Comparison of the apoptotic effects of topically applied papaverine, diltiazem, and nitroprusside to internal thoracic artery

Abstract Objective: To detect and to compare the apoptotic effects of intraoperatively topically applied diltiazem, papaverine, and nitroprusside. Methods: Internal thoracic artery segments of ten patients were obtained during coronary bypass grafting surgery. Each internal thoracic artery segment was divided into four pieces and immersed into four different solutions containing separately saline (Group S), diltiazem (Group D), papaverine (Group P), and nitroprusside (Group N). Each segment was examined with both hematoxylin-eosin and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method in order to determine and quantify apoptosis. Results: Apoptotic cells were counted in 50 microscopic areas of each segment. No significant difference was observed among the four groups according to hematoxylin-eosin staining. However, the TUNEL method revealed a significant increase in mean apoptotic cells in the diltiazem group when compared with the other three groups (Group S=4.25±1.4; Group D=13.31±2.8; Group N=9.48±2.09; Group P=10.75±2.37). The differences between groups were significant (P=0.0001). No difference was observed between the samples of the diabetic and non-diabetic patients in any of the study groups. Conclusion: The benefit of topically applied vasodilator drugs must outweigh the potential adverse effects. In terms of apoptosis, diltiazem was found to have the most deleterious effects on internal thoracic artery graft segments. Of the analyzed medical agents, nitroprusside was found to have the least apoptotic activity, followed by papaverine. Diabetes did not have significant effect on the occurrence of apoptosis in left internal thoracic artery grafts.

Effects of intraoperative diltiazem infusion on flow changes in arterial and venous grafts in coronary artery bypass graft surgery / Efeitos da infusão intraoperatória de diltiazem sobre as mudanças do fluxo em enxertos arteriais e venosos em cirurgia de revascularização do miocárdio

AbstractObjective:This study aimed to show the effects of intra-operative diltiazem infusion on flow in arterial and venous grafts in coronary artery bypass graft surgery.Methods:Hundred fourty patients with a total of 361 grafts [205 (57%) arterial and 156 (43%) venous] underwent isolated coronary surgery. All the grafts were measured by intraoperative transit time flow meter intra-operatively. Group A (n=70) consisted of patients who received diltiazem infusion (dose of 2.5 microgram/kg/min), and Group B (n=70) didn't receive diltiazem infusion.Results:Mean graft flow values of left internal mammary artery were 53 ml/min in Group A and 40 ml/min in Group B (P<0.001). Pulsatility index (PI) values of left internal mammary artery for Group A and Group B were 2.6 and 3.0 respectively (P<0.001). No statistically significant difference was found between venous graft parameters.Conclusion:We recommend an effect of diltiazem infusion in increasing graft flows in coronary artery bypass graft operations.

ResumoObjetivo:Este estudo teve como objetivo mostrar os efeitos da infusão de diltiazem intraoperatória no fluxo arterial e enxertos venosos em cirurgia de revascularização do miocárdio.Métodos:Cento e quarenta pacientes com um total de 361 enxertos [205 (57%) arteriais e 156 (43%) venosos] passaram por uma cirurgia coronária isolada. Todos os enxertos foram medidos pelo medidor de fluxo de tempo de trânsito intraoperatório. Grupo A (n=70), formado por pacientes que receberam infusão de diltiazem (dose de 2,5 micrograma/kg/min), e Grupo B (n=70), por aqueles que não receberam infusão de diltiazem.Resultados:Os valores médios de fluxo de enxerto de artéria mamária interna esquerda foram 53 ml/min no grupo A e 40 ml/min no Grupo B (P<0,001). Valores do índice de pulsatilidade da artéria mamária interna esquerda para o Grupo A e do Grupo B foram de 2,6 e 3,0, respectivamente (P<0,001). Não houve diferença estatisticamente significativa entre os parâmetros do enxerto venoso.Conclusão:Sugerimos um efeito da infusão de diltiazem em aumentar os fluxos de enxerto em operações de bypass de artéria coronária.

