Prevention of radial artery graft vasospasm after coronary bypass

Background. Pharmacologic prophylaxis for prevention of notorious radial artery (RA) spasm is critical because of the increasingly routine use of the RA conduit during coronary bypass. Therefore, we investigated the vasodilatory effect of calcium antagonist in combination with nitroglycerin (NTG) RA segments.

Methods. We evaluated the vasodilatory effect of nifedipine alone, verapamil alone, diltiazem alone, NTG alone, and calcium antagonist in combination with in endothelin-1 (ET-1)-, angiotensin II (AII)-, 5-hydroxytryptamine (5-HT)-, and norepinephrine (NE)-precontracted human RA rings mounted in organ baths.

Results. Nifedipine (10⁻⁵ M) alone, diltiazem (10⁻⁵ M) alone, verapamil (10⁻⁵ M) alone, and NTG (10⁻⁵ M) alone showed maximum vasodilatory effect in either 10⁻⁷ M ET-1-, 10⁻⁷ M AII-, 10⁻⁵ M NE-, or 10⁻⁴ M 5-HT-precontracted RA segments. The 10⁻⁵ M NTG alone-induced vasodilation (88.5% ± 7.7%) in ET-1-precontracted segments was the highest vasodilation (ANOVA, p = 0.0008) among NTG alone-induced vasodilatory effects in RA. The relaxing effect of any of the calcium antagonists alone varied from 32.7% ± 13.2% to 76.5% ± 20.5% in RA precontracted with different vasoconstrictors. Nearly 200% vasodilation was observed with calcium antagonist in combination with NTG in AII-precontracted vessels. Nonetheless, the vasodilatory effect of calcium antagonist in combination with NTG in RA segments precontracted with different vasoconstrictors other than AII was nearly 100%.

Conclusions. A calcium antagonist in combination with NTG is more potent than calcium antagonist alone or NTG alone in prevention of human RA vasospasm after coronary bypass.     

Nitroglycerin is superior to diltiazem as a coronary bypass conduit vasodilator

BACKGROUND: Recent reports of improved radial artery patency have been attributed, in part, to routine use of diltiazem to prevent vasospasm. However, diltiazem is costly, and its use may be associated with negative inotropic and chronotropic side effects. This study compares the vasodilatory properties of diltiazem to those of nitroglycerin. METHODS: In vitro, with the use of organ chambers, the vasodilatory properties of diltiazem and nitroglycerin were compared in matched segments of radial artery, internal thoracic artery, and saphenous vein that were harvested from the same patients (n = 11). The vasodilatory response of the radial artery to intravenous diltiazem or nitroglycerin was compared in vivo (n = 10) with the use of ultrasonographic measurements of radial artery diameter. RESULTS: The maximum relaxation of radial artery (100% +/- 4%), internal thoracic artery (96% +/- 4%), and saphenous vein (100% +/- 3%) to nitroglycerin were significantly greater than the response to diltiazem (33% +/- 6%, 22% +/- 7%, and 34% +/- 5%, respectively; P <.001). The thromboxane mimetic, U46619, induced radial artery spasm with a median effective concentration of 3.7 +/- 0.8 nmol/L. Physiologic concentrations of nitroglycerin (0.1+/- micromol/L) significantly inhibited the radial artery response to U46619 (median effective concentration, 6.2 +/- 1.1 nmol/L; P =.046), whereas diltiazem (1 micromol/L) did not (median effective concentration, 3.7 +/- 0.8 nmol/L; P =.64). In vivo, nitroglycerin increased radial artery diameter 22% +/- 3%, which was significantly greater than diltiazem (3% +/- 0.5%; P =.001). CONCLUSION: Nitroglycerin is a superior conduit vasodilator and is more effective in preventing graft spasm than diltiazem. Nitroglycerin should be strongly considered as the drug of choice to prevent conduit spasm after coronary bypass grafting.     

