Effects of stretch or distention on phenylephrine-induced constriction of human coronary artery bypass grafts.

OBJECTIVE: To determine the effects of grafting saphenous veins into the arterial circulation and to compare the responsiveness of saphenous veins and mammary arteries to vasoconstrictors (phenylephrine or potassium) and a vasodilator (the calcium antagonist isradipine). DESIGN: Prospective, controlled, in vitro study. SETTING: Laboratory facility in a university teaching hospital. PARTICIPANTS: Small excess segments of internal mammary arteries or saphenous veins obtained from patients undergoing coronary artery bypass graft surgery. INTERVENTIONS: Vessel segments were cut into rings to measure isometric tension development in isolated tissue chambers. The law of LaPlace for a cylinder was applied to determine tensions in vitro corresponding with arterial or venous tensions in vivo or distending pressures ex vivo. MEASUREMENTS AND MAIN RESULTS: Stretching saphenous vein rings from venous to arterial tensions reduced maximal phenylephrine-induced constriction but did not alter their dose response to phenylephrine, potassium, or isradipine. At arterial tensions, potassium, but not phenylephrine, was more potent in constricting mammary artery than saphenous vein; isradipine was more potent as a vasodilator of potassium-constricted mammary artery than saphenous vein. Maximal phenylephrine-induced or potassium-induced constriction was no different for either vessel at arterial tensions; however, prior distention of veins to tensions corresponding with pressures of 200 or 300 mmHg significantly (p < 0.01, Dunnett's test) reduced subsequent constriction. CONCLUSION: Phenylephrine may be more likely to constrict native internal mammary arteries than distended autogenous saphenous vein grafts in vivo because high-pressure distention of veins markedly inhibits their vasoreactivity.

Vascular effects of etomidate administered for electroencephalographic burst suppression in humans.

Although its status as a neuroprotectant is controversial, etomidate is often employed for pharmacologic cerebral protection in aneurysm surgery. One purported advantage of etomidate over thiopental is its hemodynamic stability. This study examined the cardiovascular effects of etomidate given for electroencephalographic (EEG) burst suppression during cerebral aneurysm clipping in humans and the direct effects of etomidate on arteries in vitro. The charts of intracranial aneurysm surgery patients were retrospectively reviewed to determine the dose of etomidate employed, the frequency of concurrent vaspressor administration, and whether hemodynamic changes were associated with etomidate use. Against a background of balanced anesthesia, the dose of etomidate to induce burst suppression was 0.73 +/- 0.49 mg/kg (mean +/- SD) and the maintenance dose was 48 +/- 30 microg/kg/min. Etomidate produced an immediate decrease in mean arterial pressure that was sustained in patients who did not receive vasopressor support. During etomidate administration, 48% of patients (10 of 21) received some form of vasopressor support such as phenylephrine or ephedrine, and 62% of patients (13 of 21) receiving isoflurane had the anesthetic discontinued or its inspired concentration decreased. Etomidate in vitro produced dose-dependent relaxation of human internal mammary arterial rings that had been preconstricted by potassium or norepinephrine. Etomidate, in EEG burst suppression doses, decreases mean arterial pressure in anesthetized patients undergoing cerebral aneurysm surgery. One mechanism of etomidate-induced hypotension may be direct relaxation of vascular smooth muscle, because etomidate directly dilates preconstricted human arteries in vitro.

Direct effects of triiodothyronine on human internal mammary artery and saphenous veins.

OBJECTIVE: Thyroid hormone (3,5,3'-triiodo-L-thyronine is under investigation as a positive inotrope and vasodilator for patients undergoing cardiac surgery. This study determined the direct effects of triiodothyronine on human blood vessels. DESIGN: Prospective, controlled, in vitro study. SETTING: Laboratory facility in a university teaching hospital. PARTICIPANTS: Small excess segments of internal mammary arteries or saphenous veins were obtained from patients undergoing coronary artery bypass surgery. INTERVENTIONS: Vessel segments were cut into rings to measure isometric tension development in isolated tissue baths containing Krebs-Ringer bicarbonate solution at 37 degrees C. Rings were prestretched in vitro to resting tensions analogous to mean arterial or central venous pressures in vivo and then constricted with potassium or phenylephrine. Rings were exposed to increasing concentrations of triiodothyronine (4 x 10(-12) to 1 x 10(-4) mol/L) to obtain dose-response curves. MEASUREMENTS AND MAIN RESULTS: High concentrations (> or = 3.3 x 10(-5) mol/L) of trilodothyronine produced dose-dependent relaxation of preconstricted rings. The relaxation was not selective for arteries or veins at arterial resting tensions, and with either potassium or phenylephrine as a vasoconstrictor. Propranolol had little effect on subsequent triiodothyronine-induced relaxation of potassium-constricted rings at resting arterial tensions. CONCLUSIONS: Triiodothyronine, in supraphysiological and suprapharmacological concentrations, dilates preconstricted rings of human blood vessels in vitro; however, triiodothyronine had no demonstrable vasomotor effects on human internal mammary artery or saphenous vein in clinically relevant concentrations (10(-9) to 10(-8) mol/L). Triiodothyronine administration in vivo most likely has little direct effect on the tone of human vascular smooth muscle, particularly coronary artery bypass conduits.

