EndothelinB receptors in rabbit pulmonary resistance arteries: effect of left ventricular dysfunction

The endothelin (ET) receptor that mediates vasoconstriction of the isolated rabbit pulmonary resistance artery was characterized using selective ET receptor agonists and antagonists. We also examined changes in ET-induced vasoconstriction brought about by left ventricular dysfunction using the rabbit coronary ligation model. The rank order of potency for contraction was sarafotoxin S6c (S6c) > ET-1 = ET-3, which is characteristic of an ETB-like receptor. The combined ETA/ETB receptor antagonist SB209670 (1 microM) antagonized responses to ET-1 and S6c with estimated pKb values of 6.8 +/- 0.2 and 7.8 +/- 0.2, respectively. BQ788 (1 microM) antagonized responses to S6c and ET-3 (but not ET-1) with estimated pKb values of 7.1 +/- 0.2 and 6.6 +/- 0.1, respectively. The ETA receptor antagonist FR139317 (1 microM), either alone or in combination with BQ788, did not inhibit responses to ET-1. The profile of the ET-1 response was not altered by left ventricular dysfunction. In control rabbits, the inhibitor of nitric oxide synthase N omega-nitro-L-arginine methyl ester (100 microM) had no significant effect on the potency of either ET-1 or S6c. In the coronary-ligated rabbits, however, it significantly increased the potency (10-15-fold) of both ET-1 and S6c. These results suggest that the ET receptor that mediates contraction in rabbit pulmonary resistance arteries has the characteristics of an ETB-like receptor. The responses to ET-1 are not altered by LVD but may be modified by increased release of nitric oxide.     

Developmental changes in endothelium-dependent vasodilation and the influence of superoxide anions in perinatal rabbit pulmonary arteries

ACh-induced vasodilation was investigated in pulmonary arteries from 8 and 2 day pre-term foetal, neonatal (0-12 h and 4 day old) and adult rabbits. The effects of superoxide anion generation [with hypoxanthine (HX, 0.1 mM)/xanthine oxidase (XO, 15 mu ml(-1))], endogenous superoxide dismutase (SOD) inhibition [with the Cu-Zn SOD inhibitor triethylenetetramine (TETA, 1 mM)], endogenous superoxide anion scavenging [by superoxide dismutase (SOD, 50 u ml(-1))] and inhibition of endothelial nitric oxide synthase (eNOS) [with, Nomega-nitro-L-arginine methylester (L-NAME, 0.1 mM)], on basal and ACh-induced NO activity were studied by examining phenylephrine-induced contraction and ACh-induced vasodilation respectively. L-NAME and endothelium removal abolished all ACh-induced vasodilation and 1 microM sodium nitroprusside fully dilated all vessels. ACh-induced vasodilation was absent in the 8 day pre-term foetus and 0-12 h neonate but present at all other ages. L-NAME itself contracted 2 day pre-term foetal vessels. At 0 12 h, SOD, but not the phosphodiesterase 5 inhibitor zaprinast (1 microM), uncovered ACh-induced vasodilation. At this age SOD reduced phenylephrine-induced contraction which was not influenced by TETA, L-NAME or HX/XO, and L-NAME itself did not cause contraction. This suggests both ACh-induced and basal NO activity are compromise in these vessels by endogenous superoxide anion production and deficiencies in endogenous SOD activity. In 4 day vessels, but not adult vessels, L-NAME, TETA and HX/XO augmented contractions to phenylephrine, and L-NAME itself induced vasoconstriction, suggesting that basal NO and SOD activities were present by 4 days but were not evident in the adult. ACh-induced NO activity, and the influence of endogenous SOD on this, were present in the adult (and 4 day) vessels as superoxide generation with HX/XO significantly reduced ACh-induced vasodilation and this effect was inhibited by SOD and augmented by TETA. Increased oxygen tensions > 500 mmHg attenuated ACh-induced vasodilation in the foetal but not neonatal rabbits. Raising the oxygen tension from approximately 20 to approximately 120 mmHg revealed ACh-induced vasodilation in the 8 day pre-term vessels. In summary, superoxide anion accumulation combined with deficiencies in SOD activity may transiently compromise basal and ACh-induced NO activity at birth. Experimental oxygen tensions markedly influence ACh-induced vasodilation in foetal rabbit pulmonary arteries.     

