Effects Of Calcium Channel Blockade Research Articles

Effect of Calcium-Channel Blockade on the Cold-Induced Vasodilation Response

Cold-induced vasodilation (CIVD) is seen in the extremities during exposure to cold. A strong vasodilation response has been associated with a decreased risk of cold injury. Increasing CIVD might further decrease this risk. The calcium-channel blocker nifedipine causes vasodilation and is used to treat Raynaud's syndrome and chilblains. Nifedipine is also used for high altitude pulmonary edema and could potentially serve a dual purpose in preventing frostbite. The effects of nifedipine on CIVD have not been studied. A double-blind crossover study comparing nifedipine (30 mg SR (sustained release) orallytwice daily) to placebo was designed using 2 sessions of 4 finger immersion in 5°C water, with 24h of medication pretreatment before each session. Finger temperatures were measured via nailbed thermocouples. The primary outcome was mean finger temperature; secondary outcomes were mean apex and nadir temperatures, first apex and nadir temperatures, subjective pain ranking, and time of vasodilation onset (all presented as mean±SD). Twelve volunteers (age 29±3 [24-34] y) completed the study. No significant difference in finger temperature (9.2±1.1°C nifedipine vs 9.0±0.7°C placebo, P=0.38) or any secondary outcome was found. Pain levels were similar (2.8±1.6 nifedipine vs 3.0±1.5 placebo, P=0.32). The most common adverse event was headache (32% of nifedipine trials vs 8% placebo). Pretreatment with 30 mg of oral nifedipine twice daily does not affect the CIVD response in healthy individuals under cold stress.

DeepNEU: Artificially Induced Stem Cell (aiPSC) and Differentiated Skeletal Muscle Cell (aiSkMC) Simulations of Infantile Onset POMPE Disease (IOPD) for Potential Biomarker Identification and Drug Discovery.

Infantile onset Pompe disease (IOPD) is a rare and lethal genetic disorder caused by the deletion of the acid alpha-glucosidase (GAA) gene. This gene encodes an essential lysosomal enzyme that converts glycogen to glucose. While enzyme replacement therapy helps some, our understanding of disease pathophysiology is limited. In this project we develop computer simulated stem cells (aiPSC) and differentiated skeletal muscle cells (aiSkMC) to empower IOPD research and drug discovery. Our Artificial Intelligence (AI) platform, DeepNEU v3.6 was used to generate aiPSC and aiSkMC simulations with and without GAA expression. These simulations were validated using peer reviewed results from the recent literature. Once the aiSkMC simulations (IOPD and WT) were validated they were used to evaluate calcium homeostasis and mitochondrial function in IOPD. Lastly, we used aiSkMC IOPD simulations to identify known and novel biomarkers and potential therapeutic targets. The aiSkMC simulations of IOPD correctly predicted genotypic and phenotypic features that were reported in recent literature. The probability that these features were accurately predicted by chance alone using the binomial test is 0.0025. The aiSkMC IOPD simulation correctly identified L-type calcium channels (VDCC) as a biomarker and confirmed the positive effects of calcium channel blockade (CCB) on calcium homeostasis and mitochondrial function. These published data were extended by the aiSkMC simulations to identify calpain(s) as a novel potential biomarker and therapeutic target for IOPD. This is the first time that computer simulations of iPSC and differentiated skeletal muscle cells have been used to study IOPD. The simulations are robust and accurate based on available published literature. We also demonstrated that the IOPD simulations can be used for potential biomarker identification leading to targeted drug discovery. We will continue to explore the potential for calpain inhibitors with and without CCB as effective therapy for IOPD.

Nicotine modulates human brain plasticity via calcium-dependent mechanisms.