Intravenous vitamin K1 prior to orthotopic heart transplantation: effects in vivo and in vitro.

BACKGROUND: Vitamin K1 is used to reverse warfarin's anticoagulant action. It is unclear whether intravenous vitamin K1 is safe or efficacious prior to urgent cardiac surgery. METHODS: We retrospectively and prospectively examined the effects of preoperative intravenous vitamin K1 in vivo (administered for warfarin reversal immediately before heart transplantation) on intraoperative blood product utilization, hemodynamics and coagulation parameters. We also determined the direct effects of vitamin K1 in vitro on rings of human saphenous vein and internal mammary artery. RESULTS: In the retrospective limb, 29 of 67 patients were administered vitamin K1 preoperatively via slow intravenous infusion. Vitamin K1 administration produced no adverse outcome but did not affect subsequent perioperative use of blood products. In the prospective limb (n = 10), vitamin K1 significantly (P < or = 0.01, Student t-test) altered mean arterial pressure (from 85 +/- 15 to 76 +/- 16 mmHg), systemic vascular resistance (from 1364 +/- 308 to 1078 +/- 252 dyn.s.cm-5), and cardiac index (from 2.3 +/- 0.3 to 2.7 +/- 0.3 L/min/m2) (mean +/- SD). Significant decreases in prothrombin time (19.8 +/- 2.7 to 17.7 +/- 1.8 s) and activated clotting time (164 +/- 26 to 137 +/- 24 s) were observed at 60 min. In vitro vitamin K1 (10(-7) to 10(-4) M) had no effect on the tone of noradrenaline-constricted rings. CONCLUSIONS: Vitamin K1, administered by intravenous infusion prior to heart transplantation, did not alter subsequent perioperative blood product administration. Vitamin K1 rapidly reversed the anticoagulant effect of warfarin and produced modest hemodynamic changes. The decrease in systemic vascular resistance is probably not due to a direct effect of vitamin K1 on vascular smooth muscle.

Porcine gastroepiploic artery as an in vitro experimental model to study vasodilators in microsurgery.

Arterial vasospasm is a common problem in microsurgery. This pharmacological study compares seven vasodilators-lidocaine, papaverine, nicardipine, verapamil, diltiazem, sodium nitroprusside, and hydralazine-for their efficacy and potency in an experimental model of vasospasm. Porcine gastroepiploic arteries were cut into rings to measure isometric tension development in vitro. The arteries were preconstricted with endothelin-1, a stable thromboxane A2 analogue, norepinephrine, or potassium, and then exposed to increasing concentrations of each vasodilator. Every vasodilator except hydralazine and sodium nitroprusside was efficacious in producing near-maximal relaxation of arteries preconstricted with any vasospastic substance. The five efficacious vasodilators differed markedly in potency, as reflected in the concentrations producing half-maximal relaxation. The order of potency was nicardipine < or = verapamil or diltiazem < papaverine < lidocaine. This study suggests that nicardipine would be the most potent vasodilator for systemic or direct intra-arterial administration. Papaverine and lidocaine, in concentrations employed clinically, were both efficacious as topical vasodilators.

The effects of N-methyl-D-aspartate agonists and antagonists on isolated bovine cerebral arteries.

This pharmacologic study examines the direct cerebrovascular effects of N-methyl-D-aspartate (NMDA) receptor agonists and antagonists to determine whether large cerebral arteries have NMDA receptors. Bovine middle cerebral arteries were cut into rings to measure isometric tension development in vitro. Two competitive agonists, L-glutamate and NMDA, each had negligible effects on ring tension in the absence of exogenous vasoconstrictors. L-glutamate (in high concentrations) produced direct relaxation of potassium (K+)-constricted arteries, but the relaxation was not selective for L-glutamate, D-glutamate, or mannitol. Relaxation with L-glutamate was abolished when it was isosmotically substituted in the K(+)-rich medium. NMDA (in the absence or presence of glycine) and two competitive antagonists, 2-amino-5-phosphopentanoic acid (AP5) and (+/-)-3-(s-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), each had little effect on the tone of arteries preconstricted with potassium or the stable thromboxane A2 analog U-46,619. Three noncompetitive antagonists (S(+)-ketamine, dizocilpine, and dextrorphan) and their steroeisomers (R(-)-ketamine, (-)MK-801, and levorphanol) each produced dose-dependent relaxation of K(+)- or U-46,619-constricted arteries; relaxation was not selective for the (+) or (-) stereoisomers. These results suggest that large cerebral arteries lack NMDA receptors mediating constriction or relaxation. All noncompetitive antagonists dilated cerebral arteries, but by mechanisms that were not stereospecific.

Ketamine directly dilates bovine cerebral arteries by acting as a calcium entry blocker.

