Vasoconstrictor Activity Research Articles

The peripheral vascular responses in non-freezing cold injury and matched controls.

What is the central question of this study? Does non-freezing cold injury (NFCI) alter normal peripheral vascular function? What is the main finding and its importance? Individuals with NFCI were more cold sensitive (rewarmed more slowly and felt more discomfort) than controls. Vascular tests indicated that extremity endothelial function was preserved with NFCI and that sympathetic vasoconstrictor response might be reduced. The pathophysiology underpinning the cold sensitivity associated with NFCI thus remains to be identified. The impact of non-freezing cold injury (NFCI) on peripheral vascular function was investigated. Individuals with NFCI (NFCI group) and closely matched controls with either similar (COLD group) or limited (CON group) previous cold exposure were compared (n=16). Peripheral cutaneous vascular responses to deep inspiration (DI), occlusion (PORH), local cutaneous heating (LH) and iontophoresis of acetylcholine and sodium nitroprusside were investigated. The responses to a cold sensitivity test (CST) involving immersion of a foot in 15°C water for 2min followed by spontaneous rewarming, and a foot cooling protocol (footplate cooled from 34°C to 15°C), were also examined. The vasoconstrictor response to DI was lower in NFCI compared to CON (toe: 73 (28)% vs. 91 (17)%; P=0.003). The responses to PORH, LH and iontophoresis were not reduced compared to either COLD or CON. During the CST, toe skin temperature rewarmed more slowly in NFCI than COLD or CON (10min: 27.4 (2.3)°C vs. 30.7 (3.7)°C and 31.7 (3.9)°C, P<0.05, respectively); however, no differences were observed during the footplate cooling. NFCI were more cold-intolerant (P<0.0001) and reported colder and more uncomfortable feet during the CST and footplate cooling than COLD and CON (P<0.05). NFCI showed a decreased sensitivity to sympathetic vasoconstrictor activation than CON and greater cold sensitivity (CST) compared to COLD and CON. None of the other vascular function tests indicated endothelial dysfunction. However, NFCI perceived their extremities to be colder and more uncomfortable/painful than the controls.

Beta-blockers in patients with liver cirrhosis: Pragmatism or perfection?

With increasing decompensation, hyperdynamic circulatory disturbance occurs in liver cirrhosis despite activation of vasoconstrictors. Here, the concept of a therapy with non-selective beta-blockers was established decades ago. They lower elevated portal pressure, protect against variceal hemorrhage, and may also have pleiotropic immunomodulatory effects. Recently, the beneficial effect of carvedilol, which blocks alpha and beta receptors, has been highlighted. Carvedilol leads to "biased-signaling" via recruitment of beta-arrestin. This effect and its consequences have not been sufficiently investigated in patients with liver cirrhosis. Also, a number of questions remain open regarding the expression of beta-receptors and its intracellular signaling and the respective consequences in the intra- and extrahepatic tissue compartments. Despite the undisputed role of non-selective beta-blockers in the treatment of liver cirrhosis, we still can improve the knowledge as to when and how beta-blockers should be used in which patients.

Evaluation of in vivo MRI for detecting midodrine-induced arteritis in rats.

There are no specific and sensitive biomarkers for arteritis, and the occurrence of arteritis in nonclinical toxicological studies of a candidate drug makes development of the drug very difficult. However, we showed in a previous study that the high signal intensity region around the artery on magnetic resonance imaging (MRI) could be a candidate biomarker for detection of arteritis. The present study was conducted to clarify the details of midodrine hydrochloride (MH)-induced arteritis lesions and whether arteritis induced by a mechanism other than the vasodilatory effect, which was evaluated in a previous study, could be detected by MRI. MH is a selective peripherally acting alpha-1 adrenergic receptor agonist, known to induce arteritis due to its vasoconstrictor action, but there is not enough information about MH-induced arteritis. Based on the data obtained under multiple dosing conditions, MH was administered subcutaneously to each rat once daily for 2 days at a dose level of 40mg/kg/day for MRI assessment. The mesenteric arteries were examined using in vivo MRI at 1day or 7 days after administration of the final dose and examined histopathologically. On the day after the final dose, high signal intensity region around the artery was observed in animals with minimal perivascular lesions confirmed by histopathology and not observed in an animal without histological changes. On the 7th day after the final dose, no abnormality was observed in histopathological examinations and no high signal intensity regions were observed by MRI in any animal. In conclusion, although further investigation is needed to confirm that high signal intensity is a reliable biomarker for humans, it is suggested that high signal intensity around the artery could be a versatile candidate biomarker with high specificity and sensitivity.

Mas receptor endocytosis and signaling in health and disease.

