Calcium Channel Blockade Research Articles

Flavonoids containing Vitex negundo extract displayed calcium channels blocking property underlying its anti-diarrheal and anti-spasmodic activities

Diarrhea is a major health problem and despite of interventions, it remains a substantial cause of mortality and morbidity. In this study, a flavonoids-rich Vitex negundo extract was mechanistically evaluated for its effectiveness in diarrheal diseases. The Vitex negundo ethanolic extract was subjected to extraction for isolation of total flavonoids and qualitative phytochemical analysis. The acute toxicity of flavonoids-extract was done in mice to assess its safety and tolerability. The anti-diarrhoeal activity was determined using the castor oil induced diarrhea mouse model at doses of 10, 30 and 100 mg/kg in relation to loperamide (10 mg/kg, oral). The antispasmodic profile was determined by using cut pieces of rabbit’s jejunum in Tyrode’s solutions, employing acetylcholine (0.03μM) as a tissue stabilizer and verapamil, as a calcium channel blocker. The preliminary qualitative analysis of extract revealed different phytochemicals, in addition to flavonoids. The acute toxicity profile showed that the flavonoids-extract is safe and tolerable (LD50 = 1678 mg/kg). In the tissue experiments, the total flavonoids exhibited an EC50 of 1.52 mg/mL and showed maximum relaxation of spontaneous contractions at 5.0 mg/mL and against high-K+ induced contractions at 3 mg/mL (EC50 = 0.43 mg/mL). The spasmolytic activity of total flavonoids was comparable to verapamil which suggests that the activity might be due to the blockade of calcium channels. The flavonoids extract (0.1, 0.3 and 1.0 mg/mL) produced an adequate right shift in the calcium concentration response curve as compared to the control (EC50 value = –2.67 mg/mL), which confirmed that the extract has calcium channel blocking activity.

Vasoactive Effect Associated With Calcium Channel Blockade Through a Pitaya Juice Concentrate (Stenocereus Huastecorum): Identification of Bioactive Compounds.

ObjectivesThe aim is to evaluate the vasodilator effect of pitaya juice concentrate (PJC) in isolated rat aortic rings and to identify the responsible vasoactive compounds, as well as their mechanism of action. MethodsThe juice was obtained from S. huastecorum fruit. First, the fruit juice was centrifuged to obtain 1200 mL of PJC, 600 mL were frozen until use and 600 mL were lyophilized (LyPJC). LyPJC was fractionated by reverse phase chromatography. he profiling of the LyPJC was analyzed by HPLC-PAD and nuclear magnetic resonance (NMR). The vasoactive effect of PJC was evaluated in rings with (n = 5) and without endothelium (n = 5), pre-contracted with 10 mM phenylephrine (Phe). Next, 40 mg/mL of LyPJC was added, during 30 min. In separate experiments, the effect of 20 mM of tetraethylammonium ion (TEA, potassium channel blocker), or 200 nM of nifedipine (Nph, calcium channel blocker) was tested. Furthermore, the LyPJC fractions were evaluated in thoracic aorta rings and by patch clamp technique. ResultsThe profiling of LyPJC by HPLC-PAD showed 16 types of betalains and 31 types of phenolic compounds. The NRM showed a type of betalain as the main compound of PJC. The LyPJC administration exhibited 4-fold greater vasodilation effect versus physiological solution (54.3% ± 14.1 vs 6.7% ± 3.7), endothelium independent. The TEA did not modify the vasodilator effect of LyPJC in rings. However, with Nph, the vasodilator effect was blocked. Finally, the 8 fractions obtained from LyPJC were evaluated in rings, only the first fraction (H2O: HOAc 1% without methanol) showed a vasodilatory effect. Patch clamp experiments showed that the LyPJC first fraction relaxing effect may be the result of its inhibitory effect on L-type calcium channels. ConclusionsPJC contains betalains and phenolic compounds, with a vasodilatory effect associated with calcium channel blockade in isolated rat aortic rings. The first fraction will be purified and analyzed by mass spectrometry and the exact compound will be determined. Funding SourcesConsejo Nacional de Ciencia y Tecnología (CONACYT- FORDECYT 296,354)-Instituto Potosino de Investigación Científica y Tecnológica A.C. (IPICYT).