Nicotine (NIC) modulates cognition and memory function by targeting the nicotinic ACh receptor and releasing different transmitter systems postsynaptically. With both NIC-generated mechanisms, calcium influx and calcium permeability can be regulated, which is a key requirement for the induction of long-term potentiation, comprising the physiological basis of learning and memory function. We attempt to unmask the underlying mechanism of nicotinic effects on anodal transcranial direct current stimulation (tDCS)-induced long-term potentiation-like plasticity based on the hypothesis of calcium-dependency. Abolished tDCS-induced neuroplasticity as a result of NIC administration is reversed by calcium channel blockade with flunarizine in a dose-dependent manner. The results of the present study suggest that there is a dose determination of NIC/NIC agonists in therapeutical settings when treating cognitive dysfunction, which partially explains the heterogeneous results on cognition observed in subjects in different experimental settings. Nicotine (NIC) modulates neuroplasticity and improves cognitive performance in animals and humans mainly by increased calcium permeability and modulation of diverse transmitter systems. NIC administration impairs calcium-dependent plasticity induced by non-invasive brain stimulation with transcranial direct current stimulation (tDCS) in non-smoking participants probably as a result of intracellular calcium overflow. To test this hypothesis, we analysed the effect of calcium channel blockade with flunarizine (FLU) on anodal tDCS-induced cortical excitability changes in healthy non-smokers under NIC. We applied anodal tDCS combined with NIC patch and FLU at three different doses (2.5, 5 and 10mg) or with placebo medication. NIC abolished anodal tDCS-induced neuroplasticity. Under medium dosage (but not under low and high dosage) of FLU combined with NIC, plasticity was re-established. For FLU alone, the lowest dosage weakened long-term potentiation (LTP)-like plasticity, whereas the highest dosage again abolished tDCS-induced plasticity. The medium dosage turned LTP-like plasticity in long-term depression-like plasticity. The results of the present study suggest a key role of calcium influx and calcium levels in nicotinic effects on LTP-like plasticity in humans. This knowledge might be relevant for the development of new therapeutic strategies in cognitive dysfunction.

Iron overload and apoptosis of HL-1 cardiomyocytes: effects of calcium channel blockade.

BackgroundIron overload cardiomyopathy that prevails in some forms of hemosiderosis is caused by excessive deposition of iron into the heart tissue and ensuing damage caused by a raise in labile cell iron. The underlying mechanisms of iron uptake into cardiomyocytes in iron overload condition are still under investigation. Both L-type calcium channels (LTCC) and T-type calcium channels (TTCC) have been proposed to be the main portals of non-transferrinic iron into heart cells, but controversies remain. Here, we investigated the roles of LTCC and TTCC as mediators of cardiac iron overload and cellular damage by using specific Calcium channel blockers as potential suppressors of labile Fe(II) and Fe(III) ingress in cultured cardiomyocytes and ensuing apoptosis.MethodsFe(II) and Fe(III) uptake was assessed by exposing HL-1 cardiomyocytes to iron sources and quantitative real-time fluorescence imaging of cytosolic labile iron with the fluorescent iron sensor calcein while iron-induced apoptosis was quantitatively measured by flow cytometry analysis with Annexin V. The role of calcium channels as routes of iron uptake was assessed by cell pretreatment with specific blockers of LTCC and TTCC.ResultsIron entered HL-1 cardiomyocytes in a time- and dose-dependent manner and induced cardiac apoptosis via mitochondria-mediated caspase-3 dependent pathways. Blockade of LTCC but not of TTCC demonstrably inhibited the uptake of ferric but not of ferrous iron. However, neither channel blocker conferred cardiomyocytes with protection from iron-induced apoptosis.ConclusionOur study implicates LTCC as major mediators of Fe(III) uptake into cardiomyocytes exposed to ferric salts but not necessarily as contributors to ensuing apoptosis. Thus, to the extent that apoptosis can be considered a biological indicator of damage, the etiopathology of cardiosiderotic damage that accompanies some forms of hemosiderosis would seem to be unrelated to LTCC or TTCC, but rather to other routes of iron ingress present in heart cells.

Salutary effect of calcium channel blockade following hypoxic and septic insult.