The renin angiotensin system (RAS) plays a major role in blood pressure regulation and electrolyte homeostasis and is mainly composed by two axes mediating opposite effects. The pressor axis, constituted by angiotensin (Ang) II and the Ang II type 1 receptor (AT1R), exerts vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory actions, while the depressor/protective axis, represented by Ang-(1-7), its Mas receptor (MasR) and the Ang II type 2 receptor (AT2R), opposes the actions elicited by the pressor arm. The MasR belongs to the G protein-coupled receptor (GPCR) family. To avoid receptor overstimulation, GPCRs undergo internalization and trafficking into the cell after being stimulated. Then, the receptor may induce other signaling cascades or it may even interact with other receptors, generating distinct biological responses. Thus, control of a GPCR regarding space and time affects the specificity of the signals transduced by the receptor and the ultimate cellular response. The present chapter is focused on the signaling and trafficking pathways of MasR under physiological conditions and its participation in the pathogenesis of numerous brain diseases.

The role of neurotransmitters and indicators of oxidative stress in the formation of disorders of central conductive structures in patients who came into contact with metallic mercury

Introduction. Studies of toxic lesions due to exposure to metallic mercury compounds do not allow us to identify the features of the violation of central afferent conducting structures in the long-term period of chronic mercury intoxication (CHMI). The contribution of various systems to the development of pathology is not sufficiently disclosed. The study aims to identify the role of neurotransmitters in pathological changes in central hemodynamics, the value of lipid peroxidation products and the activity of antioxidant protection in the demyelination of central afferent conductive structures in workers exposed to metallic mercury in the workplace. Materials and methods. The authors examined 47 people (group one) - trained chemical production workers exposed to metallic mercury, and group two (51 people) - patients in the long-term period of CHMI. The control group (CG) consisted of 30 people who had no contact with toxicants. We have determined concentration of neurotransmitters, lipid peroxidation products (LPP), superoxide dismutase (SOD) and reduced glutathione (RG), nitric oxide. Results. Experts observed statistically significant changes in indicators in subgroups with and without changes in cerebral hemodynamics and in group two when compared with group one. Comparison of persons with CHMI without changes in blood circulation with the presence of disorders revealed an increase in normetanephrine in the latter, a decrease in NT-3. Correlation analysis showed: in group jne, there was a statistically significant difference between the vasomotor reactivity index (VRI) and serotonin. In group two - between CHMI and serotonin, adrenaline and dopamine. Changes in afferent pathways are interrelated with indicators of oxidative stress. Violations are accompanied by the formation of a pathological system, are signs of dysregulatory pathology. Limitations. The disadvantage of the study is the fact that scientists determined the content of neurotransmitters and products of lipid peroxidation and antioxidant protection in the blood of the subjects, and not in the structures of the brain. Conclusion. The increased content of biogenic amines leads to a change in peripheral blood circulation and regulation of cerebral blood flow by pressor action on the regulation of the vascular bed, leading to vasoconstriction, changes in the bioelectric activity of the structures of the reticular formation of the midbrain, hypothalamus, thalamocortical structures, most pronounced in the long-term period of chronic mercury intoxication. We found that the formation of demyelination in patients with chronic mercury intoxication was accompanied by a decrease in the concentration of NT-3. It was natural to reduce the level of reduced glutathione and superoxide dismutase in neurodegenerative processes in trained workers exposed to metallic mercury at work, and in patients with a long period of chronic mercury intoxication. Ethics. The study was conducted in compliance with the principles of the Helsinki Declaration of the World Association "Ethical principles of conducting Scientific medical research with human participation" (as amended in 2008), "Rules of Clinical Practice in the Russian Federation" (approved by the Order of the Ministry of Health of the Russian Federation dated 06/19/2003 No. 266).

Circulating angiotensin converting enzyme 2 and COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a widespread outbreak since December 2019. The SARS-CoV-2 infection-related illness has been dubbed the coronavirus disease 2019 (COVID-19) by the World Health Organization. Asymptomatic and subclinical infections, a severe hyper-inflammatory state, and mortality are all examples of clinical signs. After attaching to the angiotensin converting enzyme 2 (ACE2) receptor, the SARS-CoV-2 virus can enter cells through membrane fusion and endocytosis. In addition to enabling viruses to cling to target cells, the connection between the spike protein (S-protein) of SARS-CoV-2 and ACE2 may potentially impair the functionality of ACE2. Blood pressure is controlled by ACE2, which catalyzes the hydrolysis of the active vasoconstrictor octapeptide angiotensin (Ang) II to the heptapeptide Ang-(1-7) and free L-Phe. Additionally, Ang I can be broken down by ACE2 into Ang-(1-9) and metabolized into Ang-(1-7). Numerous studies have demonstrated that circulating ACE2 (cACE2) and Ang-(1-7) have the ability to restore myocardial damage in a variety of cardiovascular diseases and have anti-inflammatory, antioxidant, anti-apoptotic, and anti-cardiomyocyte fibrosis actions. There have been some suggestions for raising ACE2 expression in COVID-19 patients, which might be used as a target for the creation of novel treatment therapies. With regard to this, SARS-CoV-2 is neutralized by soluble recombinant human ACE2 (hrsACE2), which binds the viral S-protein and reduces damage to a variety of organs, including the heart, kidneys, and lungs, by lowering Ang II concentrations and enhancing conversion to Ang-(1-7). This review aims to investigate how the presence of SARS-CoV-2 and cACE2 are related. Additionally, there will be discussion of a number of potential therapeutic approaches to tip the ACE/ACE-2 balance in favor of the ACE-2/Ang-(1-7) axis.