Diltiazem como alternativa ao betabloqueador na angiotomografia de artérias coronárias / Diltiazem as an alternative to beta-blocker in coronary artery computed tomography angiography

FUNDAMENTO: A redução da frequência cardíaca (FC) na angiografia por tomografia das artérias coronarianas (ATCCor) é fundamental para a qualidade de imagem. A eficácia dos bloqueadores de cálcio como alternativas para pacientes com contraindicações aos betabloqueadores não foi definida. OBJETIVOS: Comparar a eficácia na redução da FC e variabilidade RR do metoprolol e diltiazem na ATCCor. MÉTODOS: Estudo prospectivo, randomizado, aberto, incluiu pacientes com indicação clínica de ATCCor, em ritmo sinusal, com FC>70bpm e sem uso de agentes que interferissem com a FC. Cinquenta pacientes foram randomizados para grupos: metoprolol IV 5-15 mg ou até FC≤60 bpm(M), e diltiazem IV 0,25-0,60mg/kg ou até FC≤60 bpm (D). Pressão arterial (PA) e FC foram aferidas na condição basal, 1min, 3min e 5min após agentes, na aquisição e após ATCCor. RESULTADOS: A redução da FC em valores absolutos foi maior no grupo M que no grupo D (1, 3, 5min, aquisição e pós-exame). A redução percentual da FC foi significativamente maior no grupo M apenas no 1 min e 3 min após início dos agentes. Não houve diferença no 5 min, durante a aquisição e após exame. A variabilidade RR percentual do grupo D foi estatisticamente menor do que a do grupo M durante a aquisição (variabilidade RR/ FC média da aquisição). Um único caso de BAV, 2:1 Mobitz I, revertido espontaneamente ocorreu (grupo D). CONCLUSÃO: Concluímos que o diltiazem é uma alternativa eficaz e segura aos betabloqueadores na redução da FC na realização de angiografia por tomografia computadorizada das artérias coronarianas. (Arq Bras Cardiol. 2012; [online].ahead print, PP.0-0).

BACKGROUND: Reducing heart rate (HR) in CT angiography of the coronary arteries (CTACor) is critical to image quality. The effectiveness of calcium channel blockers as alternatives for patients with contraindications to beta-blockers has not been established. OBJECTIVES: To compare the efficacy in the reduction of HR and RR variability of metoprolol and diltiazem in CTACor. METHODS: Prospective, randomized, open study that included patients with clinical indication of CTACor in sinus rhythm with HR > 70 bpm and no use of agents that could interfere with HR. Fifty patients were randomized to the groups: metoprolol IV 5-15 mg or up to HR ≤ 60 bpm (M), and diltiazem IV 0.25 to 0.60 mg/kg or up to HR ≤ 60 bpm (D). Blood pressure (BP) and HR were measured at baseline, 1 minute, 3 minutes and 5 minutes after the agents, at the acquisition and after CTACor. RESULTS: HR reduction in absolute values was higher in group M than in group D (1, 3, 5 min, acquisition and post-test). The percentage reduction of HR was significantly higher in group M only 1 min and 3 min after the start of the agents. There was no difference in 5 min at acquisition and after examination. The percentage RR variability in group D was lower than that in group M during acquisition (RR variability/mean HR of acquisition). A single case of AVB, 2:1 Mobitz I occurred, which was spontaneously reverted (group D). CONCLUSION: We conclude that diltiazem is an effective and safe alternative to beta-blockers in the reduction of HR when performing computed tomography angiography of coronary arteries. (Arq Bras Cardiol. 2012; [online].ahead print, PP.0-0).

Histologic alterations of rat kidneys perfused with a Euro-Collins diltiazem solution / Alterações histológicas ocorridas em rins de ratos perfundidos com solução de Euro-Collins associada à diltiazem

PURPOSE: Analyse the histologic changes of rat kidneys perfused with isotonic saline solution (ISS), Euro-Collins solution (ECS) and Euro-Collins solution with diltiazem (ECSD). METHODS: Thirty-six Wistar rats were used divided equally, as follow: group A (ISS), group B (ECS) and group C (ECSD). Through a catheter placed into the abdominal aorta, a renal perfusion was performed using a solution according to the group to which the animal belonged. After the complete perfusion, bilateral nephrectomy was performed and the organs were preserved under hypothermia for five distinct periods of time. Glomerulus and tubule were evaluated through optical microscopy. RESULTS: Renal perfusion with ECS and ECSD proved effectiveness in the preservation of the organs up to 36 hours and an increase in the percentage of injured glomeruli was noticed only in the period of 48 hours. CONCLUSIONS: The results showed that exists an association between the tubular injury and the glomeruli lesion degree; kidneys with a higher degree of tubular damage were related to severe glomerular lesion. Also, the addition of a calcium channel blocker, diltiazem, to the ECS for the renal perfusion does not decrease the percentage of glomerular lesion.

