Influence of SQ 29,548 on vasoconstrictor responses in the mesenteric vascular bed of the cat

The effects of SQ 29,548 on vasoconstrictor responses were investigated in the feline mesenteric vascular bed. Injections of the thromboxane (TX) A2 mimics, U46619 and U44069, caused dose-related increases in mesenteric arterial perfusion pressure. After administration of SQ 29,548, 0.5 mg/kg i.v, vasoconstrictor responses to U46619 and U44069 were reduced markedly whereas responses to prostaglandin (PG) F2 alpha, angiotensin II, vasopressin and BAY K 8644, an agent which enhances calcium entry, were not altered. The duration of the TXA2 receptor blockade was greater than 2 h and SQ 29,548 had no significant effect on mesenteric vasodilator responses to PGE2, isoproterenol, nitroglycerin, acetylcholine or bradykinin. SQ 29,548, at a dose of 0.5 mg/kg i.v., significantly reduced the response to TXB2, which had modest vasoconstrictor activity in the mesenteric vascular bed. However, when the dose of SQ 29,548 was reduced to 0.05 mg/kg i.v., responses to TXB2 were not altered, whereas responses to U46619 were significantly decreased. SQ 29,548 had no significant effect on vasoconstrictor responses to norepinephrine or to sympathetic nerve stimulation. The TXA2 receptor antagonist blocked the vasoconstrictor component of the biphasic response to the PG precursor, arachidonic acid, and the endoperoxide, PGH2. The results of these studies suggest that SQ 29,548 is a specific TX receptor antagonist in the mesenteric vascular bed, that the vasoconstrictor component of the biphasic response to arachidonic acid and PGH2 is due to formation of TXA2, and that endogenously formed TXA2 does not modulate adrenergic responses in the mesenteric circulation of the cat.     

Effect of alpha-chymotrypsin on the nonadrenergic noncholinergic inhibitory system in cat airways

Electrical field stimulation of 5-hydroxytryptamine contracted cat trachea and bronchi in the presence of cholinergic and adrenergic blockade caused relaxation by activating intrinsic nonadrenergic noncholinergic (NANC) inhibitory nerves. Pretreatment of the tissues with the proteolytic enzyme, alpha-chymotrypsin, did not affect NANC inhibitory responses. Relaxations induced by vasoactive intestinal peptide (VIP) were abolished by alpha-chymotrypsin. These results suggest that VIP or related peptides may not act as the NANC inhibitory transmitter in cat airways. However, the possibility remains that peptides not susceptible to degradation by alpha-chymotrypsin may mediate these NANC inhibitory responses.     

Species differences in bradykinin receptor-mediated responses of the airways

1. Bradykinin (BK) is a nine amino acid peptide (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) formed from the plasma precursor kininogen during inflammation and tissue injury. The actions of BK are mediated by G protein-coupled cell surface receptors, designated B1 and B2. 2. BK has a plethora of effects in the airways including bronchoconstriction, bronchodilation, stimulation of cholinergic and sensory nerves, mucus secretion, cough and oedema resulting from promotion of microvascular leakage. These airway effects are mediated in the main by the B2 receptor subtype. 3. BK acts mainly indirectly, primarily through airway nerve activation, but also by the release of prostanoids, thromboxanes and nitric oxide (NO). 4. Airway responses to BK have been studied in detail in guinea-pigs, mice, sheep and rats. This review describes the effects of BK in these species and draws comparison with its effects in normal humans and patients with respiratory diseases. 5. Despite its many and varied effects in the airways of animals and man, the exact contribution of BK to airways disease remains unclear.     

Effects of phenytoin on sympathetic reflex responses in the cat

Phenytoin (DPH), in a low dose (2 mg/kg) was found to potentiate reflex elevations in blood pressure and responses of the nictitating membrane induced either by the electrical stimulation of the sciatic nerve or by intravenously applied pentetrazol in lightly anaesthetized cats. Pressor responses to carotid occlusion under chloralose anaesthesia were also potentiated. In contrast a high dose (20 mg/kg) of DPH exerted an inhibitory effect on these responses. These effects of DPH on sympathetic reflex responses proved to be long-lasting. Intravenously applied picrotoxin (0.05 mg/kg) or the same dose of ouabain, injected into the vertebral artery. partially reversed the inhibitory effect of DPH (20 mg/kg). Our data support the suggestion that DPH exerts its inhibitory action by affecting ionic fluxes in the CNS, mostly in inhibitory structures.     

