Brain metastases: Single-dose radiosurgery versus hypofractionated stereotactic radiotherapy: A retrospective study.

BACKGROUND: Radiosurgery is employed for the treatment of brain metastases. The aim of this study is to evaluate the efficacy and tolerability of single-dose radiosurgery (SRS) compared to hypofractionated stereotactic radiotherapy (hFSRT). MATERIALS AND METHODS: Between 2004 and 2018, we analyzed treatments of 97 patients with 135 brain metastases. Fifty-six patients were treated with SRS, and 41 patients were treated with hFSRT. Median dose was 16 Gy (12-20 Gy) for the SRS group and 30 Gy in 5-6 fractions for the hFSRT group. hFSRT was used for larger lesions and lesions located near critical structures. Kaplan-Meier curves were constructed for overall survival (OS) and local control (LC). RESULTS: Median age was 64 years (range, 32-89 years). Median survival was 10 months (1-68 months). With a median follow-up of 10 months, no significant differences in OS between groups were found (P=0.21). LC for all patients was 67%. Local progression-free survival (LPFS) at 6 months and 1 year was 71% and 60% for the SRS group, respectively, and 80% and 69% for the hFSRT group, respectively (P=0.93). Although hFSRT was used for larger lesions and lesions in adverse locations, LPFS was not inferior compared to lesions treated with SRS. We observed acute toxicity grade 1-2 in 25 patients (25.8%). Late complications were observed in 11 patients (11.3%). Acute and late toxicity was similar in the SRS- and hFSRT-treated patients (P=0.63 and P=0.11, respectively). Brain recurrence occurred in 37.5% and 14.6% in the hFSRT and SRS group, respectively (P=0.06). CONCLUSIONS: Since patients treated with hFSRT exhibited similar survival and LPFS rates without differences in toxicity compared to those treated with SRS, hFSRT can be beneficial, particularly for patients with brain metastases. RELEVANCE FOR PATIENTS: Hypofractionated schemes in stereotactic radiosurgery offers treatment alternatives to patients with large lesions or lesions near critical structures.

Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin II-induced hypertension.

BACKGROUND AND PURPOSE: Toll-like receptor 4 (TLR4) signalling contributes to inflammatory cardiovascular diseases, but its role in hypertension and the associated vascular damage is not known. We investigated whether TLR4 activation contributed to angiotensin II (AngII)-induced hypertension and the associated vascular structural, mechanical and functional alterations. EXPERIMENTAL APPROACH: AngII was infused (1.44 mg · kg(-1) · day(-1), s.c.) for 2 weeks in C57BL6 mice, treated with a neutralizing anti-TLR4 antibody or IgG (1 µg · day(-1); systolic BP (SBP) and aortic cytokine levels were measured. Structural, mechanical and contractile properties of aortic and mesenteric arterial segments were measured with myography and histology. RT-PCR and Western blotting were used to analyse these tissues and cultured vascular smooth muscle cells (VSMC) from hypertensive rats (SHR). KEY RESULTS: Aortic TLR4 mRNA levels were raised by AngII infusion. Anti-TLR4 antibody treatment of AngII-treated mice normalised: (i) increased SBP and TNF-α, IL-6 and CCL2 levels; (ii) vascular structural and mechanical changes; (iii) altered aortic phenylephrine- and ACh-induced responses; (iv) increased NOX-1 mRNA levels, superoxide anion production and NAD(P)H oxidase activity and effects of catalase, apocynin, ML-171 and Mito-TEMPO on vascular responses; and (v) reduced NO release and effects of L-NAME on phenylephrine-induced contraction. In VSMC, the MyD88 inhibitor ST-2825 reduced AngII-induced NAD(P)H oxidase activity. The TLR4 inhibitor CLI-095 reduced AngII-induced increased phospho-JNK1/2 and p65 NF-κB subunit nuclear protein expression. CONCLUSIONS AND IMPLICATIONS: TLR4 up-regulation by AngII contributed to the inflammation, endothelial dysfunction, vascular remodelling and stiffness associated with hypertension by mechanisms involving oxidative stress. MyD88-dependent activation and JNK/NF-κB signalling pathways participated in these alterations.