ID:15841 A Case of Prolonged Psychosis With Intrathecal Ziconotide

Chronic refractory pain can be difficult to manage. Intrathecal Ziconotide has proven to be effective at treating refractory nociceptive and neuropathic pain. Ziconotide’s analgesic effect is via selective blockade of N-type calcium channels. Ziconotide is trialed with a bolus of 3 mcg or 5 mcg. After intrathecal pump implant, therapy is initiated at 1.2-2.4 mcg/day. After 7-14 days the medication is exchanged and the dose kept the same. Subsequently, the dose is titrated every 7-14 days by 0.5-1.2 mcg/day.

Brain-penetrant calcium channel blockers are associated with a reduced incidence of neuropsychiatric disorders

Calcium channel blockers (CCBs) differ in their ability to penetrate into the brain. Pharmacoepidemiological studies suggest that CCBs as a class may have beneficial effects on the risks and outcomes of some psychiatric and neurological disorders. It is plausible but unknown whether this effect relates to their brain penetrance. To address this, we used the TriNetX electronic health records network to identify people prescribed a brain-penetrant CCB (BP-CCB), or those given amlodipine, a CCB with low brain penetrability. We created cohorts of patients who, prior to first CCB exposure, either had to have, or could not have had, a recorded ICD-10 diagnosis in any of the following categories: psychotic disorder; affective disorder (including bipolar disorder and major depressive disorder); anxiety disorder; substance use disorder; sleep disorder; delirium; dementia, or movement disorder. Cohort pairs were propensity score matched for age, sex, race, blood pressure, body mass index, and a range of other variables. The outcomes were the incidence of these disorders measured over a two-year exposure period. Matched cohort sizes ranged from 17,896 to 49,987. In people with no prior history of psychiatric or neurodegenerative disorder, there was a significantly lower incidence of most disorders with BP-CCBs compared to amlodipine, with risk ratios ranging from 0.64 to 0.88 and an overall risk ratio of 0.88, i.e. a risk reduction of 12%. In people who did have a prior psychiatric or neurodegenerative diagnosis, differences were much smaller, but again showed lower risks for several disorders with BP-CCBs compared to amlodipine. The differences were somewhat more marked in women and in people less than 60 years old. Results were similar when comparing BP-CCBs with verapamil and diltiazem. We also compared BP-CCBs with angiotensin receptor blockers, and found an overall risk ratio of 0.94 in favour of BP-CCBs, but with differential effects across disorders including a higher risk of psychotic disorder and dementia, but a lower risk for anxiety and sleep disorders. In some analyses, there was evidence of residual confounding even after the extensive matching, in that negative control outcomes showed a reduced incidence with BP-CCBs relative to the comparator cohort. In summary, CCBs that readily penetrate the brain are associated with a lower incidence of neuropsychiatric disorders, especially first diagnoses, compared to CCBs which do not. This may reflect their blockade of neuronal voltage-gated calcium channels. The findings encourage repurposing trials using existing BP-CCBs, and suggest that novel BP-CCBs with enhanced and more selective central actions might have greater therapeutic potential for psychiatric and neurodegenerative disorders.

Cardioprotective Effect of Rumex vesicarius Linn. Leaf Extract against Catecholamine-Induced Cardiotoxicity.

Rumex vesicarius (L.) is a folklore medicinal herb that has been used for centuries to cure cardiovascular diseases. The present work was carefully designed to ascertain the pharmacological basis for R. vesicarius’s therapeutic efficacy in cardiovascular diseases, as well as the underlying mechanism. In the ex vivo investigation, the aqueous-methanolic leaf extract of R. vesicarius was shown to have endothelium-dependent vasorelaxant effects in rabbit aorta tissue preparations, and its hypotensive responses were quantified by pressure and force transducers coupled to the Power Lab Data Acquisition System. Furthermore, when rabbits were subjected to adrenaline-induced myocardial infarction, R. vesicarius demonstrated cardioprotective characteristics. In contrast to the intoxicated group, the myocardial infarction model showed lower ALP, CK-MB, CRP, LDH, ALT, troponin, and AST levels (p > 0.005–0.000), as well as edema, necrosis, apoptosis, inflammatory cell enrolment, and necrosis. R. vesicarius exhibited significant antioxidant activity and delayed noradrenaline-induced platelet aggregation. Its cardioprotective, anticoagulant, and vasorelaxant properties in both investigations (in vivo and ex vivo) are mediated through partial endothelium-dependent, NO and calcium channel blockade mediated vasorelaxation. The minimizing of adrenaline, oxidative stress, and tissue damage demonstrate its therapeutic efficacy in cardiovascular diseases.