The effect of transcutaneous electrical nerve stimulation (TENS) on decreasing primary dysmenorrhea pain in adolescents

&lt;p&gt;&lt;strong&gt;&lt;em&gt;Background: &lt;/em&gt;&lt;/strong&gt;&lt;em&gt;Dysmenorrhea is medical condition indicated by an increase of the prostaglandin (PG) F2-alpha hormone and cyclooxygenase (COX-2) causing hypertonic as well as vasoconstriction activity to the myometrium. It leads to ischemia and stimulating pain in the uterine organs. The condition influence quality of life and productivity of majority female patients. Dysmenorrhea incidence in Indonesia is reported by 64.25% and a total of 52% of students in Yogyakarta experienced drop activity during menstruation. &lt;/em&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;&lt;em&gt;Objectives: &lt;/em&gt;&lt;/strong&gt;&lt;em&gt;This study aimed to evaluate the effect of&lt;/em&gt;&lt;em&gt; TENS&lt;/em&gt;&lt;em&gt; in reducing primary dysmenorrhea pain among female adolescents in General Ahmad Yani University Yogyakarta&lt;/em&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;&lt;em&gt;Methods: &lt;/em&gt;&lt;/strong&gt;&lt;em&gt;A quasi experiment study with pretest-posttest control group design was conducted. A total of 24 participants for intervention and control group were recruited. In order to recruit study participants, this research implemented a quota sampling approach. Primary dysmenorrhea pain measured using Numerical Rating Scale (NRS) and bivariate analysis between both groups carried out using T-test.&lt;/em&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;&lt;em&gt;Results: &lt;/em&gt;&lt;/strong&gt;&lt;em&gt;A&lt;/em&gt;&lt;strong&gt;&lt;em&gt; &lt;/em&gt;&lt;/strong&gt;&lt;em&gt;significant difference (p&amp;lt;0.05) reported from both groups before and after the intervention. Prior to the treatment, the average pain score for intervention group was 6 (1.70) and ranging from 4-10. After the treatment being delivered, the intervention group experienced lower pain intensity by average 3.42 (1.6) between 1-6 score range. Control group in this study reported average pain score before the intervention by 4 (1.16) with and ranging from 3-6. The treatment decreased control group participants pain level to average 1.50 (0.52) between the range of 1-2. TENS is effective for severe pain management. Effleurage massage suitable for moderate level pain management. TENS intervention effective to lower pain by 3.50%.&lt;/em&gt;&lt;/p&gt;&lt;strong&gt;&lt;em&gt;Conclusions: &lt;/em&gt;&lt;/strong&gt;&lt;em&gt;TENS and massage intervention potential to decrease pain intensity of primary dysmenorrhea. This study reported lower pain level associated with TENS by 3.50%. TENS had significant effect for reducing dysmenorrhea pain by 3.50%.&lt;/em&gt;

Vasoconstrictor and hemodynamic effects of a methanolic extract from Rhinella marina toad poison

