Busulphan-cyclophosphamide cause endothelial injury, remodeling of resistance arteries and enhanced expression of endothelial nitric oxide synthase.

Stem cell transplantation (SCT) is a curative treatment for malignant and non malignant diseases. However, transplantation-related complications including cardiovascular disease deteriorate the clinical outcome and quality of life. We have investigated the acute effects of conditioning regimen on the pharmacology, physiology and structure of large elastic arteries and small resistance-sized arteries in a SCT mouse model.

Inflammation-induced airway smooth muscle responsiveness is strain dependent in mice.

Different mouse strains display different degrees of inflammation-induced airway hyperresponsiveness in vivo. It is not known whether these variations are attributable to distinct properties of the airway smooth muscle. Therefore, tracheal ring segments from C57BL/6 and BALB/c mice were exposed to three different pro-inflammatory stimuli for 4 days while maintained under tissue-culture conditions: tumour necrosis factor α (100 ng/ml), the Toll-like receptor (TLR) 3 agonist polyI:C (10 μg/ml), and the TLR4 agonist LPS (10 μg/ml).

Endotoxin induces differentiated contractile responses in porcine pulmonary arteries and veins.

Background/aims: Sepsis-induced lung injury is characterized by pulmonary hypertension, edema and deteriorated gas exchange. As in vivo studies have indicated that bacterial endotoxin predominantly induces a pulmonary venous constriction, we aimed to investigate effects of endotoxin on isolated porcine pulmonary vessels.

Methods: Pulmonary arteries and veins were examined using in vitro isometric force recordings.

Adenosine A(1) receptors and vascular reactivity.

Aim: Blood pressure is higher in A(1) receptor knock-out (A(1)R-/-) mice than in wild type litter mates (A(1)R+/+) and we have examined if this could be related to altered vascular functions.

Methods: Contraction of aortic rings and mesenteric arteries were examined. To examine if the adenosine A(1) receptor-mediated contraction of aortic muscle was functionally important we examined pulse pressure (PP) and augmentation index (AIX) using a sensor that allows measurements of rapid pressure transients.

Endotoxemic pulmonary hypertension is largely mediated by endothelin-induced venous constriction.

Objective: To analyze the effect of endothelin-1 on pulmonary arterial and venous contractile force in vitro and on up- and downstream pulmonary vascular resistance in vivo under sham and endotoxemic conditions in pigs.

Materials And Methods: In vitro: paired preparations of pulmonary arteries and veins were mounted in a myograph (n=13) for measurements of contractile responses to increasing concentrations of phenylephrine, endothelin-1, and sarafotoxin (endothelin receptor type B agonist). In vivo: 20 pigs were anesthetized, mechanically ventilated, and subjected to phenylephrine (reference substance), endothelin-1, sarafotoxin, endotoxin, and tezosentan (dual endothelin receptor antagonist).

Perinatal development influences mechanisms of bradykinin-induced relaxations in pulmonary resistance and conduit arteries differently.

Objective: As bradykinin (BYK) relaxes conduit (EPA) and resistance (RPA) pulmonary arteries from both perinatal and adult lungs, we investigated whether this vasodilator's relaxation-mechanisms were altered during perinatal development, differed between EPA and RPA and differed with other endothelium-dependent vasodilators, acetyicholine (ACH) and substance P (SP).

Methods: Arteries from mature foetal (5 days), neonatal (approximately 5 min), newborn (60-84 h) and adult pigs (> or =6 months) were isolated, mounted for in vitro isometric force recording, activated with PGF(2alpha) (30 micromol/l) and relaxed with BYK (10 pmol/l-1 micromol/l), SP (10 pmol/l-0.1 micromol/l) or ACH (1 nmol/l-1 mmol/l).

Up-regulation of bradykinin response in rat and human bladder smooth muscle.

Purpose: Responses to bradykinin were investigated in vitro in isolated control and hypertrophic smooth muscle strips from rat bladder.

Materials And Methods: Bladder hypertrophy was induced by a 10-day period of partial urinary outflow obstruction. In addition, human bladder strips were also investigated.

Maturation of the response to bradykinin in resistance and conduit pulmonary arteries.

Objective: Immaturity of the endothelial-dependent relaxation is thought to be characteristic of the newborn pulmonary elastic arteries. In adulthood, the reactivity of different pulmonary arterial segments varies. Therefore, we investigated the presence of endothelial heterogeneity in perinatal porcine pulmonary arteries and compared it with the adult by studying the bradykinin-, substance P- and acetylcholine-induced relaxations in different arteries.

Changes in ANP responsiveness of normal and hypertensive porcine intrapulmonary arteries during maturation.

