上腺素(ISO)后血管张力的变化,以及去除血管内皮,一氧化氮合成酶(NOS)抑制,β_1和/或β_2受体阻断后对其的影响。结果:无论冠状动脉或股动脉ISO均产生浓度依赖的血管舒张。去除内皮,NOS抑制,β_2受体阻断不影响ISO产生的冠状动脉血管舒张,而完全消除了股动脉的血管舒张。β_1受体阻断不影响ISO产生的股动脉血管舒张,但消除了冠状动脉的血管舒张。结论:ISO产生的猪冠状动脉血管舒张通过β_1受体介导,不通过L-精氨酸/一氧化氮通路,而在股动脉通过β_2受体和L-精氨酸/一氧化氮通路。     

Effects of prostaglandin E1 on lung function in bronchial asthma

Summary 1. Prostaglandin E₁ aerosol was given to a total of 37 patients with chronic airways obstruction. — 2. In 5 patients lung function was not improved by PGE₁. In 18 others it improved, but in 3 of these isoprenaline caused a further improvement. — 3. In the majority of the patients it caused transient cough followed by a definite improvement of vital capacity and peak flow, which reached its peak after 30–40 min after the inhalation. The prostaglandin cough could not be prevented by isoprenaline aerosol given beforehand. It is thought possible that this cough was mediated by special receptors. — 4. It is concluded that prostaglandin E₁ is a potent bronchodilator in man, the action of which is possibly mediated by a mechanism different from that of isoprenaline. Given in maximum effective doses isoprenaline had, at least in some patients, a stronger dilator action.     

Enhanced Renin Secretion in Adrenalectomized Rats with Glucocorticoid-induced Hypertension

The role of circulating epinephrine in the regulation of renin release was studied in unanesthetized rats with glucocorticoid-induced hypertension. Biadrenalectomized Wistar rats were made hypertensive with methylprednisolone (20 mg/kg s.c. weekly) for 2 weeks and supplemented with deoxycorticosterone pivalate (10 mg/kg s.c. weekly). Sham-operated controls received the same treatment. Baseline weight, mean intra-arterial blood pressure and heart rate of the groups were the same. In both adrenalectomized and sham-operated rats plasma renin activity was determined after a 30 min infusion of the beta-adrenoceptor stimulant isoproterenol (40 ng/min) or its vehicle. Isoproterenol had no blood pressure effect and accelerated heart rate to a similar extent in rats with and without adrenals. Plasma renin activity was significantly higher in epinephrine-deficient than in sham-operated rats. Renin secretion was significantly enhanced by isoproterenol in both groups of rats. These data therefore indicate that in rats with glucocorticoid-induced hypertension the renin-angiotensin system is activated by adrenalectomy, despite the fact that adrenal insufficiency cannot develop. It also appears that rats lacking of circulating epinephrine for a prolonged period do not exhibit an abnormal responsiveness of renin secretion to the stimulation of renal beta-adrenoceptors.