Combined Histamine H1 Research Articles

Effects of combined histamine H1 and H2 receptor blockade on hemodynamic responses to dynamic exercise in males with high-normal blood pressure.

While postexercise hypotension is associated with histamine H1 and H2 receptor-mediated postexercise vasodilation, effects of histaminergic vasodilation on blood pressure (BP) in response to dynamic exercise are not known. Thus, in 20 recreationally active male participants (10 normotensive and 10 with high-normal BP) we examined the effects of histamine H1 and H2 receptor blockade on cardiac output (CO), mean atrial pressure (MAP), aortic stiffness (AoStiff), and total vascular conductance (TVC) at rest and during progressive cycling exercise. Compared with the normotensive group, MAP, CO, and AoStiff were higher in the high-normal group before and after the blockade at rest, while TVC was similar. At the 40% workload, the blockade significantly increased MAP in both groups, while no difference was found in the TVC. CO was higher in the high-normal group than the normotensive group in both conditions. At the 60% workload, the blockade substantially increased MAP and decreased TVC in the normotensive group, while there were no changes in the high-normal group. A similar CO response pattern was observed at the 60% workload. These findings suggest that the mechanism eliciting an exaggerated BP response to exercise in the high-normal group may be partially due to the inability of histamine receptors. Novelty Males with high-normal BP had an exaggerated BP response to exercise. The overactive BP response is known due to an increase in peripheral vasoconstriction. Increase in peripheral vasoconstriction is partially due to inability of histamine receptors.

Histamine-Receptor Antagonists Slow 10-km Cycling Performance in Competitive Cyclists.

Determine the effects of histamine-receptor antagonism on cycling time trial performance in humans, with and without a preceding bout of sustained steady-state exercise. Eleven (3F) competitive cyclists performed six 10-km time trials on separate days. The first two time trials served as familiarization. The next four time trials were performed in randomized-block order, where two were preceded by 120 min of seated rest (rest) and two by 120 min of cycling exercise (Exercise) at 50% V˙O2peak. Within each block, subjects consumed either combined histamine H1 and H2 receptor antagonists (Blockade) or Placebo, before the start of the 120-min Rest/Exercise. Blockade had no discernible effects on hemodynamic or metabolic variables during Rest or Exercise. However, Blockade increased time-to-completion of the 10-km time trial compared with Placebo (+10.5 ± 3.7 s, P < 0.05). Slowing from placebo to blockade was not different between rest (+8.7 ± 5.2 s) and Exercise (+12.3 ± 5.8 s, P = 0.716). Exercise-related histaminergic signaling appears inherent to endurance exercise and may play a role in facilitating optimal function during high-intensity endurance exercise.

Histaminergic Regulation of Angiogenic Potential in Human Umbilical Vein Endothelial Cells

Histamine has been shown to be a pro-angiogenic mediator, and may contribute to physiological angiogenesis associated with exercise training. Endothelial cells are a key effector of angiogenesis, and express histamine H1 and H2 receptors. Within the skeletal muscle vasculature, combined histamine H1 and H2 receptor blockade blunts the sustained post-exercise vasodilation after an acute bout of dynamic exercise. However, whether histamine receptor activation with exercise contributes to angiogenesis is unknown. The ability of endothelial cells to form capillary-like tubules when seeded on a basement membrane-like matrix can be used to investigate angiogenic signaling pathways in vitro. PURPOSE: To test the hypothesis that histamine receptor activation contributes to angiogenic potential in human umbilical vein endothelial cells (HUVEC). METHODS: HUVEC from passage number 2 were plated in Matrigel-coated wells on a 96-well cell culture plate at a density of 1.0x105 cells/mL. Each well was then treated with a single dose (range: 10-9 to10-3M) of one of the following: histamine, fexofenadine or pyrilamine (H1-receptor blockers), and ranitidine or cimetidine (H2-receptor blockers). HUVEC plated in cell growth media served as controls. The HUVEC were then incubated at 37°C and 5% CO2 for 8hr. After 8hr, images of each well were acquired using phase-contrast microscopy. Total tubule length was quantified as a measure of endothelial tube formation using Image J. RESULTS: Compared to control conditions, histamine had no effect on endothelial tube formation (p=0.71). Additionally, preliminary data suggests neither H1 nor H2 receptor blockade alone have any effect on endothelial tube formation compared to control conditions. However, preliminary data indicates that combination of H1 and H2 receptor blockade with 10-3M pyrilamine plus cimetidine reduces total endothelial tubule length by 24%. CONCLUSION: Histamine does not increase angiogenic potential, and blocking either H1 or H2 receptors alone does not diminish angiogenic potential in vitro. However, combining H1 and H2 receptor blockade at 10-3M concentration appears to blunt angiogenic potential in the HUVEC endothelial tube formation assay.