Intraoperative radiotherapy-containing multidisciplinary management of trunk-wall soft-tissue sarcomas

PURPOSE: A joint analysis of data from centers within the intraoperative radiotherapy (IORT)-Spanish cooperative initiative was performed to investigate the main contributions of IORT to the multidisciplinary treatment of trunk-wall soft-tissue sarcoma (TW-STS). MATERIALS AND METHODS: Patients with a histologic diagnosis of TW-STS (primary tumor 53 %; locally recurrent 47 %) with absence of distant metastases, undergoing surgery with radical intent and IORT (median dose 12.5 Gy) were considered eligible for participation in this study. In addition, all primary tumors received external-beam radiotherapy (median dose 50 Gy). RESULTS: From 1986 to 2012, a total of 68 patients were analyzed in the study from three Spanish institutions. With a median follow-up time of 53 months (range 4-316), 5-year local control (LC) was 58 %. Five-year IORT in-field control, disease-free survival (DFS) and overall survival were 70, 45 and 51 %, respectively. On multivariate analysis, only microscopically involved margin (R1) resection status retained significance in relation to LC (HR 3.97, p < 0.001). In regard to IORT in field control, incomplete resection (HR 3.23, p = 0.008) and recurrent disease status (HR 2.52, p = 0.04) retained a significant association in multivariate analysis. CONCLUSION: From this joint analysis emerges the fact that margin and disease status influences local and central control, but DFS remains modest, given the high risk of distant metastases. Intensified local treatment needs to be tested in the context of more efficient concurrent, neo-, and adjuvant systemic therapy (AU)

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Intraoperative radiotherapy-containing multidisciplinary management of trunk-wall soft-tissue sarcomas.

PURPOSE: A joint analysis of data from centers within the intraoperative radiotherapy (IORT)-Spanish cooperative initiative was performed to investigate the main contributions of IORT to the multidisciplinary treatment of trunk-wall soft-tissue sarcoma (TW-STS). MATERIALS AND METHODS: Patients with a histologic diagnosis of TW-STS (primary tumor 53 %; locally recurrent 47 %) with absence of distant metastases, undergoing surgery with radical intent and IORT (median dose 12.5 Gy) were considered eligible for participation in this study. In addition, all primary tumors received external-beam radiotherapy (median dose 50 Gy). RESULTS: From 1986 to 2012, a total of 68 patients were analyzed in the study from three Spanish institutions. With a median follow-up time of 53 months (range 4-316), 5-year local control (LC) was 58 %. Five-year IORT in-field control, disease-free survival (DFS) and overall survival were 70, 45 and 51 %, respectively. On multivariate analysis, only microscopically involved margin (R1) resection status retained significance in relation to LC (HR 3.97, p < 0.001). In regard to IORT in field control, incomplete resection (HR 3.23, p = 0.008) and recurrent disease status (HR 2.52, p = 0.04) retained a significant association in multivariate analysis. CONCLUSION: From this joint analysis emerges the fact that margin and disease status influences local and central control, but DFS remains modest, given the high risk of distant metastases. Intensified local treatment needs to be tested in the context of more efficient concurrent, neo-, and adjuvant systemic therapy.

Pilot study of feasibility and dosimetric comparison of prone versus supine breast radiotherapy

PURPOSE: The aim of this study was to demonstrate feasibility and analyze dosimetric differences in prone and supine position breast cancer radiotherapy in women with large or pendulous breast. METHODS: Ten post-lumpectomy breast cancer patients underwent supine and prone computed tomography-based treatment plan. On each data set, the whole breast, the ipsilateral lung and the heart were outlined. Multisegment tangential-fields plans were generated for each position. Target coverage, homogeneity, overdosage outside breast and organ at risk sparing were analyzed and compared for supine and prone position. RESULTS: Coverage and dose homogeneity of the PTV measured by D 90 and V(95)% were similar for both plans although breast maximum dose was higher in the supine plan (p = 0.017). Prone position reduced the percentage of ipsilateral lung receiving 20 Gy (V(20Gy)) from 26.5 to 2.9 % (p = 0.007), medium lung dose, as well as the percentage of the heart receiving 35 Gy heart (V(35Gy)) from 3.4 to 1.2 % (p = 0.038). Overdosage of areas outside breast PTV was also consistently reduced with prone position (p = 0.012). In addition, average number of segments and monitor units needed was reduced in prone position. CONCLUSIONS: Prone position in large breast women appears to favor normal tissue sparing in breast radiotherapy as compared to supine position, without diminishing the target coverage (AU)