Additive effects of calcium antagonists on cyclosporin A-induced inhibition of T-cell proliferation

The purpose of this study was to investigate possible additive effects of calcium antagonists on the cyclosporin A (CsA)-induced inhibition of cellular immunity. Human T-cells were isolated using standard methods and stimulated with phytohaemagglutinin (PHA, n = 8), the monoclonal antibody OKT3 (n = 6), or mixed lymphocyte reaction (MLR, n = 5). Verapamil, nifedipine, nimodipine or diltiazem were added (5 x 10(-7) - 5 x 10(-5) M) to the cultures, either alone, or in combination with CsA (62.5, 125, and 250 ng/ml). 3H-thymidine uptake was measured to estimate the proliferative responses and dose response curves were constructed for the Ca antagonists and their combinations with CsA. A 50% inhibition of T-cell proliferation in the different stimulation assays was achieved with 3.2 x 10(-5) - 5.3 x 10(-5) M verapamil, 2.5 x 10(-5) -4.3 x 10(-5) M nifedipine, 3.7 x 10(-6) - 5 x 10(-6) M nimodipine, and greater than 5 x 10(-5) M diltiazem. In combination with CsA a dose-dependent additive inhibitory effect of the Ca antagonists on T-cell proliferation was observed. This effect was less pronounced in the OKT3 assay, intermediate after PHA stimulation and most pronounced in MLR. Even in low concentrations, which correspond to therapeutic serum concentrations, Ca antagonists have an additive inhibitory effect in MLR. We conclude that Ca antagonists exert a dose-dependent inhibitory effect on T-cell proliferation. A combination of CsA with verapamil, nifedipine, nimodipine, or diltiazem is more effective than each drug given alone. This additive effect of Ca antagonists and CsA may possibly contribute to a better graft survival in clinical transplantation.     

Interaction between vasodilators and vasopressin in internal mammary artery and clinical significance

BACKGROUND: Arginine vasopressin (AVP) has recently been demonstrated as an alternative in the treatment of severe refractory vasodilatation in coronary artery bypass grafting. However, AVP may be a spasmogen for graft spasm. We compared the in vitro antispastic effect among calcium-channel antagonists (nifedipine, diltiazem, and verapamil), nitroglycerin, and the highly selective AVP (V1) receptor antagonist [1-deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin. METHODS: Human internal mammary artery segments (n = 218) were studied in organ baths. The inhibitory effects of the above vasodilators on AVP-mediated contraction were studied in two ways: relaxation with AVP precontraction and depression of the AVP-induced contraction after pretreatment with vasodilators. RESULTS: All three calcium-channel antagonists caused limited relaxation (18.3%+/-5.4% for nifedipine, n = 11; 22.2%+/-3.8% for verapamil, n = 10; and 26.2%+/-7.5% for diltiazem, n = 9). The plasma concentration of calcium-channel antagonists had no significant depression effect on the AVP-induced contraction. In contrast, [1-deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin caused full (100%, n = 11) and nitroglycerin caused nearly full (93%+/-3%, n = 10) relaxation. Pretreatment with [1-deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin (10(-8), 10(-7), or 10(-6) mol/L, respectively) significantly increased the effective concentration for 50% of the AVP-induced contraction (10(-8.6)+/-10(0.1) mol/L, p = 0.009; 10(-7.8)+/-10(0.07) mol/L, p = 0.000; or 10(-6.9)+/-10(0.11) mol/L, p = 0.000 versus the control, 10(-9.24)+/-10(0.16) mol/L). However, nitroglycerin only slightly depressed the AVP-induced contraction. CONCLUSIONS: [1-Deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin may provide specific antispastic effect in either prophylaxis or treatment of the AVP-related vasospasm in the internal mammary artery. Nitroglycerin may be effective in treatment but has little effect on prophylaxis. Use of calcium-channel antagonists may have little benefit in AVP-related vasospasm.     