Rhinella marina toad is abundant in Brazil. Its poison contains cardiac glycosides called bufadienolides, which are extensively investigated for their bioactivity. Our aim was to characterize the vasoactivity of Rhinella marina poison (RmP) on the aorta of male Wistar rats. For this, the RmP was first collected and processed to obtain an alcoholic extract. To determine cardiovascular effects of RmP, we performed in vivo tests by administering RmP intravenously in doses of 0.1–0.8 mg/kg. Vascular reactivity was also performed through concentration-response curves to RmP (10 ng/mL to 200 μg/mL) in aortic segments with and without endothelium. RmP induced a concentration-dependent contraction in rat aorta which was partly endothelium-mediated. Nitric oxide contributes with this response in view that incubation with L-NAME increased the contractile response. Additionally, treatment with indomethacin [cyclooxygenase, (COX) inhibitor], nifedipine (L-type voltage-gated calcium channels blocker), and BQ-123 (ETA receptors antagonist) decreased maximum response, and ketanserin (5-HT2 receptors antagonist) decreased pEC50, suggesting active participation of these pathways in the contractile response. On the other hand, apocynin (NADPH oxidase inhibitor) did not alter contractility. Incubation with prazosin (α1-adrenergic receptor antagonist) abolished the contractile response, suggesting that the RmP-induced contraction is dependent on the adrenergic pathway. In the Na+/K+ ATPase protocol, a higher Emax was observed in the RmP experimental group, suggesting that RmP potentiated Na+/K+ATPase hyperpolarizing response. When this extract was injected (i.v.) in vivo, increase in blood pressure and decrease in heart rate were observed. The results were immediate and transitory, and occurred in a dose-dependent manner. Overall, these data suggest that the poison extract of R. marina toad has an important vasoconstrictor action and subsequent vasopressor effects, and its use can be investigated to some cardiovascular disorders.

Abstract 075: The Kidney-OVLT Neuroaxis Mediates Neurogenic Hypertension And Polydipsia In 2-Kidney, 1-Clip Rats

Renal afferent nerves mediate activation of the sympathetic nervous system and hypertension in rats with unilateral renal artery stenosis (2K1C-HTN). However, the central neural structures that mediate this response are unclear. The organum vasculosum of the lamina terminalis (OVLT), has also been implicated in the regulation of mean arterial pressure (MAP) and sympathetic activity in preclinical models of hypertension. We tested the hypothesis that afferent renal nerves and the OVLT share a common neural pathway required for the development of 2K1C-HTN. Two experiments were conducted. 1: Male rats (n=5-9) were implanted with telemeters to measure MAP. 1-week later they received a clip on the left renal artery and were subjected to afferent renal denervation (ARDN) by periaxonal capsaicin (2K1C-ARDN) or sham (2K1C-sham) treatment of the clipped kidney. 2: Male rats (n=6-8) were subjected to lesioning of the OVLT (OVLTx) or sham operation. 1-week later telemeters were implanted and 7 days later the left renal artery was stenosed by application of a silver clip. In both experiments, MAP was measured continuously for 6 weeks, and water intake (WI) was measured once a week. Neurogenic pressor activity (NPA) was assessed by measuring the peak MAP response to ganglionic blockade. EXPT 1 Results: At the end of the protocol, MAP was 165±5 mmHg in 2K1C-sham compared to 131±10mmHg in 2K-1C-ARDN rats (p&lt;0.001). WI increased in 2K1C-sham rats peaking at 110±13 ml/day at week 2. In contrast, WI was markedly reduced in 2K1C-ARDN rats at this same time point (41±3 ml/day). NPA was increased in 2K1C-sham (-50 ± 4 mmHg) but was reduced in 2K1C-ARDN (-25 ± 3 mmHg) rats (p&lt;0.05). EXPT 2 Results: At end of the protocol MAP was 162±6 mmHg in sham-2K1C rats compared to 135±8 mmHg in OVLTx-2K1C rats (p&lt;0.001). WI peaked at 74±9 ml/day in sham lesion-2K1C compared to 52±9 ml/day in OVLTx-2K1C rats at week 2 (p&lt;0.05). NPA was increased in sham-2K1C rats (-51 ± 3 mmHg) but was reduced in OVLTx-2K1C rats (-31 ± 4 mmHg) (p&lt;0.05). Since both ARDN and OVLTx attenuated MAP, WI, and NPA similarly in 2K1C rats, we hypothesize that afferent renal nerves and the OVLT are linked in a common neural pathway required for the development of hypertension following renal artery stenosis.

The role of thiazole acetate derivatives on isolated heart and blood vessels in experimental rats