Retreatment with radiotherapy for symptomatic bone, brain or visceral metastases

BACKGROUND: The need for reirradiation in the metastatic disease appears when other modalities of treatment lose their efficacy. The aim of reirradiation in the metastatic disease is mainly palliative to control a particular symptom. However, this theoretical benefit must be confronted against the risk of an undesirable toxicity. MATERIALS AND METHODS: Experience with reirradiation for symptomatic bone, brain or visceral metastases are reviewed. Twenty-two patients were found to have a second palliative radiotherapy on the same location. Locatión of metastases were visceral in 5 (23 %) patients, brain in 4 (18 %) patients, spine in 1 (4.5 %) patient and bone metastasis other than spine in 12 (54.5 %) patients. Median dose delivered in the first treatment was 30 Gy (range 20-30 Gy) and 20 Gy for the second treatment (range 6-32.4 Gy). RESULTS: A good symptomatic response after first irradiation (complete response or disappearance of >50 % of symptoms) was reached in 21 (95.5 %) of the 22 patients analyzed. After second irradiation, 82 % (18 patients) achieved a good response, 3 (14 %) patients had a moderate response (relief of symptoms <50 %) whereas no response was observed in 1 (4 %) patient. Acute toxicity was limited to grade 1-2 proctitis in 2 and 3 patients after the first and second irradiation, respectively. No cases of late toxicity after the first or second irradiation were recorded. CONCLUSION: A second treatment with palliative radiotherapy is feasible and well tolerated and offers the possibility of symptomatic relief in a high percentage of patients with symptomatic metastases (AU)

Retreatment with radiotherapy for symptomatic bone, brain or visceral metastases.

BACKGROUND: The need for reirradiation in the metastatic disease appears when other modalities of treatment lose their efficacy. The aim of reirradiation in the metastatic disease is mainly palliative to control a particular symptom. However, this theoretical benefit must be confronted against the risk of an undesirable toxicity. MATERIALS AND METHODS: Experience with reirradiation for symptomatic bone, brain or visceral metastases are reviewed. Twenty-two patients were found to have a second palliative radiotherapy on the same location. Locatión of metastases were visceral in 5 (23 %) patients, brain in 4 (18 %) patients, spine in 1 (4.5 %) patient and bone metastasis other than spine in 12 (54.5 %) patients. Median dose delivered in the first treatment was 30 Gy (range 20-30 Gy) and 20 Gy for the second treatment (range 6-32.4 Gy). RESULTS: A good symptomatic response after first irradiation (complete response or disappearance of >50 % of symptoms) was reached in 21 (95.5 %) of the 22 patients analyzed. After second irradiation, 82 % (18 patients) achieved a good response, 3 (14 %) patients had a moderate response (relief of symptoms <50 %) whereas no response was observed in 1 (4 %) patient. Acute toxicity was limited to grade 1-2 proctitis in 2 and 3 patients after the first and second irradiation, respectively. No cases of late toxicity after the first or second irradiation were recorded. CONCLUSION: A second treatment with palliative radiotherapy is feasible and well tolerated and offers the possibility of symptomatic relief in a high percentage of patients with symptomatic metastases.

Pilot study of feasibility and dosimetric comparison of prone versus supine breast radiotherapy.