Hirudin (desulfated, 54-65) contracts canine coronary arteries: extracellular calcium influx mediates hirudin-induced contractions

OBJECTIVE: Although the anticoagulatory properties of hirudin are well known, its direct vasoactive effects have not been investigated extensively. Hirudin stimulates nitric oxide and prostacyclin production in noncoronary vascular beds, but its actions on coronary arteries are unknown. MATERIALS AND METHODS: Five-millimeter segments of canine left circumflex coronary arteries were obtained for organ chamber experiments. Some segments were denuded of endothelium before study. Segments were exposed to hirudin (10(-10)-10(-6) mol/L) following precontraction with prostaglandin F(2alpha) with or without pretreatment with indomethacin or calcium channel blockers (verapamil and nifedipine). RESULTS: Hirudin stimulated endothelium-independent contraction in coronary arterial segments. Maximum tension (hirudin 10(-6) mol/L) above precontraction baseline was 33.6 +/- 9.0% (n = 10, P < 0.05) for endothelium-intact and 31.8 +/- 11.5% (n = 8, P < 0.05) for endothelium-denuded arterial segments. Differences between endothelium-intact and endothelium-denuded segments were not significant. Contractile responses to hirudin were unaffected by the presence of indomethacin. Pretreatment with either verapamil or nifedipine (10(-4) mol/L) for 1 h attenuated these contractions. The maximal increase in tension above baseline (hirudin 10(-6) mol/L) for verapamil and nifedipine was only 6.2 +/- 12.4 and 3.8 +/- 7.0% (n = 6, P < 0.05 versus endothelium-intact control), respectively. CONCLUSIONS: Hirudin stimulates endothelium-independent contractions of canine coronary arteries in vitro. Pretreatment with calcium channel blockers attenuates this response, suggesting that extracellular influx of calcium has an important mechanistic role in hirudin-mediated coronary artery constriction.     

Combined negative inotropic effects of calcium entry blockers and isoflurane on canine isolated heart muscles

The combined negative inotropic effects of isoflurane and calcium entry blockers (verapamil, diltiazem, nifedipine, nicardipine) were studied utilizing isolated heart preparations of ventricular muscles from dogs. All of these calcium entry blockers exerted dose-dependent decreases in maximal velocity of shortening (Vmax), maximal developed isometric force (Fm), and the maximal first derivative of Fm (maximal dF/dt). Dose-dependent decreases of these variables of muscle mechanics were augmented in isoflurane-depressed myocardium. At equimolar concentrations, direct myocardial depression was demonstrated in the following order of severity: nifedipine > diltiazem = verapamil > nicardipine. Percent depressions of Vmax, Fm and maximal dF/dt were significantly greater in muscles when calcium entry blockers were combined with 1MAC isoflurane than in muscles of calcium entry blockers alone. These data suggest that the negative inotropic effects of verapamil, diltiazem, nifedipine, and nicardipine were potentiated by isoflurane.(Nakata F, Kemmotsu O: Combined negative inotropic effects of calcium entry blockers and isoflurane on canine isolated heart muscles. J Anesth 5: 48–55, 1991)     

Contractile effects of arginine analogues on human internal thoracic and radial arteries

OBJECTIVES: Plasma levels of endogenous guanidino-substituted analogues of L -arginine are increased in various pathologic conditions. In the present study we determined the effects of some of these compounds on basal and stimulated release of nitric oxide in human internal thoracic and radial arteries. METHODS: Rings of human internal thoracic and radial arteries were obtained from 16 multiorgan donors. The rings were suspended in organ baths for isometric recording of tension. RESULTS: N(G)-monomethyl L -arginine (10(-6) to 10(-3) mol/L) and N(G),N(G)-dimethyl L -arginine (10(-6) to 10(-3) mol/L) caused concentration- and endothelium-dependent contractions. Maximal force of contractions for N(G)-monomethyl L -arginine and N(G),N(G)-dimethyl L -arginine in the internal thoracic artery were 18.0% +/- 4.3% and 17.8% +/- 3.8%, respectively, of the contraction to 100 mmol/L KCl, and those found in the radial artery were 9.6% +/- 2.5% and 9.1% +/- 2.4%, respectively. Aminoguanidine (10(-5) to 3 x 10(-3) mol/L) and methylguanidine (10(-5) to 3 x 10(-3) mol/L) produced endothelium-independent contractions. L -Arginine (10(-3) mol/L) prevented the contractions by N(G)-monomethyl L -arginine and N(G),N(G)-dimethyl L -arginine but did not change contractions induced by aminoguanidine and methylguanidine. N(G)-monomethyl L -arginine and N(G),N(G)-dimethyl L -arginine inhibited, in a concentration-dependent manner, the endothelium-dependent relaxation to acetylcholine in the internal thoracic artery and had little attenuating effect in the radial artery; aminoguanidine and methylguanidine were without effect. CONCLUSIONS: The results suggest that the contractions induced by N(G)-monomethyl L -arginine and N(G),N(G)-dimethyl L -arginine are due to inhibition of both basal and stimulated nitric oxide production, whereas aminoguanidine and methylguanidine do not affect the synthesis of nitric oxide. An increase in the plasma concentration of N(G)-monomethyl L -arginine and N(G),N(G)-dimethyl L -arginine is likely to represent a risk factor for abnormal vasomotor tone in conduit arteries used as coronary grafts.     