Background and objectivesThough various drugs are available in the market for cardiovascular diseases, search for an efficacious and patient friendly drug is an ongoing process. The effect of synthesized thiazole compounds on isolated rat heart and isolated rat blood vessel to determine their potential as newer therapeutic agents. Materials and methodsSix thiazole acetate compounds were examined for their function on isolated heart and blood arteries utilizing standardized experimental models after being characterized and identified in the laboratory. Anesthetized Wistar albino rats' hearts were removed and placed on a Langendorff setup. The percentage change in developed tension and heart rate owing to injecting each thiazole acetate compound in the developed tension and heart rate were seen and recorded in an isolated heart that was mounted in a retrograde fashion using Krebs Henseleit solution. Similarly, anesthetized rats' thoracic aortas were separated, and responses to the standard drug phenylephrine and different thiazole acetate derivatives were examined. The pharmacological effect of the specific thiazole compound was determined by the percentage change in contractile response. ResultEach of the six thiazole acetate derivatives was injected at 1 nM, 10 nM, 100 nM, 1 M, 10 M, and 100 M concentrations. All six (T1 to T6) chemicals investigated in the present study had no significant effect on developed tension or heart rate. There was a nosignificant change in the percentage contraction after injecting 1 nM 3 nM,10 nM, 30 nM, 100 nM, 300 nM, 1 M, 3 M, 10 M, and 30 M,100 M,300 M (cumulative dose) of T1, T3, T4, T5, and T6, while T2 (- ethyl-4-methyl-2-aminothiazole) showed contractile effect in the form of vasoconstrictor activity, which was 30 % of that produced by phenylephrine. Interpretation and conclusionThiazole acetate derivatives did not show any cardiovascular effects except ethyl-4-methyl-2-aminothiazole, which showed a slight vascular contractile response as compared to phenylephrine. A more thorough examination of the utilization of thiazole derivatives is required to establish their potential significance in the cardiovascular system.

Pipersentan: A De Novo Synthetic Endothelin Receptor Antagonist that Inhibits Monocrotaline- and Hypoxia-Induced Pulmonary Hypertension.

Background: Although major advances have been made in the pathogenesis and management of pulmonary arterial hypertension (PAH), the endothelin system is still considered to play a vital role in the pathology of PAH due to its vasoconstrictive action. Endothelin receptor antagonists (ERAs), either as monotherapy or in combination with other drugs, have attracted much attention in the treatment of this lethal disease, and research is continuing. Methods: A novel ERA, pipersentan 5-(1,3-Benzodioxol-5-yl)-6-[2-(5-bromopyrimidin-2-yl)oxyethoxy]-N-(2-methoxyethylsulfamoyl)pyrimidin-4-amine, was recently synthesized and the physicochemical characterizations and the pharmacology both in vitro and in vivo were studied. Results: This orally administered ERA can both competitively and selectively inhibit the binding of endothelin-1 (ET-1) to its receptors with good physicochemical characteristics. Pipersentan efficaciously antagonized the effects of ET-1 on pulmonary artery smooth muscle cell proliferation, migration and calcium mobilization and effectively improved right ventricular hypertrophy and pulmonary arterial pressure in both monocrotaline- and hypoxia-induced pulmonary hypertension (PH) rat models. Conclusions: This profile identifies pipersentan as a new agent for treating ET-1 system activation-related PH.

Renin-angiotensin system in normal pregnancy and in preeclampsia: A comprehensive review.

The activation of the Renin Angiotensin System (RAS) is required during pregnancy and it seems that RAS dysfunction has some important effects on pathological pregnancy conditions, including preeclampsia (PE). The objective of this review is to summarize and to discuss the role of the RAS in normal pregnancy and in PE. We found evidence that the RAS is important for the evolution of pregnancy under physiological conditions and plays an important role in the pathogenesis of PE. In normal gestation, almost all circulating components of RAS are increased and there is a general state of non-reactivity to the vasoconstrictor actions of Angiotensin (Ang) II. In PE, changes in the circulating levels of RAS components occur, especially with an intense decrease in the levels of Ang I, Ang II and Ang-(1-7). Our findings endorse the idea that PE is a disease whose cornerstone relies on altered placental physiology. There are high tissue levels of Ang II type 1 receptor (AT1R) in the musculature of the blood vessels and in the placenta, generating a state of increased sensitivity to the vasoconstrictor action of Ang II. AT1R autoantibodies (AT1R-AA) might be one of the key points for the vicious cycle of PE, as these molecules are synthesized in situations of hypoxia and enhance placental vasoconstriction, causing even more hypoxia. Further studies are needed to investigate the role of circulating RAS, uteroplacental RAS and local RAS molecules from other tissues related to the pathogenesis of PE.

Vascular Effects of Polyphenols from Agrimonia eupatoria L. and Role of Isoquercitrin in Its Vasorelaxant Potential in Human Arteries

Agrimonia eupatoria L. has been traditionally used for the treatment of inflammatory diseases but also as a hypotensive. To our knowledge, only one study has previously suggested an improvement in vascular endothelial function in diabetic conditions, as the underlying mechanisms and responsible compounds are unknown. In this study, we aimed to assess the direct vascular effects of Agrimonia eupatoria L. in human arteries. The infusion elicited a mild increase in basal vascular tone and a significant potentiation of the adrenergic contraction of 49.18% at 0.02 mg/mL, suggesting the presence of compounds with mild vasoconstrictor activity. In contrast, the ethyl acetate fraction inhibited adrenergic contraction by 80.65% at 2 mg/mL and elicited no effect on basal vascular tone. A potent concentration-dependent vasorelaxation was observed for both the infusion and the ethyl acetate fraction (maximal relaxation above 76% and 47%, respectively). Inhibition of nitric oxide synthase and cyclooxygenase elicited significant decreases in the vasorelaxation to the infusion, as, for the ethyl acetate fraction, only the cyclooxygenase pathway appeared to be involved. Isoquercitrin elicited a vasoactivity consistent with the ethyl acetate fraction, suggesting this is a major component responsible for the vasorelaxant properties of A. eupatoria. Further research is warranted to fully evaluate its vasoprotective properties with therapeutic potential in several conditions, e.g., atherosclerosis.