Real‐Time dynamics of renal autoregulatory responses to BP changes in conscious, normotensive and hypertensive rat strains

Renal autoregulatory (AR) mechanisms are believed to insulate RBF and GFR from the continuously fluctuating systemic pressures and protect the glomerular capillaries from barotrauma by preventing glomerular transmission of systemic hypertension. However, renal AR has usually only been assessed by the degree to which RBF is restored to baseline after step changes in BP are imposed, generally under anesthesia. AR indices (% changes in RBF / % changes in BP) are used to quantitate the magnitude of the AR compensation. However, such methods do not provide an assessment of the real time dynamics of AR responses to the spontaneously occurring BP fluctuations in real time. We have recently described novel analytic methods to characterize both the magnitude and the kinetics of such AR responses to BP fluctuations in conscious Sprague‐Dawley rats with intact (controls) and impaired AR (3/4 nephrectomy) and/or calcium channel blockade (JASN 31(2):324‐336, 2020). Essentially, AR indices were calculated for adjacent segments of varying lengths (0.5 – 20 sec) which exhibited a MAP difference of at least 5 mmHg. These studies indicated a much greater rapidity of the normal AR response than observed using standard methods under anesthesia with the bulk of AR compensation (>50%) occurring within 2.5 sec with complete compensation occurring more slowly by ~10 sec. This rapid initial and likely myogenic component of the response was noted to be significantly slower in states of impaired renal AR with <40% of AR compensation being achieved by 5 sec. To assess the generalizability of these pattern of AR responses and interpretations of rapid myogenic protection, similar AR analysis were performed on concurrent BP and RBF recordings of 1‐4 hr duration that had been obtained in conscious chronically instrumented hypertensive and normotensive rat strains in our laboratory for transfer function analysis in control SHR, SHRsp, Dahl S (DS) and R (DR) rats, and Sprague‐Dawley (SD) rats over the past 20 years (Fig. 1). The pattern of AR responses and compensation is remarkably similar in all rat strains except that the responses are even faster and stronger in hypertensive rats with ~80% compensation being achieved by 2.5 sec (Fig. 2). To further examine the impact of ambient BP on AR responses, AI were separately calculated when the ambient MAP was within 30 mmHg below (low BP) or above (high BP) the average MAP during the recordings for each strain. There was a clear trend for the AR responses to be stronger at higher ambient MAP, although statistical significance was not achieved in all strains because of the scatter in individual animal data (Fig. 3). These data suggest that in addition to genetic factors, ambient BP per se may modulate the dynamics of protective renal AR responses in conscious rats.

Design, synthesis and biological evaluation of new dihydropyridine derivatives as PD-L1 degraders for enhancing antitumor immunity

Immune checkpoint blockade (ICB) by targeting programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway is a promising strategy for tumor immunotherapy. Developing small-molecules inducing PD-L1 protein degradation has been proven as an alternative and useful approach for targeting the immunotherapy pathway. Our previous study showed that Lercanidipine could down-regulate the expression of PD-L1 protein, but its calcium influx antagonistic activity hampers further development. For attenuating the unexpected calcium channel blockade effect, a series of compounds were synthesized and evaluated through structure-activity relationship (SAR) exploration. Amongst, compound F4 exhibited a loss of calcium antagonistic activity, while the PD-L1 degradation activity can still retain. Further studies indicated that F4 degraded PD-L1 dose- and time-dependently, and may function through a lysosomal-dependent manner. Furthermore, compound F4 showed a good bioavailability value of 24.9% in mice. Moreover, the F4-induced PD-L1 degradation strengthened the T cell-mediated killing of tumor cells. Our findings show the discovery of a new PD-L1 degrader, providing a potential strategy for immunotherapy.

Translational Pharmacology of PRAX-944, a Novel T-Type Calcium Channel Blocker in Development for the Treatment of Essential Tremor.