PURPOSE: The aim of this study was to demonstrate feasibility and analyze dosimetric differences in prone and supine position breast cancer radiotherapy in women with large or pendulous breast. METHODS: Ten post-lumpectomy breast cancer patients underwent supine and prone computed tomography-based treatment plan. On each data set, the whole breast, the ipsilateral lung and the heart were outlined. Multisegment tangential-fields plans were generated for each position. Target coverage, homogeneity, overdosage outside breast and organ at risk sparing were analyzed and compared for supine and prone position. RESULTS: Coverage and dose homogeneity of the PTV measured by D 90 and V(95)% were similar for both plans although breast maximum dose was higher in the supine plan (p = 0.017). Prone position reduced the percentage of ipsilateral lung receiving 20 Gy (V(20Gy)) from 26.5 to 2.9 % (p = 0.007), medium lung dose, as well as the percentage of the heart receiving 35 Gy heart (V(35Gy)) from 3.4 to 1.2 % (p = 0.038). Overdosage of areas outside breast PTV was also consistently reduced with prone position (p = 0.012). In addition, average number of segments and monitor units needed was reduced in prone position. CONCLUSIONS: Prone position in large breast women appears to favor normal tissue sparing in breast radiotherapy as compared to supine position, without diminishing the target coverage.

Dynamic skin changes of acute radiation dermatitis revealed by in vivo reflectance confocal microscopy.

BACKGROUND: A better knowledge of the dynamic biological changes that the skin undergoes in response to ionizing radiation is advisable to improve the management of radiation dermatitis, allowing selection of patients needing treatment or close monitoring. OBJECTIVE: To describe the evolution of the skin in response to ionizing radiation through the reflectance confocal microscopy (RCM) features of acute radiation dermatitis. METHODS: In this prospective descriptive study, six women (median age, 55 years; range, 45-80 years) diagnosed with breast cancer in stages IA-IB undergoing adjuvant radiotherapy were included in the study through consecutive sampling. Clinical, dermoscopic and RCM evaluation of the skin were performed prior to treatment and on days 1, 15, 30 and 45 after radiotherapy. RESULTS: While clinical features of radiation dermatitis emerged after 30 days on average, histopathological changes were detectable by RCM after a mean time of 15 days. The main RCM features included initial appearance of spongiosis, exocytosis and inflammatory cells followed by the presence of dendritic-shaped cells, 'streaming-like figures', 'broken geographic papillae', epidermal architectural disarray, effacement of rete ridges, melanophages and, finally, hyperpigmentation of the basal layer. CONCLUSIONS: RCM may safely detect the dynamic biological changes that the skin undergoes in response to ionizing radiation, even before than clinical onset of acute radiation dermatitis. Therefore, RCM may be useful to make an early and non-invasive diagnosis of radiation dermatitis during radiotherapy, allowing an early selection of patients needing treatment or close monitoring and avoiding skin biopsies.

High-dose-rate (HDR) plesiotherapy with custom-made moulds for the treatment of non-melanoma skin cancer

BACKGROUND: Non-melanoma skin tumours (NMSC) are one of the most frequent types of cancer, accounting for nearly one third of newly diagnosed tumours. NMSC are frequently diagnosed in elderly patients and while mortality rates are low, NMSC can be associated with significant morbidity in terms of cosmetic and functional impairment. OBJECTIVE: Surgical excision is nowadays considered the standard treatment for NMSC, although this approach might not be suitable for all the patients. Good rates of local control and cosmetic outcome are achieved by using high-dose-rate (HDR) plesiotherapy. METHODS: Nine consecutive patients with 11 NMSC were treated with custom-made moulds and HDR plesiotherapy reaching a fi nal dose of 44-48 Gy in 11-12 fractions of 4 Gy over 4 weeks. RESULTS: No local or distant relapses have been observed after a mean follow-up of 15 months (range 4-36 months). Acute toxicity was acceptable and cosmetic result was considered as excellent/good in 7 patients. CONCLUSIONS: This modality of treatment offers an alternative for those patients not candidates for surgical procedures because of medical contraindications or risk of disfigurement or functional impairment (AU)

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Radioterapia de las áreas ganglionares locorregionales en el cáncer de mama / No disponible