Potentiation of local lignocaine-induced sensory block by calcium channel blockers in rats

We have studied the effects of three different types of calcium channel blockers (verapamil, diltiazem, and nicardipine) on local lignocaine sensory block. The standardized tail flick test was used to measure the duration and degree of lignocaine-induced conduction block in rats. After obtaining baseline tail flick latencies (mean 3.2 s), two 100- microliter doses of 0.3% lignocaine alone, a combination of verapamil 25, 100 or 200 micrograms, diltiazem 25, 100 or 200 micrograms, or nicardipine 0.5, 1.0 or 2.0 micrograms, and a large dose of calcium channel blockers (verapamil 200 micrograms, diltiazem 200 micrograms or nicardipine 2.0 micrograms) were injected on opposite sites of the tail base and the tail flick test was performed every 5 min for 45 min. A large dose of the calcium channel blockers showed no prolongation of tail flick latencies. Administration of 0.3% lignocaine alone produced a significant increase in tail flick thresholds and the peak effect of the percentage maximum possible effect (% MPE) was demonstrated at 5 min after drug injection (mean % MPE 28.8%; P < 0.01 vs baseline). Co- administration of 0.3% lignocaine and three doses of verapamil produced significant increases in area under the curve (AUC) in a dose-dependent fashion. Mean AUC values for 0.3% lignocaine alone and a combination of verapamil 25, 100 or 200 micrograms were 217.5, 502.5, 529.1 and 1600.3, respectively. Almost similar patterns of augmentation in AUC values were demonstrated after addition of different doses of diltiazem or nicardipine to 0.3% lignocaine. We conclude that the use of mixtures of local anaesthetic and calcium channel blocker potentiated lignocaine sensory block at the level of the peripheral nerves.      

不同血管保存液对人桡动脉血管移植物的抗痉挛作用

目的 研究不同的血管保存液对人离体桡动脉痉挛的缓解与预防能力。方法 非体外循环冠状动脉旁路手术(OPCAB)19例患者,应用“无接触(No Touch)”外科技术获取自体桡动脉,保留未处理的远段0.8～1.5cm。应用血管环灌流技术(Organ Bath)比较不同保存液的抗痉挛作用和预防痉挛作用。结果 血管环灌流实验显示,在对痉挛状态桡动脉的舒张能力方面,PS、VG、DG、NG溶液均可以在10min内100％舒张血管,舒张曲线显示舒张能力依次为VG、DG、NG、PS,但差异无显著性(P>0.05),在预先浸泡处理桡动脉45～60min后,除对照组(Ringer's Solution)外,所有血管保存液均可以有效地预防离体桡动脉的痉挛,各组间差异无显著性(P>0.05)。结论 罂粟碱溶液、VG、DG、NG溶液均有较好的抗血管痉挛作用,单从抗血管痉挛角度考虑可以用作CABG手术中桡动脉的准备液。     

Effects of cerivastatin on vascular function of human radial and left internal thoracic arteries

Background. Statins may enhance vascular function independently of effects on cholesterol. This study investigated the ability of statins to modulate the vascular recovery of arteries used as coronary bypass grafts.

