Cerebral arterial spasm: part 10. Reversal of acute and chronic spasm in dogs with orally administered nifedipine.

In vivo experiments in dogs demonstrated angiographically that the subarachnoid injection of blood produced cerebral arterial apasm both immediately after the injection of blood and 2 days later. The sublingual adminstration of nifedipine reversed both the acute and the delayed cerebral arterial spasm. In addition, sublingual administration of nifedipine 20 minutes before the subarachnoid injection of blood prevented the acute spasm.     

Comparison between nifedipine and carvedilol in the treatment of de novo arterial hypertension after liver transplantation: preliminary results of a controlled clinical trial

There is no controlled clinical trial on the treatment of de novo arterial hypertension after liver transplantation (LT) a common complication using calcineurin inhibitors (CNI) for immunosuppressive therapy. The aim of this study was to compare the efficacy and safety of nifedipine, a calcium channel blocker, and carvedilol, an alpha1- and beta-blocker. The study included 50 patients who developed arterial hypertension after LT. The data on the first 30 patients who have completed 12-month follow-up are reported herein. Eighteen patients received nifedipine, and 12 patients received carvedilol. Patients were evaluated monthly at the outpatient clinic for 1 year. If patients developed severe adverse effects to nifedipine, they were switched to carvedilol and vice versa (therapy failure). The two groups were similar for clinical features, indications for LT, immunosuppressive therapy, and baseline blood pressures. A failure of treatment was observed in 9 of 18 patients treated with nifedipine (50.0%) and one of 12 patients treated with carvedilol (8%, P < .025). Nifedipine was effective in 4 of 18 patients, carvedilol, in 4 of 12 patients (22.21% vs 33.3%, P = NS). Two of the nine nonresponders to nifedipine responded to carvedilol. The efficacy of monotherapy was observed in 11 of 40 randomized patients (27.5%). Carvedilol monotherapy is as effective as nifedipine but far better tolerated.     

Effects of bupivacaine and calcium antagonists on the rat uterine artery

Bupivacaine is a commonly used local anesthetic in obstetrical practice, but since this compound also has a constrictor action on vascular smooth muscle it can be hazardous to the fetus. The aim of the present study was to analyze the effect of bupivacaine on the uterine vasculature using the rat uterine artery as a model. Small arterial segments were mounted in tissue chambers for isometric recording of vascular tension using a specially designed teflon-steel gauge. Bupivacaine induced marked vasoconstriction and this vasoconstriction was reduced considerably by two different Ca antagonists, verapamil and nifedipine. Verapamil (10(-5) mol.l-1) reduced bupivacaine-produced arterial contraction by a mean of 78% and nifedipine (2.9 x 10(-7) mol.l-1) reduced arterial contraction by a mean of 57%.     

Haemodynamic effects of nifedipine in patients undergoing coronary artery bypass surgery

Forty patients scheduled for elective aortocoronary bypass surgery were entered in a double-blind study set up to compare the haemodynamic effects of 20 mg nifedipine (n = 20) and placebo (n = 20), both administered with the premedication. Global left ventricular function was normal in all patients. Anaesthesia was induced and maintained with standardized doses of fentanyl, flunitrazepam, and pancuronium together with 50% N2O. Cardiovascular responses to anaesthesia, intubation, skin incision, sternal retraction, and aortic manipulation were investigated. Throughout the study nifedipine produced a marked decrease in systemic vascular resistance. The reduction of left ventricular afterload was associated with an increase in cardiac index. In contrast to other reports, we observed no severe hypotension after nifedipine administration. Mean arterial pressure in patients from the nifedipine group was lower than in the placebo group only prior to anaesthesia. Since no negative drug interactions between nifedipine and the anaesthetic agents were observed, we conclude that the established cardiovascular benefit of nifedipine should be continued during anaesthesia.     