Indole‐3‐propionic Acid, Bacterial Metabolite of Tryptophan, Increases Blood Pressure in Normotensive and Hypertensive Rats

Tryptophan is an exogenous amino acid, undergoing complex metabolism in mammals, including formation of gut microbiota‐derived metabolites. Tryptophan was proven to increase blood pressure in rats and humans, however; it has not been profoundly investigated, whether its impact on cardiovascular system might be due to the action of microbiota derived indoles, especially indole‐3‐propionic acid (IPA).Acute hemodynamic experiments were performed on 12‐week‐old Wistar‐Kyoto (WKY) and 16‐week‐old Spontaneously‐Hypertensive (SHR) male anesthetized rats. Mean arterial blood pressure (MABP) and heart rate (HR) were evaluated for 120 minutes after intravenous infusion of 10% DMSO (Vehicle) and IPA in increasing doses (1.6‐53 µM/kg body wt). In separate series of experiments impact of IPA on vascular contractility was evaluated in ex vivo experiments performed on mesenteric resistance arteries (MRAs).IPA increased significantly blood pressure in normotensive and hypertensive rats. In normotensive rats at highest dose IPA revealed less pronounced hypertensive effect, accompanied by decrease in HR. This effect was not observed in hypertensive rats, where IPA increased MABP in dose dependent matter, with concomitant tachycardic response. In ex vivo experiments IPA increased contractility of endothelium‐denuded MRAs and reduced acetylcholine‐dependent dilatation of MRAs.Our study suggest, that IPA takes part in regulation of blood pressure, by revealing hypertensive and vasoconstrictive activity. These effects are in line with actions of its precursor tryptophan, suggesting important role of bacterial metabolism of tryptophan in its cardiovascular effects.

Prostaglandin F 2α evokes vasoconstrictor and vasodepressor activities that are both independent of the F prostanoid receptor

The F prostanoid receptor (FP), which accounts for the therapeutic effect of PGF2α in uterine atony that leads to postpartum hemorrhage and maternal morbidity, could possibly mediate vasoconstrictor effect in small or resistance arteries to elevate blood pressure that limits the clinical use of the agent in patients with cardiovascular disorders. This study aimed to test the above hypothesis with genetically altered mice. Ex vivo and in vivo experiments were performed on control wild-type (WT) mice and mice with deficiencies in FP (FP-/- ) or thromboxane (Tx)-prostanoid receptor (the original receptor of TxA2 ; TP-/- ), and/or those with an additional deficiency in E prostanoid receptor-3 (one of the vasoconstrictor receptors of PGE2 ; EP3-/- ). Here, we show that PGF2α indeed evoked vasoconstrictor responses in the above-mentioned tissues of WT mice, which were however unaltered by FP-/- . Interestingly, such contractile responses were reversed into dilations by TP-/- /EP3-/- . A similar pattern of results was observed with the pressor effect of PGF2α under in vivo conditions. However, TP-/- alone (which could largely remove the contractile responses) did not result in relaxation to PGF2α . Also, either the ex vivo vasodilator effect or the in vivo depressor response of PGF2α obtained after the removal of TP and EP3-mediated actions was unaltered by FP-/- . Therefore, both the ex vivo vasoconstrictor action in small or resistance arteries and the systemic pressor effect of PGF2α can reflect vasoconstrictor activities derived from the non-FP receptors TP and EP3 outweighing a concurrently activated dilator effect, which is again independent of FP.

Brain-Derived Extracellular Vesicles Induce Vasoconstriction and Reduce Cerebral Blood Flow in Mice.