Methods. Specimens of radial artery and left internal thoracic artery were obtained during coronary artery bypass grafting. The specimens were divided into vascular rings, which were incubated in the absence or presence of cerivastatin (10⁻⁶ mol/L) for either 2 or 24 hours. Using an organ bath technique, endothelial function was examined using acetylcholine (10⁻⁹ to 10⁻⁵ mol/L) after contraction by 3×10⁻⁸ mol/L of endothelin-1.

Results. Time-related endothelial dysfunction was shown in the control group of radial artery but not in the cerivastatin group: maximal endothelium-dependent vasodilation in the control and cerivastatin groups were 56.8% ± 10.2% and 65.9% ± 10.1% at 2 hours and 39.4% ± 4.7% and 68.4% ± 5.0% (p < 0.01, vs control) at 24 hours, respectively. On the other hand, in the left internal thoracic artery, those in the control and cerivastatin groups were 38.3% ± 8.2% and 45.0% ± 5.5% at 2 hours and 38.1% ± 8.2% and 56.5% ± 8.8% at 24 hours, respectively (NS).

Conclusions. In radial artery, cerivastatin significantly preserved endothelium-dependent vasodilation, which diminished with time in the control group. This could have very important implications in the clinical practice of coronary artery bypass grafting.     

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%.     

Calcium channel blockade in smooth muscle of the human upper urinary tract. I. Effects on depolarization-induced activation

The effects of the calcium blockers nifedipine, verapamil, D600 and diltiazem on mechanical activity were studied in isolated preparations of the human upper urinary tract. Two types of activity were used: spontaneous phasic-rhythmic activity in calyceal segments and potassium-induced depolarization in ureteral muscle strips. Nifedipine (10(-6) mol./l.), verapamil, D600 and diltiazem (all 10(-5) mol./l.) completely suppressed spontaneous phasic-rhythmic activity. Elevation of extracellular potassium concentration induced contractions concentration-dependently. A log-linear relationship between the extracellular calcium concentration and the 85 mmol./l. potassium-induced activation was demonstrated. Concentration-response relationships of the compounds were found by activating the muscle strips with 85 mmol./l. potassium in the Tyrode solution. This activation model produced stable and reproducible contractures. The compounds antagonized depolarization-induced activations concentration-dependently, nifedipine being the drug with the lowest EC50 value; its relative potency with reference to papaverine was about 8,000 to 1. The order of potency of the other drugs was in the following sequence: D600 greater than verapamil greater than diltiazem. It is concluded that processes in the human upper urinary tract which are triggered by depolarization (action potential or high potassium concentrations) are highly sensitive to calcium channel blockers.     

Effects of calcium antagonists on intracerebral penetrating arterioles in rats

There is no direct information on the effect of calcium antagonists on intracerebral penetrating arterioles, which are responsible for a significant part of total cerebrovascular resistance. In a study on rats, the effects of four calcium antagonists (diltiazem, verapamil, nifedipine, and nimodipine) on isolated intracerebral penetrating arterioles with mean resting diameters (+/- standard error of the mean) of 52.3 +/- 3.0 micron were investigated. Vessel diameters were monitored in vitro by means of a video microscope dimensional analyzer under constant transmural pressure (60 mm Hg) after cannulation. Each calcium antagonist produced maximal dilation of about 50% (diltiazem 46.4% +/- 5.6%, verapamil 53.1% +/- 6.0%, nifedipine 46.9% +/- 6.1%, and nimodipine 47.1% +/- 5.4%) with varied sensitivity (median effective dose (ED50): diltiazem 1.52 X 10(-6) M, verapamil 1.08 X 10(-7) M, nifedipine 8.65 X 10(-9) M, and nimodipine 1.62 X 10(-9) M). Dilation effects persisted for a significantly longer time after washout with calcium antagonists such as diltiazem (15.5 +/- 1.8 minutes), nifedipine (19.0 +/- 3.9 minutes), and nimodipine (30.0 +/- 1.6 minutes) than after washout with adenosine (8.5 +/- 1.0 minutes). It appeared that the magnitude of vasodilation was greater and the duration of dilation after washout longer in intracerebral penetrating arterioles than that reported for pial arterioles, although sensitivity to each calcium antagonist was quite similar to that reported for larger cerebral arteries. These data provide a possible explanation for the apparent disparity between clinical efficacy and angiographically determined vessel diameter when patients with cerebral vasospasm are treated with calcium antagonists. These agents may have a greater effect on intracerebral penetrating arterioles than on angiographically visible larger arteries.     