ChemInform Abstract: Synthesis and Combined Histamine H1- and H2-Receptor Antagonist Activity of Mepyramine, Pheniramine, and Cyclizine Derivatives with Cyanoguanidine, Urea, and Nitroethenediamine Groups.

ChemInform Abstract: Synthesis and Combined Histamine H1- and H2-Receptor Antagonist Activity of Mepyramine, Pheniramine, and Cyclizine Derivatives with Cyanoguanidine, Urea, and Nitroethenediamine Groups.

Is Postexercise Hyperemia Abolished with Combined Histamine H1 and H2 Receptor Antagonism in Healthy Humans?

In normally active individuals, postexercise hypotension after a single bout of aerobic exercise is due to a peripheral hyperemia. Histamine H1 and H2 receptors have individually been shown to contribute to this postexercise hyperemia, although the primary contribution of each receptor occurs at different times. H1- receptors have the greatest effect on postexercise hyperemia at 30 min after exercise, while H2- receptors have the greatest effect at 60 through 90 min postexercise. PURPOSE: To determine if the combined blockade of H1- and H2- receptors can abolish the 90 min period of postexercise hyperemia. METHODS: We studied 14 healthy, sedentary and normally active men and women (ages 25.1 ±4.6 yr) before and through 90 min after a 60 min bout of cycling at 60% VO2eak on randomized control and combined H1- and H2-receptor antagonist days (540 mg fexofenadine plus 300 mg ranitidine). Arterial blood pressure (automated auscultation) and femoral blood flow (Doppler ultrasound) were measured. Femoral vascular conductance was calculated as flow/pressure. RESULTS: Prior to exercise, the histamine antagonists had no effect on femoral vascular conductance or mean arterial pressure P < 0.3). At 30 minutes postexercise, the combined H1- and H2- receptor antagonism abolished the increase in femoral vascular conductance by 86.7 % (control: ? 57.3 ±13.8 % from preexercise; antagonist: Δ 7.6 ± 7.9 % from preexercise; P = 0.01). At 60 minutes postexercise, the histamine receptor antagonists diminished the rise in femoral vascular conductance by 74.3 % (control: Δ 57.3 ± 12.0 % from preexercise; antagonist: Δ 14.7 ± 5.7 % from preexercise; P = 0.01). At 90 minutes postexercise, the histamine receptor antagonists abolished the increase in femoral vascular conductance by 77.4 % (control: Δ 54.1 ± 13.8 % from preexercise; antagonist: Δ 12.2 ± 6.7 % from preexercise; P = 0.01). The histamine receptor antagonists abolished the reduction in mean arterial pressure through out the 90 min postexercise period with the peak difference at 60 min postexercise (control: Δ −5.3 ± 0.9 mmHg from preexercise; antagonist: Δ −1.9 ± 0.8 mmHg from preexercise; P = 0.01). CONCLUSION: Combined H1- and H2- receptor antagonism markedly reduces postexercise hyperemia and ensuing hypotension throughout recovery from exercise. Supported by AHA grant: 555623Z

Pharmacological interventions and outcome measurements in the unified airway

SummaryIn view of the large body of evidence for the role of histamine and cysteinyl leukotrienes (CysLT1) in the pathogenesis of allergic rhinitis (AR) and asthma, there has been a surge in the development of histamine H1 and CysLT1 receptor antagonists (H1 antihistamines and leukotriene antagonists, respectively) for the treatment of these conditions. Current treatment guidelines recommend the use of oral H1 antihistamines as first‐choice treatment for intermittent or persistent AR and the leukotriene antagonists, either as alternative or add‐on therapy to inhaled corticosteroids, for mild‐to‐moderate persistent asthma. However, recent studies, using a variety of traditional and novel outcome measures, have suggested that the H1 antihistamines and leukotriene receptor antagonists (LTRAs) may be effective in both asthma and AR. However, these studies have provided conflicting evidence as to whether H1 antihistamines and the leukotriene antagonists have the potential for additivity of response, when used as combination therapy in AR. There are also preliminary data showing that H1 antihistamines, like LTRAs, may further reduce inflammation, when used as add‐on therapy to inhaled corticosteroids in patients with mild‐to‐moderate persistent asthma. The clinical relevance of these findings, however, is presently not clear and also, the observed effects of these agents are likely to be dependent on the type of outcome measures used in these studies. Further studies are therefore clearly required to evaluate the effects of combined histamine H1 and CysLT1 receptor antagonists in patients with more severe disease over the longer term, particularly to evaluate asthma exacerbations and airway remodelling. Furthermore, it will be important to assess the potential for treating the unified airway in patients with concomitant asthma and AR in terms of comparing combined mediator antagonism with topical corticosteroid therapy.