Chronic blockade of endothelin ETA receptors improves flow dependent dilation in resistance arteries of hypertensive rats

PURPOSE: To compare findings with magnetic resonance (MR) cholangiography with rapid acquisition with relaxation enhancement (RARE) and half-Fourier acquisition with single-shot turbo spin-echo (hereafter, half Fourier RARE) snapshot imaging techniques to those with endoscopic retrograde cholangiography (ERC). MATERIALS AND METHODS: Heavily T2-weighted thick-section (RARE) and thin-section (half-Fourier RARE) MR cholangiography were performed prospectively, on a 1.5-T imager, in the biliary tree of 61 consecutive patients before ERC. Findings at ERC were considered the standard of reference. The radiologist and endoscopist were blinded to each other's report. On- and off-site MR cholangiographic readings were performed to detect stones (n = 24), biliary dilatation (n = 34), or stenosis (n = 36). RESULTS: The sensitivity and specificity of MR cholangiography, respectively, calculated on a lesion-by-lesion basis, were 92.3% and 95.8% for cholangiolithiasis, 94.1% and 92.6% for duct dilatation, and 88.8% and 84.0% for stenosis. With snapshot MR cholangiography, on a patient-by-patient basis, differentiation between normal (n = 15) and abnormal (n = 46) results yielded a sensitivity of 92.4%, a specificity of 83.4%, and a positive predictive value of 95.6%. Pitfalls were caused by flow artifacts, compression by vessels, and low contrast between calculi and surrounding parenchyma. CONCLUSION: Snapshot MR cholangiography allowed noninvasive, accurate detection of biliary stones, strictures, and dilatation similar to that with ERC. Discrepancies regarding low-grade dilatation and strictures had no clinical relevance at retrospective review.     

Increased reactivity to endothelin of pulmonary arteries in long-term post-obstructive pulmonary vasculopathy in rats

Some sigma receptor ligands have been shown to bind with low affinity to the dopamine transporter and to inhibit [3H]dopamine uptake. It has not previously been shown whether any of these compounds influence release of dopamine via facilitated exchange diffusion. To further examine the nature of the interaction between sigma receptor ligands and the dopamine transporter, the effects of sigma receptor ligands on amphetamine-stimulated [3H]dopamine release were examined in slices prepared from rat caudate putamen. In the absence of exogenous Ca2+, both (+)-pentazocine and (-)-pentazocine potentiated amphetamine-stimulated [3H]dopamine release at concentrations consistent with their affinities for sigma2 receptors. In contrast, BD737 (1S.2R-(-)-cis-N-?2-(3,4-dichlorophenyl)ethyl?-N-methyl-2-(1-pyrrolidiny l)cyclohexylamine), a sigma1 receptor agonist, had no effect on amphetamine-stimulated release. Neither isomer of pentazocine alone had any effect on basal [3H]dopamine release under these conditions. Three antagonists at sigma receptors, one of which is non-selective for subtypes, and two of which are sigma2-selective, all blocked the enhancement of stimulated release produced by (+)-pentazocine. Enhancement of stimulated release by (-)-pentazocine was similarly blocked by sigma2 receptor antagonists. Our data support the contention that it is possible to regulate transporter-mediated events with drugs that act at a subpopulation of sigma receptors pharmacologically identified as the sigma2 subtype.     