EFFECT OF NIFEDIPINE ON CARDIOVASCULAR RESPONSES TO LARYNGOSCOPY AND INTUBATION

The efficacy of sublingual nifedipine in attenuating the pressorresponses to laryngoscopy and intubation was studied in 40 patientsundergoing elective surgery. Anaesthesia was induced with thiopentone5.5 mg kg^–1 i.v. and tracheal intubation was facilitatedwith suxamethonium 1.5 mg kg^–1 i.v. Patients were allocatedrandomly to receive sublingual nifedipine 10 mg or placebo capsules10 min before induction. Patients receiving placebo capsuleshowed significant increases in heart rate and arterial pressureassociated with tracheal intubation (P<0.001). The increasesin arterial pressure and rate-pressure product were reducedin nifedipine treated patients (P<0.001). Heart rate increasedsignificantly in both groups immediately after intubation.     

Effects of nifedipine on intracranial pressure in neurosurgical patients with arterial hypertension

The effects of nifedipine, 20 mg administered via a nasogastric tube, on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were examined. Nifedipine was administered to treat arterial hypertension (greater than 180 mm Hg, systolic). Ten measurements were made in eight patients with cerebrovascular disease or head trauma. The mean arterial blood pressure (MABP) and ICP were measured before and for 30 minutes after the administration of nifedipine. The MABP gradually decreased and reached its lowest value at approximately 10 minutes after initiation of nifedipine administration, and thereafter remained unchanged. The MABP decreased significantly from 128 +/- 8 (mean +/- standard deviation) to 109 +/- 7 mm Hg, and the CPP decreased from 105 +/- 11 to 84 +/- 10 mm Hg. The ICP increased by 1 to 10 mm Hg in eight of 10 measurements, and the mean change of ICP from 19 +/- 7 to 22 +/- 6 mm Hg was statistically significant. These changes were not accompanied by alterations in neurological signs. The results suggest that enteral nifedipine produces a small but statistically significant increase in ICP. Accordingly, neurological signs must be closely observed to detect deterioration, which can be caused by an increase in ICP and/or a decrease in CPP.     

Intravenous nifedipine to treat hypertension after coronary artery revascularization surgery. A comparison with sodium nitroprusside.

We administered sodium nitroprusside (SNP) or nifedipine intravenously to patients who became hypertensive after elective coronary revascularization and compared their effects on hemodynamics and the electrocardiogram in a parallel, randomized, open-label study. Four of 21 patients treated with nifedipine required the addition of SNP to maintain mean arterial pressure less than 90 mm Hg, compared with 4 of 28 patients in the SNP group who required the addition of nifedipine. The success rates of nifedipine (81%) and SNP (86%) were not significantly different. There was no difference in the incidence of adverse ST-segment changes during drug infusion (4% versus 5%) or perioperative myocardial infarction (9.5% versus 10.7%) in the nifedipine versus SNP groups, respectively. The plasma nifedipine concentration (mean value +/- SD) at steady state for 21 patients receiving nifedipine was 119 +/- 42.5 ng/mL. The pharmacokinetic variables for nifedipine were as follows (mean values +/- SD): systemic clearance, 0.525 +/- 0.228 L.h-1.kg-1; apparent volume of distribution, 0.738 +/- 0.446 L/kg; and elimination half-life, 1.02 +/- 0.51 h. These values are similar to those reported previously in healthy volunteers. We conclude that intravenous nifedipine can be used safely to control hypertension after coronary revascularization but were unable to demonstrate an advantage of nifedipine compared with SNP in preventing postoperative ischemia or infarction in this group of patients who had good left ventricular function.     

Hemo- and cardiodynamic action of halothane or isoflurane following peroral long-term pretreatment with nifedipine. An animal experimental study