Traumatic brain injury (TBI) impairs cerebrovascular autoregulation and reduces cerebral blood flow (CBF), leading to ischemic secondary injuries. We have shown that injured brains release brain-derived extracellular vesicles (BDEVs) into circulation, where they cause a systemic hypercoagulable state that rapidly turns into consumptive coagulopathy. The BDEVs induce endothelial injury and permeability, leading to the hypothesis that they contribute to TBI-induced cerebrovascular dysregulation. In a study designed to test this hypothesis, we detected circulating BDEVs in C57BL/6J mice subjected to severe TBI, reaching peak levels of 3 × 104/μL at 3 h post-injury (71.2 ± 21.5% of total annexin V-binding EVs). We further showed in an adaptive transfer model that 41.7 ± 5.8% of non-injured mice died within 6 h after being infused with 3 × 104/μL of BDEVs. The BDEVs transmigrated through the vessel walls, induced rapid vasoconstriction by inducing calcium influx in vascular smooth muscle cells, and reduced CBF by 93.8 ± 5.6% within 30 min after infusion. The CBF suppression was persistent in mice that eventually died, but it recovered quickly in surviving mice. It was prevented by the calcium channel blocker nimodipine. When being separated, neither protein nor phospholipid components from the lethal number of BDEVs induced vasoconstriction, reduced CBF, and caused death. These results demonstrate a novel vasoconstrictive activity of BDEVs that depends on the structure of BDEVs and contributes to TBI-induced disseminated cerebral ischemia and sudden death.

Neurohypophyseal Peptides from Prague and Swedish Laboratories Used as Pharmaceuticals. Part 2: Desmopressin, Terlipressin, Carbetocin – Pharmacology and Clinical Applications

Licence agreements between the Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences, Prague (IOCB), and the pharmaceutical company Ferring AB Malmö enabled the Swedish company to produce and commercialize worldwide a number of neurohypophyseal peptides designed at the IOCB. Several of them found therapeutic applications.&#x0D; dDAVP: 1-deamino-8-ᴅ-arginine-vasopressin was designed in one of the IOCB peptide laboratories (M. Zaoral and F. Šorm) in 1967. It displayed an extremely high antidiuretic activity (various tests indicate a 2- to 50-fold increase, as compared to arginine vasopressin) and a very low pressor activity. The peptide (covered by the U.S. Patent No. 3,497,491, 1970) has been used as a preferred drug in the substitution therapy of the central form of diabetes insipidus (Minirin®, today as Desmopressin INN). Besides, as later discovered (Mannucci et al. 1977), dDAVP increases the plasma concentration of the blood-clotting factor VIII. This fact extended its clinical use as haemostatics in cases of milder forms of haemophilia A, von Willebrand-Jürgens syndrome and some thrombocyte dysfunctions. Despite of the clinical success of dDAVP, a closer look reveals certain inadequacies in the presently available pharmacological data: several reports declare activity values and the prolongation effect (index of persistence) in very broad ranges.&#x0D; Triglycyl-8-lysine-vasopressin (Terlipressin), a peptide with lysine vasopressin chain extended at the N‑terminal by a triglycine residue, acts mainly as a prodrug (releasing lysine vasopressin after aminopeptidase splitting at the Nα group). The analogue belongs to the so-called „synthetic hormonogens“; individual peptides carrying various acylating groups were synthesized in the mid-sixties at the IOCB and legally protected by U.S. Patent No. 3,558,590 (1968). It was a part of the licence agreements mentioned above. The activities of triglycyl-8-lysine-vasopressin (both antidiuretic and vasopressor) are about 100 times lower than those of lysine vasopressin, but its persistence is 5 times longer. As such, it is occasionally used in emergency medicine in cases of esophageal (and other gastroenteral) bleeding, traumatic or septic shock, in cirrhotic patients and patients with portal hypertension. Its use as an early abortion drug was discussed but not pursued.&#x0D; Carbetocin (deaminocarba1-2-O-methyltyrosin-oxytocin) was synthetized in the laboratory of Karel Jošt at the IOCB before 1971; its synthesis was covered by a Czechoslovak patent (CS-149,028 B1) in June 1973 (at that time, Czechoslovak patent law did not provide for the patentability of substances as such) and first published in a biophysical communication by Frič et al., 1974). As a part of the licence agreement, it was included in the production program of Ferring AB, but marketed later also by several other pharmaceutical companies due to an incomplete patent protection. The peptide is a moderately active uterotonic partial agonist and as such has been utilized in veterinary obstetrics for delivery induction in cows and (multiparous) pigs: its milder and better-controlled uterotonic action was found preferential as compared to oxytocin so far used for these purposes. In the last two decades, carbetocin has been commonly used also in the human obstetrics, especially to prevent the peri- and post-partum haemorrhage, from the maternal side the most frequent and most severe delivery complication. It became a life-saving drug in emergency obstetrics.

Association of Arterial pH With Hemodynamic Response to Vasopressin in Patients With Septic Shock: An Observational Cohort Study.