Endothelin receptors mediating contraction of rat and human pulmonary resistance arteries: effect of chronic hypoxia in the rat

1. We examined the endothelin (ET) receptors mediating contractions to ET-1, ET-3 and sarafotoxin S6c (SX6c) in rat pulmonary resistance arteries by use of peptide and non-peptide ET receptor antagonists. Changes induced by pulmonary hypertension were examined in the chronically hypoxic rat. The effect of the mixed ET(A)/ET(B) receptor antagonist SB 209670 on endothelin-mediated contraction was also examined in human pulmonary resistance arteries. 2. In rat vessels, the order of potency for the endothelin agonists was SX6c = ET-3 > ET-1 (pEC50 values in control rats: 9.12+/-0.10, 8.76+/-0.14 and 8.12+/-0.04, respectively). Maximum contractions induced by ET-3 and ET-1 were increased in vessels from chronically hypoxic rats. 3. The ET(A) receptor antagonist FR 139317 (1 microM) had no effect on the potency of ET-1 in any vessel studied but abolished the increased response to ET-1 in the chronically hypoxic vessels. The ET(A) receptor antagonist BMS 182874 (1 microM) increased the potency of ET-1 in control rat vessels without effecting potency in the pulmonary hypertensive rat vessels. 4. Bosentan (non-peptide mixed ET(A)/ET(B) receptor antagonist) increased the potency of ET-1 in control rat vessels but was without effect in the pulmonary hypertensive rat vessels. Bosentan (1 microM) inhibited responses to SX6c in control and chronically hypoxic rat vessels with pKb values of 5.84 and 6.11, respectively. The ET(B) receptor antagonist BQ-788 (1 microM) did not inhibit responses to ET-1 in any vessel tested but did inhibit responses to both SX6c and ET-3 (pKb values in control and chronically hypoxic rat vessels respectively: SX6c 7.15 and 7.22; ET-3: 6.68 and 6.89). BQ-788 (1 microM) added with BMS 182874 (10 microM) did not inhibit responses to ET-1 in control vessels but caused a significant inhibition of responses to ET-1 in chronically hypoxic preparations. 5. SB 209670 inhibited responses to ET-1 in both control and chronically hypoxic vessels with pKb values of 7.36 and 7.39, respectively. SB 209670 (0.1 and 1 microM) virtually abolished responses to ET-1 in the human pulmonary resistance artery. 6. In conclusion, in rat pulmonary resistance arteries, vasoconstrictions induced by ET-1, SX6c and ET-3 are mediated predominantly by activation of an ET(B)-like receptor. However, lack of effect of some antagonists on ET-1 induced vasoconstriction suggests that ET-1 stimulates an atypical ET(B) receptor. The increase in potency of ET-1 in the presence of some antagonists suggests the presence of an inhibitory ET(A)-like receptor. The influence of this is reduced, or absent, in the chronically hypoxic rats. Increased responses to ET-1 are observed in the chronically hypoxic rat and may be mediated by increased activation of ET(A) receptors. SB 209670 is unique in its potency against responses to ET-1 in both control and chronically hypoxic rats, as well as human, isolated pulmonary resistance arteries.     

Relaxation of canine pulmonary arteries caused by stimulation of atypical beta-adrenergic receptors

BACKGROUND: Although in some cases delayed hypersensitivity may be observed, beta-lactam antibiotics frequently induce immediate allergic IgE-mediated reactions with the specificity localized in the acyl-side chain structure. Generally, delayed immunologic reactions are related to sensitized T lymphocytes and major histocompatibility complex restricted. OBJECTIVE: To investigate the prevalence of HLA class I and II antigens in patients with delayed hypersensitivity to aminopenicillins in order to evaluate a relationship between major histocompatibility complex immune response genes and aminopenicillins hypersensitivity. METHODS: We assessed 24 patients with history of delayed hypersensitivity to aminopenicillins using (1) skin test with penicilloyl polylysine, minor determinant mixture, benzylpenicillin, amoxicillin, and ampicillin; (2) patch tests with benzylpenicillin, amoxicillin, and ampicillin; (3) RAST for penicilloyls G and V; and (4) oral challenges with amoxicillin, ampicillin, and penicillin V in 18/24 patients. All patients were typed by microlymphotoxicity standard test for HLA class I and II antigens. Statistical analysis by chi2 test 2 x 2 contingency tables, according to Svejgaard, were used for comparison between patients and random Italian population (522 subjects). RESULTS: In the patients group we found higher prevalence of HLA A2 (12/24 = 50%, RR = 6.76 P < .001, EF = 0.425), DRw52 (20/24 = 83.3%, RR = 9.28, P < .001, EF = 0.74), and lower frequency of DR4 (3/24 = 12% ns). CONCLUSIONS: These data suggest that the immune mechanisms involved in adverse reactions to aminopenicillins in vivo are related to genetic markers of immune response and confirms that the presentation of penicillin-hapten determinants to lymphocyte is major histocompatibility complex restricted.     

