cardiovascular-agents and Hypercapnia

To further our understanding of central sleep apnea (CSA) at high altitude during acclimatization, we tested the hypothesis that pharmacologically altering cerebral blood flow (CBF) would alter the severity of CSA at high altitude.. The study was a randomized, placebo-controlled single-blind study.. A field study at 5,050 m in Nepal.. We studied 12 normal volunteers.. Between days 5 to 10 at high altitude, CBF velocity (CBFv) was increased by intravenous (IV) acetazolamide (10 mg/kg) and reduced by oral indomethacin (100 mg).. Arterial blood gases, hypoxic and hypercapnic ventilatory responses, and CBFv and its reactivity to carbon dioxide were measured awake. Overnight polysomnography was performed. The central apnea-hypopnea index was elevated following administration of indomethacin (89.2 ± 43.7 to 112.5 ± 32.9 events/h; mean ± standard deviation; P < 0.05) and was reduced following IV acetazolamide (89.2 ± 43.7 to 47.1 ± 48.1 events/h; P < 0.001). Intravenous acetazolamide elevated CBFv at high altitude by 28% (95% confidence interval [CI]: 22-34%) but did not affect ventilatory responses. The elevation in CBFv was partly mediated via a selective rise in partial pressure of arterial carbon dioxide (PaCO2) (28 ± 4 to 31 ± 3 mm Hg) and an associated fall in pH (P < 0.01). Oral indomethacin reduced CBFv by 23% (95% CI: 16-30%), blunted CBFv reactivity, and increased the hypercapnic ventilatory response by 66% (95% CI: 30-102%) but had no effect on PaCO2 or pH.. Our findings indicate an important role for cerebral blood flow regulation in the pathophysiology of central sleep apnea at high altitude.

Topics: Acclimatization; Acetazolamide; Administration, Intravenous; Administration, Oral; Adult; Altitude; Carbon Dioxide; Cardiovascular Agents; Cerebrovascular Circulation; Female; Humans; Hypercapnia; Hypoxia; Indomethacin; Male; Middle Aged; Polysomnography; Single-Blind Method; Sleep Apnea, Central; Wakefulness; Young Adult

Impaired cerebral vasoreactivity to endothelium-dependent stimuli were described in type 2 diabetes mellitus (T2DM), but the mechanisms underlying that impairment are still unclear. The aim of this study was to investigate the role of cyclooxygenases' metabolites in response to acute hypercapnic stimulus in cerebral vessels, in patients with T2DM.. Vascular responses in the breath-holding test (BHT) were assessed in the absence/presence of a non-selective, reversible-inhibitor of cyclooxygenases, indomethacin (INDO), by functional transcranial Doppler sonography of the middle cerebral artery (N of patients=50; 33 men and 17 women). The functional hemodynamic parameter mean flow velocity (MFV) was assessed at rest, before and 90min after 100mg of INDO, and during the BHT. Breath holding index (BHI) [(MFV at the end of BHT minus MFV at rest)/MFV at rest)×100/s of breath-holding] was calculated after BHT performed before and 90min after INDO.. MFV at rest significantly decreased after INDO administration compared with a control condition before INDO (at rest before INDO from 49.36±15.09 to 36.72±8.45 after INDO, p<0.001) However, overall cerebral vessel vasoreactivity to hypercapnia, evaluated with BHI, was significantly improved after INDO administration compared with the BHI before INDO administration (from 0.68±0.4 to 1.27±0.42, p<0.001).. The improvement in cerebral vasoreactivity in response to BHT after INDO administration suggests that the production of a vasoconstrictor metabolite of cyclooxygenase in diabetic patients was reduced by indomethacin consumption.

Topics: Adolescent; Adult; Aged; Brain; Cardiovascular Agents; Cerebrovascular Circulation; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Hemodynamics; Humans; Hypercapnia; Indomethacin; Male; Middle Aged; Middle Cerebral Artery; Prognosis; Prospective Studies; Ultrasonography, Doppler, Transcranial; Young Adult

The origin of dyspnea in chronic heart failure (HF) is multifactorial, and excessive ventilation is thought to play a role in inducing this symptom. Chemosensivity is augmented in HF, correlates with increased pulmonary ventilation (VE), and is an adverse prognostic marker. Despite increased blood levels of natriuretic peptides in clinical conditions associated with dyspnea, their effect on pulmonary VE and chemoreceptor activity remains unexplored.. We tested in a prospective, placebo-controlled, three-way cross-over, double-blind randomized study the effects of the recombinant form of the natural human B-type natriuretic peptide (R-BNP) in comparison with placebo and levosimendan on chemoreflex sensitivity at rest, as well as their effects on pulmonary VE, systemic blood pressure, heart rate and sympathetic serum activity both at rest and during exercise.. Eleven stable chronic HF patients were randomized to sessions of 6-min treadmill-walking tests during placebo, or levosimendan or R-BNP intravenous infusion in the following conditions: room air, hypoxia, and hypercapnia. R-BNP administration determined higher pulmonary ventilatory response at rest and during exercise (P < 0.001) consequent to a boost of respiratory rate (P < 0.001) under room air and hypoxia conditions. Norepinephrine blood levels increased from rest to exercise in all conditions without differences among placebo, levosimendan, and R-BNP effects. BNP blood levels remained unchanged.. The novelty of the present findings is that R-BNP infusion in HF patients can boost pulmonary ventilatory response at rest and during exercise.