Intestinal ischemia and reperfusion is a major problem associated with a high morbidity and mortality following trauma and hemorrhagic shock. Apoptosis is the major mode of cell death following reperfusion. The cytoskeleton damage precedes the apoptotic final microscopic features. Calcium plays a central role in apoptosis. Therefore, we studied whether verapamil could preserve the function of the cytoskeleton in an in vitro intestinal model following hypoxia-reoxygenation (H/R). Our goal was to assess mainly the cytoskeleton functions, which includes IgA transport and the cell monolayer barrier integrity. Confluent HT29 intestinal monolayers grown in a two-chamber cell culture system were held under hypoxic (5% CO2) conditions for 90 minutes followed by normoxia (21% O2) (H/R). Cell subsets were exposed to lipopolysaccharide (10 μg/mL) before H/R. Verapamil (8 μM) was added to HT29 cell subsets after H/R treatment. Dimeric IgA was added to the basal compartment, and apical media were sampled at intervals to quantitate IgA transcytosis using enzyme-linked immunosorbent assay. HT29 cells held under normoxic conditions served as controls. HT29 permeability to FD4 was assessed at the end of each experiment. In a separate experiment, HT29 cells were stained for F actin using rhodamine-labeled phalloidin. Intestinal monolayer permeability was increased following treatment with H/R and/or lipopolysaccharide. Verapamil treatment prevented increased permeability in HT29 cells and led to an increase in IgA transport. Disruption of actin microfilaments was demonstrated following H/R insult but was abrogated by the addition of verapamil following H/R insult. Reperfusion can lead to both physical and immune derangement of epithelial cell barrier function. Verapamil may be important in preserving gut barrier function. Additional studies including in vivo confirmation in animal shock models are needed to validate these findings.

The effects of calcium channel blockade on proliferation and differentiation of cardiac progenitor cells

Cardiogenesis depends on a tightly regulated balance between proliferation and differentiation of cardiac progenitor cells (CPCs) and their cardiomyocyte descendants. While exposure of early mouse embryos to Ca2+ channel antagonists has been associated with abnormal cardiac morphogenesis, less is known about the consequences of Ca2+ channel blockade on proliferation and differentiation of CPCs at the cellular level. Here we showed that at embryonic day (E) 11.5, the murine ventricles express several L-type and T-type Ca2+ channel isoforms, and that the dihydropyridine Ca2+ channel antagonist, nifedipine, blunts isoproterenol induced increases in intracellular Ca2+. Nifedipine mediated Ca2+ channel blockade was associated with a reduction in cell cycle activity of E11.5 CPCs and impaired assembly of the cardiomyocyte contractile apparatus. Furthermore, in cell transplantation experiments, systemic administration of nifedipine to adult mice receiving transplanted E11.5 ventricular cells (containing CPCs and cardiomyocytes) was associated with smaller graft sizes compared to vehicle treated control animals. These data suggest that intracellular Ca2+ is a critical regulator of the balance between CPC proliferation and differentiation and demonstrate that interactions between pharmacological drugs and transplanted cells could have a significant impact on the effectiveness of cell based therapies for myocardial repair.

Antispasmodic and Antidiarrheal Activities of Valeriana hardwickii Wall. Rhizome Are Putatively Mediated through Calcium Channel Blockade

Valeriana hardwickii is indigenous to Pakistan, Burma and Ceylon, where it is traditionally being used as an antispasmodic and antidiarrheal, besides its culinary use as spice. The aim of this paper was to provide pharmacological validation to these medicinal uses. The crude aqueous-methanolic extract of Valeriana hardwickii rhizome (Vh.Cr) was studied on isolated rabbit jejunum and castor oil-induced diarrhea in mice for spasmolytic and antidiarrheal properties, respectively. Vh.Cr caused concentration-dependent (0.01–1 mg/mL) relaxation of spontaneous contractions in isolated rabbit jejunum and inhibited K+-induced contractions (0.01–0.3 mg/mL), similar to verapamil, suggestive of calcium channel blockade (CCB). The CCB effect was confirmed when pretreatment of the jejunum preparations with Vh.Cr produced a concentration-dependent (0.03–0.1 mg/mL) rightward shift in the Ca++ concentration-response curves, as caused by verapamil. Vh.Cr exhibited dose-dependent (100–300 mg/kg) protection against castor oil-induced diarrhea in mice. Loperamide, a standard antidiarrheal drug, similarly prevented the diarrhea. These data indicate the presence of CCB effect in the extract of Valeriana hardwickii rhizome, possibly mediating its antispasmodic and antidiarrheal activities and provide a scientific base for its traditional use in hyperactive gut disorders.

