Histamine-induced Vasodilatation Research Articles

Endothelial Nox4 NADPH Oxidase Enhances Vasodilatation and Reduces Blood Pressure In Vivo

Increased reactive oxygen species (ROS) production is involved in the pathophysiology of endothelial dysfunction. NADPH oxidase-4 (Nox4) is a ROS-generating enzyme expressed in the endothelium, levels of which increase in pathological settings. Recent studies indicate that it generates predominantly hydrogen peroxide (H(2)O(2)), but its role in vivo remains unclear. We generated transgenic mice with endothelium-targeted Nox4 overexpression (Tg) to study the in vivo role of Nox4. Tg demonstrated significantly greater acetylcholine- or histamine-induced vasodilatation than wild-type littermates. This resulted from increased H(2)O(2) production and H(2)O(2)-induced hyperpolarization but not altered nitric oxide bioactivity. Tg had lower systemic blood pressure than wild-type littermates, which was normalized by antioxidants. Endothelial Nox4 exerts potentially beneficial effects on vasodilator function and blood pressure that are attributable to H(2)O(2) production. These effects contrast markedly with those reported for Nox1 and Nox2, which involve superoxide-mediated inactivation of nitric oxide. Our results suggest that therapeutic strategies to modulate ROS production in vascular disease may need to separately target individual Nox isoforms.

Histamine-induced vasodilation in the perfused kidney of STZ-diabetic rats: role of EDNO and EDHF

In this study, we have examined the contribution of endothelium-derived nitric oxide (EDNO) and endothelium-derived hyperpolarizing factor (EDHF) to histamine-induced endothelium-dependent relaxation in the perfused kidney of rats treated with streptozotocin (STZ) to induce diabetes. Histamine-induced vasodilatation in the perfused kidney preparations of both control and diabetic animals, which was not significantly different. Sodium nitroprusside (SNP)-induced relaxation was also not affected in diabetic and control rats. In order to isolate the EDHF component of histamine-induced vasodilator response, L-NAME (10 −4 M) and indomethacin (10 −6 M) were added to the Krebs’ solution throughout the experiment. TBA (0.5 mM) produced a significant reduction in histamine-induced maximal vasodilator response in both preparations from control and diabetic animals, indicating the involvement of K + channels in mediating this response. Charybdotoxin (0.05 μM) but not glibenclamide (0.1 μM) produced significant reduction in histamine-induced vasodilator responses. To test the contribution of EDNO in mediating histamine-induced vasodilatation, the vascular preparations were perfused with 20 mM K +-Krebs’ solution to inhibit the EDHF component of the response. Under this condition, histamine-induced vasodilator response was not significantly different in both preparations from control and diabetic rats. Pre-treatment with L-NAME (10 −4 M) attenuated histamine-induced vasodilatation. There was a more significant attenuation in histamine-induced vasodilatation in the vascular preparations from diabetic rats. The vasodilator effect of calcium ionophore A23187 was investigated in preparations from control and diabetic rats to examine receptor dysfunction associated with diabetes. A23187 produced dose-dependent vasodilator response in the preparations from both control and diabetic rats. In conclusion, our results indicate that histamine-induced vasodilatation in the perfused kidney of the STZ-induced diabetic rats is mediated by the two vasodilator components, namely EDHF and EDNO. The EDHF component was not significantly affected by diabetes. However, histamine-induced vasodilatation mediated by the EDNO component was more significantly reduced in diabetic rats. Results have also indicated that the EDHF component of histamine-induced vasodilatation was mediated through Ca 2+-activated K + channels in perfused kidney preparations from both control and diabetic rats.

Histamine Induces Opposing Vasoactive Effects at Different Levels of the Ocular Vasculature

Purpose: To characterize the vasoactive properties and receptors of histamine in porcine retinal arterioles compared to that in the long posterior ciliary artery. Methods: Isolated perfused porcine retinal arterioles were used to study vessel diameter in response to histamine (10−10 to 10−4 M). Ring segments from the long posterior ciliary artery were used to study contractile force in response to histamine. Results: Histamine-induced vasodilatation in pig retinal arterioles but contraction in the long posterior ciliary artery. In retinal arterioles, the involvement of H2 receptors was implied by the attenuation of the histamine response in the presence of cimetidine. Further attenuation of the histamine response by pyrilamine suggests the involvement of H1 receptors. In retinal arterioles denuded of endothelial cells, the histamine response was only slightly reduced.Conclusion: Histamine induces opposing vasoactive effects at different levels of the porcine ocular vasculature.