Pulmonary vascular resistance falls rapidly after birth, but endothelium-dependent relaxation is relatively poor during the perinatal period. Atrial natriuretic peptide (ANP) is a potent vasodilator; however, its role in the process of perinatal adaptation is uncertain. Porcine intrapulmonary conduit arteries (IPA) from fetal, newborn (< 5 min), 3-, 6-, and 17-d-old, and adult pigs, and from piglets made hypoxic from 0 to 3, 3 to 6, or 14 to 17 d, were isolated and mounted for isometric force recording.

Expression and function of atrial myosin light chain 1 in the porcine right ventricle of normal and pulmonary hypertensive animals.

We investigated the expression of atrial myosin light chain 1 (ALC-1) and myosin cycling kinetics in the normal and hypertrophied right ventricle of the neonatal porcine heart. Right ventricular hypertrophy was induced by exposing piglets immediately after birth to hypobaric hypoxia for 3 days. Control piglets were kept under normal conditions for the same time.

Developmental changes in binding sites and reactivity for CGRP and VIP in porcine pulmonary arteries.

During postnatal adaptation pulmonary arteries dilate. CGRP and VIP are pulmonary vasodilators. In this report, porcine lungs from newborn to adult were studied.

ATP-dependent K+ channel activation in isolated normal and hypertensive newborn and adult porcine pulmonary vessels.

The role of an ATP-dependent K+ channel (K(ATP)+) relaxation in the porcine pulmonary vasculature from birth to adulthood was investigated in vitro using levcromakalim on isolated, prostaglandin F2alpha (30 microM)-precontracted conduit arteries (CA), resistance arteries (RA), and veins (PV). Vessels from neonatal pulmonary hypertensive piglets exposed to chronic hypobaric hypoxia (CHH, 51 kPa) for 3 d, either from birth or from 3 d of age were also studied. Levcromakalim relaxed all vessels in a concentration- and glibenclamide-sensitive manner.

Chronic hypoxia inhibits postnatal maturation of porcine intrapulmonary artery relaxation.

Neonatal pulmonary hypertension is associated with increased pulmonary vascular reactivity. We studied the responses of isolated porcine intrapulmonary arteries after exposure of piglets to chronic hypobaric hypoxia (CHH) from 0 to 2.5, 3 to 6, or 14 to 17 days of age.

Growth resistance-sized arteries in response to bladder hypertrophy in the rat: time-course, DNA-synthesis and LDH-isoform pattern.

Bladder growth was induced by partial urethral obstruction. Bladder hypertrophy was evident at 53 h after obstruction and continued over a 6 weeks period. Small bladder arteries were taken from fixed anatomical locations of the bladder circulation, mounted in a small vessel myograph and the optimal diameter for maximal isometric force development was determined (Lmax K+ = 125 mM stimulation).

Structure and mechanics of growing arterial microvessels from hypertrophied urinary bladder in the rat.

Rat bladder hypertrophy, induced by a partial ligation of the urethra, was used to study the accompanying changes of microvascular smooth muscle mechanics, pharmacology and morphology. A segment of a microarterial vessel to the bladder was taken from a defined anatomical location and studied in a wire myograph in vitro at the length for maximal isometric force development (Lmax). After 10 days of ligation, bladder hypertrophy resulted in a microvascular growth response compared to non-operated controls which was characterized by (i) an increase of the calculated diameter at Lmax from 134 +/- 5 microns to 222 +/- 19 microns; (ii) an increase of the media thickness from 22.

Relaxant effect of phalloidin on Triton-skinned microvascular and other smooth muscle preparations.

Guinea pig mesenteric microarteries (diameter 60-100 microns), the main branch of the mesenteric artery and taenia coli were skinned with 1% Triton X-100 for 4 h at 4 degrees C. Microarteries, mounted for circumferential force measurement, developed maximal active force in response to elevation of the free Ca2+ (pCa = 4.52, in EGTA buffer) in the presence of ATP (7.

The influence of cold stress on the myosin heavy chain expression of cardiac and smooth muscle in normotensive and spontaneously hypertensive female rats.

Cold exposure (6 weeks at 4 degrees C) of normotensive (Wistar-Kyoto) and stroke-prone spontaneously hypertensive female rats led to cardiac hypertrophy (in stroke-prone spontaneously hypertensive rats), increased the level of plasma thyroxine, and increased the alpha-myosin heavy chain expression in the left ventricle. In contrast, myosin heavy chain expression of both main mesenteric artery and uterus was not affected by cold stress and chronic hypertension, suggesting different regulation of myosin heavy chain expression in smooth and cardiac muscle in vivo.