Studies on spasmogenic and spasmolytic activities of Calendula officinalis flowers

The aqueous-ethanol extract of Calendula officinalis flowers (Co.Cr) was studied for its possible spasmolytic and spasmogenic effects in isolated gut preparations. In rabbit jejunum, Co.Cr caused a dose-dependent (0.03-3.0 mg/mL) relaxation of spontaneous and K+-induced contractions, suggestive of calcium channel blockade (CCB). In a few preparations, a mild non-reproducible spasmogenic effect was observed at lower doses, followed by relaxation. The CCB effect was confirmed when pretreatment of the jejunum preparations with Co.Cr produced a dose-dependent rightward shift in the Ca(++) dose-response curves, similar to that of verapamil. Activity-directed fractionation revealed that the spasmolytic activity of the plant was concentrated in its organic fractions. The aqueous fraction exhibited a marked atropine sensitive spasmogenic effect but was found to be devoid of any spasmolytic effect. These data indicate that the crude extract of Calendula officinalis flowers contains both spasmolytic and spasmogenic constituents, exhibiting these effects through calcium channel blocking and cholinergic activities and this study provides a scientific base for its traditional use in abdominal cramps and constipation.

Cholinomimetic and calcium channel blocking activities of Carthamus oxycantha

The crude extract of Carthamus oxycantha (Co.Cr) and its fractions were studied in vitro for their possible spasmogenic and spasmolytic activities. Co.Cr (0.03-10 mg/mL) caused an atropine sensitive spasmogenic effect in guinea-pig ileum. In spontaneously contracting rabbit jejunum preparations, Co.Cr caused a dose-dependent (0.03-3.0 mg/mL) spasmogenic effect, followed by relaxation at the next higher doses of 5.0-10.0 mg/mL. In the presence of atropine, the spasmogenic effect was blocked and the relaxant effect was observed at lower doses (0.1-5.0 mg/mL), shifting the inhibitory dose-response curves to the left. Co.Cr also inhibited K(+) (80 mm)-induced contractions in atropinized preparations at similar doses, suggesting calcium channel blockade (CCB) activity. The CCB effect was further confirmed when pretreatment of the tissue with Co.Cr produced a dose-dependent shift in the Ca(++) dose-response curves to the right, similar to that caused by verapamil. Activity-directed fractionation revealed that the spasmolytic effect was concentrated in organic fractions in the following order of potency: hexane > ethylacetate > chloroform, while the aqueous fraction exhibited spasmogenic and weak spasmolytic effects. These results indicate that Carthamus oxycantha contains a combination of spasmogenic (cholinergic) and spasmolytic (calcium antagonist) constituents.

Blood pressure lowering effect of olive is mediated through calcium channel blockade

Olive (Olea europea) is used in traditional medicine as a remedy for hypertension. The aqueous–methanolic crude extract of O. europea fruit (OeF.Cr) was studied in anaesthetized rats and its possible mechanism was elucidated using isolated cardiovascular preparations. Intravenous administration of OeF.Cr produced a dose-dependent (30–100 mg/kg) fall in arterial blood pressure in normotensive anaesthetized rats. This effect remained unaltered in atropinized animals. In the in vitro studies OeF.Cr (0.1–3.0 mg/ml) inhibited spontaneously beating guinea-pig atria. Moreover, it relaxed K+ and/or phenylephrine-induced contractions of rabbit aortic preparations over a dose range of 0.1–3.0 mg/ml, suggesting calcium channel blockade (CCB). The CCB effect was confirmed when pretreatment of the vascular preparations with OeF.Cr produced a dose-dependent rightward shift of the Ca2 + dose–response curves, similar to verapamil. These results suggest that the blood pressure lowering effect of olive is mediated through CCB, justifying its use in hypertension.

Pharmacological basis for the use of Fumaria indica in constipation and diarrhea

The crude extract of Fumaria indica whole plant (Fi.Cr) and its fractions were studied in vitro for spasmogenic and spasmolytic effects to rationalize some of the traditional uses. Fi.Cr (1.0–5.0 mg/mL) caused a moderate degree of atropine-sensitive spasmogenic effect in guinea-pig ileum. In spontaneously contracting rabbit jejunum, Fi.Cr (0.03–0.3 mg/mL) caused a mild spasmogenicity followed by relaxation at the higher doses. In the atropinized preparations, Fi.Cr inhibited spontaneous and K +-induced contractions at the similar doses (0.1–1.0 mg/mL), which suggests calcium channel blockade (CCB). CCB effect was confirmed when pretreatment of the tissue with the Fi.Cr produced a dose-dependent shift in the Ca 2+ dose–response curves to the right, similar to that produced by verapamil. Activity-directed fractionation revealed that the spasmolytic effect is concentrated in the petroleum ether fraction, while dichloromethane fraction contains both spasmogenic and spasmolytic constituents. These data indicate that the presence of cholinergic and CCB constituents in Fi.Cr may explain the respective traditional use of Fumaria indica in constipation and diarrhoea.