Histamine-induced vasodilatation in the perfused mesenteric arterial bed of diabetic rats

In this study, we have examined the contribution of endothelium-derived nitric oxide (EDNO) and endothelium-derived hyperpolarizing factor (EDHF) to histamine-induced endothelium-dependent relaxation in the perfused mesenteric arterial bed of rats treated with streptozotocin (STZ) to induce diabetes. Histamine (10 −10 to 5×10 −6 mol) produced dose-dependent vasodilator response in the perfused mesenteric arterial bed of both control and diabetic animals. In order to isolate the EDHF component of histamine-induced vasodilator response, N G-nitro- l-arginine-methyl ester hydrochloride ( l-NAME) (10 −4 M) and indomethacin (10 −6 M) were added to the Krebs solution throughout the experiment. Histamine induced vasodilatation in the perfused mesenteric bed in preparations from both control and diabetic rats. The vasodilator response to histamine was slightly potentiated in the diabetic rat preparations. Sodium nitroprusside (SNP)-induced relaxation was similar in diabetic and control rats. The role of EDNO in histamine-induced vasodilatation was also examined. Vascular preparations were perfused with 20 mM K +-Krebs solution to inhibit the EDHF contribution to histamine-induced vasodilatation. Under this condition, histamine induced a vasodilator response in preparations from both control and diabetic rats. However, relative to nondiabetic control animals, histamine-induced maximal response was significantly reduced in preparations from diabetic animals. Pretreatment with l-NAME (10 −4 M) attenuated histamine-induced vasodilatation in both preparations, indicating an NO-mediated vasodilator response. There was a significant attenuation in histamine-induced vasodilatation in the vascular preparations from diabetic rats. The vasodilator effect of calcium ionophore A23187 was investigated in preparations from control and diabetic rats to investigate receptor dysfunction associated with diabetes. A23187 (10 −11 to 10 −7 mol)-induced vasodilator response was not significantly different in the preparations from control and diabetic animals. In conclusion, our results indicated that histamine-induced vasodilation in the perfused mesenteric arterial bed of the STZ-induced diabetic rats is mediated by two vasodilator components, namely EDHF and EDNO. Under diabetic conditions, the EDHF component was potentiated, while histamine-induced vasodilation mediated by the EDNO component was attenuated.

Modulatory effect of two novel CGRP receptor antagonists on nasal vasodilatatory responses to exogenous CGRP, capsaicin, bradykinin and histamine in anaesthetised pigs

Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide and potent vasodilatator agent located in sensory C fibres. Several functional studies suggest that CGRP could be involved in the vasodilatation of different vascular beds during neurogenic inflammation. We have studied, in pentobarbital anaesthetised pigs, the antagonistic effect of local intra-arterial (i.a.) pretreatment with the analogues CGRP 8–37, [D31, P34, F35]CGRP 27–37 and [N31, P34, F35]CGRP 27–37 on the vasodilatation of the nasal vascular bed induced by exogenous CGRP, capsaicin, bradykinin (BK) and histamine. The attenuating effect of CGRP 8–37 analogue on exogenous CGRP-induced vasodilatation, previously described in other in vivo animal models, was confirmed in the pig nasal mucosa. It also interfered with BK—and, to a lesser extent, with capsaicin—and histamine-induced decrease in vascular resistance. CGRP 27–37 analogues reduced the duration of CGRP-, capsaicin- and BK-induced vasodilatation by more than 50%. Peak values of vasodilatation were attenuated by more than 25% overall. Attenuation of histamine-induced decrease in vascular resistance was less pronounced. It is concluded that CGRP 27–37 analogues antagonise the action of exogenous CGRP, capsaicin, BK and histamine by attenuating their vasodilatation effect, both in intensity and duration. These results strongly suggest that BK- and histamine-induced vasodilatation is partly mediated by CGRP. CGRP 8–37 and 27–37 appear to be potential contributors to the study of CGRP and its physiological role in neurogenic inflammation. In addition, they may have putative therapeutic applications in the treatment of rhinitic patients suffering from chronic nasal obstruction.

