Further characterization of the receptors involved in the positive inotropic effect of histamine on rabbit papillary muscle

The effects of histamine on the force of contraction and calcium-dependent action potentials were studied in rabbit ventricular papillary muscles. The positive inotropic effect of histamine seems to be dependent on stimulation of H1 and H2 receptors. The H1 antagonist chlorpheniramine produced a competitive blockade of the positive inotropic effects of histamine. Cimetidine produced a competitive blockade, which was apparent only after blockade of H1 receptors. Histamine increased the maximum upstroke velocity of slow action potentials. This effect can be entirely accounted for by stimulation of H2 receptors. The phosphodiesterase inhibitor 3-isobutyl-methyl-xanthine potentiated the H2 receptor mediated effects of histamine on the force of contraction and slow action potentials. We conclude that rabbit ventricular muscle possesses both H1 and H2 receptors that mediate the positive inotropic effect of histamine. The H2-mediated effect seems to be causally related to an increase in the calcium slow inward current and is probably linked to an enhanced cellular cyclic adenosine monophosphate content. The mechanism of the H1-mediated positive inotropic effect remains unknown.     

Spasmolytic effect of histamine in the isolated intestine of the hamster (Cricetus auratus)]

A comparative study of the effects produced by histamine on 15 different sections of the small intestine of hamsters (Cricetus auratus) from the stomach to the ileocecal valve was performed to find a substitute for that of guinea pigs and to ascertain which of the sections was the most sensitive. Changes in tone, amplitude and frequency of contractions with respect to control (spontaneous motility, were significant (P less than 0.01); the variance analysis showed no significant variations in the sensitivity or the motility of the different sections.     

Inhibitory effect of GnRH on isolated rat uterine muscle contractility

The effect of GnRH upon uterine contractions of both non-pregnant and pregnant rats was examined in vitro. In the non-pregnant rat uterus, GnRH inhibited in a concentration-and-time dependent manner the contractions induced by acetylcholine and oxytocin, but not those caused by bradykinin and angiotensin II. GnRH also inhibited the rhythmic contractions induced by oxytocin in uterine strips from late pregnant rats. These findings show that GnRH has a direct inhibitory effect on the rat uterine contractions, suggesting that GnRH-like substances may exert modulatory influences upon rat uterine contractility.     

The effect of histamine on the growth of cultured fibroblasts isolated from normal and keloid tissue

Cultured fibroblasts derived from human keloid tissue are presented as a possible model system for studying the genetic regulation of cell growth. Histamine is shown to have a marked effect on the growth of cultured fibroblasts. A small increase in growth rate is seen during the log phase of the culture cycle and a 50% increase in cell number is observed during the plateau phase. Differences in the extent of growth stimulation are observed between strains isolated from different individuals. While most strains showed approximately 50% stimulation, a few were not stimulated and some strains gave a 100% or greater increase in cell number due to histamine. This phenotypic difference in extent of growth stimulation in response to histamine cannot be attributed to the gene or genes for keloid formation. However, elevated levels of histamine in vivo may be a contributing factor to the abnormal cell growth observed in this disorder. The extent of growth stimulation due to histamine decreases with repeated subculturing.     

The effect of acidosis on excitation-contraction coupling in isolated ferret heart muscle

The contractile response to acidosis is the final product of a number of different changes in the excitation-contraction coupling pathway: (i) Ca_i increases and subsequently decreases during acidosis; (ii) the action potential becomes longer; (iii) the sensitivity of the contractile proteins to Ca²⁺ decreases. The increase of Ca_i and the lengthening of the action potential may help to maintain contractile function, although this advantage may be offset if spontaneous Ca^2– release from the s.r. occurs, secondary to the increase of Ca_i. The recovery of force shown in figure 1 occurs at a time when the calcium transient is decreasing, and therefore represents an increasing sensitivity of the contractile proteins to Ca_i, probably due to a recovery of intracellular pH(6), although it is also possible that a disappearance of spontaneous Ca²⁺ releases from the s.r. may be contributing [2].     

The effect of methacholine and histamine on cyclic AMP-dependent protein kinase activity in the guinea-pig isolated trachea.

The effects of methacholine and histamine were examined on cyclic AMP-dependent protein kinase (A-kinase) activity in guinea-pig isolated trachea, using kemptide as a substrate for phosphorylation during the determination of the enzyme activity. Methacholine (EC90, 10 microM) induced a rapid reduction in the basal A-kinase activity ratio, which was maximal after 30 s. This initial reduction coincided with the early phase of isometric tension development, and returned to control levels 4 min after the addition of methacholine. Pretreatment with atropine inhibited the methacholine response. In contrast, histamine (EC90, 30 microM) was without effect upon A-kinase activity ratio. The results establish the sensitivity of the A-kinase assay using kemptide and demonstrate that not all contractile agonists have the capacity to inhibit basal activity of A-kinase in airway smooth muscle.     