BackgroundEssential tremor is the most common movement disorder with clear unmet need. Mounting evidence indicates tremor is caused by increased neuronal burst firing and oscillations in cerebello‐thalamo‐cortical circuitry and may be dependent on T‐type calcium channel activity. T‐type calcium channels regulate sigma band electroencephalogram (EEG) power during non‐rapid eye movement sleep, representing a potential biomarker of channel activity. PRAX‐944 is a novel T‐type calcium channel blocker in development for essential tremor.ObjectivesUsing a rat tremor model and sigma‐band EEG power, we assessed pharmacodynamically‐active doses of PRAX‐944 and their translation into clinically tolerated doses in healthy participants, informing dose selection for future efficacy trials.MethodsHarmaline‐induced tremor and spontaneous locomotor activity were used to assess PRAX‐944 efficacy and tolerability, respectively, in rats. Sigma‐power was used as a translational biomarker of T‐type calcium channel blockade in rats and, subsequently, in a phase 1 trial assessing pharmacologic activity and tolerability in healthy participants.ResultsIn rats, PRAX‐944 dose‐dependently reduced tremor by 50% and 72% at 1 and 3 mg/kg doses, respectively, without locomotor side effects. These doses also reduced sigma‐power by ~30% to 50% in rats. In healthy participants, sigma‐power was similarly reduced by 34% to 50% at 10 to 100 mg, with no further reduction at 120 mg. All doses were well tolerated.ConclusionsIn rats, PRAX‐944 reduced sigma‐power at concentrations that reduced tremor without locomotor side effects. In healthy participants, comparable reductions in sigma‐power indicate that robust T‐type calcium channel blockade was achieved at well‐tolerated doses that may hold promise for reducing tremor in patients with essential tremor. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Regulation of Hippocampal Gamma Oscillations by Modulation of Intrinsic Neuronal Excitability.

Ion channels activated around the subthreshold membrane potential determine the likelihood of neuronal firing in response to synaptic inputs, a process described as intrinsic neuronal excitability. Long-term plasticity of chemical synaptic transmission is traditionally considered the main cellular mechanism of information storage in the brain; however, voltage- and calcium-activated channels modulating the inputs or outputs of neurons are also subjects of plastic changes and play a major role in learning and memory formation. Gamma oscillations are associated with numerous higher cognitive functions such as learning and memory, but our knowledge of their dependence on intrinsic plasticity is by far limited. Here we investigated the roles of potassium and calcium channels activated at near subthreshold membrane potentials in cholinergically induced persistent gamma oscillations measured in the CA3 area of rat hippocampal slices. Among potassium channels, which are responsible for the afterhyperpolarization in CA3 pyramidal cells, we found that blockers of SK (KCa2) and KV7.2/7.3 (KCNQ2/3), but not the BK (KCa1.1) and IK (KCa3.1) channels, increased the power of gamma oscillations. On the contrary, activators of these channels had an attenuating effect without affecting the frequency. Pharmacological blockade of the low voltage-activated T-type calcium channels (CaV3.1–3.3) reduced gamma power and increased the oscillation peak frequency. Enhancement of these channels also inhibited the peak power without altering the frequency of the oscillations. The presented data suggest that voltage- and calcium-activated ion channels involved in intrinsic excitability strongly regulate the power of hippocampal gamma oscillations. Targeting these channels could represent a valuable pharmacological strategy against cognitive impairment.

6-Amino-3-Methyl-4-(2-nitrophenyl)-1,4-Dihydropyrano[2,3-c]Pyrazole-5-Carbonitrile Shows Antihypertensive and Vasorelaxant Action via Calcium Channel Blockade.

Several 4H-pyran derivatives were designed and synthesized previously as vasorelaxant agents for potential antihypertensive drugs. In this context, the objective of the present investigation was to determine the functional mechanism of vasorelaxant action of 6-amino-3-methyl-4-(2-nitrophenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1: ) and its in vivo antihypertensive effect. Thus, compound 1: showed significant vasorelaxant action on isolated aorta rat rings pre-contracted with serotonin or noradrenaline, and the effect was not endothelium-dependent. Compound 1: induced a significant relaxant effect when aortic rings were contracted with KCl (80 mM), indicating that the main mechanism of action is related to L-type calcium channel blockade. Last was corroborated since compound 1: induced a significant concentration-dependent lowering of contraction provoked by cumulative CaCl2 adding. Moreover, compound 1: was capable to block the contraction induced by FPL 64176, a specific L-type calcium channel agonist, in a concentration-dependent manner. On the other hand, docking studies revealed that compound 1: interacts on two possible sites of the L-type calcium channel and it had better affinity energy (-7.80+/-0.00 kcal/mol on the best poses) than nifedipine (-6.86+/-0.14 kcal/mol). Finally, compound 1: (50 mg/kg) showed significant antihypertensive activity, lowering the systolic and diastolic blood pressure on spontaneously hypertensive rats (SHR) without modifying heart rate.