Heparin-induced vasodilation in human hand veins.

To investigate whether heparin produces vasodilation in human veins and to explore the underlying mechanisms. Eleven healthy volunteers were studied with the dorsal hand vein compliance technique. Dose-response curves to heparin and enoxaparin were generated. Dose-response curves to heparin were also constructed before and after heparin was infused with the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine (L-NMMA) or combined histamine H1- and H2-receptor blockade. Heparin but not enoxaparin caused significant dose-dependent relaxation with an average apparent maximal response (at an infusion rate of 20 IU/min) of 47% +/- 23%. L-NMMA attenuated heparin-induced relaxation (P < .001). The combination of H1-and H2-receptor antagonists attenuated heparin-induced relaxation to a lesser extent (P < .05). Heparin-induced relaxation decreased by 52%, 73%, and 35% in the presence of L-NMMA, indomethacin (INN, indometacin) plus L-NMMA, and combined H1- and H2-receptor blockade, respectively. Heparin is an endothelium-dependent venodilator in humans. The mechanism of heparin-induced relaxation involves an increased availability of nitric oxide, possibly partially related to local release of histamine.

Combined histamine H1 and H3 receptor blockade produces nasal decongestion in an experimental model of nasal congestion.

We studied the pharmacological actions of combined histamine H1/H3 receptor blockade on the increase in nasal airway resistance (NAR) and decrease in nasal cavity volume produced by nasal exposure to compound 48/80, a mast cell degranulator. In the anesthetized cat compound 48/80 (1%) produced a maximum increase in NAR of 9.1 +/- 0.7 cmH20.L/minute. The increase in NAR in animals pretreated with a combination of the H1 antagonist, chlorpheniramine (CTM; 0.8 mg/kg i.v.) and increasing doses of the H3 antagonist, thioperamide (THIO; 1.0, 3.0, and 10.0 mg/kg i.v.) were 6.1 +/- 2.1, 4.2 +/- 1.0 and 2.2 +/- 0.7 cmH20.L/minute, respectively. A second H3 antagonist, clobenpropit (CLOB; 0.03, 0.3, and 1.0 mg/kg i.v.) combined with CTM (0.8 mg/kg i.v.) also inhibited the nasal effects of compound 48/80. When the nonsedating H1 antihistamine, loratadine (3.0 mg/kg i.v.), was substituted for CTM, it also reduced nasal congestion when given in combination with THIO (10 mg/kg i.v.). In contrast, treatment with CTM (1.0 mg/kg i.v.) and the H2 antagonist, ranitidine (RAN; 1.0 mg/kg i.v.) were without activity. Loratadine, CTM, CLOB, RAN, or THIO administered alone were inactive. The alpha-adrenergic agonist, phenylpropanolamine (PPA; 1.0 mg/kg i.v.) demonstrated decongestant effects, but in contrast to H1/H3 blockade, PPA produced a significant hypertensive effect. Using acoustic rhinometry (AcR) we found that combined i.v. CTM (1.0 mg/kg) and THIO (10 mg/kg) and combined oral CTM (10 mg/kg) and THIO (30 mg/kg) blocked the decrease in nasal cavity volume produced by intranasal compound 48/80 (1%, 50 microL). We conclude that combined H1/H3 histamine receptor blockade enhances the efficacy of an H1 antagonist by conferring decongestant activity to the H1 antihistamine. We propose that the decongestant activity of combined H1/H3 blockade may provide a novel approach for the treatment of allergic nasal congestion without the hypertensive liability of current therapies.

ChemInform Abstract: Synthesis and Pharmacology of Combined Histamine H1‐/H2‐Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and pharmacology of combined histamine H1-/H2-receptor antagonists containing diphenhydramine and cyproheptadine derivatives.