5-Hydroxytryptamine1D-like receptors mediate contraction of partially depolarized rabbit renal arteries

OBJECTIVE: Our purpose was to correlate measures of Doppler-detected fetal movements with standard fetal heart rate parameters and perinatal outcomes. STUDY DESIGN: This prospective, multiinstitutional trial used the Hewlett-Packard M1350A monitor to record simultaneous fetal heart rate baseline, variability, accelerations, decelerations, and number of fetal movements, and duration and percent of total time. These data were compared at 10- and 30-minute intervals during nonstress tests and were correlated with fetal heart rate baseline parameters and maternally perceived fetal movements and with outcomes of infants delivered within 7 days of the last test. RESULTS: At six centers 1704 actocardiograms from 884 third-trimester patients were analyzed. Doppler-detected fetal movement counts, durations, and percent of total time correlated weakly with all baseline fetal heart rate parameters (all values < 0.20). All fetal movement parameters increased significantly in successive 10-minute blocks and in periods of increased or normal fetal heart rate variability compared with those with fetal heart rate variability. The sensitivity, specificity, and predictive values of the percent of total movement time were comparable to those of standard nonstress test parameters. The risk of poor perinatal outcomes after nonreactive nonstress tests was lower in cases with fetal movements than in those without. CONCLUSIONS: Doppler actocardiography may help to discriminate fetal states during antepartum testing. It may prevent inappropriate diagnosis of fetal compromise when the nonstress test is nonreactive or nonreassuring.     

Functional cross-talk between endothelial muscarinic and alpha2-adrenergic receptors in rabbit cerebral arteries

Interactions between two classes of receptors have been observed in several cell lines and preparations. The aim of this work was to assess the impact of simultaneous stimulation of endothelial muscarinic and alpha2-adrenergic receptors (alpha2-AR) on vascular reactivity. Rabbit middle cerebral arteries were isolated and changes in isometric tension were recorded in the presence of indomethacin. Inhibition of nitric oxide (NO) synthase with Nomega-nitro-L-arginine (L-NOARG, 100 micromol l(-1)) revealed alpha-AR-dependent contractions. Pre-addition of acetylcholine (ACH, 1 micromol l(-1)) augmented oxymetazoline (OXY, 10 micromol l(-1), alpha2-AR agonist)-, but decreased phenylephrine (PE, 10 micromol(-1), alpha1-AR agonist)-induced contraction (P<0.05). The effects of ACH were endothelium-dependent. Vessels were precontracted with 40 mmol l(-1) KCl-physiological salt solution (PSS) in the absence of L-NOARG, or PE or OXY in the presence of L-NOARG. In the presence of high external K+ or PE, ACH induced a potent relaxation (P<0.05). In the presence of OXY, however, ACH mediated contraction (P<0.05). After pertussis toxin (PTX, inactivator of Galpha(i/o) proteins) pre-treatment, alpha2-AR-dependent contractions were abolished. Forty mmol l(-1) KCl-PSS induced contraction was not altered by PTX whereas ACH-induced relaxation was augmented (P<0.05). To investigate if endothelin-1 (ET-1) intervened in the endothelium-dependent contractile response to ACH in the presence of OXY-dependent tone, vessels were incubated in the presence of BQ123 (1 micromol l(-1)), an ETA receptor antagonist. OXY-mediated tone was not affected by BQ123; however, ACH-induced contraction was reversed to a relaxation (P<0.05). These data indicate that activation of endothelial alpha2-AR triggers an endothelium-dependent, ET-1 mediated, contraction to ACH. This suggests that activation of alpha2-AR affects muscarinic receptor/G protein coupling leading to an opposite biological effect.     