Short-Term Extremely Low-Frequency Electromagnetic Field Inhibits Synaptic Plasticity of Schaffer Collateral-CA1 Synapses in Rat Hippocampus via the Ca2+/Calcineurin Pathway.

In this study, we investigate the intrinsic mechanism by which an extremely low-frequency electromagnetic field (ELF-EMF) influences neurons in the Schaffer collateral-CA1 (SC-CA1) region of rat hippocampus using electrophysiological techniques. ELF-EMF has an interesting effect on synaptic plasticity: it weakens long-term potentiation and enhances long-term depression. Here, the magnetic field effect disappeared after a blockade of voltage-gated calcium channels and calcineurin, which are key components in the Ca2+/calcineurin pathway, with two blockers, cadmium chloride and cyclosporin A. This fully establishes that the effect of ELF-EMF on synaptic plasticity is mediated by the Ca2+/calcineurin pathway and represents a novel technique for studying the specific mechanisms of action of ELF-EMF on learning and memory.

Effect of Cleistanthins A and B on the Isolated Aorta of Guinea Pig

<p style="text-align: justify;"><strong>Objectives: </strong>Cleistanthins A and B are the active compounds isolated from<em> Cleistanthus collinus</em> leaves. The hypotensive activity of both cleistanthins A and B and the leaf extract has been previously demonstrated, but the exact mechanism of action is not clear. So, this study was designed to test the vasorelaxant property of cleistanthins A and B and delineate its mechanism of action. <strong>Methods: </strong>Variable force transducers were used to record the force of contraction from the aortic rings of 24 male guinea pigs. The effect of cleistanthin A, cleistanthin B, prazosin and vehicle on the phenylephrine-induced contractions and potassium chloride-induced contractions was demonstrated and compared. <strong>Results: </strong>Cleistanthin B inhibited the phenylephrine-induced contractions in a dose-dependent manner and demonstrated potency (pIC₅₀ = 6.8 &plusmn; 1.06) comparable to prazosin (pIC₅₀ = 5.7 &plusmn; 0.7). Cleistanthin A potency could not be calculated. Both cleistanthin A (4 &mu;g) and cleistanthin B (40 &mu;g) caused a reduction of the maximal response of phenylephrine demonstrating irreversible blockade. They did not affect the potassium chloride-induced contractions. This illustrates that cleistanthins A and B are noncompetitive &alpha;₁ adrenergic blockers and the potency of cleistanthin B is comparable to prazosin.<strong> Conclusion: </strong>Both cleistanthins A and B have vasodilatory action on guinea pig aorta. The action is through non-competitive &alpha;₁ adrenergic receptor inhibition and calcium channel blockade does not contribute to the inhibition. <p style="text-align: justify;"><strong> Key words:</strong> &alpha;₁ adrenergic antagonist, Cleistanthin A, Cleistanthin B, <em>Cleistanthus collinus</em>, Guinea pig, Isolated aortic rings.

Computational and Molecular Properties of Starburst Amacrine Cell Synapses Differ With Postsynaptic Cell Type

A presynaptic neuron can increase its computational capacity by transmitting functionally distinct signals to each of its postsynaptic cell types. To determine whether such computational specialization occurs over fine spatial scales within a neurite arbor, we investigated computation at output synapses of the starburst amacrine cell (SAC), a critical component of the classical direction-selective (DS) circuit in the retina. The SAC is a non-spiking interneuron that co-releases GABA and acetylcholine and forms closely spaced (<5 μm) inhibitory synapses onto two postsynaptic cell types: DS ganglion cells (DSGCs) and neighboring SACs. During dynamic optogenetic stimulation of SACs in mouse retina, whole-cell recordings of inhibitory postsynaptic currents revealed that GABAergic synapses onto DSGCs exhibit stronger low-pass filtering than those onto neighboring SACs. Computational analyses suggest that this filtering difference can be explained primarily by presynaptic properties, rather than those of the postsynaptic cells per se. Consistent with functionally diverse SAC presynapses, blockade of N-type voltage-gated calcium channels abolished GABAergic currents in SACs but only moderately reduced GABAergic and cholinergic currents in DSGCs. These results jointly demonstrate how specialization of synaptic outputs could enhance parallel processing in a compact interneuron over fine spatial scales. Moreover, the distinct transmission kinetics of GABAergic SAC synapses are poised to support the functional diversity of inhibition within DS circuitry.