The classical histamine H1-receptor antagonists diphenhydramine (3a) and cyproheptadine (9) and their derivatives (3b-d, 10) were connected with a 2-guanidinothiazole containing structure (28) derived from the H2-receptor antagonist tiotidine in order to obtain combined H1-/H2-receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that proved in vitro to possess high H1- and H2-receptor antagonist activity at the isolated guinea-pig ileum (H1) and the isolated guinea-pig right atrium (H2), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H1-receptors. The tricyclic cyproheptadine and its 10,11-dihydro derivative (30-32, 34), however, cause a decrease of H2-receptor antagonist potency compared to the diphenhydramines (29a-d, 33a-d). Using nitroethenediamine as the polar group is apparently more favourable to H1- and H2-receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4-fluoro- or 4-methyl-substituted diphenhydramine as H1-receptor antagonist moiety (29c, d) display the most potent H1- and H2-receptor antagonist effects. The presented concept is a very promising way to combine H1- and H2-receptor antagonist properties in one molecule.

Synthesis and combined H1-/H2 antagonist activity of mepyramine, pheniramine and cyclizine derivatives with cyanoguanidine, urea and nitroethenediamine partial structures

Compounds with combined histamine H1- and H2-receptor antagonist activity were synthesized by connecting H1- and H2-receptor substructures via cyanoguanidine, urea, or nitroethenediamine moieties. Loss of the strongly basic side-chain nitrogen results in a decrease of H1-receptor activity compared to single reference compounds. At the guinea-pig right atrium (H2-receptor model) compounds with mepyramine or cyclizine structure are also less active than the single references tiotidine, ranitidine, or lamtidine. Nevertheless substances with a pheniramine like partial structure proved to be potent histamine H2-receptor antagonists at the atrium model (about 27 times more active than cimetidine).

Adrenergic and histaminergic neural interactions in dog paws.

The mechanisms underlying the vascular responses of superficial fibular nerve stimulation (SFNS) have not been defined. Right hindpaws of anesthetized heparinized dogs were vascularly and neurally isolated, enclosed in a volume recorder, and perfused with controlled pressure. Vascular volume (VV) (131I-labeled albumin) and rate of tissue volume changes (VT) (plethysmography) were determined. SFNS increased blood flow resistance, reduced capillary filtration coefficient (CFC) and permeability-surface area product (PS) of 86Rb, increased VV, and reduced 131I-albumin recovery. VT increased at the rate of 3.35 +/- 0.45 ml/min. SFNS during terbutaline increased resistance, CFC, PS, and VV were unchanged, 131I-albumin recovery was complete, and VT increased at one-fourth the control rate. Phentolamine and yohimbine blocked all responses to SFNS. Prazosin with SFNS attenuated hemodynamic changes and VT increased to two-thirds of control, decreased VV, albumin, and Rb recovery but not PS and CFC. SFNS during pyrilamine maleate reduced VT increase to two-thirds of control rate and blocked decreases in PS and CFC. Metiamide did not change the SFNS responses, except to reduce vascular volume and VT. The combined histamine H1 and H2 blockers reduced VT increase to one-third of control and attenuated albumin loss, prevented histamine dilation, attenuated vasopressin and norepinephrine but not angiotensin constriction. SFNS stimulation increased precapillary resistance by alpha 1- and alpha 2-receptors and venous resistance by alpha 2-receptors and increased permeability by histamine release from endothelium.

Measurement of plasma concentrations of a combined histamine H1- and H2-receptor antagonist (SK&amp;F 93319)

Measurement of plasma concentrations of a combined histamine H1- and H2-receptor antagonist (SK&amp;F 93319)

Histamine Release From a Gastric Carcinoid: Provocation by Pentagastrin and Inhibition by Somatostatin

We have previously reported that flushing associated with a gastric carcinoid tumor can be provoked by pentagastrin and inhibited by either somatostatin or combined histamine H1- and H2-receptor blockade. In this report, the effects of pentagastrin and somatostatin on histamine release in a patient with a metastatic gastric carcinoid tumor were examined. Small doses of intravenous pentagastrin (0.1-0.4 micrograms) produced a dose-dependent increase in the level of circulating plasma histamine. Graded infusions of somatostatin suppressed both basal and pentagastrin-stimulated plasma histamine levels in a dose-dependent fashion. A close correlation was found between circulating plasma histamine levels and attendant changes in blood pressure and pulse rate. This study documents that pentagastrin directly evokes the release of histamine from this patient's gastric carcinoid tumor and that the release of histamine is inhibited by somatostatin. In addition, this study provides additional evidence that the primary mediator of the flushing in this patient with foregut carcinoid syndrome is histamine.