Unselective inhibition of endothelin receptors reduces renal dysfunction in experimental diabetes

OBJECTIVE: To examine the current supply and distribution of obstetrician-gynecologists and project future supply under various scenarios. METHODS: A discrete actuarial supply model was developed, and practice patterns were analyzed. Supply projections under different scenarios, distributions, and practice profiles were examined. RESULTS: Women are expected to become the majority of practitioners by 2014. Continuation of current residency output will result in slow to no growth in obstetrician-gynecologist-to-female population ratios over the next 20 years. A minor (10%) reduction in specialty training would slow specialty growth over the next decade, followed by a slight reduction in supply. Services provided chiefly involve ambulatory reproductive health care, pregnancy, and surgical correction of conditions specific to the female genitourinary system. Even though the proportion of deliveries performed by midwives has increased and family practitioners have maintained their share, obstetrician-gynecologists provide the vast majority of obstetric care and virtually all services for perinatal complications. Generalist services represent relatively minor aspects of their practices. Care of the aged female population is highly fragmented among specialties; more than 50% of all aged Medicare beneficiaries who saw an obstetrician-gynecologist at least once failed to receive a majority of services from any one physician specialty. CONCLUSION: On the basis of trends in patient demographics and care patterns, obstetrician-gynecologists must resolve whether to provide more generalist office-based care, especially to the rapidly growing older female population, or to invest more intensively in surgical specialty care. The specialty's unique contributions to women's health should influence this decision.     

Flow-induced responses in cat isolated pulmonary arteries

Isolated, cannulated, endothelium-intact cat pulmonary arteries, averaging 692 +/- 104 microns in diameter, were set at a transmural pressure of 10 mmHg and monitored with a video system. Intraluminal flow was increased in steps from 0 to 1.6 ml/min by using a syringe pump. An electronic system held pressure constant by changing outflow resistance. Flow-diameter curves were generated in physiological saline solution. At constant transmural pressure, the arteries constricted in response to increased intraluminal flow. Constriction was not affected by removing extracellular Ca2+ but was abolished after treatment with ryanodine to deplete intracellular Ca2+ stores, with the endothelin-1 synthesis inhibitor phosphoramidon, with the endothelin A-receptor antagonist BQ-123, with the protein kinase C inhibitor staurosporine, or with glutaraldehyde to reduce endothelial cell deformability. The results indicate that isolated pulmonary arteries can constrict in response to intraluminal flow and suggest that constriction is mediated by endothelin-1 and depends on intracellular Ca2+ release and protein kinase C activation.     

Characterization of endothelin receptors in the human umbilical artery and vein

The aim of the present study was to characterize pharmacologically endothelin receptors that are present in human umbilical vessels. 2. Endothelin-1 (ET-1) and endothelin-2 (ET-2) are potent stimulants of both the human umbilical artery (pEC50 7.9 and 7.5) and vein (pEC50 8.1 and 8.0). Endothelin-3 (ET-3) is inactive on the artery but contracts the vein (pEC50 7.6). IRL1620 is inactive in both vessels. The order of potency of agonists is suggestive of a typical ET(A) receptor in the artery (ET-1 = ET-2 > > ET-3) and a mixture of ET(A) and ET(B) receptors in the vein (ET-1 = ET-2 > or = ET-3). 3. The selective ET(A) receptor antagonist, BQ123, competitively inhibits the effect of ET-1 in the human umbilical artery (pA2 6.9), while in the vein, only a mixture of BQ123 and BQ788 (a selective ET(B) antagonist) weakly displaces to the right of the cumulative concentration-response curve to ET-1. Contractions induced by ET-3 in the vein are inhibited by BQ788 (pA2 7.6), but not by BQ123. 4. Inhibition of Ca2+ channels by nifedipine (0.1 microM) is accompanied by a significant decrease of the maximal response to ET-1 by 40% in the artery and by 30% in the vein. The response of the vein to ET-3 is almost abolished by nifedipine. 5. The results indicate that: (i) endothelins contract the human isolated umbilical artery via stimulation of an ET(A) receptor type; (ii) the contraction induced by ET-1 in the vein is mediated by both ET(A) and ET(B) receptors, while ET-3 stimulates the ET(B) receptor; (iii) the contribution of Ca2+ channels to the contraction mediated by the ET(B) receptor appears to be more important than to that mediated by the ET(A) receptor.     