This study investigated the influence of chronic oral nifedipine on the hemodynamic effects of halothane or isoflurane anesthesia in dogs. Under general anesthesia with fentanyl 0.3 microgram/kg/min i.v. and 3:1 N2O/O2 inhalation mixture a left thoracotomy was performed and two needle force probes were placed in the left ventricular wall to measure myocardial force of contraction. In the halothane group (n = 12) a Hall-effect sensor was placed on the anterior surface of the left ventricle, which in combination with a magnet on the posterior surface allowed measurements of left ventricular diameter. In the isoflurane group (n = 15) a Widney gauge was placed around the left ventricle to measure left ventricular circumference changes. The dogs were also monitored with left ventricular tip manometers, pulmonary arterial thermodilution catheters, and femoral arterial and venous catheters. Prior to surgery, in the halothane group 6 dogs were pretreated with nifedipine 6 mg/kg p.o. for 10 days; the other 6 served as controls. In the isoflurane group, 8 dogs were pretreated with nifedipine in the same way and 7 served as controls. Three hours after instrumentation baseline hemodynamic measurements were performed and repeated 15 min after adding 1 MAC and then 2 MAC halothane or isoflurane. Oral pretreatment with nifedipine caused vasodilation with a significant decrease in systemic vascular resistance (SVR) and mean arterial pressure (MAP); heart rate (HR) and dp/dt max were unchanged in comparison to the control group. The cardiac output (CO) increased. Halothane (1 MAC/2 MAC) had a dose-related circulatory depressant effect. This occurred to the same extent in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nifedipine attenuates the hypertensive response to tracheal intubation in pregnancy-induced hypertension

Thirty women with pregnancy-induced hypertension (PIH) scheduled for Caesarean section under general anaesthesia were studied to evaluate the efficacy of sublingual nifedipine in attenuating the pressor response to laryngoscopy and tracheal intubation. The patients were randomly given either the contents of a nifedipine capsule 10 mg or placebo sublingually 20 min before induction of anaesthesia. Blood pressure and heart rate were recorded at various time intervals. There was a decrease in mean arterial blood pressure (MAP) after pre-treatment with nifedipine (P < 0.01). The increase in MAP during laryngoscopy and intubation was higher in the control group compared with nifedipine pretreatment group (P < 0.01). During laryngoscopy and intubation, MAP decreased by 3 mmHg in the nifedipine pretreatment group, while there was an increase of 14 mmHg in the control group. Heart rate increased in both the groups during the laryngoscopy and tracheal intubation (P < 0.01) but the increase was higher in the nifedipine group than in the control group (P <0.05). Neonatal Apgar scores in both the groups were comparable. These results suggest that sublingual nifedipine is effective in attenuating the hypertensive response to laryngoscopy and intubation but not the tachycardiac response in parturients with PIH.     

Antihypertensive action of calcium blockade in hypertensive patients with chronic renal disease

The concentration of ionic calcium (Ca2+ in the smooth muscular cells of the resistance vessels is a determining factor of their contraction. It depends on the influx of Ca2+ to the interior of the cells through the calcium channels in the sarcolemma. The effect of a specific Ca2+-channel blocking agent - nifedipine - on arterial hypertension in a group of 18 patients with chronic renal hypertension is reported in this study. The combination of nifedipine and propranolol in the control of hypertension in 6 of these patients in a long-term follow-up was also studied. It was concluded: (1) Ca2+ blockade had a rapid and powerful antihypertensive effect in all patients; (2) the antihypertensive effect was higher with high initial blood pressure levels; this fact was especially evident and appeared particularly useful in hypertensive emergencies; (3) in some patients, the action of nifedipine was dose-dependent; (4) nifedipine had a short-lived action; (5) the combination nifedipine-propranolol was efficient in the long-term control of hypertension.     

Effects of nifedipine of pial arteriolar calibre: an in vivo study

In cats the response of individual pial arterioles to perivascular microapplication of the Ca++-antagonistic drug nifedipine was studied using the image-splitting technique developed by Baez. It has previously been shown that the coefficient of variation for repeated measurements of pial vessel diameter using this system is 1%, under conditions of steady arterial pressure and blood gas tensions. All investigated pial arterioles invariably responded with a dilatation at an injected nifedipine concentration of 10 microM. The dilatatory response was inversely proportional to the resting vessel calibre, i.e., arterioles less tham 70 microns responded with a significantly stronger dilatation as compared with arterioles greater than 100 microns in diameter. In experiments where a minor subarachnoid hemorrhage was made by the injection micropipette injuring capillaries just before the perivascular microapplication of nifedipine, a dilatatory response invariably ensued in spite of the perivascular blood which in itself constricted the arterioles under examination.     