OBJETIVO: Analisar as alterações histológicas nos rins de ratos perfundidos com solução salina isotônica (ISS), solução Euro-Collins (ECS) e solução Euro-Collins com diltiazem (ECSD). MÉTODOS: Foram divididos, de forma igual, 36 ratos Wistar, como se segue: grupo A (ISS), grupo B (ECS), grupo C (ECSD). Através de um cateter localizado na aorta abdominal, foi realizada a perfusão renal com a solução de acordo com o grupo ao qual o animal pertencia. Após a perfusão total, realizou-se nefrectomia bilateral com a preservação dos órgãos sob hipotermia por cinco períodos distintos de tempo. Glomérulos e túbulos foram avaliados por microscopia óptica. RESULTADOS: Tanto a perfusão renal com ECS quanto a com ECSD provaram sua efetividade na preservação dos órgãos em até 36 horas e aumento da porcentagem de glomérulos injuriados foi notada apenas no período de 48 horas. CONCLUSÕES: Os resultados mostraram haver uma correlação entre a injúria tubular e o grau de lesão glomerular; rins com um maior grau de dano tubular foram relacionados com lesão glomerular severa. Além disso, a adição de um bloqueador de canal de cálcio, diltiazem, à ECS para a perfusão renal não diminui a porcentagem de lesão glomerular.

Influence of diltiazem in combination with a sucrose-rich diet on gingival alterations in rats

The aim of this study was to evaluate the influence of diltiazem in combination with a sucrose-rich diet on gingival alterations in rats. One hundred and twenty male Holtzman rats were randomly assigned to 10 groups (n = 12), being 2 control groups treated with saline and 8 test groups treated with diltiazem in daily doses of 5, 25, 50 and 100 mg/kg during 40 or 60 days. Afterwards, the mandibles were removed for macroscopic, histologic and histometric analyses of the buccal gingiva of the mandibular right first molar. No macroscopic characteristic of gingival overgrowth was observed in any of the groups. The microscopic analysis showed characteristics of normality with inflammatory cells only adjacent to the crevicular epithelium in all groups for both periods. The histometric analysis showed significant differences only for the epithelial tissue area in the 40-day period (Kruskal-Wallis; P = 0.032). Comparing the periods, significant differences regarding the connective and epithelial tissue areas were observed only in the group treated with a 25 mg/kg dose (Mann-Whitney; P = 0.004 and P = 0.007, respectively). Oral administration of diltiazem in combination with a sucrose-rich diet did not induce gingival alterations in rats.

Vasorreactividad a adenosina en los pacientes con hipertensión pulmonar arterial: prevalencia y respuesta clínica, funcional y hemodinámica al tratamiento con diltiazem / Acute vasodilatador test using adenosine in patients with pulmonary arterial hypertension: prevalence and clinical, functional and hemodynamic response after diltiazem treatment

Pulmonary arterial hypertension (PAH) is a severe and progressive disease. Invasive hemodynamic study (HS) is required to confirm the diagnosis of PAH and to perform the vasodilator test (VT) with adenosine. Vasodilator acute responders (VAR) may have a sustained benefit with diltiazem. There is not national information regarding these issues. All patients with probable PAH were evaluated with HS and VT. VAR were treated with diltiazem and followed up with functional class score (FC) and 6 minute walk test. After 6 months, a second HS was performed. Results: Between 2003 and 2008, 6/54 (11%) were VAR. All were women, 45 +/- 14 years old, 4 with idiopathic PAH, 4 in FCIII and 2 in FCII. After two years of treatment, all patients clinically improved. Walked distance significantly increased by 83 and 87 m at month 12 and 24 respectively. Hemodynamic parameters also improved. Therapy with diltiazem is effective in VAR patients supporting the convenience to perform the VT.