Radial artery patency and clinical outcomes: five-year interim results of a randomized trial

OBJECTIVE: This study was undertaken to compare elective angiographic patency and cardiac event-free survival of the radial artery graft with that of the free right internal thoracic artery or saphenous vein during a 10-year period after primary coronary artery bypass surgery. METHODS: This prospective, randomized, single-center trial was conducted on two groups of patients undergoing primary coronary artery bypass surgery. In a younger group (group 1, n = 285, <70 years), the radial artery was compared with the free right internal thoracic artery. In an older group (group 2, n = 153, >/=70 years), the radial artery was compared with the saphenous vein. The trial conduit was grafted to the largest available coronary artery other than the left anterior descending coronary artery. Angiography was scheduled at intervals between 0 and 10 years according to a second random assignment. Patients were followed up at yearly intervals to assess clinical outcomes. Clinical outcomes were analyzed on an intent-to-treat basis during the 10-year follow-up with time-related analyses. This interim study reports angiographic and clinical outcome results during the first 5 years. RESULTS: Graft patency estimates were as follows: 0.95 (95% confidence interval 0.85-0.99) in 39 radial arteries versus 1.0 in 29 right internal thoracic arteries (P =.4) in group 1, and 0.86 (95% confidence interval 0.67-0.99) in 24 radial arteries versus 0.95 (95% confidence interval 0.83-0.99) in 22 saphenous veins (P =.5) in group 2. Cardiac event-free survival estimates were as follows: 0.91 (95% confidence interval 0.76-0.99) for the radial artery versus 0.82 (95% confidence interval 0.63-0.99) for the right internal thoracic artery (P =.7) in group 1, and 0.84 (95% confidence interval 0.64-0.99) for the radial artery versus 0.89 (95% confidence interval 0.72-0.99) for the saphenous vein (P =.9) in group 2. CONCLUSION: The 5-year interim results do not support the hypothesis that the radial artery has superior patency to or is associated with fewer clinical events than free right internal thoracic artery or saphenous vein grafts.     

Right vagal nerve stimulation for coronary anastomosis without cardiopulmonary bypass: investigation in dogs

BACKGROUND: The purpose of this study is to assess the potential of right vagal nerve stimulation for reducing the heart rate during coronary anastomosis without cardiopulmonary bypass. METHODS: Through the fourth left intercostal space, left internal thoracic artery grafts were sutured to the left anterior descending artery with the heart beating. In Group I (n=7), two dogs underwent right cervical vagal stimulation alone and five dogs underwent right cervical vagal stimulation during intravenous infusion of diltiazem or verapamil. In Group II (n=3), one dog underwent right thoracic vagal stimulation alone and two dogs underwent right thoracic vagal stimulation during intravenous infusion of diltiazem or verapamil. The thoracic vagal nerve was isolated endoscopically. The electrocardiogram and aortic pressure were monitored during interventions. RESULTS: In Group I, cervical vagal stimulation reduced the heart rate from 190 to 45 and 180 to 42 b/min. During intravenous infusion of diltiazem or verapamil, cervical vagal stimulation caused ventricular arrest. In Group II, thoracic vagal stimulation decreased the heart rate from 205 to 70 b/min, and stimulation during intravenous infusion of diltiazem caused ventricular arrest. CONCLUSIONS: Right vagal stimulation during intravenous infusion of diltiazem or verapamil has potential value as a technique for reducing the heart rate during coronary anastomosis without cardiopulmonary bypass.     

