Calcitonin gene-related peptide (CGRP) exerts membrane, cellular and synaptic actions on serotonergic dorsal raphe neurons ex vivo: Functional implications for a role in dorsal raphe-controlled functions.

Serotonin (5-HT) plays a role in limbic-controlled behaviors and is implicated in migraine, which is often co-morbid with cognitive-based affective disorders. The neuropeptide calcitonin gene-related peptide (CGRP) regulates vascular tone. Serotonin-acting drugs and CGRP receptor antagonists have proved therapeutic in management of migraine.

Heterogeneous vasomotor responses in segments from Göttingen Minipigs coronary, cerebral, and mesenteric artery: A comparative study.

Göttingen Minipigs (GM) are used as an important preclinical model for cardiovascular safety pharmacology and for evaluation of cardiovascular drug targets. To improve the translational value of the GM model, the current study represents a basic characterization of vascular responses to endothelial regulators and sympathetic, parasympathetic, and sensory neurotransmitters in different anatomical origins. The aim of the current comparative and descriptive study is to use myography to characterize the vasomotor responses of coronary artery isolated from GM and compare the responses to those obtained from parallel studies using cerebral and mesenteric arteries.

Lasmiditan and 5-Hydroxytryptamine in the rat trigeminal system; expression, release and interactions with 5-HT receptors.

Background: 5-Hydroxytryptamine (5-HT) receptors 1B, 1D and 1F have key roles in migraine pharmacotherapy. Selective agonists targeting these receptors, such as triptans and ditans, are effective in aborting acute migraine attacks and inhibit the in vivo release of calcitonin gene-related peptide (CGRP) in human and animal models. The study aimed to examine the localization, genetic expression and functional aspects of 5- HT receptors in the trigeminal system in order to further understand the molecular sites of action of triptans (5-HT) and ditans (5-HT).

Image-derived and physiological markers to predict adequate adenosine-induced hyperemic response in Rubidium-82 myocardial perfusion imaging.

Aims: This study aimed to investigate the potential of different markers to identify adequate stressing in subjects with and without caffeine intake prior to Rubidium-82 myocardial imaging.

Methods And Results: This study comprised 40 healthy subjects who underwent four serial Rubidium-82 rest/adenosine stress MPI; two with 0mg caffeine consumption (baseline MPIs) and two with controlled consumption of caffeine (arm 1: 100 and 300mg, or arm 2: 200 and 400mg). We report the sensitivity and specificity of seven markers ability to predict adequate adenosine-induced hyperemic response: (1) the splenic response ratio (SRR); (2) splenic stress-to-rest intensity ratios (SIR); (3) changes in heart rate (ΔHR); (4) percentwise change in heart rate (Δ%HR); (5) changes in the rate pressure product (ΔRPP); (6) changes in the systolic blood pressure (ΔSBP); and (7) changes in the cardiovascular resistance (ΔCVR).

Neurokinins and their receptors in the rat trigeminal system: Differential localization and release with implications for migraine pain.

Substance P (SP) and calcitonin gene-related peptide (CGRP) have both been considered potential drug candidates in migraine therapy. In recent years, CGRP receptor inhibition has been established as an effective treatment, in particular as a prophylactic for chronic migraine. Curiously, inhibition of neurokinin receptor 1 (NK1R) failed to alleviate acute migraine attacks in clinical trials, and the neurokinins were consequently abandoned as potential antimigraine candidates.

Sex Differences and Caffeine Impact in Adenosine-Induced Hyperemia.

Caffeine consumption before adenosine stress myocardial perfusion imaging (MPI) is known to affect the hemodynamic response and, thus, reduce the stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) assessments. However, it is not clear if any sex-specific differences in the hemodynamic response after caffeine consumption exist. This study aimed to evaluate if such differences exist and, if so, their impact on MBF and MFR assessments.

The Effect of K Channel Blocker Glibenclamide on CGRP-Induced Headache and Hemodynamic in Healthy Volunteers.

Background: Calcitonin gene-related peptide (CGRP) dilates cranial arteries and triggers headache. The CGRP signaling pathway is partly dependent on activation of ATP-sensitive potassium (K ) channels. Here, we investigated the effect of the K channel blocker glibenclamide on CGRP-induced headache and vascular changes in healthy volunteers.

Effect of Increased Potassium Intake on Adrenal Cortical and Cardiovascular Responses to Angiotensin II: A Randomized Crossover Study.