La Hipertensión Pulmonar Arterial (HAP) es una entidad grave y progresiva. El estudio hemodinámica (EH) permite certificar el diagnóstico y evaluar la vasorreactividad mediante adenosina. Los pacientes vaso-reactivos podrían responder a terapia con diltiazem. No existe información nacional al respecto. En nuestro programa todo paciente con sospecha de HAP es sometido a EH diagnóstico y de vasorreactividad. Los positivos son tratados con diltiazem y seguidos semestralmente según capacidad funcional (CF) y con test de caminata. Al 6º mes se efectúa un 2º EH. Entre 2003-2008, 6/54 (11%) de los pacientes con HAP fueron vasorreactivos. Todas mujeres, 45 +/- 14 años, 4 con HPA idiopática, 4 en CFIII y 2 en CFII. A los 2 años, todos mejoraron clínicamente. La distancia recorrida aumentó significativamente en los meses 12 y 24 en 83 y 87 m respectivamente. Todas las variables hemodinámicas mejoraron. La terapia con diltiazem es efectiva en los pacientes vaso-reactivos lo que justifica usar el test de vasorreactividad.

Neuroprotective effects of diltiazem in rabbits with occluded aorta

OBJECTIVE: In the present study, we aimed to determine the protective effect of the perfusion of the distal aorta with diltiazem and ringer lactate solution on the spinal cord. METHODS: Twenty-seven New Zealand rabbits were used in which spinal cord ischemia was provided by occlusion of the aorta for thirty minutes. Experimental animals were divided into four groups: group A (n=4), the sham operation group; group B (n=8) in which intraaortic balloon occlusion alone was applied; group C (n=7), ringer lactate group in which ringer lactate was perfused into distal aorta at a rate of 40 ml/kg, hr, following intraaortic balloon occlusion; group D (n=8) diltiazem group in which diltiazem 40 mg/kg, hr, in Ringer lactate was perfused into distal aorta following intraaortic balloon occlusion. Motor function of hind limbs was evaluated by Tarlov's scoring system. After observation, spinal cords were removed for histopathological evaluation. RESULTS: The degree of histopathological injury was well correlated with neurological function. The most severe histopathological injury and neurological dysfunction occurred in group B, followed by group C, D and A respectively. No injury or neurological dysfunction occurred in the sham group. CONCLUSIONS: The protective effect of diltiazem on both histopathological injury and neurological function was significant in comparison with control groups.

OBJETIVO: O objetivo do presente trabalho é determinar o efeito protetor da perfusão na aorta distal com diltiazem e solução de Ringer lactato na medula espinal. MÉTODOS: Foram usados 27 coelhos da raça New-Zeland, nos quais se provocou isquemia da medula espinal por meio de oclusão da aorta durante 30 minutos. Os animais experimentais foram divididos em quatro grupos: grupo A (n=4), o grupo de cirurgia simulada (pseudocirurgia); o grupo B (n=8) no qual se aplicou somente a oclusão do balão intraaórtico; grupo C (n=7), o grupo do Ringer lactato, no qual a solução de Ringer lactato foi perfundida na aorta distal após oclusão do balão intra-aórtico; grupo D (n=8), grupo do dialtiazem, no qual 40 mg/kg/h de diltiazem, em solução de Ringer lactato, foram perfundidas na aorta distal após oclusão do balão intra-aórtico. A função motora dos membros posteriores foi avaliada pelo sistema de escore de Tarlov. Após observação, as medulas espinais foram removidas para avaliação histopatológica. RESULTADOS: O grau de lesão histopatologica estava bem correlacionado com a função neurológica. Lesões histopatológicas e disfunções neurológicas mais graves ocorreram no grupo B, seguido pelos grupos C, D e A, respectivamente. Não ocorreu nenhuma lesão ou disfunção neurológica no grupo de cirurgia simulada. CONCLUSÕES: O efeito protetor do diltiazem na lesão histopatológica e na função neurológica foi significativo em comparação com os grupos-controle.

Comparative interaction of few antihypertensive drugs with cyclosporine-A in rats.

The maximal endothelial dependent relaxation of isolated aortic rings to cumulative doses of acetylcholine was significantly decreased in the Cyclosporine-A (CSA, 20 mg kg(-1) day(-1)) treated animals compared to olive oil (CSA vehicle) treated control. Administration of antihypertensive drugs like diltiazem, enalapril or propranolol to CSA treated animals augmented the endothelial damage induced by CSA. These drugs also increased the bioavailability of CSA. However, administration of losartan to CSA treated animals produced a significant increase in endothelial dependent relaxation as compared to CSA treated control but did not affect the bioavailability of CSA significantly. The results suggest that losartan is safer compared to other antihypertensives for the treatment of CSA induced hypertension.

Treating metabolic impairment and myocardial stunning with phosphodiesterase inhibitor type III, milrinone, administered prior to coronary artery occlusion in the presence of calcium channel blockade in pigs.