The effect of antihypertensive drugs on the anaesthetic effect of lidocaine in hypertensive patients who need dental treatment

The study evaluated the influence of atenolol/nifedipine on the local anaesthesia with lidocaine in 64 patients with essential arterial hypertension following dietetic regimen and divided in: control group (21 patients), atenolol-treated group (21 patients with atenolol therapy) and nifedipine-treated group (22 patients with nifedipine therapy). Atenolol/nifedipine was administrated three hours before anaesthesia (1.5 mg lidocaine/kg body weight) applied on Spix Spina. The atenolol/nifedipine influence on the anaesthetic intensity was evaluated both by the patient and dentist using scales for the appreciation of pain intensity (Visual Analogue Scale, Numerical Rating Scale) at 0 minutes (before anaesthesia), 5, 10, 20, 30, 60 minutes (moments for the determination of lidocaine plasmatic concentrations). There were no statistically significant differences between the values appreciated by the patient and dentist. Our data demonstrated a significant decrease of pain intensity in patients treated with atenolol/nifedipine. Very good inverse correlation was found between lidocaine concentrations and pain intensity.     

Hemodynamic effects of intranasal nifedipine during clamping of the abdominal aorta

The haemodynamic changes due to cross-clamping of the abdominal aorta below the renal arteries were studied in ten patients. Anaesthesia was induced with thiopentone and maintained with fentanyl and vecuronium and inhalation of 60% nitrous oxide in oxygen. At the fifth minute, clamping increased mean arterial pressure (Pa) by 11%, systemic vascular resistance (Rsa) by 26% and decreased cardiac output (CO) by 20%. Nifedipine was administered intranasally at this time. Heart rate remained unchanged; mean pulmonary arterial and mean pulmonary wedge pressures were slightly decreased. Pa and Rsa fell to significantly lower levels between the fifth and fifteenth minutes (24 and 43% respectively). Although CO increased by 28%, this was not significant. The administration of intranasal nifedipine during anaesthesia was well tolerated. This study demonstrated that intranasal nifedipine prevented adverse haemodynamic effects of cross-clamping of the aorta below the renal arteries.     

The effects of calcium channel blockers on random skin flap survival in the pig model

Summary This study was designed to evaluate the influence of two calcium channel blockers, verapamil and nifedipine, on skin flap survival. These agents were selected because they inhibit the passage of calcium through calcium selective channels in the plasma membrane, thereby blocking calcium mediated electromechanical coupling in contractile tissue and resulting in peripheral arterial vasodilation. Three groups of pigs were used in this study. All skin flaps in this study were 3 cm wide and 12 cm long. The first group (10 flaps) served as controls with no pharmacologic manipulations. Pigs in group II (15 flaps) received verapamil (80 mg orally, three times a day) for 7 days postoperatively. Pigs in group III (15 flaps) received nifedipine (10 mg orally, three times a day) for 7 days postoperatively. Statistical analysis of the results demonstrated that both verapamil and nifedipine resulted in significant enhancement of skin flap survival. The increased survival of the skin flaps produced by nifedipine as compared to verapamil was statistically significant.This study is supported in part by PHS Research Grant DE00853 from the National Institute of Dental Research     

Cardiovascular responses to acute loading with nifedipine alone and nifedipine plus propranolol during inhalation anesthesia in monkeys

The cardiovascular effects of the administration of nifedipine and nifedipine combined with propranolol were examined in 15 monkeys during 0.75 and 1.25 MAC of anesthesia with isoflurane, enflurane, or halothane. Hemodynamic variables measured included heart rate (HR), mean arterial pressure (MAP), left ventricular end-diastolic pressure (LVEDP), maximum rate of increase of the Left ventricular pressure (max LV dP/dt), and thermodilution cardiac output (CO). The infusion of nifedipine at a rate adequate to produce therapeutic blood levels during 0.75 MAC with each anesthetic decreased MAP and SVR, but had no effect on cardiac index (CI), max LV dP/dt, or HR. Increasing the anesthetic concentration from 0.75 to 1.25 MAC during nifedipine administration decreased HR and MAP in all groups and decreased CI with halothane and enflurane, but not with isoflurane. Addition of propranolol by infusion in amounts adequate to produce 75% beta-adrenergic blockade caused a further depression of CI, max LV dP/dt, HR, and MAP. However, the hemodynamic depression was significantly greater with halothane and enflurane than with isoflurane. Intravenous administration of calcium chloride (10 mg/kg) after calcium channel and beta-adrenergic blockade only partially reversed the hemodynamic depression that occurred with all three anesthetics. It was concluded that acute loading with nifedipine with and without propranolol exerts a greater cardiovascular depressant effect during enflurane or halothane anesthesia than during isoflurane anesthesia. The myocardial depressant effects of nifedipine and propranolol myocardial depressant effects of nifedipine and propranolol may be synergistic with the depressant effects of potent inhalation anesthetics.     