Nifedipine Prevents Apoptosis of Endothelial Cells Induced By Oxidized Low-density Lipoproteins

Calcium channel blockade has been shown to inhibit experimental atherosclerosis, and early clinical trials suggest that it also reduces atherosclerosis in humans. However, the mechanisms underlying the direct protective effect of calcium channel blockade on endothelial cell injury are not fully understood. The apoptosis of endothelial cells induced by oxidized low-density lipoproteins (oxLDL) may provide a mechanistic clue to the "response-to-injury" hypothesis of atherogenesis. Here we report that the calcium channel blocker, nifedipine, prevents the apoptosis of human umbilical venous endothelial cells (HUVECs) induced by oxLDL via downregulation of the endothelial receptor for oxidized LDL (LOX-1) and inhibition of CPP32-like protease activity. The incubation of HUVEC with oxLDL increased LOX-1 mRNA levels and CPP32-like protease activity, and induced apoptosis. Preincubation of HUVEC with nifedipine before incubation with oxLDL significantly suppressed the increase in LOX-1 mRNA levels and CPP32-like protease activity, preventing apoptosis in a dose-dependent manner. These results suggest that nifedipine blocks the suicide pathway leading to the apoptosis of endothelial cells by decreasing LOX-1 mRNA levels and CPP32-like protease activity. Thus, nifedipine seems to play a protective role against the "response-to-injury" hypothesis of atherogenesis.

Calcium channel blockade with felodipine does not affect metabolic coronary vasodilation in patients with coronary artery disease.

The effect of calcium channel blockers may affect the feedback mechanism between myocardial metabolic activity and coronary blood flow. To test this hypothesis the effect of calcium channel blockade on metabolic coronary flow regulation was studied. In 10 patients with stable coronary artery disease, coronary sinus blood flow and myocardial oxygen supply and consumption (MVO2) were measured both at sinus rhythm and during atrial pacing (30 beats/min above sinus rate), at control and during infusion of felodipine, a vasoselective dihydropyridine. The myocardial oxygen supply-consumption ratio at control (i.e., the slope of the regression line characterizing normal metabolic flow regulation) was 1.58 (95% CI, 1.38-1.80). Following infusion of felodipine, systemic and coronary vascular resistance during sinus rhythm decreased by 20 +/- 11% and 23 +/- 15%, respectively, and coronary venous oxygen saturation increased from 36 +/- 6% at control to 42 +/- 7% (p = 0.047) during infusion of felodipine. The myocardial oxygen supply-consumption ratio, characterizing metabolic flow regulation during felodipine, was 1.52 (95% CI, 1.26-1.78) and thus not different from control. Metabolic coronary flow regulation was not affected by administration of felodipine, although the setpoint of this regulation mechanism might have been offset by the initial drug-induced coronary vasodilation, which persisted during pacing.

The presence of Cholinomimetic and calcium channel antagonist constituents in Piper betle Linn.

The crude aqueous extract of Piper betle leaves (Pb.Cr) was studied for the possible presence of cholinomimetic and calcium channel antagonist constituents. Pb.Cr at doses of 1-10 mg/mL caused a moderate spasmogenic effect in isolated guinea-pig ileum and this activity was concentrated in the aqueous fraction, which was found to be about 5 times more potent. Pretreatment of the tissue with atropine (1 microM) but not hexamethonium (100 microM) completely abolished the contractile effect of the aqueous fraction indicating a cholinergic (muscarinic) mechanism. In isolated rabbit jejunum preparations Pb.Cr did not produce a significant increase in the spontaneous contractions, but instead produced a dose-dependent (0.03-3.0 mg/mL) inhibition of spontaneous activity. Activity-directed fractionation revealed that the spasmolytic action was concentrated in the ethyl acetate fraction. When tested against K(+)-induced contractions, both Pb.Cr and its ethyl acetate fraction (Pb.EtAc) caused a dose-dependent inhibition, suggesting calcium channel blockade (CCB). The potent CCB effect of the crude extract and its ethyl acetate fraction was confirmed when pretreatment of the tissue with Pb.Cr or Pb.EtAc shifted the Ca(++) dose-response curves to the right in a dose-dependent manner. These data indicate that the plant contains cholinomimetic and possible calcium channel antagonist constituents, which are concentrated in the aqueous and ethyl acetate fractions respectively. It is suggested that some of the traditional uses of this plant may be explained on the basis of these activities.