Evaluation of influence of 24-hour cold preservation on endothelin production and on endothelin receptors in the bone vasculature

Endothelin-1 is a vasoactive peptide produced by the vascular endothelium. It is one of the most potent endogenous vascular smooth muscle constrictors. Two subtypes of the endothelin receptor have been cloned and sequenced and denoted endothelin-A and endothelin-B. The aim of this study was to define the influence of cold ischemia on the production of endothelin-1 and on the endothelin receptors. Two different preservation techniques (cold storage only and cold storage with microperfusion with University of Wisconsin solution) also were compared. The study was performed in an in vitro bone perfusion model to isolate the vascular endothelium from blood components. The production of endothelin-1 by the bone vasculature was not altered after 24 hours of cold ischemia. No contractions were observed with S6c, a selective endothelin-B agonist, and this effect was not influenced by cold ischemia. The response mediated by the endothelin-A receptor was increased significantly, an effect that was not influenced by preservation with University of Wisconsin solution. This latter finding was the only significant alteration in the vascular function detected in the in vitro model after 24 hours of cold ischemia. With regard to the pharmacologic properties of endothelin-1, this mediated response could be implicated in the pathogenesis of vasospasm.     

Evaluation of bosentan, pinacidil and nitroprusside on human pulmonary arteries: comparison with rat pulmonary arteries

OBJECTIVE: The general objective of the Etude du Viellissement Arterial (EVA) program is to follow vascular aging and the decline in cognitive functions at the cerebrovascular level longitudinally over a 4-year period. One of the specific objectives of this EVA study is to examine epidemiologically the relationship between the markers of oxidative stress (lipid peroxidation), the antioxidant micronutrient status (particularly of selenium, vitamin E, and the carotenoids) and the prevalence of chronic disorders occurring during the pre-aging period. METHODS: 1389 subjects aged from 59 to 71 years were studied. RESULTS: The concentration of plasma lipid peroxides was higher than in young adults (2.91 +/- 0.38, men; 2.97 +/- 0.40, women (mumol/l). On the other hand, plasma Se (1.09 +/- 0.21, men; 1.10 +/- 0.19, women (mumol/l)), erythrocyte vitamin E (5.32 +/- 1.29, men; 5.52 +/- 1.28, women (mumol/l)), and total plasma carotenoids (2.19 +/- 0.98, men; 3.07 +/- 1.33, women (mumol/l)) were comparable to values in young adults. In our cohort, 40% of subjects had unremarkable medical histories. The disorders most often encountered were lipemia (29.8% of men, 36.1% of women), and hypertension (28.9% of men, 30.4% of women). CONCLUSION: Se and vitamin E levels were raised in cases of lipemia, especially in those treated with fibrates. The mechanism of the increase is unknown. In hypertensives and diabetics, there was a decrease in total carotenoids associated with increased peroxidative risk.     

Cholinesterase activity in human pulmonary arteries and veins

We present two cases of unusually large skull base paragangliomas. The first tumor was accompanied by marked bony destruction of the central skull base and multiple associated cysts. The second tumor arose along the petrous ridge, with a large intracranial component. The CT, MR imaging, angiographic, histologic, and electron microscopic findings of these unusual lesions are described.     