大黄素对大鼠离体空肠平滑肌收缩的影响

目的：观察大黄素（emodin）对大鼠离体空肠平滑肌收缩功能的影响,并探讨其作用机制。方法：大鼠离体空肠标本随机分为7组（n=6）：对照组,大黄素剂量组（1,5,10,20μmol／L）,普萘洛尔（PRO）加大黄素组,格列苯脲（GLI）加大黄素组,NG-基-L厂精氨酸甲酯（1．NAME）加大黄素组,无钙K-H液对照组及无钙K-H液大黄素组。采用颈椎离断法处死大鼠并分离其空肠,将肠段标本与张力换能器相连并置于氧饱和的K-H液中。采用BL-420E＋生物信号采集处理系统记录大鼠空肠平滑肌的收缩张力（TE）,幅度（AM）和频率（FR）的影响。结果：①大黄素能使大鼠离体空肠平滑肌的收缩张力和幅度明显下降,且呈剂量依赖性（P〈0．05,P〈0．01）;对频率无明显影响。②普萘洛尔（P〈0．05）、格列苯脲（P〈0．01）可部分阻断大黄素对空肠平滑肌的抑制作用。③L．NAME对大黄素所引起的空肠平滑肌的抑制作用无影响。④氯化钙所引起的空肠平滑肌收缩可被大黄素所抑制（P〈0．01）。结论：大黄素能明显减弱大鼠离体空肠平滑肌的收缩张力和收缩幅度,对收缩频率无影响。这种作用可能是通过兴奋肾上腺素8受体、兴奋ATP敏感钾通道、阻断细胞膜上钙离子通道实现。     

The effect of low-level activation on the mechanical properties of isolated frog muscle fibers

The mechanical properties, as revealed by minute length changes, of isolated twitch fibers of the frog have been studied at rest and during low-level activation. Resting tension is 77 ± 23 mN/cm² (mean ± SD) at 2.2 µm sarcomere length.¹ The slope of the tension curve (ΔP/ΔL) recorded during a constant-speed length change of a resting fiber is initially large. At length changes exceeding about 0.18 % of the initial length of the fiber ΔP/ΔL falls abruptly and remains close to zero during the rest of the length change. The amplitude of the tension response is reduced after a length change and returns to normal in about 3 min. Hypertonic sucrose-Ringer solutions cause a small, maintained rise in tension up to 1.4–1.6 times normal osmotic strength. Higher sucrose concentrations cause relatively large, transient tension responses. The initial ΔP/ΔL is increased in moderately hypertonic solutions; it may be reduced in more strongly hypertonic solutions. Elevated [K]_o (range 10–17.5 mM) causes a marked reduction in ΔP/ΔL. In this range of [K]_o the reduction is not accompanied by changes in resting tension. Addition of 1–1.5 mM caffeine to the Ringer solution affects the resting tension very little but also reduces ΔP/ΔL. The results suggest that stiffness and tension development are not related in a simple way.     

Chaperone-like effect of the linker on the isolated C-terminal domain of rabbit muscle creatine kinase

Intramolecular chaperones (IMCs), which are specific domains/segments encoded in the primary structure of proteins, exhibit chaperone-like activity against the aggregation of the other domains in the same molecule. In this research, we found that the truncation of the linker greatly promoted the thermal aggregation of the isolated C-terminal domain (CTD) of rabbit muscle creatine kinase (RMCK). Either the existence of the linker covalently linked to CTD or the supply of the synthetic linker peptide additionally could successfully protect the CTD of RMCK against aggregation in a concentration-dependent manner. Truncated fragments of the linker also behaved as a chaperone-like effect with lower efficiency, revealing the importance of its C-terminal half in the IMC function of the linker. The aggregation sites in the CTD of RMCK were identified by molecular dynamics simulations. Mutational analysis of the three key hydrophobic residues resulted in opposing effects on the thermal aggregation between the CTD with intact or partial linker, confirming the role of linker as a lid to protect the hydrophobic residues against exposure to solvent. These observations suggested that the linkers in multidomain proteins could act as IMCs to facilitate the correct folding of the aggregation-prone domains. Furthermore, the intactness of the IMC linker after proteolysis modulates the production of off-pathway aggregates, which may be important to the onset of some diseases caused by the toxic effects of aggregated proteolytic fragments.     

Role of histamine in the antitumour activity of endotoxin

Summary The role of histamine in the antitumour activity of endotoxin against solid syngeneic Meth-A sarcoma in BALB/c mice was studied. Endotoxin induces haemorrhagic necrosis and regression of this tumour. Histamine and the selective H₁ receptor agonist 2-pyridylethylamine mimicked the induction of necrosis but did not cause regression. The selective H₂ receptor agonist dimaprit did not cause any tumour damage. The effect of histamine could be inhibited by the H₁ receptor antagonists diphenhydramine and promethazine but not by the H₂ receptor antagonist cimetidine. Endotoxin-induced necrosis was slightly affected by diphenhydramine, and the incidence of regression was reduced by both H₁ antagonists. Cimetidine potentiated endotoxin-induced regression. Similar effects were observed concerning the effects of H-receptor antagonists on necrosis and regression induced by tumour necrosis serum (TNS). Histological examination revealed no marked additional effects of diphenhydramine or cimetidine on endotoxin-induced hyperaemia, haemorrhagic necrosis, and mitotic arrest of the tumour cells. Only cimetidine increased the extent of nonhaemorrhagic necrosis. The endotoxin-induced release of tumour necrosis factor and cytostatic activity in TNS was clearly reduced by diphenhydramine, but hardly affected by cimetidine.Data indicate that intact H₁ receptors are required for the induction of tumour regression and antitumour factors by endotoxin. Concomitant H₂ blockade may facilitate this by stimulating H₁ receptor-mediated processes upon endotoxin-induced histamine release, although a cimetidine-induced inhibition of T-suppressor cell activation might also be involved.