Effects of Calcium-Channel Blockade in Older Patients with Diabetes and Systolic Hypertension

Background Recent reports suggest that calcium-channel blockers may be harmful in patients with diabetes and hypertension. We previously reported that antihypertensive treatment with the calcium-channel blocker nitrendipine reduced the risk of cardiovascular events. In this post hoc analysis, we compared the outcome of treatment with nitrendipine in diabetic and nondiabetic patients. Methods After stratification according to center, sex, and presence or absence of previous cardiovascular complications, 4695 patients (age, ≥60 years) with systolic blood pressure of 160 to 219 mm Hg and diastolic pressure below 95 mm Hg were randomly assigned to receive active treatment or placebo. Active treatment consisted of nitrendipine (10 to 40 mg per day) with the possible addition or substitution of enalapril (5 to 20 mg per day) or hydrochlorothiazide (12.5 to 25 mg per day) or both, titrated to reduce the systolic blood pressure by at least 20 mm Hg and to less than 150 mm Hg. In the control group, matching placeb...

Effects of calcium channel blockade on intravenous self-administration of ethanol in rats

In the present study the involvement of voltage-operated calcium channels (VOCCs) in the acquisition and maintenance of operant i.v. ethanol (EtOH) self-administration was investigated in rats. Rats readily learned to self-administer EtOH (unit dose range: 0.5–4% v/v) within five daily 2-h sessions, when infusions were made contingent upon nose-poking in a hole containing infrared sensors. Response rate was related to the EtOH concentration in an inverted U-shaped manner, the maximal rate and intake being observed at a unit dose of 1% v/v (0.27 mg EtOH/infusion). Self-administration of EtOH appeared to be behaviorally specific, as responding in the reinforced hole did not coincide with increased responding in a nonreinforced hole. Daily treatment with the dihydropyridine VOCC blocker nimodipine (2.5–20 mg/kg, i.p., t-15 min) dose-dependently attenuated acquisition of EtOH self-administration; the 5 mg/kg dose resulting in a partial, and the 10 and 20 mg/kg doses in a complete prevention of i.v. self-administration behavior. The effects of nimodipine (2.5–5.0 mg/kg) were considered to be relatively specific, as an inhibition of the reinforced responding could be demonstrated in the absence of a significant effect on nonreinforced responding. When tested in rats showing stable self-administration behavior (unit dose: 1% v/v EtOH), nimodipine showed biphasic dose–response effects; with 2.5 and 5 mg/kg resulting in a mild increase, and 10 and 20 mg/kg resulting in a decrease of self-administration behavior, respectively. The present study suggests that blockade of VOCCs attenuates the reinforcing stimulus effects of EtOH; and, as such, the data may offer an explanation for the previously reported EtOH intake-reducing effects of dihydropyridine calcium channel ligands obtained in two-bottle choice paradigms. Dihydropyridine derivatives, such as nimodipine, may therefore offer an interesting approach to the pharmacotherapy of alcoholism.

Beneficial effects of calcium channel blockade on acute glomerular hemodynamic changes induced by cyclosporine.

Experimental and human studies have documented that cyclosporine (CsA) acutely reduces glomerular filtration rate (GFR). It has been reported that this effect can be partially prevented by calcium (Ca) channel blockade; however, the mechanisms by which this combination exerts its beneficial effects are unknown. We evaluated glomerular ultrafiltration determinants during acute CsA administration in the rat. First, we determined that maximal whole-kidney functional changes occur between 120 and 150 minutes after CsA administration and confirmed that pretreatment of MWF rats with the Ca channel blocker lacidipine effectively prevents a reduction in GFR. Micropuncture measurements in CsA-treated animals showed that a reduction in GFR (0.49 +/- 0.24 v 0.88 +/- 0.26 mL/min; P < 0.05; CsA-treated v untreated rats) is associated with a significant increase in glomerular capillary pressure (Pgc; 63.1 +/- 2.1 v 52.8 +/- 2.8 mm Hg; P < 0.01) and efferent arteriolar resistance, whereas single-nephron (SN) GFR and ultrafiltration coefficient (Kf) are both importantly reduced (34.0 +/- 11.7 v 68.9 +/- 23.8 nL/min; P < 0.05 and 1.04 +/- 0.33 v 4.40 +/- 2.36 nL/min/mm Hg; P < 0.01, respectively). Lacidipine partially prevented SNGFR (43.1 +/- 14.3 nL/min) and Kf decline (2.08 +/- 1.10 nl/min/mm Hg) despite the presence of elevated Pgc. This study further documents that Ca channel blockade has favorable effects on CsA-induced acute renal dysfunction. The mechanism of protection includes the prevention of glomerular hemodynamic changes induced by CsA, mainly GFR decline and reduction in glomerular Kf.