Aging and cardiovascular disease: a summary of the Eighth Münster International Arteriosclerosis Symposium.

This unique symposium focused on the remarkable increase in the older population that is occurring in many countries of the world. The international experts spoke on the effects of aging on cardiovascular disease, which is by far the most prominent cause of morbidity and mortality in the elderly. The program highlighted some of the most prominent changes that occur in the elderly and influence the toll that cardiovascular disease takes. The program was divided into four sessions: (1) the effects of aging on some of the cardiovascular risk factors; (2) the effects of aging on the heart muscle; (3) reports on recent studies of the effects of aging on morphology and function of the conduction system; and (4) a session featuring outstanding authorities on aging and the elastin, collagen, and calcium of the vessel wall, all of which are frequently added to the artery wall during aging. The speakers were carefully selected from top scholars in England, Germany, Finland, France, Italy, Japan, and the United States. Professor W.H. Hauss, who pioneered the development of the Institute for Arteriosclerosis Research at the University of Munster, Germany, and is now in his 80s, opened the symposium and introduced four prominent officials in health, education, and other German government posts, who added their words of welcome. The first session was chaired by Professor G. Assmann, who is the current director of the Arteriosclerosis Research Institute in Munster, Germany. He gave the opening presentation on genetic determinants of life expectancy, a subject on which he is a world authority. He began his presentation with a brief description of the very large PROCAM study of more than 35 000 individuals, two thirds of whom are male, being carried out at the University of Munster Arteriosclerosis Institute in Westphalia. This long-term study of the natural history …

Modulation of autoregulatory escape by capsaicin-sensitive afferent nerves in rat stomach.

Visceral C fibers are stimulated by ischemia and hypoxia, which can be produced by intense vasoconstriction. Epinephrine applied to the gastric submucosa produces a marked vasoconstriction followed by autoregulatory escape. We hypothesize that the autoregulatory escape from epinephrine-induced vasoconstriction in the rat stomach is mediated partly by capsaicin-sensitive C fibers. Functional ablation of these afferent fibers by high-dose systemic capsaicin pretreatment will significantly reduce the magnitude of the autoregulatory escape. Rats received capsaicin (125 mg/kg sc) 10 days before blood flow studies to produce functional impairment of the capsaicin-sensitive afferent nerves. Control rats received vehicle. Under urethan anesthesia, a small area (2 mm diam) of the serosa from the anterior gastric wall was removed to expose the submucosa. The tip of a side-viewing laser-Doppler flow probe was placed inside the stomach directly beneath the exposed submucosa. At 20-min intervals, 20 microliters of buffer, 5 x 10(-4) M epinephrine, 1.6 x 10(-4) M capsaicin, or 3.3 x 10(-2) M histamine was applied topically to the exposed submucosa, with saline washes between applications at 10 min after each application. Blood pressure and laser-Doppler flow signals were monitored continuously. The escape index during the period of epinephrine application was significantly lower in the capsaicin-pretreated rats (0.239 +/- 0.046) than in the vehicle-pretreated rats (0.474 +/- 0.079). Functional ablation of the capsaicin-sensitive afferent fibers was confirmed by a significant blockade of the vasodilatation induced by topical capsaicin. Histamine-induced vasodilatation was unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-associated decrease in histamine-induced vasodilation may be due to reduction of cyclic GMP formation.