Postoperative hypertension: a comparison of diltiazem, nifedipine, and nitroprusside

In previous studies, the treatment of postoperative hypertension with sodium nitroprusside induced ischemic metabolism without a decrease in coronary sinus blood flow. In contrast, the calcium antagonists diltiazem and nifedipine reduce blood pressure and may improve myocardial metabolism. A prospective randomized trial was performed in 62 patients, in whom hypertension developed (mean arterial pressure greater than 95 mm Hg) after coronary bypass procedures, to compare diltiazem (n = 22), nifedipine (n = 20), and nitroprusside (n = 20). All three agents reduced blood pressure equally (p less than 0.0001, by analysis of variance). Heart rate decreased with diltiazem (p = 0.006) but increased with nifedipine and nitroprusside (p less than 0.05). Left ventricular diastolic function (the relation between left atrial pressure and left ventricular end-diastolic volume) was not changed with the three drugs. Systolic function (the relation between systolic blood pressure and left ventricular end-systolic volume) was depressed with diltiazem (p = 0.05 by analysis of covariance) and nifedipine (p = 0.05) but not with nitroprusside. Myocardial performance (the relation between left ventricular stroke work index and end-diastolic volume) was depressed most by diltiazem (p = 0.001 by analysis of covariance), and to a lesser extent with nifedipine (p = 0.03), but not with nitroprusside. Myocardial lactate flux in response to the stress of atrial pacing decreased with nitroprusside but not with diltiazem or nifedipine (p = 0.03 by analysis of variance). Diltiazem and nifedipine are effective agents for treating postoperative hypertension after coronary artery bypass operations.     

The effect of high-dose nifedipine on renal hemodynamics of cyclosporine-treated renal allograft recipients.

Cyclosporine has been shown to reduce renal perfusion and to decrease glomerular filtration rate. Experimental studies suggest that nifedipine might reverse this renal vasoconstrictive effect of cyclosporine. We studied renal hemodynamics of 5 cyclosporine-treated renal transplant recipients before and after 2 weeks of therapy with high-dose nifedipine (up to 120 mg/day). Pretreatment GFR and renal plasma flow (RPF) were decreased. Following administration of nifedipine, RPF increased by 18% (P less than 0.01), while GFR did not change. Filtration fraction decreased by 10.5% (P less than 0.01). Mean arterial pressure declined from 111 +/- 5 to 96 +/- 3 mmHg (P less than 0.01). Renal vascular resistance dropped by 25% (P less than 0.01). Calculated postglomerular plasma flow increased by 20.5% (P less than 0.01). Urinary albumin excretion rate was unaffected. Cyclosporine whole blood levels were unchanged. The increase in RPF and in postglomerular plasma flow suggests that high-dose nifedipine might lessen cyclosporine-induced glomerular and interstitial ischemia in renal allograft recipients.     

Effect of nifedipine on arterial hypoxaemia occurring after methacholine challenge in asthma.

To investigate whether the effects of nifedipine on methacholine induced broncho-constriction could impair pulmonary gas exchange in bronchial asthma a randomised, double blind, crossover study in 13 symptom free asthmatic subjects was designed. Each patient underwent a methacholine bronchial challenge test on two separate days one week apart, after having either oral nifedipine (20 mg thrice daily) or placebo for three days. Arterial blood gases were measured before and after methacholine challenge in nine subjects. Prechallenge values of forced expiratory volume in one second (FEV1) and arterial oxygen tension (Pao2) were similar after nifedipine and after placebo. After challenge, the cumulative doses of methacholine required to produce a 20% fall in FEV1 (PD20 FEV1) were significantly larger after nifedipine (280 (SD 347)) cumulative breath units (CBU) than after placebo (120 (183) CBU; p less than 0.01). After challenge the fall in Pao2 values (17.1 (1.6) mm Hg; (2.28 (0.21) kPa)) was significantly greater than after placebo (11.7 (2.4) mm Hg; (1.56 (0.32) kPa) p less than 0.03). Our data show that although oral nifedipine significantly reduces airway reactivity in patients with mild bronchial asthma, it also adversely affects pulmonary gas exchange, resulting in a lowered postchallenge Pao2, probably because of worsening ventilation-perfusion relationships.     