The response of cat airways to histamine in vivo and in vitro.

The effects of histamine have been examined in anaesthetized cats and on cat cat isolated lung parenchyma strip. Histamine infused intravenously for 2 min produced a small and inconsistent effect on central airways and a small but consistent constriction of peripheral airways. Histamine bronchoconstriction of the central airways was unmasked by non-selective and beta 2-adrenoceptor blockade but not by beta 1-adrenoceptor blockade. This bronchoconstriction was antagonized by atropine but not by cimetidine or prazosin. Bronchoconstriction of the peripheral airways was not affected in a dose-related manner by beta-adrenoceptor blockade. The bronchoconstriction was antagonized by mepyramine but not by atropine or prazosin. beta-Adrenoceptor antagonists produced a bell-shaped dose-response curve on histamine contractions in cat isolated lung parenchyma strip. Strips of lung parenchyma obtained from reserpine-treated cats produced a larger contraction to histamine which was not potentiated by propranolol. It is concluded that in the central airways, histamine bronchoconstriction produced by an action on irritant receptors is masked by an action on beta 2-adrenoceptors of catecholamines released locally and from the adrenal glands. In the peripheral airways, histamine bronchoconstriction is mediated by H1-receptors and beta 2-adrenoceptor blockade may either potentiate or antagonize the histamine response depending on the concentration.     

Potency of several non-steroidal antiinflammatory drugs on airways responses to histamine

The effects of four non-steroidal antiinflammatory drugs (NSAIDs, indomethacin, flufenamate, aspirin and phenylbutazone) were investigated in anesthetized guinea-pigs. Bronchoconstriction (increased airways resistance and decreased conductance and compliance) was obtained to histamine (1-3 micrograms/kg i.v.). Each of the NSAIDs (0.1-20 mg/kg i.v.) enhanced bronchoconstriction to histamine. Maximum effects were obtained 12-44 min after administration of the NSAID. The order of potency of the drugs in causing a 50% increase in resistance responses to histamine was indomethacin greater than flufenamate greater than aspirin greater than phenylbutazone.     

不同部位气道对电场刺激和辣椒素反应的差异

目的:探讨豚鼠不同部位气道神经支配的差异．方法：采用便于定位的离体豚鼠3个不同部位气道环（气管、左主支气管和肺门支气管）标本，比较对电场刺激（EFS）和辣椒素（Capsaicin，Cap）反应的生理性差异。结果：EFS显示，气管抑制性NANC反应（iNANC）占63．4％±9．5％；肺门支气管兴奋性NANC（eNANC）却占64％±7．1％;而主支气管NANC却不明显．Cap量-效反应显示：肺门支气管对Cap反应明显高于气管和主支气管．结论：表明豚鼠气管神经支配，其iNANC明显地高于主支气管和肺门支气管；主支气管主要为肾上腺素能和胆碱能种经支配；而肺门支气管却明显存在与感觉神经C-纤维相关的eNANC。     

Contractile responses and noradrenaline release evoked by serotonin in cat femoral artery: Influence of pentobarbital

• 1.1. 5-Hydroxytryptamine (5-HT) induced dose-dependent contractions in the isolated cat femoral artery, which were reduced by LSD, methysergide, phentolamine and reserpine pretreatment (only at low doses).
• 2.2. Pentobarbital (PB) and Mn²⁺ relaxed the arteries previously contracted with 5-HT. These drugs reduced the contraction evoked by this amine as it was Ca²⁺-suppression.
• 3.3. High concentrations of 5-HT and K⁺ induced tritium release from vessels prelabelled with ³H-noradrenaline. Ca²⁺-deprivation and PB unmodified the release caused by 5-HT, but that elicited by K⁺ was abolished.
• 4.4. These data indicate that 5-HT-induced contraction is essentially due to direct interaction of this agent with 5-HT-receptors, and that PB interferes with Ca²⁺ entry to the cell.