La radioterapia constituye una parte fundamental en el tratamientoconservador del cáncer de mama. La irradiación dela mama restante tras una tumorectomía o una cuadrantectomíaha demostrado aumentar tanto el control local como la supervivenciaglobal y causa específica en las pacientes con cáncerde mama. De igual forma, cuando existe afectacióntumoral de las áreas ganglionares regionales puede ser necesariola realización de radioterapia sobre las mismas. En el presenteartículo se revisan las indicaciones de radioterapia en loscasos de cáncer de mama con afectación no sólo local sinotambién de las cadenas ganglionares axilar, supraclaviculary/o mamaria interna(AU)

Radiotherapy alter breast conserving surgery remains as afundamental aspect of breast cancer management. The treatmentof the whole breast after lumpectomy or quadrantectomyis associated with a significant improvement in local control,cancer survival and even overall survival. Irradiation ofregional lymphatic areas is a challenging issue subjected tocontinuous revision. The aim of this paper is to review the roleof the radiation therapy of the lymphatic areas of the axilla,supraclavicular fossa and internal mammary node chain in thetreatment of breast cancer(AU)

Chronic ouabain treatment increases the contribution of nitric oxide to endothelium-dependent relaxation.

The aim of this study was to analyze the contribution of nitric oxide, prostacyclin and endothelium-dependent hyperpolarizing factor to endothelium-dependent vasodilation induced by acetylcholine in rat aorta from control and ouabain-induced hypertensive rats. Preincubation with the nitric oxide synthase inhibitor N-omega-nitro-L-arginine methyl esther (L-NAME) inhibited the vasodilator response to acetylcholine in segments from both groups but to a greater extent in segments from ouabain-treated rats. Basal and acetylcholine-induced nitric oxide release were higher in segments from ouabain-treated rats. Preincubation with the prostacyclin synthesis inhibitor tranylcypromine or with the cyclooxygenase inhibitor indomethacin inhibited the vasodilator response to acetylcholine in aortic segments from both groups. The Ca2+-dependent potassium channel blocker charybdotoxin inhibited the vasodilator response to acetylcholine only in segments from control rats. These results indicate that hypertension induced by chronic ouabain treatment is accompanied by increased endothelial nitric oxide participation and impaired endothelium-dependent hyperpolarizing factor contribution in acetylcholine-induced relaxation. These effects might explain the lack of effect of ouabain treatment on acetylcholine responses in rat aorta.

Chronic ouabain treatment increases the contribution of nitric oxide to endotheliumdependent relaxation

The aim of this study was to analyze the contribution of nitric oxide, prostacyclinand endothelium-dependent hyperpolarizing factor to endothelium-dependentvasodilation induced by acetylcholine in rat aorta from control and ouabain-inducedhypertensive rats. Preincubation with the nitric oxide synthase inhibitor N-omeganitro-L-arginine methyl esther (L-NAME) inhibited the vasodilator response toacetylcholine in segments from both groups but to a greater extent in segments fromouabain-treated rats. Basal and acetylcholine-induced nitric oxide release were higherin segments from ouabain-treated rats. Preincubation with the prostacyclin synthesisinhibitor tranylcypromine or with the cyclooxygenase inhibitor indomethacininhibited the vasodilator response to acetylcholine in aortic segments from bothgroups. The Ca2+-dependent potassium channel blocker charybdotoxin inhibited thevasodilator response to acetylcholine only in segments from control rats. Theseresults indicate that hypertension induced by chronic ouabain treatment is accompaniedby increased endothelial nitric oxide participation and impaired endotheliumdependenthyperpolarizing factor contribution in acetylcholine-induced relaxation.These effects might explain the lack of effect of ouabain treatment on acetylcholineresponses in rat aorta (AU)

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Role of NADPH oxidase and iNOS in vasoconstrictor responses of vessels from hypertensive and normotensive rats.