Reperfusion-induced arrhythmias in the conscious rat: a comparative study with three calcium antagonists

The effects of three calcium antagonists (diltiazem, verapamil, and nifedipine) on reperfusion-induced arrhythmias were compared in a conscious rat preparation with coronary artery occlusion and implanted electrocardiogram limb electrodes. Upon reperfusion after a 5-min period of occlusion, all (15/15) untreated control rats exhibited immediate ventricular tachycardia, which rapidly deteriorated to ventricular fibrillation; 87% (13/15) of the rats died as a consequence of these rhythm disturbances. In the groups treated with calcium antagonists, each drug (diltiazem, verapamil, or nifedipine) was given as an intravenous bolus 10 min prior to coronary occlusion (n = 12 in each group). The incidence of ventricular fibrillation was significantly reduced by all three calcium antagonists and this antifibrillatory effect resulted in a significantly lower mortality in all drug-treated groups. With diltiazem (0.5 and 2.0 mg/kg) mortality fell from 87 to 42% (P less than 0.05) and 35% (P less than 0.01), respectively; with verapamil (0.5 and 5.0 mg/kg) it fell to 25% (P less than 0.01) and 0% (P less than 0.001); and with nifedipine (5.0 and 50 micrograms/kg), it fell to 25% (P less than 0.01) and 8% (P less than 0.001). At a dose of 5.0 mg/kg, verapamil caused a large reduction in heart rate both prior to and during coronary occlusion and reperfusion; however, with other doses and drugs no significant changes in heart rate were observed. ST segment elevation during the 5-min ischemic period was reduced by pretreatment with all drugs. In conclusion, in the conscious rat, pretreatment with diltiazem, verapamil, or nifedipine affords some protection against reperfusion-induced arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exogenous hyaluronidase induces release of nitric oxide from the coronary endothelium

OBJECTIVE: Hyaluronidase, an endogenous enzyme that hydrolyzes mucopolysaccharides, has been shown to enhance myocardial protection when added to preservation solutions. In addition, hyaluronidase infusion reduces injury to ischemic myocardium. Endothelium-derived nitric oxide is an endogenous vasodilator that prevents leukocyte adhesion to the intima and inhibits platelet adhesion and aggregation in the coronary artery. Experiments were undertaken to determine whether the protective action of hyaluronidase could be mediated by the endogenous release of nitric oxide. METHODS: Segments of coronary artery, with and without endothelium, were placed in organ chambers (25 mL) to measure isometric force. Blood vessel segments were contracted with prostaglandin F(2)(alpha) (2 x 10(-6) mol/L) and exposed to hyaluronidase (3-15 units). RESULTS: Hyaluronidase induced vasodilation of arteries with intact endothelium but not of arteries without endothelium (n = 6, P<.05). Endothelium-dependent vasodilation to hyaluronidase was blocked by N(G)-monomethyl-L -arginine (10(-5) mol/L), an inhibitor of nitric oxide synthesis from L -arginine (n = 6, P<.05). Inhibition of vasodilation by N(G)-monomethyl-L -arginine was reversed by L -arginine (10(-4) mol/L) but not D -arginine (10(-4) mol/L; n = 6, each group). Vasodilation to hyaluronidase also was inhibited by hemoglobin (2 x 10(-6) mol/L), a scavenger of the nitric oxide radical (n = 6, P<.05). CONCLUSIONS: Hyaluronidase induces the release of nitric oxide from the coronary endothelium. Because nitric oxide, an endogenous vasodilator, inhibits leukocyte adhesion to the intima in addition to inhibiting platelet adhesion and aggregation, stimulated production of endothelium-derived nitric oxide by exogenous hyaluronidase could be the mechanism of the protective action of hyaluronidase infusion.     