     

The effect of reserpine on the pressor responses to angiotensin in the conscious cat

1. Blood pressure recordings have been made in conscious cats in an attempt to reveal a possible indirect component to the angiotensin pressor response.2. Reserpine (50 to 250 mug/kg per day) caused a maximal reduction of about 50% in the pressor response to angiotensin whilst virtually abolishing the responses to tyramine and McN-A-343. Responses to noradrenaline were only slightly and transiently reduced.3. Syrosingopine (0.5 mg/kg) and reserpine (250 mug/kg) reduced the responses to angiotensin, McN-A-343 and tyramine to much the same extent, but tetrabenazine only reduced the responses to all these agents in a dose (25 mg/kg) which probably had effects on the catecholamine stores of smooth muscle.4. The reduction in the responses to angiotensin, tyramine and McN-A-343 by reserpine was partly reversed by tranylcypromine. Noradrenaline and (+/-)-dopa infusions were ineffective by themselves, but increased the effects of tranylcypromine in restoring the responses to angiotensin, tyramine and McN-A-343 after reserpine.5. Infusion of alpha-methyldopa markedly increased the responses to angiotensin, tyramine and McN-A-343 after these had been reduced by reserpine.6. The results suggest that the pressor response to angiotensin in the conscious cat is partly mediated by release of noradrenaline from peripheral neuronal stores.     

The effect of CP-99994 on the responses to provocative motion in the cat

1. The NK₁ receptor antagonist CP-99994 has been shown to prevent vomiting elicited by both peripherally and centrally acting emetogens in ferrets and dogs. These results have now been extended to another stimulus, provocative motion, and another species, the cat.
2. CP-99994 displaced [³H]-substance P from cat cortex with IC₅₀ of 0.52±0.08 nM. Following s.c. administration, peak plasma drug levels were achieved at 30 min. The plasma drug half life was 1.4 h.
3. Subcutaneous administration of CP-99994 inhibited motion-induced vomiting in the cat with an ED₅₀ of 144 μg kg⁻¹ but did not change the epiphenomena associated with provocative motion in the cat over the dose range of 30 to 300 μg kg⁻¹. The antiemetic effect of CP-99994 can be attributed to antagonism of the NK₁ receptor because its enantiomer, CP-100,263, which is 900 fold weaker as an NK₁ antagonist, had no effects on any response to provocative motion.
4. The inhibitory effect of CP-99994 on motion-induced retching and vomiting is consistent with a central site of antiemetic action, potentially at the level of the motor nuclei responsible for these behaviours.
5. An investigation into whether the failure of CP-99994 to alter the epiphenomena will also predict a lack of anti-nausea effects in man will provide critical information on the neural organization of the emetic reflex.

     

Nisoldipine inhibits adrenergic responses in the hindquarters vascular bed of the cat

The effects of the calcium entry blocking agent nisoldipine on adrenergic vasoconstrictor responses were investigated in the hindquarters vascular bed of the cat under conditions of controlled blood flow. Nisoldipine dilated the hindquarters vascular bed and inhibited vasoconstrictor responses to Bay K 8644, a nifedipine analog which promotes calcium entry. During infusion of nisoldipine, vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine, and tyramine were inhibited in a reversible manner. In addition to blocking responses to nerve-released and exogenous norepinephrine, the calcium entry antagonist decreased responses to methoxamine and BHT 933, alpha 1- and alpha 2-adrenoceptor agonists. Responses to methoxamine were reduced by prazosin, an alpha 1-adrenoceptor antagonist, but not by yohimbine, an alpha 2-adrenoceptor blocking agent, whereas responses to BHT 933 were decreased by yohimbine but not by prazosin. The results of these studies suggest that vasoconstrictor responses to neuronally released and exogenous norepinephrine, as well as to selective alpha 1- and alpha 2-adrenoceptor agonists, are dependent in part on an extracellular source of calcium in resistance vessels of the feline hindquarters vascular bed. The inhibitory effect of nisoldipine on vasoconstrictor responses to neuronally released norepinephrine may be important in the antihypertensive actions of calcium entry blocking agents.     

Induction of suppressor cell activity in vivo and suppression of lymphoproliferative responses in vitro by SK&F 105.685 in the dog.