Identification of a novel distension-evoked motility pattern in the mouse uterus.

The dynamic changes in uterine contractility in response to distension are incompletely understood. Rhythmic, propagating contractions of nonpregnant uterine smooth muscle occur in the absence of nerve activity (i.e., myogenic), events that decline during pregnancy and reemerge at parturition. We therefore sought to determine how myogenic contractions of the nonpregnant uterus are affected by distension, which might provide mechanistic clues underlying distension-associated uterine conditions such as preterm birth. Uteri isolated from nulliparous adult female mice in proestrus were video imaged to generate spatiotemporal maps, and myoelectrical activity simultaneously recorded using extracellular suction electrodes. Motility patterns were examined under basal conditions and following ramped intraluminal distension with fluid to 5 and 10 cmH2O. Intraluminal distension caused pressure-dependent changes in the frequency, amplitude, propagation speed, and directionality of uterine contractions, which reversed upon pressure release. Altered burst durations of underlying smooth muscle myoelectric events were concurrently observed, although action potential spike intervals were unchanged. Voltage-gated sodium channel blockade [tetrodotoxin (TTX); 0.6 µM] attenuated both the amplitude of contractions and burst duration of action potentials, whereas all activity was abolished by L-type calcium channel blockade (nifedipine; 1 µM). These data suggest that myogenic motility patterns of the nonpregnant mouse uterus are sensitive to changes in intraluminal pressure and, at high pressures, may be modulated by voltage-gated sodium channel activity. Future studies may investigate whether similar distension-evoked changes occur in the pregnant uterus and the possible pathophysiological role of such activity in the development of preterm birth.

Parvalbumin subtypes of cerebellar Purkinje cells contribute to differential intrinsic firing properties

Purkinje cells (PCs) are central to cerebellar information coding and appreciation for the diversity of their firing patterns and molecular profiles is growing. Heterogeneous subpopulations of PCs have been identified that display differences in intrinsic firing properties without clear mechanistic insight into what underlies the divergence in firing parameters. Although long used as a general PC marker, we report that the calcium binding protein parvalbumin labels a subpopulation of PCs, based on high and low expression, with a conserved distribution pattern across the animals examined. We trained a convolutional neural network to recognize the parvalbumin subtypes and create maps of whole cerebellar distribution and find that PCs within these areas have differences in spontaneous firing that can be modified by altering calcium buffer content. These subtypes also show differential responses to potassium and calcium channel blockade, suggesting a mechanistic role for variability in PC intrinsic firing through differences in ion channel composition. It is proposed that ion channels drive the diversity in PC intrinsic firing phenotype and parvalbumin calcium buffering provides capacity for the highest firing rates observed. These findings open new avenues for detailed classification of PC subtypes.

Preoperative Amlodipine Is More Efficacious Than Prazosin in Preventing Intraoperative Haemodynamic Instability in Pheochromocytoma/Paraganglioma Patients: Interim Analysis of a Pilot Randomized Controlled Study

Background: Preoperative blockade with α-blockers is recommended in patients with pheochromocytoma/paraganglioma (PPGL). The data on calcium channel blockade (CCB) in PPGL is scarce. We aim to compare the efficacy of CCB and α-blockers on intraoperative haemodynamic instability (HDI) in PPGL. Methods: In the interim analysis of this monocentric, pilot, open-label, randomized controlled trial, patients with solitary, secretory, and nonmetastatic PPGL were randomized to oral prazosin (maximum 30mg, n=9) or amlodipine (maximum 20mg, n=11). The primary outcomes were the episodes and duration of hypertension (SBP≥160mmHg) and hypotension (MAP<60mmHg) and duration of HDI (hypertension and/or hypotension) as a percentage of total surgical time (from induction of anaesthesia to skin closure). Findings: The median (IQR) episodes (2 [1–3] vs. 0 [0–1], p 0·002) and duration of hypertension (19 [14–42] min vs. 0 [0–3] min, p 0·001) and intraoperative HDI duration (22·85±18.4% vs 2·44±2·4%, CI 8·68-32·14%, p 0·002) were significantly higher in the prazosin arm than the amlodipine arm whereas episodes and duration of hypotension did not differ between the two groups. There was no perioperative mortality whereas one patient had intraoperative ST depression on the electrocardiogram. The drug-related adverse effects were pedal edema (1 in amlodipine), dizziness (1 in prazosin), and tachycardia (6 in prazosin and 3 in amlodipine). Interpretation: Preoperative blockade with amlodipine was more efficacious than prazosin in preventing intraoperative HDI in PPGL. Larger studies that compare preoperative blockade with amlodipine and both competitive and noncompetitive α-blockers inPPGL patients of various biochemical phenotypes are warranted.