Cardiovascular consequences of the concomitant administration of nifedipine and magnesium sulfate in pigs

There is concern regarding the interaction of magnesium sulfate and nifedipine used concomitantly in obstetrical patients, because both are calcium channel antagonists and may induce myocardial depression as well as peripheral vasodilatation. The objective of this study was to determine the hemodynamic consequences of concomitant administration of nifedipine and magnesium sulfate in anesthetized pigs. Twelve pigs were anesthetized with sodium pentobarbital, intubated mechanically ventilated. Following placement of invasive monitors, baseline hemodynamic measurements were made. Animals were randomized to one of two groups. Group I received nifedipine first, and then magnesium sulfate. Group II received magnesium sulfate first, and then nifedipine. Hemodynamic measurements were recorded. Hypotension was treated with calcium chloride, ephedrine and phenylephrine. Nifedipine alone (Group I) decreased peripheral vascular resistance and mean arterial pressure (MAP) (P<0.05). Magnesium sulfate alone in group II decreased the first derivative of left ventricular pressure (LVdP/dt) and increased left ventricular end-diastolic pressure (LVEDP) (P<0.05). Magnesium sulfate also decreased peripheral vascular resistance and MAP The concomitant administration of nifedipine and magnesium sulfate in both groups I and 11 led to a further decrease in myocardial contractility, as evidenced by a decrease in LVdP/dt and increase in LVEDP (P<0.05). Treatment with calcium chloride or ephedrine was only partially successful in improving myocardial contractility. Phenylephrine increased peripheral vascular resistance and MAP, but did not improve myocardial function. In conclusion, the depressive effects of nifedipine and magnesium sulfate on the cardiovascular system are potentiated when administered concomitantly.     

Nitric oxide and prostacyclin as test agents of vasoreactivity in severe precapillary pulmonary hypertension: predictive ability and consequences on haemodynamics and gas exchange

BACKGROUND: In patients with primary pulmonary hypertension who respond to vasodilators acutely, survival can be improved by the long term use of calcium channel blockers. However, testing for such a response with calcium channel blockers or prostacyclin (PGI2) may cause hypotension and adversely affect gas exchange. Nitric oxide (NO), which does not have these effects, could be a better test agent. METHODS: NO (10, 20, and 40 ppm for 15 minutes), PGI2 (1-->10 ng/kg/min), and oral nifedipine (10 mg, then 20 mg/h) were administered sequentially to 10 patients after determination of the 24 hour spontaneous variability of their pulmonary and systemic mean arterial pressures. Patients were considered responders if the mean pulmonary artery pressure or pulmonary vascular resistance decreased by 20% or more. RESULTS: Six patients (60%) responded to all three agents, and three to none of the agents. One patient responded to PGI2 only. In those who responded to vasodilators, NO had no major effect on gas exchange or systemic haemodynamics, while PGI2 and nifedipine both induced systemic hypotension (mean (SD) systemic arterial pressure 72 (14) versus 89 (19) mm Hg with PGI2 and 72 (15) versus 86 (17) mm Hg with nifedipine, p < 0.05) and hypoxaemia (PaO2 8.7 (1.4) versus 10.8 (1.0) kPa with PGI2 and 8.6 (1.4) versus 10.2 (1.5) kPa with nifedipine, p < 0.05) and increased venous admixture (28 (9) versus 14 (4)% with PGI2 and 22 (9) versus 13 (5)% with nifedipine, p < 0.05). CONCLUSIONS: NO inhalation can accurately predict a vasodilator response to nifedipine in patients with severe pulmonary hypertension without adverse effects on systemic haemodynamics and gas exchange. This absence of side effects may make it a more appropriate agent for testing the vasodilator response.