This study examined milrinone effects on ischaemic myocardial metabolism and function with calcium blockade. We studied 15 pigs in 3 groups: group C received no drugs; group D received diltiazem 5 mg bolus followed by infusion; group D+M received diltiazem and milrinone (50microg/Kg). The left anterior descending (LAD) artery was then occluded for 15 minutes. Left ventricular (LV) function data obtained included rate, pressures, output, Emax, and dP/dT. Blood lactate was obtained from the LAD and circumflex vessels at baseline, end of occlusion, early (15 min) and late (1 hour) reperfusion. In group D+M, less depression of LV function occurred during ischaemia and early reperfusion. Lactate extraction in the LAD region was less negative in D+M group than in the group without milrinone during ischaemia and late reperfusion. We conclude the preemptive administration of milrinone prior to ischaemia added to calcium blockade improved myocardialfunction and ischaemic metabolic effects.

Hypothyroid state reduces calcium channel function in 18-day pregnant rat uterus.

Hypothyroidism significantly reduced the mean amplitude and increased the mean frequency of spontaneous rhythmic contractions in 18 day pregnant rat uterus. Nifedipine (10(-12)-10(-9) M) and diltiazem (10(-10)-10(-6) M) caused concentration related inhibition of the myogenic responses of the uterine strips obtained from both pregnant and hypothyroid state. However, nifedipine was less potent (IC50:2.11 x 10(-11) M) in pregnant hypothyroid state as compared to pregnant control (IC50: 3.1 x 10(-12) M). Similarly, diltiazem was less potent (IC50: 3.72 x 10(-9) M) in inhibiting the uterine spontaneous contractions in hypothyroid than in pregnant rat uterus (IC50:5.37 x 10(-10) M). A similar decrease in the sensitivity to nifedipine and diltiazem for reversal of K+ (100 mM)-induced tonic contraction and K(+)-stimulated 45Ca2+ influx was observed with these calcium channel antagonists in uterus obtained from hypothyroid pregnant rats compared to the controls. Nifedipine-sensitive influx of 45Ca(2+)-stimulated either by K+ (100 mM) or by Bay K8644 (1,4-dihydro-2,6-methyl-5-nitro-4-[2'-(trifluromethyl)phenyl]-3-pyridine carboxylic acid methyl ester) (10(-9) M) was significantly less in uterine strips from hypothyroid rats compared to controls. The results suggest that the inhibition of uterine rhythmic contractions may be attributable to a reduction in rat myometrial Ca2+ channel function in the hypothyroid state.

Diltiazem did not induce gingival overgrowth in rats: a clinical, histological and histometric analysis / Diltiazem não induziu crescimento gengival em ratos. Análise clínica, histológica e histométrica

A administração de bloqueadores dos canais de cálcio tem sido associada com crescimento gengival; entretanto, existem poucos estudos em humanos e animais que avaliaram o efeito do diltiazem nos tecidos gengivais. O presente trabalho tem como objetivo avaliar o efeito do diltiazem, em diferentes dosagens e tempos de tratamento, no tecido gengival de ratos, por meio de análises clínica, histológica e histométrica. Oitenta ratos jovens machos foram divididos em oito grupos de acordo com a dosagem e o tempo de administração. Os animais foram tratados por 20 ou 40 dias com uma dosagem diária de diltiazem de 5, 20 ou 50 mg/kg de peso corporal, por via subcutânea. Os resultados confirmaram que o diltiazem não induziu crescimento gengival em ratos. Para todos os animais a avaliação não demonstrou alterações gengivais, independentemente da dosagem e do período de tratamento. A análise histométrica evidenciou ausência de alteração significante na área de tecidos epitelial e conjuntivo, embora, após 40 dias de tratamento, tenha sido observada diminuição na área de tecido conjuntivo, não significante estatisticamente. Dentro dos limites deste estudo, sugerimos que o diltiazem não induziu crescimento gengival.

Effect of aqueous extract from Nigella sativa L. on guinea pig isolated heart.

A potent inhibitory effect of aqueous extract from N. sativa on calcium channel of guinea pig heart was found comparable and even greater than that of diltazem. The results may also indicate an opening effect for the plant on potassium channel of isolated heart.

Effects of calcium, strontium, and barium on isolated phrenic nerve-diaphragm preparation of rat and their interactions with diltiazem and nifedipine.

