Kenneth Törnebrandt

Cooling augments contractile response to 5-hydroxytryptamine via an endothelium-dependent mechanism.

The interaction between cooling and vasoactive substances, e.g. 5-hydroxytryptamine (5-HT), plays an important role in the pathophysiology of cold-induced vasospasm. Our objective was to study the effect of cooling on the 5-HT vascular response, classify the involved 5-HT receptors, and to analyze the role of the endothelium. Ring segments from the rat jugular vein, a preparation without alpha-adrenergic receptors, were suspended in organ baths to record the circular motor activity. The temperature was initially 37 degrees C and was thereafter either continuously lowered to 10 degrees C or kept constant at different temperatures within this range. 5-HT at low concentrations (10(-11) to 3 x 10(-8) M) induced relaxation at 37 degrees C in segments precontracted by prostaglandin F2 alpha. The relaxation was recognized to be mediated via an endothelium-dependent 5-HT1-like receptor mechanism presumably involving the release of endothelium-derived relaxing factor (EDRF). Cooling to 29 and 20 degrees C diminished the relaxation, probably due to an attenuated release of EDRF. 5-HT at concentrations of more than 10(-8) M induced a contraction in all vessels at 37 degrees C mediated via a 5-HT2 receptor. An increased 5-HT-induced contraction was seen at temperatures below 37 degrees C in vessels with an intact endothelium. Endothelial denudation diminished the cold-induced enhancement of the contraction to 5-HT. These studies suggest that endothelial mechanisms contribute to a cold-induced augmented response to 5-HT.

Pharmacological Characterization of Alpha-Adrenergic Receptor Subtypes Mediating Contraction in Human Mesenteric Arteries and Veins

Approximately 200 isolated human mesenteric arteries (diameter less than 1 mm) and veins (diameter less than 2 mm) were tested in vitro for their contractile and dilator responses to adrenergic agonists under standardized conditions. This allowed for quantitative estimation of various receptor characteristics: relative agonist potency; concentration for half maximum response (EC50); amount of maximum response (EAm), and affinity of antagonist to receptor (KB and pA2). The contractile response of the vessels to the various sympathomimetic amines involved alpha-adrenoceptors. Postjunctionally, the alpha 1 type of receptor predominated in the arteries whereas the alpha 2-receptor subtype was mainly found in the veins. None of the amines produced any vasodilatory effects in the vessels tested after previous contraction with prostaglandin F2 alpha.

Heterogeneity of contractile 5-HT receptors in human hand veins

To increase our knowledge of human peripheral vasospasm we characterized the contractile 5-hydroxytryptamine (5-HT) receptors in human superficial hand vein segments in vitro. The 5-HT1 receptor agonist, sumatriptan, the 5-HT2 receptor agonist, dl-alpha-methyl-5-HT, and the 5-HT3 receptor agonist, 2-methyl-5-HT, all induced concentration-dependent contractions. The contractile response to sumatriptan was antagonized by the non-selective 5-HT receptor antagonist, methiothepin, but was unaffected by the 5-HT2 receptor antagonist, ketanserin. The contractile response to dl-alpha-methyl-5-HT was antagonized by both methiothepin and ketanserin. The contraction elicited by 2-methyl-5-HT was not affected by the 5-HT3 receptor antagonist, MDL 72222, but was antagonized by ketanserin. The results suggest that serotonergic contraction in the human superficial hand vein involves both 5-HT1 and 5-HT2 but not 5-HT3 receptors. Such receptor heterogeneity in human blood vessels should be considered when using drugs and when designing future compounds for medical use.

Bactericidal/permeability‐increasing protein inhibits endotoxin‐induced vascular nitric oxide synthesis

Background: Endotoxin (lipopolysaccharide, LPS) up‐regulates inducible nitric oxide synthase (iNOS) in blood vessels during septic shock. This promotes the production of nitric oxide (NO), leading to dilation of the vessels. The aim of the study was to investigate the effects of the LPS‐binding endogenous antibiotic bactericidal/permeability‐increasing protein (BPI) on the action of LPS on the blood vessels wall and to identify possible influence on underlying NO‐related mechanisms.