Background Increased potassium intake lowers blood pressure in patients with hypertension, but increased potassium intake also elevates plasma concentrations of the blood pressure-raising hormone aldosterone. Besides its well-described renal effects, aldosterone is also believed to have vascular effects, acting through mineralocorticoid receptors present in endothelial and vascular smooth muscle cells, although mineralocorticoid receptors-independent actions are also thought to be involved. Methods and Results To gain further insight into the effect of increased potassium intake and potassium-stimulated hyperaldosteronism on the human cardiovascular system, we conducted a randomized placebo-controlled double-blind crossover study in 25 healthy normotensive men, where 4 weeks treatment with a potassium supplement (90 mmol/day) was compared with 4 weeks on placebo.

Pirfenidone Is a Vasodilator: Involvement of K7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice.

Endothelial cell dysfunction and fibrosis are associated with worsening of the prognosis in patients with cardiovascular disease. Pirfenidone has a direct antifibrotic effect, but vasodilatation may also contribute to the effects of pirfenidone. Therefore, in a first study we investigated the mechanisms involved in the relaxant effect of pirfenidone in rat intrapulmonary arteries and coronary arteries from normal mice.

Cannabinoid CB1 receptor mediates METH-induced electrophysiological and morphological alterations in cerebellum Purkinje cells.

Our previous studies on cannabinoid type1 receptor (CB1R) activation on Methamphetamine (METH)-induced neurodegeneration and locomotion impairments in male rats suggest an interaction between CB1Rs and METH. However, the role of these receptors in METH-neurotoxicity has not been fully identified. Therefore, the purpose of the present study is to investigate the involvement of CB1Rs in these effects.

Endothelial Dysfunction and Passive Changes in the Aorta and Coronary Arteries of Diabetic db/db Mice.

Endothelial cell dysfunction and vessel stiffening are associated with a worsened prognosis in diabetic patients with cardiovascular diseases. The present study hypothesized that sex impacts endothelial dysfunction and structural changes in arteries from diabetic mice. In diabetic (db/db) and normoglycaemic (db/db+) mice, the mechanical properties were investigated in pressurized isolated left anterior descending coronary arteries and aorta segments that were subjected to tensile testing.

Effect of increased potassium intake on the renin-angiotensin-aldosterone system and subcutaneous resistance arteries: a randomized crossover study.

Background: Increased potassium intake lowers blood pressure (BP) in hypertensive patients. The underlying mechanism is not fully understood but must be complex because increased potassium intake elevates circulating concentrations of the BP-raising hormone aldosterone.

Methods: In a randomized placebo-controlled crossover study in 25 normotensive men, we investigated the effect of 4 weeks of potassium supplement (90 mmol/day) compared with 4 weeks of placebo on the renin-angiotensin-aldosterone system (RAAS), urine composition and 24-h ambulatory BP.

Differences in pituitary adenylate cyclase-activating peptide and calcitonin gene-related peptide release in the trigeminovascular system.

Background: Several neurotransmitters are expressed in the neurons of the trigeminal ganglion. One such signalling molecule is the pituitary adenylate cyclase-activating peptide (PACAP). PACAP signalling has been suggested to have a possible role in the pathophysiology of primary headaches.

The effects of CGRP in vascular tissue - Classical vasodilation, shadowed effects and systemic dilemmas.

Vascular tissue consists of endothelial cells, vasoactive smooth muscle cells and perivascular nerves. The perivascular sensory neuropeptide CGRP has demonstrated potent vasodilatory effects in any arterial vasculature examined so far, and a local protective CGRP-circuit of sensory nerve terminal CGRP release and smooth muscle cell CGRP action is evident. The significant vasodilatory effect has shadowed multiple other effects of CGRP in the vascular tissue and we therefore thoroughly review vascular actions of CGRP on endothelial cells, vascular smooth muscle cells and perivascular nerve terminals.

CGRP in rat mesenteric artery and vein - receptor expression, CGRP presence and potential roles.

CGRP is a potent dilator of arteries and despite rich perivascular CGRP immunoreactivity in both arteries and veins the role of CGRP in veins remains unknown. The aim of the current study was to compare perivascular CGRP immunoreactivity and expression of CGRP receptor mRNA and CGRP receptor immunoreactivity in rat mesenteric arteries and veins. Furthermore, potential vasomotor effects of CGRP were explored in veins.

Fluorescent Analogues of Human α-Calcitonin Gene-Related Peptide with Potent Vasodilator Activity.