Calcium (Ca2+), strontium (Sr2+), and barium (Ba2+) are expected to exert similar chemical and pharmacological effects. The effects of barium, strontium and calcium were studied on the contractions of rat phrenic nerve-diaphragm preparations, following electrical stimulation and their interactions with nifedipine (nif) and diltiazem (DZM) were also studied. Low doses of strontium chloride (SrCl2), barium chloride (BaCl2) and calcium chloride (CaCl2) were able to increase the force of contraction of the rat diaphragm when actively stimulated. Diltiazem inhibited the stimulant effects of Sr2+, Ba2+, and Ca2+. On the other hand, nifedipine blocked the effects of Sr2+ and Ca2+ but potentiated the effects of Ba2+. Strontium, barium, and calcium restored the contractility of the muscle following electrical stimulation when the tissue was in biological fluid absolutely depleted of calcium. These findings suggest that Sr2+ and Ba2+ may be able to substitute Ca2+ in the rat diaphragm for its contractions and nifedipine and diltiazem may follow different mechanisms of actions or channels in their blocking effects.

mechanism of action of calcium channel blockers in the treatment of diabetic nephropathy

Three types of calcium channels have been identified voltage-sensitive, receptor operated [cardiac muscle and vascular smooth muscle] and stretch operated [in some blood vessels] channels. Using electrophysiological and pharmacological techniques, three different types of voltage-gated calcium channels have been identified, namely, L-type [for long lasting, large channels], T-type [for transient, tiny channels] and N-type [for neuronal, neither L nor T]. Many compounds are known to have a calcium channel inhibitory effect. Calcium antagonists, based on the specificity of inhibition of the slow calcium current, can be classified into three groups: Group A: for 90 to 100 percent inhibition of calcium influx without change in the sodium current [verapamil, diltiazem and the dihydropyridines]; Group B: for 50 to 70 percent inhibition of calcium influx current without change in the sodium current [bepridil, cinnarizine and prenylamine] and Group C: for agents exhibiting some inhibition of calcium influx [phenytoin, indomethacin and propranolol]. There is now increasing evidence that, certain calcium channel blockers especially the dihydropyridines are more strongly associated with vasodilation of afferent arterioles than of efferent arterioles and also with increase intraglomerular pressure and albuminuria. Thus they have a beneficial effect in terms of reducing proteinuria and slowing the progression of diabetic renal failure

Potentiation of analgesia and reversal of tolerance to morphine by calcium channel blockers.

Effect of four calcium channel blockers (CCBs) belonging to different chemical classes, alone and in combination with morphine was investigated on two models of pain sensitivity, i.e. formalin and tail flick tests in mice. All the studied CCBs, i.e. diltiazem, flunarizine, nimodipine and verapamil inhibited formalin-induced pain responses; however, with verapamil, though there was a trend towards a reduction of paw-licking response to formalin, it was not found to be statistically significant. In contrast, none of the CCBs affected the tail flick latency at any of the doses studied. Morphine, a mu-receptor agonist exerted a significant analgesic effect in formalin as well in tail flick tests. Pretreatment with all CCBs significantly enhanced the analgesic effect of morphine in both tests of nociception. Further, concomitant administration of one of the CCBs, diltiazem with morphine prevented the development of tolerance to the latter. However, combination of diltiazem with morphine, like morphine alone was found to be ineffective in morphine tolerant animals. Results, thus, show that CCBs produced an analgesic effect of their own in formalin-induced tonic pain and potentiated the analgesic activity of morphine. They also modulated opioid-induced tolerance.

Molecular mechanisms involved in human platelet aggregation by synergistic interaction of platelet-activating factor and 5-hydroxytryptamine

Our recent studies have shown that co-activation of Gq and Gi proteins by 5-hydroxytryptamine (5-HT) and adrenaline show synergism in human platelet aggregation. This study was conducted to examine the mechanism(s) of synergistic interaction of 5-HT and platelet activating factor (PAF) in human platelets. We show that PAF, but not 5-HT, increased platelet aggregation in a concentration-dependent manner. However, low concentrations of 5-HT (2 microM) potentiated platelet aggregation induced by subthreshold concentration of PAF (40 nM) indicating a synergistic interaction between the two agonists and this synergism was blocked by receptor antagonists to either 5-HT or PAF. 5-HT also potentiated the effect of PAF on thromboxane A2 (TXA2) formation and phosphorylation of extracellularly regulated mitogen-activated protein kinases (ERK1/2). The synergism of 5-HT and PAF in platelet aggregation was inhibited by calcium (Ca2+) channel blockers, verapamil and diltiazem, phospholipase C (PLC) inhibitor, U73122, cyclooxygenase (COX) inhibitor, indomethacin, and MEK inhibitor, PD98059. These data suggest that synergistic effect of 5-HT and PAF on human platelet aggregation involves activation of PLC/Ca2+, COX and MAP kinase pathways.