Preoperative Amlodipine Is Efficacious in Preventing Intraoperative HDI in Pheochromocytoma: Pilot RCT.

Preoperative blockade with α-blockers is recommended in patients with pheochromocytoma/paraganglioma (PPGL). The data on calcium channel blockade (CCB) in PPGL are scarce. We aimed to compare the efficacy of CCB and α-blockers on intraoperative hemodynamic instability (HDI) in PPGL. In the interim analysis of this monocentric, pilot, open-label, randomized controlled trial, patients with solitary, secretory, and nonmetastatic PPGL were randomized to oral prazosin gastrointestinal therapeutic system (GITS) (maximum 30 mg, n = 9) or amlodipine (maximum 20 mg, n = 11). The primary outcomes were the episodes and duration of hypertension (systolic blood pressure ≥ 160 mmHg) and hypotension (mean arterial pressure < 60 mmHg) and duration of HDI (hypertension and/or hypotension) as a percentage of total surgical time (from induction of anesthesia to skin closure). The median (IQR) episodes (2 [1-3] vs 0 [0-1]; P = 0.002) and duration of hypertension (19 [14-42] vs 0 [0-3] minutes; P = 0.001) and intraoperative HDI duration (22.85 ± 18.4% vs 2.44 ± 2.4%; CI, 8.68-32.14%; P 0.002) were significantly higher in the prazosin GITS arm than the amlodipine arm, whereas episodes and duration of hypotension did not differ between the 2 groups. There was no perioperative mortality. One patient had intraoperative ST depression on the electrocardiogram. The drug-related adverse effects were pedal edema (1 in amlodipine), dizziness (1 in prazosin GITS), and tachycardia (6 in prazosin GITS and 3 in amlodipine). Preoperative blockade with amlodipine is an efficacious alternative to prazosin GITS in preventing intraoperative HDI in PPGL. Larger studies that compare preoperative blockade by amlodipine with other α-blockers like phenoxybenzamine and/or doxazosin in PPGL patients are warranted.

Antihypertensive and vasorelaxant effect of leucodin and achillin isolated from Achillea millefolium through calcium channel blockade and NO production: In vivo, functional ex vivo and in silico studies

Ethnopharmacological relevanceAchillea millefolium L. (Asteraceae), known as yarrow (milenrama), is a plant used in Mexican traditional medicine for the treatment of hypertension, diabetes, and related diseases. AimTo determine the vasorelaxant and antihypertensive effect of A. millefollium and to isolate the main bioactive antihypertensive agents. Materials and methodsOrganic (hexane, dichloromethane and methanol) and hydro-alcohol (Ethanol-H2O: 70:30) extracts obtained from flowers, leaves and stems were evaluated on isolated aorta rat rings with and without endothelium to determine their vasorelaxant effect. Hexane extract from flowers (HEAmF) was studied to evaluate its antihypertensive effect on spontaneously hypertensive rats (SHR). From HEAmF, bioactive compounds were obtained by bio-guided phytochemical separation through chromatography. ResultsOrganic extracts showed the best vasorelaxant activity. Hexane extract from flowers was the most potent and efficient ex vivo vasorelaxant agent, showing significant decrease of systolic and diastolic blood pressure in SHR (p < 0.05). Phytochemical separation of HEAmF yielded two epimeric sesquiterpene lactones: leucodin (1) and achillin (2), the major components of the extract. Both 1 and 2 showed similar vasorelaxant action ex vivo (p < 0.05), and their effects where modified by L-NAME (10 μM, nitric oxide synthase inhibitor), by ODQ (1 μM, soluble guanylyl cyclase inhibitor), and also relaxed the contraction induced by KCl (80 mM). Finally, 1 and 2 intragastric administration (50 mg/kg) decreased systolic and diastolic blood pressure in SHR. ConclusionsAchillea millefolium showed antihypertensive and vasorelaxant effects, due mainly to leucodin and achillin (epimers). Both compounds showed antihypertensive activity by vasorelaxation putatively by endothelium-dependent NO release and cGMP increase, as well as by calcium channels blockade.