Differences in contractile properties of anorectal smooth muscle and the effects of calcium channel blockade.

Pharmacological manipulation of the anal sphincter is hampered by a lack of specificity. This study aimed to determine differences in the role of intracellular and extracellular calcium in the development of tone and agonist-induced contractions between internal anal sphincter (IAS) and rectal circular muscle which might allow targeted manipulation. Smooth muscle strips from the IAS and rectal circular muscle of 24 Large White pigs were mounted for isometric tension recording in a superfusion organ bath in the presence of different perfusates. IAS developed tone and spontaneous activity that were abolished by nifedipine, which also reduced contractions to noradrenaline to 72 per cent of control values. Rectal smooth muscle developed spontaneous activity but no tone. Nifedipine abolished the activity and reduced contractions to carbachol to 17 per cent of control. Contractile activity was abolished in both tissues in calcium-free solution. Transient exposure to a high calcium concentration reloaded the stores, and the ability of agonists to release stored calcium was tested after 3 min in calcium-free solution. In IAS, noradrenaline contraction was 76 per cent of control and in rectal circular muscle carbachol contraction was 57 per cent of control. Store loading was prevented by nifedipine in rectal smooth muscle but not IAS. Cyclopiazonic acid reduced store filling in both tissues. Agonist-induced contraction of IAS is largely due to release of stored calcium and L-type calcium channels are not needed for store filling. Rectal circular smooth muscle depends more on extracellular calcium and uses L-type calcium channels for agonist-induced contraction and store filling. These differences suggest that targeted manipulation may be possible in patients with anorectal disorders.

Spasmogenic and Spasmolytic Constituents in Sida Pakistanica

The ethanolic extract of Sida pakistanica (SP) was studied for the possible presence of spasmogenic and spasmolytic constituents. SP at the dose of 0.1–5.0 mg/ml caused spasmogenic effects both in isolated guinea-pig ileum and rabbit jejunum. In the presence of atropine (0.1 µM), SP did not exhibit a spasmogenic effect, instead spasmolytic activity was enhanced at similar doses. When tested against K + -induced contraction, SP caused a dose-dependent relaxation in the concentration range of 0.3–10 mg/ml, suggestive of the involvement of calcium channel blockade (CCB). The crude extract was subjected to activity-directed fractionation to separate spasmogenic (cholinergic) and spasmolytic (CCB) constituents. The results revealed the spasmogenic component was separated in the aqueous fraction whereas the spasmolytic component was concentrated in the ethyl acetate fraction. The potent CCB effect of the ethyl acetate fraction wasln confirmed when the pretreatment of tissue with SP (0.03–0.3 mg/ml) shifted Ca ++ dose-response curves to the right in a dose-dependent manner.

Calcium channel blockade reduces noise-induced vascular permeability in cochlear stria vascularis.

Exposure to noise results in multiple perturbations of cochlear microcirculation, including increases in vascular permeability. There is evidence that these events are mediated, in part, by calcium channels. The current study examined the effects of calcium channel blockade on the diameter and permeability of cochlear vessels during noise exposure. Subjects were exposed to either noise alone or noise after verapamil pretreatment. Vessels of the cochlear stria vascularis were imaged using intravital microscopy. Animals exposed to noise showed decreases in diameter and increased permeability above baseline levels. Animals pretreated with the calcium channel blocker verapamil and exposed to noise demonstrated increases in vessel diameter and no changes in permeability. These data indicate that calcium channel blockade reduces noise-induced microvascular permeability. Treatment strategies designed to protect from increases in vascular permeability due to noise exposure may reduce temporary threshold shifts.