BACKGROUND AND PURPOSE: To analyse the influence of hypertension in the modulation induced by inducible NOS (iNOS)-derived NO and superoxide anion (O(2) (*-)) of vasoconstrictor responses and the sources of O(2) (*-) implicated. EXPERIMENTAL APPROACH: Vascular reactivity experiments were performed in segments of aorta from normotensive, Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR); protein and mRNA expressions were respectively measured by western blot and quantitative reverse transcription-polymerase chain reaction and O(2) (*-) production was evaluated by ethidium fluorescence. KEY RESULTS: The contractile responses to phenylephrine (1 nM-30 microM) and 5-hydroxytryptamine (0.1-100 microM) were greater in aortic segments from SHR than WKY. The selective iNOS inhibitor, 1400W (10 microM), increased the phenylephrine contraction only in WKY segments; however, iNOS protein and mRNA expressions were greater in aorta from SHR than WKY. Superoxide dismutase (SOD, 150 U ml(-1)) reduced phenylephrine and 5-hydroxytryptamine responses only in aorta from SHR; the NAD(P)H oxidase inhibitor apocynin (0.3 mM) decreased phenylephrine and 5-hydroxytryptamine responses more in vessels from SHR than WKY. Co-incubation with SOD plus 1400W potentiated the phenylephrine and 5-hydroxytryptamine responses more in segments from SHR than WKY. O(2) (*-) production was greater in aorta from SHR than WKY; apocynin abolished this difference. CONCLUSIONS AND IMPLICATIONS: Increased O(2) (*-) formation from NADP(H) oxidase in vessels from hypertensive rats contributes to the vasoconstrictor responses and counteract the increase of NO from iNOS and the consequent modulation of these responses.

Atención farmacéutica geriátrica / Pharmaceutical care process in aged

Los problemas relacionados con los medicamentosson causa frecuente de accidentes enlas personas mayores. Suponen un número importantede los ingresos hospitalarios y causa demuerte. Este hecho, unido a que el consumo demedicamentos y material sanitario incrementapaulatinamente el gasto farmacéutico de estegrupo de población, hace imprescindible la profesionalizaciónde la Atención Farmacéutica Geriátricacon el objetivo de minimizar los problemas,mejorar la eficiencia y por tanto mejorar lacalidad de vida de las personas mayores y disminuirel gasto sanitario. En este articulo se explicala estructuración del proceso de atención farmacéuticaen las organizaciones sociosanitarias deFundación Matia

The problems related with drug therapy are thefrequent reason of accidents in elderly people.They are supposed to be a big number of hospitaladmittances and death cause. This fact, linkedto the consumption of drugs and sanitary materialincreases gradually the pharmaceutical cost ofthis group of population, makes essential to professionalizethe Geriatric Pharmaceutical Carewith the objective of minimize the problems, improvethe efficiency and therefore improve thequality of life of elderly people and diminish thesanitary cost. In this article Matia`s Foundationexperience in the Pharmaceutical geriatric careprocess is described

Radioterapia paliativa en niños: presentación de un caso clínico y recuerdo de sus indicaciones / Palliative radiotherapy in children: presentation of a clinical case and recall of indications

- Propósito: conocer el papel de la radioterapia como tratamiento paliativo en la patología oncológica pediátrica.- Caso clínico: se comenta el caso de un niño de 10 años con neuroblastoma estadio IV de inicio que a pesar de sucesivos esquemas de tratamiento por progresión presentó metástasis cerebral única a los tres años del diagnóstico.- Resultados y conclusiones: revisada la literatura, se puede afirmar que la radioterapia es un tratamiento paliativo eficaz y adecuado cuando nuestro objetivo es controlar síntomas y ofrecer calidad de vida (AU)

University of Wisconsin solution increases hyperpolarizing mechanisms in response to bradykinin.