Human α-calcitonin gene-related peptide (h-α-CGRP) is a highly potent vasodilator peptide that belongs to the family of calcitonin peptides. There are two forms of CGRP receptors in humans and rodents: α-CGRP receptor predominately found in the cardiovascular system and β-CGRP receptor predominating in the gastrointestinal tract. The CGRP receptors are primarily localized to C and Aδ sensory fibers, where they are involved in nociceptive transmission and migraine pathophysiology.

C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system.

Background: Monoclonal antibodies (mAbs) towards CGRP or the CGRP receptor show good prophylactic antimigraine efficacy. However, their site of action is still elusive. Due to lack of passage of mAbs across the blood-brain barrier the trigeminal system has been suggested a possible site of action because it lacks blood-brain barrier and hence is available to circulating molecules.

The Presence of Calcitonin Gene-Related Peptide and Its Receptors in Rat, Pig and Human Brain: Species Differences in Calcitonin Gene-Related Peptide Pharmacology.

Aim: The aim of present study is to investigate the binding characteristics of non-peptide calcitonin gene-related peptide (CGRP) receptor antagonists (i.e., gepants) in the brain membranes of rat, pig and human.

Hypermetabolism and impaired endothelium-dependent vasodilation in mesenteric arteries of type 2 diabetes mellitus db/db mice.

Besides being a metabolic disease, diabetes is considered a vascular disease as many of the complications relate to vascular pathologies. The aim of this study was to investigate how vascular tone and reactivity and vascular cell metabolism were affected in type 2 diabetes mellitus and whether β-hydroxybutyrate could have a positive effect as alternative energy substrate. Isolated mesenteric arteries of db/db and control mice were incubated in media containing [U-C]glucose or [U-C]β-hydroxybutyrate, and tissue extracts were analysed by mass spectrometry.

Telomere length and genotoxicity in the lung of rats following intragastric exposure to food-grade titanium dioxide and vegetable carbon particles.

Vegetable carbon (E153) and titanium dioxide (E171) are widely used as black and white food colour additives. The aim of this study was to assess gastrointestinal tight junction and systemic genotoxic effects in rats following exposure to E153 and E171 for 10 weeks by oral gavage once a week. The expression of tight junction proteins was assessed in intestinal tissues.

Vascular pathology of large cerebral arteries in experimental subarachnoid hemorrhage: Vasoconstriction, functional CGRP depletion and maintained CGRP sensitivity.

Subarachnoid hemorrhage (SAH) is associated with increased cerebral artery sensitivity to vasoconstrictors and release of the perivascular sensory vasodilator CGRP. In the current study the constrictive phenotype and the vasodilatory effects of exogenous and endogenous perivascular CGRP were characterized in detail applying myograph technology to cerebral artery segments isolated from experimental SAH and sham-operated rats. Following experimental SAH, cerebral arteries exhibited increased vasoconstriction to endothelin-1, 5-hydroxytryptamine and U46419.

Role of pannexin and adenosine triphosphate (ATP) following myocardial ischemia/reperfusion.

Objectives: The purinergic system has not been investigated in detail following ischemia/reperfusion (I/R) injury in the heart. In the present study, we focus on both release and response to extracellular adenosine triphosphate (ATP). Pannexin (Panx) channels have been shown to be involved in ATP release from myocytes and can activate P2X1 and P2Y2 receptors on the coronary artery.

Vasomotor dysfunction in human subcutaneous arteries exposed ex vivo to food-grade titanium dioxide.

Animal studies have shown that titanium dioxide (TiO) exposure affects arterial vasomotor function, whereas little is known about the effects in arteries from humans. This study investigated vasomotor responses after direct exposure of human subcutaneous arteries to food-grade TiO (E171) (14 or 140 μg/ml) for 30 min and 18 h. Vasomotor responses to bradykinin, 5-hydroxytryptamine (5-HT), sarafotoxin 6c (S6c) and nitroglycerin were recorded in wire-myographs.

Vascular and molecular pharmacology of the metabolically stable CGRP analogue, SAX.

The main purpose of this study was to compare in vitro pharmacological properties of human αCGRP (CGRP) and a recently discovered metabolically stable CGRP analogue, SAX, in isolated rat and human artery segments. In rat, CGRP and SAX induced similar vasodilatory responses in isolated mesenteric artery with the potency of SAX being lower than that of CGRP (vasodilatory pEC 8.2 ± 0.