Methanol (80%) leaf extract of Otostegia integrifolia Benth (Lamiaceae) lowers blood pressure in rats through interference with calcium conductance

BackgroundOtostegia integrifolia Benth. (Lamiaceae) leaves are used to treat hypertension in Ethiopian folk medicine. However, the claim has so far not been investigated scientifically. Thus, the objective of this study was to evaluate the antihypertensive activity of 80% methanol leaf extract of O. integrifolia in animal model of hypertension and possible underlying mechanisms in isolated rat aorta.MethodsAntihypertensive effect of various oral doses of the extract (250, 500 and 1000 mg/kg) was determined in fructose-induced hypertensive rats using the non-invasive tail-cuff method. Thoracic aortic strips of rats were isolated and suspended in organ bath, and the vasodepressor effect as well as the possible mechanism (s) of action were studied by means of isometric tension recording experiments ex vivo. Phytochemical analysis was also performed to suggest possible constituents related to the activity.ResultsBlood pressure was significantly lowered in a dose-dependent manner following extract administration, suggesting that the extract possesses antihypertensive activity. The extract also caused a dose-dependent relaxation of aortic strip precontracted with KCl at a concentration of 6.25–125 μg/L, with a maximum relaxation (100%) achieved at a cumulative concentration of 318.75 μg/ml. The relaxation mechanism was found to be independent of muscarinic receptors, prostanoids, histamine receptors, ATP dependent K+ channels, sarcoplasmic reticulum stored Ca2+ and the endothelium system. The extract shifted the Ca2+ concentration-response curve to the right similar to that caused by nifedipine, suggesting that vasorelaxation could possibly be mediated via calcium channel blockade. The extract was found to contain phenolic compounds (164.3 mg/g, expressed as gallic acid equivalents) and flavonoids (125.7 mg/g, expressed as quercetin equivalents).ConclusionThe findings revealed that the plant is endowed with antihypertensive activity, providing evidence for its traditional use. The effect maybe, at least in part, due to dilation of blood vessels through blockade of Ca+ 2 channels mediated by phenolic and flavonoid constituents.

Genetically Predicted Blood Pressure and Risk of Atrial Fibrillation.

Observational studies have shown an association between hypertension and atrial fibrillation (AF). Aggressive blood pressure management in patients with known AF reduces overall arrhythmia burden, but it remains unclear whether hypertension is causative for AF. To address this question, this study explored the relationship between genetic predictors of blood pressure and risk of AF. We secondarily explored the relationship between genetically proxied use of antihypertensive drugs and risk of AF. Two-sample Mendelian randomization was performed using an inverse-variance weighted meta-analysis with weighted median Mendelian randomization and Egger intercept tests performed as sensitivity analyses. Summary statistics for systolic blood pressure, diastolic blood pressure, and pulse pressure were obtained from the International Consortium of Blood Pressure and the UK Biobank discovery analysis and AF from the 2018 Atrial Fibrillation Genetics Consortium multiethnic genome-wide association studies. Increases in genetically proxied systolic blood pressure, diastolic blood pressure, or pulse pressure by 10 mm Hg were associated with increased odds of AF (systolic blood pressure: odds ratio [OR], 1.17 [95% CI, 1.11-1.22]; P=1×10-11; diastolic blood pressure: OR, 1.25 [95% CI, 1.16-1.35]; P=3×10-8; pulse pressure: OR, 1.1 [95% CI, 1.0-1.2]; P=0.05). Decreases in systolic blood pressure by 10 mm Hg estimated by genetic proxies of antihypertensive medications showed calcium channel blockers (OR, 0.66 [95% CI, 0.57-0.76]; P=8×10-9) and β-blockers (OR, 0.61 [95% CI, 0.46-0.81]; P=6×10-4) decreased the risk of AF. Blood pressure-increasing genetic variants were associated with increased risk of AF, consistent with a causal relationship between blood pressure and AF. These data support the concept that blood pressure reduction with calcium channel blockade or β-blockade could reduce the risk of AF.