OBJECTIVES:Vasopressin is reported to retain vasoconstrictive activity in the setting of acidemia, but preclinical models are inconsistent and studies have not evaluated the clinical effectiveness of vasopressin based on arterial pH. This study sought to determine the association between arterial pH and blood pressure after vasopressin initiation in septic shock.DESIGN:This retrospective, multicenter, observational cohort study evaluated the association of arterial pH at the time of vasopressin initiation with hemodynamic response to vasopressin and change in catecholamine dose after vasopressin initiation. Hemodynamic response was defined as a catecholamine dose decrease with mean arterial pressure greater than or equal to 65 mm Hg at 6 hours after vasopressin initiation.SETTING:Patients from eight hospitals in a health system were evaluated.PATIENTS:Patients with septic shock initiated on vasopressin as a catecholamine adjunct between January 2012 and November 2017 were screened for inclusion.INTERVENTIONS:None.MEASUREMENTS AND MAIN RESULTS:A total of 1,350 patients were included. At the time of vasopressin initiation patients were severely ill with arterial pH 7.28 ± 0.13, Sequential Organ Failure Assessment 14.1 ± 3.5, lactate 5.6 ± 4.6 mmol/L, and norepinephrine-equivalent catecholamine dose 32.3 ± 25.4 µg/min. After adjusting for lactate and Sequential Organ Failure Assessment with multivariable logistic regression, lower arterial pH was independently associated with lower odds of hemodynamic response to vasopressin (for each 0.1 unit arterial pH was below 7.40, response odds ratio 0.79; 95% CI, 0.72–0.87). For each 0.1 unit the pH was below 7.40 at vasopressin initiation, the norepinephrine-equivalent catecholamine dose increased by 1.5 µg/min (95% CI, 0.5–2.5 µg/min) at 1 hour, and increased by 2.5 µg/min (95% CI, 1.4–3.5 µg/min) at 6 hours after vasopressin initiation.CONCLUSIONS:Compared with higher arterial pH, patients with septic shock and low arterial pH had lower odds of vasopressin response and higher catecholamine doses after vasopressin initiation. Similar to other vasopressors, the clinical effectiveness of vasopressin appears to be impaired in the setting of acidemia.

Successful Pain Relief of Chronic Myofascial Pain Using Trigger Point Injection and Fascia Hydrorelease with Local Anesthetics Capable of Exerting a Vasoconstrictive Action : Two Case Reports

Successful Pain Relief of Chronic Myofascial Pain Using Trigger Point Injection and Fascia Hydrorelease with Local Anesthetics Capable of Exerting a Vasoconstrictive Action : Two Case Reports

Crosstalk relationship between adiponectin receptors, PPAR-γ and α-adrenoceptors in renal vasculature of diabetic WKYs

Hypoadiponectinemia is associated with renal dysfunctions. Irbesartan and pioglitazone activate Peroxisome proliferator-activated gamma receptor (PPAR-γ) as partial and full agonists. We investigated a crosstalk interaction and synergistic action between adiponectin receptors, PPAR-γ agonists in attenuating renal hemodynamics to adrenergic agonists in diabetic Wistar Kyoto rats (WKY). Streptozotocin (40 mg/kg) was used to induce diabetes, whereas, pioglitazone (10 mg/kg/day), irbesartan (30 mg/kg/day) administered orally for 28 days and adiponectin intraperitoneally (2.5 μg/kg/day) for last 7 days. Metabolic and plasma samples were analyzed on days 0, 8, 21, and 28. During the acute study (day 29), renal vasoconstrictor actions to adrenergic agonists and angiotensin-II were determined. Diabetic WKYs had lower plasma adiponectin, higher creatinine clearance, urinary and fractional sodium excretion but were normalized to a greater extent in pioglitazone and adiponectin combined treatment. Responses to intra-renal administration of adrenergic agonists including noradrenaline (NA), phenylephrine (PE), methoxamine (ME), and angiotensin-II (ANG-II) were larger in diabetic WKY, but significantly blunted with adiponectin treatment in diabetic WKYs to 35–40%, and further reduced by 65–70% in combination with pioglitazone. Attenuation to ANG-II responses in adiponectin and combination with irbesartan was 30–35% and 75–80%, respectively (P < 0.05). Pharmacodynamically, a crosstalk interaction exists between PPAR-γ, adiponectin receptors (adipo R1 & R2), alpha adrenoceptors, and angiotensin-I (ATI) receptors in the renal vasculature of diabetic WKYs. Exogenously administered adiponectin with full PPAR-γ agonist substantially attenuated renal hemodynamics and improved excretory functions, signifying their renoprotective action. Additionally, a degree of synergism exists between adiponectin and pioglitazone to a large extent compared to combination therapy with irbesartan (partial PPAR-γ agonist) in attenuating the renal vascular receptiveness to adrenergic agonists.