Effects of bupivacaine and calcium antagonists on human uterine arteries in pregnant and non-pregnant women

Bupivacaine is a local anesthetic commonly used in obstetrical practice. Although not generally constrictive, it has a constricting effect on blood vessels in clinically used doses, and when administered close to the uterine vasculature, as in a paracervical blockade, it can induce severe fetal bradycardia and thus be hazardous to the fetus. The bupivacaine-induced vasoconstriction on uterine arteries from pregnant and non-pregnant women was effectively reduced by two different calcium antagonists, verapamil and nifedipine. In non-pregnant women, nifedipine (2.9 x 10(-7) mol.l-1) administered simultaneously with bupivacaine (5.8 x 10(-4) mol.l-1) caused a 96% and verapamil (10(-5) mol.l-1) an 84% reduction as compared with the control vessel where only bupivacaine (5.8 x 10(-4) mol.l-1) was administered. In pregnant women, nifedipine 2.9 x 10(-7) mol.l-1 and 2.9 x 10(-6) mol.l-1 produced 66% and 79% reductions, respectively. It is possible that calcium antagonists administered together with bupivacaine in paracervical blockade could reduce the risk of fetal bradycardia.     

Heart rate and blood pressure power spectral analysis during calcium channel blocker induced hypotension

PURPOSE: To observe heart rate (HRV) and blood pressure variability (BPV) as indices of neurocirculatory responses to induced hypotension with diltiazem and/or nicardipine for hip surgery. METHODS: Thirty-six ASA I-II patients received diltiazem (group D, n = 12), nicardipine (group N, n = 12) or combination of diltiazem/nicardipine (group DN, n = 12). The intensity of HRV and BPV, was determined by spectral analysis of HRV and BPV before anesthesia (T0), just before induced hypotension (T1), and at 10 and 30 min after the start of induced hypotension (T2 and T3, respectively). The logarithmic HRV and BPV were integrated: sympathetic and parasympathetic mediated low frequency area (0.06-0.1 Hz, LF), parasympathetic related high frequency area (0.15-0.4 Hz, HF) and total frequency area (0.01-0.4 Hz). Blood loss was assessed by weighing gauzes and measuring suction. RESULTS: Group DN had less blood loss (466 +/- 46 ml, mean +/- SEM) than group D (733 +/- 100 ml, P < 0.05). Diltiazem (11.4 +/- 0.9 microg x kg(-1) x min(-1)), and combination of diltiazem (0.25 +/- 0.01 mg x kg(-1)) and nicardipine (5.9 +/- 0.9 microg x kg(-1) x min(-1)) decreased LF-HRV at T2 and T3 (P < 0.05 vs T0 and T1), while nicardipine (8.1 +/- 0.8 microg x kg(-1) x min(-1)) showed increase in LF-HRV at T2 (P < 0.05 vs T1). HF-HRV unchanged through hypotension except for a decrease in group N at T3 (P < 0.05 vs T1). There were no increases in HF-BPV, and LF-BPV, except for a diltiazem induced decrease in LF-BPV at T3 (P < 0.05 vs T0 and T1). CONCLUSION: Group D and group DN can be used for deliberate hypotension without an increase in sympathetically mediated LF-HRV.     

The effect of ambient temperature on papaverine-induced relaxations in canine saphenous veins.

This study was designed to measure the effect of ambient temperature (25 degrees C) on papaverine-induced relaxations in canine saphenous veins. Segments of vein were suspended in water-jacketed tissue baths at 37 degrees C, and isometric tension was recorded. After equilibration, veins were preconstricted by a median effective dose of norepinephrine 2 x 10(-6) mol/L at either 25 degrees C or 37 degrees C. Consequent dose-dependent relaxations showed that papaverine (10(-7) to 10(-3) mol/L was three times more potent as a dilator at 37 degrees C than at 25 degrees C, with half-maximal relaxations occurring at 2.2 x 10(-5) mol/L and 6.4 x 10(-5) mol/L, respectively. A 10(-4) mol/L dose of papaverine completely relaxed veins at 37 degrees C, whereas veins at 25 degrees C never fully relaxed even at ten times the standard concentration. In addition, the time for half-maximal relaxation with a 10(-4) mol/L dose of papaverine averaged 40 minutes at 25 degrees C compared with 22 minutes at 37 degrees C; this is indicative of a reduced relaxation rate at the lower temperature. These data show that papaverine is a slower and less potent dilator of canine saphenous veins at 25 degrees C than at 37 degrees C. This may have implications for the use of papaverine in the operating room, where it is usually applied at ambient temperature to reduce vasospasm of the saphenous vein during coronary artery bypass procedures.