1. The effects of aging on histamine-induced vasodilatation and cyclic GMP production in rat thoracic aorta were investigated. 2. This histamine-induced dilatation of the aorta was mediated by H1-receptors and was dependent on the endothelium. 3. Histamine induced the greatest dilatation of arteries of 3-4 week old rats, progressively less of those of rats of 8 to 56 weeks old, and scarcely detectable dilatation of those of 100 week old rats. 4. Histamine induced cyclic GMP production in aorta from rats of 4 weeks old, with no change in the cyclic AMP level. This increase in the cyclic GMP level induced by histamine also decreased with age, being about 70% as great at 8 weeks, 50% as great at 50-60 weeks, and 10% as great at 130 weeks of age. 5. Removal of the endothelium completely abolished the histamine-induced increase in cyclic GMP. 6. The dilator effect of nitroprusside, which enhances cyclic GMP production by stimulating guanylate cyclase directly (not indirectly via the endothelium derived relaxing factor, EDRF), also showed age-related attenuation. 7. The dilator effect of 8-bromo cyclic GMP, which stimulates cyclic GMP-dependent protein kinase, also decreased during aging. 8. These results suggest that aging reduces the ability of the endothelium to produce EDRF, which stimulates guanylate cyclase, and so decreases cyclic GMP production. Thus the decreased dilator response of the arteries to histamine during aging is probably due to both loss of endothelial function and reduction of guanylate cyclase activity. Alteration of cyclic GMP-dependent protein kinase activity may also participate in the age-related changes.

Influence of prostaglandin-synthesis inhibitors on carbachol- and histamine-induced vasodilatation in perfused rat hindquarters.

In perfused rat hindquarters, in which vascular tone was maintained by norepinephrine, carbachol-induced dilatations were blocked by atropine (10(-7) M), while histamine dilatations were inhibited as well by mepyramine (10(-6) M) as by cimetidine (10(-5) M) indicating a histamine effect through both H1- and H2-receptors. This double-receptor histamine effect was confirmed by the observation that specific H1- and H2-receptor agonists, respectively PEA (2-pyridyl-ethyl-aminedihydrochloride) and dimaprit also produced a vasodilatation. Carbachol- and histamine-induced dilatations were also inhibited by ETYA (5,8,11,14-eicosatetraynoic acid) and quinacrine but not by indomethacin. The inhibition of the histamine vasodilatation appeared to rest on an interference with the H1-receptor mechanism. It is concluded that metabolites of arachidonic acid possibly mediate the dilating effect of carbachol, acting through muscarine receptors, and of histamine, acting through H1-receptors.

Reticuloendothelial system function and histamine release in shock and trauma: relationship to microcirculation.

The material reviewed, and presented, here lends credence to the concept that the severity or course of the shock syndrome can be evaluated, quantitatively, at a tissue level by assessing RES phagocytic function. In general, the available data indicate that RE cell stimulants can adapt animals (and probably man) to the insults of circulatory shock and trauma; such substances could have important value in pretreating patients scheduled for massive surgery. The fact that a number of biologically active materials with vasotropic, and RE cell depressant, effects appear in the tissues and blood in shock, particularly when the organism becomes refractory to therapy, suggests that the final functional deterioration of the cardiovascular system may be due to the specific action of one or more of these biologically active materials; such a contender is, without doubt, histamine. Histamine has all the attributes of a typical shock-toxin. Evidence is presented that histamine can be a potent splanchnic (shock target-organ) arteriolar (microcirculatory) dilator even in physiologic (circulating) concentrations. Concentrations of histamine found in plasma of shocked animals and human subjects would produce extremely potent splanchnic vasodilator actions at the microcirculatory level. Evidence is also presented to indicate that microvessels can synthesize and release free, pharmacologically-active histamine. Endogenous release of histamine (e.g., with compound 48/80) produces dose-dependent and lethal shock-like anaphylactic actions; such release also produces, dose-dependently, RES phagocytic depression. Repeated administration of the histamine releaser, compound 48/80, results in almost a 400% enhancement of RES phagocytic function and cross-tolerance to lethal doses of whole-body trauma. Such results raise the possibility that the RES plays a pivotal role in the circulatory manifestations of compound 48/80 and anaphylactic-type (histamine release) shock syndromes. Evidence is presented to indicate that H1-receptor antihistamines can ameliorate circulatory shock (and trauma) and prevent RES phagocytic depression, whereas H2-receptor antihistamines do the reverse. Direct in situ microscopy revealed that the former types of histamine receptor blockers prevent tissue ischemia, whereas H2-receptor blockers exacerbate tissue ischemia in circulatory shock. Histamineinduced vasodilatation via H2-receptors may thus be a beneficial effect in circulatory shock and trauma; one must think seriously about the potential value of antihistamines as adjuvant drugs in the treatment of low-flow states and as preoperative medication. Collectively, the data reviewed herein could be taken as strong support for a pivotal role for the release (and possible synthesis) of free, pharmacologically-active histamine in shock.