Molecular mechanisms involved in human platelet aggregation by synergistic interaction of platelet-activating factor and 5-hydroxytryptamine

Our recent studies have shown that co-activation of Gq and Gi proteins by 5-hydroxytryptamine (5-HT) and adrenaline show synergism in human platelet aggregation. This study was conducted to examine the mechanism(s) of synergistic interaction of 5-HT and platelet activating factor (PAF) in human platelets. We show that PAF, but not 5-HT, increased platelet aggregation in a concentration-dependent manner. However, low concentrations of 5-HT (2 microM) potentiated platelet aggregation induced by subthreshold concentration of PAF (40 nM) indicating a synergistic interaction between the two agonists and this synergism was blocked by receptor antagonists to either 5-HT or PAF. 5-HT also potentiated the effect of PAF on thromboxane A2 (TXA2) formation and phosphorylation of extracellularly regulated mitogen-activated protein kinases (ERK1/2). The synergism of 5-HT and PAF in platelet aggregation was inhibited by calcium (Ca2+) channel blockers, verapamil and diltiazem, phospholipase C (PLC) inhibitor, U73122, cyclooxygenase (COX) inhibitor, indomethacin, and MEK inhibitor, PD98059. These data suggest that synergistic effect of 5-HT and PAF on human platelet aggregation involves activation of PLC/Ca2+, COX and MAP kinase pathways.

Vasodilatadores en arterias radiales humanas aisladas / Vasodilators in isolated human radial arteries

Este trabajo se diseñó para evaluar la efectividad de diversos vasodilatadores aplicados tópicamente para prevenir la hiperreactividad de las arterias radiales (AR) implantadas como bypass aortocoronario. De cada uno de los remanentes de AR provenientes de 20 pacientes operados se obtuvieron 4 anillos que se incubaron por 30 minutos en condiciones control (n = 20) o en presencia de 30 µM de diltiazem (DILT, n = 6), mibefradil (MIBE, n = 4) o mezcla de verapamil + nitroglicerina (VP-NTG, n = 6). La subsiguiente exposición a CIK 80 mM (en ausencia de vasodilatadores) provocó una contracción sostenida en los anillos control, que fue atenuada en un 35 ñ 9 por ciento por DILT, 48 ñ 13 por ciento por VP-NTG y 69 ñ 20 por ciento por MIBE (p < 0.05). La preincubación con vasodilatadores provocó también la disminución de frecuencia e intensidad de contracciones rítmicas espontáneas de la AR. En anillos almacenados en frío por 24 hs y luego reestimulados con CIK 80 mM el efecto depresor fue aun evidente: DILT 53 ñ 6 por ciento, VP-NTG 46 ñ 14 por ciento y MIBE 61 ñ 9 por ciento (p < 0.05). El efecto del MIBE fue más intenso y persistente que el de DILT o VP-NTG, aún a concentraciones que provocan un igual efecto depresor inicial. Se concluye que la exposición a vasodilatadores durante un período equivalente a la duración de la preparación de la AR a implantar produce una atenuación de la reactividad arterial que proporcionaría una protección adicional contra el espasmo durante el postoperatorio inmediato.

Modulatory effects of diltiazem on inotropic responses to amrinone on rabbit isolated atria.

The effect of pretreatment with graded concentration of diltiazem on the inotropic responses to amrinone were studied on isolated atria of rabbit. The responses to amrinone were modified by diltiazem in a biphasic manner; initial potentiation followed by inhibition. The potentiation is proposed to be due to synergistic rise in cytosolic calcium ion concentration by diltiazem and amrinone. The inhibition by diltiazem in higher concentration may be due to blockade of calcium ion influx and depletion of intracellular calcium ion from storage sites.

Calcioantagonistas: acciones e indicaciones / Calcioantagonists: actions and indications

Constituyen un grupo importante de medicamentos ampliamente utilzados en la práctica diaria, que farmacológicamente se caracterizan por bloquear los canales lentos del calcio.