SK&F 105.685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine+ ++ dihydrochloride) is a novel azaspirane with beneficial activity in rat models of adjuvant-induced arthritis and experimental autoimmune encephalomyelitis as well as in the murine lupus model. The mechanism of action in these models appears to be the induction of non-specific suppressor cell activity which is measured by the ability of cells from treated animals to partially inhibit the proliferative response of lymphocytes from control animals to concanavalin A (ConA) in a co-culture assay. In this study we have shown that oral administration of 0.1-3 mg/kg/day of SK&F 105.685 to purebred beagle dogs induced suppressor cell activity in the spleen and bone marrow but not in the peripheral blood. In vitro, SK&F 105.685 partially suppressed the proliferative response of dog splenocytes to the mitogens phytohemagglutinin (PHA), ConA and, to a lesser extent, pokeweed mitogen (PWM). Peripheral blood lymphocytes (PBLs) differed from spleen cells in their susceptibility to suppression by SK&F 105.685. While the PWM and ConA responses of PBLs and spleen cells showed similar levels of inhibition, the PHA response of PBLs, in marked contrast to spleen cells, was resistant to suppression by the compound. Our results show that the immunoregulatory effects of SK&F 105,685 are not limited to rodents and that suppressor cell activity in dogs is induced quickly and by relatively low doses of the compound.     

Effects of isoetharine on airways resistance, heart rate, and contractions of the soleus muscle of the anaesthetised cat

The actions of the sympathomimetic bronchodilator, isoetharine, were compared with those of laevoisoprenaline, racemic isoprenaline and salbutamol, on the heart and lungs and on contractions of the soleus muscle of cats under chloralose anaesthesia. Isoetharine and salbutamol injected i.v. were approximately equipotent in all tests, and were about 8 times less potent than laevoisoprenaline both in decreasing the tension and degree of fusion of incomplete tetanic contractions of the cat soleus muscle, and in opposing the bronchoconstrictor action of 5-hydroxytryptamine. They were about 22 times less potent than laevoisoprenaline in increasing heart rate. In all tests, racemic isoprenaline was about 2 times less potent than laevoisoprenaline. The results suggest that the configuration of soleus β-receptors is closely similar to that of β-receptors in the lungs, and that the systemic administration of isoetharine might produce muscle tremor as a side-effect in man.     

Some effects of inhibiting endogenous prostaglandin formation on the responses of the cat spleen

1. The influence of barbiturates on neuromuscular transmission at end-plates of frog sartorius muscles was investigated electrophysiologically on preparations bathed in Ringer solution containing a low concentration of calcium and a high concentration of magnesium.2. Effects of a convulsant barbiturate, 5-(2-cyclohexylideneëthyl)-5-ethyl barbituric acid (CHEB), were compared with those of phenobarbitone.3. CHEB and phenobarbitone increased the mean quantum content of the end-plate potentials and decreased the mean amplitude of the miniature end-plate potentials.4. Both barbiturates enhanced the duration of the nerve-terminal action potential and had little or no effect on the effective resistance of the skeletal muscle membrane.     

Cardiovascular activity of SK&F 64139 in the hypertensive rat

SK&F 64139 (7,8-dichloro-1,2,3,4-tetrahydroisoquinoline) produces a dose-related antihypertensive effect in rats treated with desoxycorticosterone acetate and administered saline in their drinking water (DOCA-salt rats), lowering both systolic and diastolic blood pressure by 40 mm Hg after an oral dose of 25 mg/kg in a conscious animal. This antihypertensive effect can also be observed after intravenous infusion in an anesthetized DOCA rat. The fall in blood pressure is accompanied by bradycardia, which can be blocked by the combination of propranolol plus vagotomy, and a decrease in peripheral vascular resistance. In contrast to the results in the DOCA rat, only minimal effects on blood pressure were produced in normotensive rats. Although SK&F 64139 is a potent inhibitor of phenylethanolamine N-methyltransferase (PNMT), the time course of blood pressure reduction is not consistent with PNMT inhibition as a mechanism for its antihypertensive action. SK&F 64139 decreases the turnover rate of cardiac norepinephrine in DOCA-salt rats, suggesting that its antihypertensive effect may results from a centrally mediated inhibition of sympathetic outflow to the periphery.     

Effects of cooling on in vitro responses of human peripheral airways to inflammatory mediators and neurotransmitters

In asthma, inhalation of cold dry air induces bronchoconstriction. It has been suggested that cooling of the airway wall might induce this bronchoconstriction. Therefore the effects of cooling on the contractility of human peripheral airways were studied in vitro before and during lowering of the temperature. Cooling relaxed human airways in vitro and reduced responsiveness to methacholine, histamine and LTC4 both in terms of -logEC50 and maximal effect. It also reduced the maximal effect of isoprenaline. There was no measurable alpha-adrenergic activity before or during cooling. We conclude that cooling does not sensitize human airways to any of these agonists and that cold-induced bronchoconstriction in vivo is not due to a direct effect of cooling on airway smooth muscle.