Endothelin receptors mediating vasoconstriction in rat pressurized small arteries

The effects of endothelin-1 (ET-1), a nonselective ETA and ETB receptor agonist, and sarafotoxin S6c, a selective ETB agonist, were investigated in the presence and absence of BQ123 and BQ788, ETA- and ETB-selective antagonists, respectively, in rat mesenteric small arteries, using a perfusion pressurized arteriograph in which segments of vessels were cannulated and exposed to constant pressure and flow. ET-1 (10(-13)-10(-7) M) induced vasoconstriction in both intact and endothelium-denuded arteries in a concentration-dependent manner. BQ123 (10(-7) and 10(-6) M) inhibited the effect of ET-1, displacing the concentration-response curve to the right in a concentration-dependent manner. The effect of ET-1 was not significantly affected by BQ788 (10(-7) and 10(-6) M), a selective antagonist of ETB receptors. Sarafotoxin S6c (10(-11)-10(-7) M) also induced a slight concentration-dependent vasoconstriction. The effect of sarafotoxin S6c (10(-8) M) was inhibited by the ETB-selective antagonist BQ788 (10(-7) M), but was not significantly changed by BQ123 (10(-7) M). Vasoconstriction induced by sarafotoxin S6c (10(-8) M) in a single bolus concentration was significantly greater than the contraction induced by the same concentration as part of a cumulative concentration-response curve, indicating desensitization or downregulation of ETB receptors during the latter. Repeated application of single concentrations of sarafotoxin S6c (10(-8) M) caused progressively smaller contraction of arteries. These results show the existence of both ETA and ETB vasoconstrictor receptors located on smooth muscle of small arteries. They also show that ETB receptors induce a smaller constrictor effect, and rapidly undergo desensitization after sustained or repeated activation.     

The pathology of the pulmonary arteries in lung tumors

A study was undertaken to analyse the type and extent of pathological changes in the pulmonary arteries in non-small cell malignant tumours of the lung. Large-section histological preparations were made from 33 squamous cell carcinomas and 30 adenocarcinomas (T1 and T2 tumours) and classified according to tumour margin area (zone 1), intermediate area (zone 2) and tumour centre (zone 3). Transmural tumour growth with intraluminal cell formations in the pulmonary artery branches were found in the centre of all adenocarcinomas and 86% of squamous cell carcinomas, involving subsegment, prelobular and lobular arteries. Obstructive and obliterative changes in the pulmonary arteries as the result of tumour compression and secondary fibrosing changes predominantly occurred in the centre of all tumours. They were less common and less marked in zones 1 and 2. -Pulmonary artery branches in lung tumours of stages T1 and T2 showed marked infiltrating, obliterative and secondary inflammatory changes as far as complete vascular occlusions. These observations indicate that cytotoxic drugs, introduced via the systemic circulation, cannot reach and therefore not exert their effects in extensive areas of tumour.     

Characterization of angiotensin receptors in rabbit isolated atria

Bremsstrahlung x-rays are produced when energetic beta-particles are emitted and absorbed. Measurements of total-body bremsstrahlung efficiencey (x-ray photon output per muCi 90Sr in the body, relative to that in water) have been made in the intact mouse, rat, rabbit, and dog sacrificed 2 weeks after the injection of 90Sr + 85Sr. Efficiencies were determined by a comparison of the bremsstrahlung output from 90Sr + its daughter 90Y and the gamma-ray emission of 85Sr. Results were checked by a beta-assay of the ashed animals. Bremsstrahlung efficiencies averaged 1.10 in a 0.04 kg mouse, 1.14 in a 0.13 kg rat, 1.23 in a 2.6 kg rabbit, and 1.32 in an 8.5 kg beagle. Extrapolating to a 70 kg human, a relative bremsstrahlung efficiency of about 1.4 is predicted. An estimate was made of the 90Sr body content in a former dial painter based on in vivo counting and a bremsstrahlung efficiency of 1.39 predicted for a 55 kg human female by these animal data. Our value of 1.42 +/- 0.08 muCi 90Sr was in good agreement with corresponding results reported for this subject by 8 other laboratories.     