This in vitro study was performed to determine the role of calcium in ketamine-induced cerebral vasodilation. Isolated bovine middle cerebral arteries were cut into rings to measure isometric tension development or into strips to measure radioactive 45Calcium (45Ca) uptake. Ketamine produced direct relaxation of arterial rings; the relaxation was attenuated in Ca(2+)-deficient media. Ketamine produced dose-related relaxation of arteries preconstricted with potassium, a stable thromboxane A2 analogue, or endothelin. Endothelial stripping with Triton X-100 had no effect on subsequent ketamine-induced relaxation. In Ca(2+)-deficient media containing potassium or the stable thromboxane A2 analogue, ketamine produced competitive inhibition of subsequent Ca(2+)-induced constriction. Ketamine blocked potassium- and thromboxane A2-stimulated 45Ca uptake in a dose-dependent manner, but had no effect on basal 45Ca uptake, the externally bound 45Ca content, or the volume of the 3H-sorbitol space. These results indicate that ketamine can directly dilate cerebral arteries by acting as a calcium channel antagonist; ketamine inhibits 45Ca uptake through both potential-operated (potassium) and receptor-operated (thromboxane A2) channels in cerebrovascular smooth muscle.

Effects of prostaglandin F2 alpha and thromboxane A2 analogue on bovine cerebral arterial tone and calcium fluxes.

We determined sources of activator calcium for prostanoid-induced cerebrovascular constriction by measuring isometric tension and calcium-45 (45Ca) fluxes in bovine middle cerebral arteries. Constriction induced by prostaglandin F2 alpha or the stable thromboxane A2 analogue SQ-26,655 was near-maximally inhibited in calcium-deficient solutions but only partially inhibited by calcium antagonists (10(-5) M verapamil or 3.3 x 10(-7) M nifedipine). Studies of 45Ca binding at different external Ca2+ concentrations showed that cerebral arteries possess two calcium binding sites, a high-affinity site and a low-affinity site. Each prostanoid significantly increased low-affinity 45Ca uptake (external Ca2+ concentration = 1.2 mmol/l) during 5 minutes of 45Ca loading; for prostaglandin F2 alpha 45Ca uptake increased from 69 to 108 nmol/g and for SQ-26,655, from 78 to 141 nmol/g. The prostanoid-induced increases in low-affinity 45Ca uptake were completely abolished by pretreatment with verapamil or nifedipine. Prostaglandin F2 alpha, SQ-26,655, verapamil, and nifedipine had no effect on high-affinity 45Ca uptake (external Ca2+ concentration = 45 mumol/l) or 45Ca efflux (after 60 minutes' preincubation in calcium-deficient media). Prostaglandin F2 alpha and SQ-26,655 each appear to constrict cerebral arteries by two mechanisms: first, by promoting calcium uptake from low-affinity binding sites through receptor-operated channels sensitive to the calcium antagonists, and second, by releasing calcium from depletable internal stores.

Effects of calcium antagonists on isolated bovine cerebral arteries: inhibition of constriction and calcium-45 uptake induced by potassium or serotonin.

The purpose of this study was to determine the mechanisms by which organic calcium channel blockers inhibit cerebral vasoconstriction. Isolated bovine middle cerebral arteries were cut into rings to measure contractility or into strips to measure radioactive calcium (45Ca) influx and efflux. Calcium channel blockers (10(-5) M verapamil or 3.3 X 10(-7) M nifedipine) and calcium-deficient solutions all produced near-maximal inhibition of both potassium- and serotonin-induced constriction. In calcium-deficient solutions containing potassium or serotonin, verapamil and nifedipine each blocked subsequent calcium-induced constriction in a competitive manner. Potassium and serotonin significantly increased 45Ca uptake into cerebral artery strips during 5 minutes of 45Ca loading; for potassium 45Ca uptake increased from 62 to 188 nmol/g, and for serotonin from 65 to 102 nmol/g. Verapamil or nifedipine had no effect on basal 45Ca uptake but significantly blocked the increase in 45Ca uptake induced by potassium or serotonin. Potassium, and to a lesser extent serotonin, each induced a brief increase in the rate of 45Ca efflux into calcium-deficient solutions. Verapamil or nifedipine had no effect on basal or potassium-stimulated 45Ca efflux. The results demonstrate that verapamil and nifedipine block 45Ca uptake through both potential-operated (potassium) and receptor-operated (serotonin) channels in bovine middle cerebral arteries.

Comparative actions of pentobarbital and verapamil on canine cerebral and peripheral arteries in vitro.

Verapamil and pentobarbital were compared for their actions on isolated canine cerebral (basilar and middle cerebral) and peripheral (mesenteric) arteries of similar diameter. The two agents shared several nonselective actions on canine arteries, but differed widely in potency. Both agents produced direct relaxation of cerebral, but not peripheral, arteries, and both agents inhibited constriction of cerebral and peripheral arteries by KCl and CaCl2 (in K+-depolarizing, Ca2+-deficient media). However, 1 mM pentobarbital was required to produce the same maximal effects as 4 uM verapamil. In addition, verapamil selectively blocked constriction of cerebral arteries by a receptor-mediated agent, prostaglandin F2a, while pentobarbital was nonselective in its blockade. On the basis of their comparative actions on isolated cerebral and peripheral arteries, calcium channel blockers such as verapamil may be a more rational choice in the treatment of cerebral ischemia than the barbiturates.