Effect of histamine on uterine vasculature in rats

The effects of histamine infusions on the rat uterine vasculature have been studied using the radioactive microsphere technique. Histamine produced a marked uterine vasodilatation which could be partly mimicked by infusion of either the H 1-receptor agonist, 2-(2-aminoethyl)pyridine, or the H 2-receptor agonist, 4-methylhistamine. Histamine-induced uterine vasodilatation could only be reduced significantly by administration of a combination of the H 1- and H 2-receptor antagonists mepyramine and metiamide but not by either antagonist given alone. It was concluded that histamine-induced vasodilatation in the rat uterus is mediated by both H 1- and H 2-receptors.

Histamine, histamine antagonists and regional blood flow

The effects of mepyramine, a selective histamine H 1-receptor antagonist, and metiamide, a selective histamine H 2-receptor antagonist, have been determined on the cardiovascular response to intravenous infusions of a large dose of histamine, 1 × 10 −7 mol/kg/min. Pretreatment with either mepyramine, 2.5 × 10 −6 mol/kg, or metiamide, 2 × 10 −6 mol/kg/min, had no significant effect on the fall pressure or fall in total peripheral resistance during histamine infusion. Pretreatment with mepyramine, 2.5 × 10 −6 mol/kg, and metiamide, 2 × 10 −6 mol/kg/min, abolished the fall in blood pressure and total peripheral resistance during infusion of histamine. Histamine-induced vasodilatation in the stomach was unaltered by pretreatment with mepyramine but abolished by pretreatment with metiamide. Histamine-induced coronary vasodilatation was reduced slightly by pretreatment with mepyramine and substantially by pretreatment with metiamide. Coronary vasodilatation was abolished by treatment with mepyramine and metiamide.

Effects of psychoactive agents on the conditioning of the microcirculation in the rat.

Normal vascular tonus and permeability of the microcirculatory network is mediated by catecholamines, histamine and serotonin. Following electroconvulsive treatment (ECT), histamine did not provoke local vasodilatation. The inhibition was further potentiated by drugs which prevent the enzymatic or physical inactivarion of free catecholamines and by locally administered norepinephrine. This system became conditioned to a visual stimulus when rats were presented in six consecutive occasions with the visual stimulus preceedingly coincided with the administration of ECT. In the conditioned rats, light alone inhibited the histamine-induced vasodilatation, and this inhibition was potentiated by sub-effective doses of injected norepinephrine and by drugs which prevent the enzymatic or physical inactivation of catecholamines. Sedatives, antidepressants, MAO inhibitors and the chlorpromazine-type agents as well as the psychotomimetic drugs characteristically influence either the acquisition or the extinction of the conditioned reflex. Results suggest that the obtained conditioning of the microcirculatory functions are mediated by tie centrally released catecholamines.

Histamine and reflex vasodilatation in the rat

These results indicate that norepinephrine induces a reflex vasodilatation in the rat which is essentially abolished by tripelennamine, and is reduced by Compound 48/80 pretreatment. It was shown that tripelennamine did not depress vascular reactivity and that its blocking effect appears specific for histamine-induced vasodilatation. These data support the concept that active reflex vasodilatation exists in the rat and suggest histamine involvement.

A histamine analogue that does not cause itching.

Much of our knowledge about cutaneous vascular physiology stems from work with histamine. A variety of techniques have been utilized to investigate histamine-induced vasodilatation and whealing. Vascular studies with a very sensitive method in our laboratory have made it clear that itching, which frequently accompanies injection of histamine, has an untoward disruptive effect on delicate measurements. Accordingly, we sought a histamine-like compound devoid of pruritogenic activity. A series of histamine analogues had already been prepared by Lee and Jones. 1 One of these, betazole, had been shown to stimulate gastric secretion usually without causing undesirable effects in other organs. 2 We injected this drug intradermally in a few subjects and observed good wheals and flares but no pruritus. The injections were repeated. Pruritus occurred only once in over 100 random observations. Wheals appeared unabated in size or fluid content; erythema was not inhibited. Experiments were designed to help clarify the