Comparison of Ethanol Absorption During Continuous and Intermittent Flow Irrigation in Transurethral Resection

Transurethral resection of the prostate was performed using intermittent-flow bladder irrigation (n = 50), or by continuous-flow irrigation, using a suprapubic trocar (n = 50). The irrigant solution contained 1.5% glycine +1% ethanol and fluid absorption was measured from the ethanol content of the expired breath. Fluid absorption was significantly lower in patients receiving continuous-flow irrigation (p less than 0.007) although major absorption occurred in one of these patients. The immediate detection of absorption with the ethanol method allowed us to stop one of the operations performed with intermittent bladder irrigation, at which 2 l of fluid had been absorbed in 20 min. With correction for the amount of removed prostatic tissue, there were no differences in operation time or blood loss between the two types of irrigation.

Binding of [3H]-5-hydroxytryptamine to human coronary artery and bypass graft vessels

OBJECTIVES 5-Hydroxytryptamine (5-HT) has a wide range of vascular effects mediated via specific receptors and it has been suggested to be a mediator in ischemic heart disease. The aim of the present study was to localise the 5-HT receptors within the vessel wall. METHODS Epicardial coronary arteries obtained from patients undergoing cardiac transplantation, internal mammary arteries from heart donors and saphenous veins from patients undergoing coronary bypass surgery, were sectioned and incubated with [3H]-5-HT for in vitro receptor autoradiography. RESULTS Microscopic analysis of high resolution autoradiographic images revealed a similar pattern of [3H]-5-HT binding in epicardial coronary and internal mammary artery, where it predominated in the lamina muscularis. In the saphenous vein, binding increased towards the adventitia which showed dense, displaceable binding to the vasa vasorum as well as to nerve-like structures, from which binding was only partially displaced. Computer-assisted densitometric analysis of low resolution autoradiographs revealed a high degree of specific binding to all vessels examined. CONCLUSIONS The distribution of the [3H]-5-HT binding is different in the saphenous vein compared to epicardial coronary and internal mammary artery. The dense binding to vasa vasorum in the saphenous vein suggests a role for 5-HT in closure of these nutrient vessels, which could contribute to the formation of atherosclerotic changes in saphenous vein grafts.

Substance P Relaxes Rat Bronchial Smooth Muscle via Epithelial Prostanoid Synthesis

Background: Substance P is present in bronchial nerve fibres. The physiological actions of substance P are mediated via tachykinin NK1 receptors. Immunochemical studies have demonstrated tachykinin NK1 receptors in the rat airway epithelium. Objective: To elucidate how epithelial tachykinin NK1 receptors affect smooth muscle response to substance P. Methods: Contractile response of isolated rat bronchial trunk with or without epithelium was recorded. Results: In intact segments precontracted by 5-hydroxytryptamine, relaxation was induced by substance P and the nitric oxide donor, sodium nitroprusside. Removal of the epithelium abolished relaxation induced by substance P but did not affect relaxation induced by sodium nitroprusside. The cyclo-oxygenase inhibitor, indomethacin, but not the nitric oxide synthase inhibitor, L-NG-monomethylarginine, reduced the relaxation in response to substance P. Conclusions: Epithelial tachykinin NK1 receptors mediate substance-P-induced relaxation of rat bronchial smooth muscle via release of prostanoids but not nitric oxide.

Effects of propofol on desipramine-sensitive [3H]-noradrenaline uptake kinetics in rat femoral artery

Background: The intravenous anaesthetic propofol inhibits the neuronal uptake of noradrenaline (uptake1) from the vascular sympathetic neuromuscular junction, resulting in an enhancement of the sympathetic neurotransmission. This could be important for maintenance of blood pressure during propofol anaesthesia. The aim of the present study was to determine how propofol influences the kinetics of uptake1.