Higher Ca2+ sensitivity of triton-skinned guinea pig mesenteric microarteries as compared with large arteries.

Small mesenteric resistance arteries and the main branch of the mesenteric artery (outer in situ diameter 115 +/- 3 microns [n = 76] and greater than 1,000 microns, respectively) were skinned with 1% Triton X-100. Both preparations were mounted as rings for circumferential force measurement in an EGTA solution (free Ca2+, less than 10 nM; calmodulin, 0.3 microM; pH 6.

Differential skinning of smooth muscle: a new approach to excitation-contraction coupling.

In intact smooth muscle, the calcium sensitivity of force may increase as well as decrease. Using differently skinned smooth muscle preparations, two pathways involved in the change of calcium sensitivity of force have been identified: in microarteries skinned with beta-escin, GTP (possibly via a G protein) is involved in sensitization to Ca2+, while in porcine coronary arteries skinned with Triton X-100 cyclic AMP and possibly cyclic GMP are involved in desensitization. In both cases, there is a corresponding change in the phosphorylation of the regulatory light chain of myosin, suggesting that the balance of phosphorylating to dephosphorylating reactions is altered at constant [Ca2+].

Effects of beta-antagonists on contraction of bovine retinal microarteries in vitro.

Contractile responses of bovine retinal microarteries (BRA) (diameter: 198 +/- 5 microns, n = 49) to beta-antagonists, local anesthetics and Ca2(+)-antagonists were studied in vitro. Propranolol (10(-8)-10(-5) M) relaxed K(+)-activated BRA dose-dependently, whereas timolol (10(-8)-10(-5) M) relaxed K(+)-activated BRA only weakly at the highest doses. The relaxation by propranolol was not mediated through interaction with adrenergic nerve endings, since fluorescence histochemistry showed absence of such nerve endings in BRA.

Mechanics of K(+)-induced isotonic and isometric contractions in isolated canine coronary microarteries.

The effects of shortening in isotonic contractions on the mechanics of microvascular smooth muscle were investigated. Intramyocardial canine coronary microarteries (in situ diameter 60 +/- 3 microns) were mounted as rings, connected to a newly developed photoelectromagnetic force-length transducer, and activated with 125 mM K+. Shortening during isotonic contractions depressed the length-force relation (shortening deactivation) compared with the length-force relation obtained from isometric contractions; the effect was present at the earliest moments after activation, suggesting that a fundamental mechanism associated with the actual sliding of contractile filaments delayed onset of contractile activity in isotonic contractions compared with isometric contractions.

Effect of alpha-1 and beta agonists on contraction of bovine retinal resistance arteries in vitro.

Contractile responses of bovine retinal arteries (BRA) (diameter: 179 +/- 9 micron, n = 25) to high K+, circumferential stretch and adrenergic stimulation were studied in vitro. BRA could be activated by rapid circumferential stretch. Under resting conditions, phenylephrine consistently activated BRA at the highest dose of the drug used (10(-5) M).

Positive inotropic and vasodilating effects of amrinone and milrinone in isolated canine heart.

The question has been raised whether the in vivo positive inotropic effect of amrinone and milrinone is a primary effect or secondary to vasodilation. The effects of each drug on isolated trabeculae and resistance vessels obtained from the same dog hearts were determined separately. The positive inotropic and vasodilatory effects coincided over the same concentration range for amrinone.

Moderate cooling depresses the accumulation and the release of newly synthesized catecholamines in isolated canine saphenous veins.

Moderate cooling (from 37 degrees to 24 degrees C) depressed the formation of 3H-dopamine and 3H-norepinephrine from 3H-tyrosine by isolated canine saphenous veins. Cooling reduced the evoked release of newly synthesized catecholamine to the same extent as that of stored norepinephrine. Hence the augmentation by cold of the contractile response to sympathetic nerve stimulation observed in earlier work is not accompanied by an augmented release of newly synthesized norepinephrine.

Tissue accumulation and release of newly synthesized 3H-dopamine and 3H-noradrenaline in canine saphenous veins incubated with 3H-(--)-tyrosine.

Experiments were designed to study the release of newly synthesized catecholamines in the isolated canine saphenous vein. Unlabelled (--)-tyrosine did not affect the contractions caused by electrical stimulation or exogenous noradrenaline and did not influence the basal efflux and the stimulation-induced overflow of 3H-noradrenaline in veins, previously incubated with the radiolabelled transmitter. The precursor increased the stimulation-induced overflow of the principal intraneuronal metabolite of 3H-noradrenaline, 3H-3,4-dihydroxyphenylglycol, and augmented the concentration of endogenous dopamine.