Heterogeneity of tachykinin receptors in the rabbit lung

The tachykinins, substance P (SP) and neurokinin A (NKA), are agonists for the NK(1) and NK(2) receptors, respectively. Tachykinins have various respiratory effects, including bronchoconstriction. This study characterizes tachykinin binding sites in the rabbit lung. We hypothesize that (2-[(125)I]iodohistidyl(1))Neurokinin A ([(125)I]NKA) interacts with NK1 and NK2 binding sites in the rabbit lung. The K d determined from saturation isotherms was 0.69 times/divided by 1.14 nM (geometric mean times/divided by SEM) and the B max was 4.15 + or - 0.22 femtomole/mg protein (arithmetic mean + or - SEM). Competitive inhibition studies with NKA, SP and various selective tachykinin agonists showed the rank order of potency; [beta-Ala(8)]-Neurokinin A 4-10 = SP > NKA > [Sar(9),Met(02)11]-Substance P. [beta-Ala(8)]-Neurokinin A 4-10, a selective NK(2) agonist, and SP inhibition of [(125)I]NKA binding were best described using a two-site model. Competitive inhibition studies using the selective nonpeptide NK(2) antagonist (SR 48968) and the selective nonpeptide NK(1) antagonist (CP 96,345) revealed Ki's of 5.5 nM and 8.1 nM, respectively. Our data therefore suggest that [(125)I]NKA binds to both the NK(1) and NK(2) receptors in the lung.     

Variation in the size and distensibility of the pulmonary arteries in d-transposition of the great arteries

The relative size of the main pulmonary artery was determined from cineangiograms of 117 patients with d-transposition of the great arteries by calculating the ration between the diameters of the main pulmonary artery and aorta. The pulmonary artery was largest in patients with ventricular septal defect or patent ductus arteriosus, or both, because of increased pulmonary arterial pressure and flow. In patients with an intact ventricular septum or with left ventricular outflow tract obstruction, or both, the main pulmonary artery was approximately the size of the aorta. Two cases of d-transposition and gross dilatation of the main pulmonary artery and hypoplastic first branch pulmonary arteries are presented. In these cases the ratio between the diameters of the main pulmonary artery and aorta was greater than in any of the other 117 cases studied...     

Role of endothelin receptors, calcium and nitric oxide in the potentiation by endothelin-1 of the sympathetic contraction of rabbit ear artery during cooling

1. To examine further the potentiation by endothelin-1 on the vascular response to sympathetic stimulation, we studied the isometric response of isolated segments, 2 mm long, from the rabbit central ear artery to electrical field stimulation (1-8 Hz), under different conditions, at 37 degrees C and during cooling (30 degrees C). 2. Electrical stimulation produced frequency-dependent contraction, which was reduced (about 63% for 8 Hz) during cooling. At 30 degrees C, but not at 37 degrees C, endothelin-1 (1, 3 and 10 nM) potentiated the contraction to electrical stimulation in a dose-dependent way (from 43 +/- 7% to 190 +/- 25% for 8 Hz). 3. This potentiation by endothelin-1 was reduced by the antagonist for endothelin ETA receptors BQ-123 (10 microM) but not by the antagonist for endothelin ETB receptors BQ-788 (10 microM). The agonist for endothelin ETB receptors IRL-1620 (0.1 microM) did not modify the contraction to electrical stimulation. 4. The blocker of L-type Ca2+ channels verapamil (10 microM l-1) reduced (about 72% for 8 Hz) and the unspecific blocker of Ca(2+)-channels NiCl2 (1 mM) practically abolished (about 98%), the potentiating effects of endothelin-1 found at 30 degrees C. 5. Inhibition of nitric oxide synthesis with NG-nitro-L-arginine (L-NOARG, 0.1 mM) increased the contraction to electrical stimulation at 30 degrees C more than at 37 degrees C (for 8 Hz, this increment was 297 +/- 118% at 30 degrees C, and 66 +/- 15% at 37 degrees C). Endothelium removal increased the contraction to electrical stimulation at 30 degrees C (about 91% for 8 Hz) but not at 37 degrees C. Both L-NOARG and endothelium removal abolished the potentiating effects of endothelin-1 on the response to electrical stimulation found at 30 degrees C. 6. These results in the rabbit ear artery suggest that during cooling, endothelin-1 potentiates the contraction to sympathetic stimulation, which could be mediated at least in part by increasing Ca2+ entry after activation of endothelin ETA receptors. This potentiating effect of endothelin-1 may require the presence of an inhibitory tone due to endothelial nitric oxide.