BACKGROUND: The aim of this study was to determine the effect of University of Wisconsin solution (UWS) incubation on bradykinin-induced vasodilation. METHODS: Porcine coronary arteries were incubated in Krebs-Henseleit solution (KHS) or UWS at 4 degrees C for 20 hours. Endothelium-dependent relaxation to bradykinin and endothelium-independent relaxation to nitric oxide were tested after U46619 or KCl pre-contraction. Nitric oxide synthase activity and protein expression was determined by [3H]-L-citrulline formation and western blot analysis, respectively. RESULTS: The relaxation to bradykinin (0.1 to 300 nmol/liter) after U46619 (30 to 300 nmol/liter) pre-contraction was similar with both KHS and UWS pre-incubation; however, it was reduced after KCl pre-contraction (15 to 20 mmol/liter), this reduction being greater after UWS incubation. The inhibitory effect of N(G)-nitro-L-arginine methylester (0.1 mmol/liter) on bradykinin-induced relaxation was lower in UWS- than KHS-incubated segments after U46619 pre-contraction, but similar after KCl pre-contraction; however, the inhibitory effect of 0.5 mmol/liter ouabain was unaffected. Tetraethylammonium (5 mmol/liter) reduced the response to bradykinin more strongly after UWS pre-incubation. UWS did not modify relaxation to nitric oxide (0.1 to 30 micromol/liter) in pre-incubated UWS or KHS segments. UWS failed to modify both total nitric oxide synthase activity and endothelial nitric oxide synthase expression. CONCLUSIONS: UWS incubation decreased nitric oxide participation and increased the hyperpolarizing mechanisms produced by bradykinin.

Mechanisms involved in relaxation induced by exogenous nitric oxide in pig coronary arteries.

The aim of the present study was to analyze the mechanisms involved in the vasodilator responses elicited by nitric oxide (NO) in segments of porcine posterior descending coronary artery. Exogenous NO (0.1-30 microM) induced concentration-dependent relaxations in segments precontracted with a concentration of the thromboxane A2 mimetic, U-46619 (30-300 nM) that produced a contraction 70% (submaximal contraction) of that elicited by 75 mM K+ (maximal contraction). The relaxations were almost abolished by 6-anilinoquinoline-5,8-quinone (LY-83583, 10 microM), an inhibitor of guanylate cyclase, and with precontraction with 40 or 60 mM K+. Relaxations were reduced by 5 mM tetraethylammonium (TEA), a blocker of Ca(2+)-activated K+ channels (Kca channels) and unaltered by ouabain (500 microM), 4-aminopyridine (1 mM), glibenclamide (10 microM), apamin (1 microM) and charybdotoxin (0.3 microM), inhibitors of sodium pump, voltage-sensitive, ATP-sensitive, small-conductance Kca and large-conductance KcaK+ channels, respectively. These results suggest that the relaxation caused by exogenous NO is mediated by guanylate cyclase activation, with only a slight participation of a hyperpolarizing mechanism mediated by activation of Kca channels.

Mechanisms of bradykinin-induced relaxation in pig coronary arteries.

Bradykinin (BK) induced endothelium- and concentration-dependent relaxations in segments of porcine posterior descending coronary arteries submaximally precontracted with the thromboxane A2 mimetic, U-46619. The effects of BK were reduced by L-NG-monomethylarginine (L-NMMA) and 6-anilinoquinoline-5,8-quinone (LY-83583), respective inhibitors of nitric oxide (NO) synthase and guanylate cyclase, but were unaffected by the cytochrome P450 monoxygenase blocker, thiopentone sodium; however, BK effects were slightly reduced by dimethyl sulfoxide (DMSO), an hydroxyl radical scavenger. Relaxant responses were reduced markedly by ouabain, a sodium pump inhibitor but only slightly by tetraethylammonium (TEA) and charybdotoxin, respective blockers of Ca-activated (KCa) and large-conductance (BKCa) K+ channels. However, BK responses were practically abolished by TEA + L-NMMA + ouabain while unaffected by apamin, 4-aminopyridine and glibenclamide, blockers of small-conductance KCa voltage-sensitive and ATP-sensitive K+ channels, respectively. In segments submaximally precontracted with K+, BK-induced relaxation was lower than that of those precontracted with U-46619, and was further reduced by L-NMMA, LY-83583 and especially, ouabain; L-NMMA + ouabain + TEA abolished the effect. Precontraction of segments with higher K+ concentrations almost abolished the relaxation. These results suggest that the relaxation to BK is mediated: 1) by endothelial NO release which activates guanylate cyclase of smooth muscle cells; 2) by hydroxyl radicals; and 3) by an endothelial hyperpolarizing factor, that does not seem to be a metabolite derived from cytochrome P450 monoxygenases and that relaxes activating K+ channels (mainly BKCa), and especially, the sodium pump.