Topics: Adult; Brazil; Cardiovascular Agents; Chemoreceptor Cells; Chronic Disease; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Heart Failure; Hemodynamics; Humans; Hydrazones; Hypercapnia; Hyperventilation; Hypoxia; Infusions, Intravenous; Lung; Male; Middle Aged; Natriuretic Peptide, Brain; Prospective Studies; Pyridazines; Recombinant Proteins; Respiratory Rate; Simendan; Time Factors; Treatment Outcome

We tested whether breath hold divers (BHD) and obstructive sleep apnea (OSA) subjects had similar middle cerebral artery velocity (MCAV) responses to hypercapnea and hypocapnea. We analyzed changes in MCAV (cm/s) in response to hypocapnea and hyperoxic hypercapnea during placebo or after 90 min of oral indomethacin (100 mg) in BHD (N=7) and OSA (N=7). During control hypercapnea MCAV increased for 54.4% in BHD and 48.4% in OSA. Indomethacin blunted the MCAV increase in response to hypercapnea in BHD (P=0.02), but not in OSA. Indomethacin attenuated the mean arterial pressure response in BHD, but not in OSA. The blunted MCAV responses to hypercapnea with indomethacin in BHD, but not in OSA patients suggests that (a) the normal contribution of local vasodilating mechanisms to the cerebrovascular responses to hypercapnea is absent in OSA patients and (b) exposure to chronic/repeated apneas is not causal per se in limiting the contribution of vasodilating mechanisms to the cerebrovascular responses to hypercapnea in OSA.

Topics: Adult; Blood Flow Velocity; Blood Pressure; Cardiovascular Agents; Cerebrovascular Circulation; Cross-Over Studies; Diving; Double-Blind Method; Heart Rate; Humans; Hypercapnia; Hypocapnia; Indomethacin; Male; Middle Aged; Oxygen Consumption; Respiratory Mechanics; Sleep Apnea, Obstructive

Babies are frequently exposed to cerebral hypoxia and ischemia (H/I) during the perinatal period as a result of stroke, problems with delivery, or postdelivery respiratory management. The sole approved treatment for acute stroke is tissue type plasminogen activator. H/I impairs pial artery dilation (PAD) induced by hypercapnia and hypotension, the impairment aggravated by type plasminogen activator and attenuated by the plasminogen activator inhibitor-1-derived peptide EEIIMD. Mitogen-activated protein kinase (MAPK), a family of at least three kinases, ERK, p38, and JNK, is upregulated after H/I and ERK contribute to impaired cerebrovasodilation. This study determined the roles of p38 and JNK MAPK in the impairment of dilation post-H/I in pigs equipped with a closed cranial window and the relationship between alterations in MAPK isoforms and EEIIMD-mediated cerebrovascular protection. Cerebrospinal fluid-phosphorylated (activated) p38 MAPK, but not JNK MAPK, was increased after H/I, an effect potentiated by intravenous EEIIMD administered 1 h postinjury. PAD in response to hypercapnia and hypotension was blunted by H/I, but dilation was maintained by EEIIMD. PAD was further impaired by the p38 antagonist SB-203580 but unchanged by the JNK antagonist SP-600125. Isoproterenol-induced PAD was unchanged by H/I, EEIIMD, SB-203580, and SP-600125. These data indicate that postinjury treatment with EEIIMD attenuated impaired cerebrovasodilation post-H/I by upregulating p38 but not JNK. These data suggest that plasminogen activator inhibitor-1-based peptides and other approaches to upregulate p38 may offer a novel approach to increase the benefit-to-risk ratio of thrombolytic therapy for diverse central nervous system disorders associated with H/I.

Topics: Animals; Animals, Newborn; Anthracenes; Blood Pressure; Carbon Dioxide; Cardiovascular Agents; Cerebrovascular Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Female; Hypercapnia; Hypotension; Hypoxia-Ischemia, Brain; Imidazoles; Injections, Intravenous; Isoproterenol; JNK Mitogen-Activated Protein Kinases; Male; Oligopeptides; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pia Mater; Protein Kinase Inhibitors; Pyridines; Swine; Time Factors; Up-Regulation; Vasodilation; Vasodilator Agents

Our previous work showed a diminished cerebral blood flow (CBF) response to changes in Pa(CO(2)) in congestive heart failure patients with central sleep apnea compared with those without apnea. Since the regulation of CBF serves to minimize oscillations in H(+) and Pco(2) at the site of the central chemoreceptors, it may play an important role in maintaining breathing stability. We hypothesized that an attenuated cerebrovascular reactivity to changes in Pa(CO(2)) would narrow the difference between the eupneic Pa(CO(2)) and the apneic threshold Pa(CO(2)) (DeltaPa(CO(2))), known as the CO(2) reserve, thereby making the subjects more susceptible to apnea. Accordingly, in seven normal subjects, we used indomethacin (Indo; 100 mg by mouth) sufficient to reduce the CBF response to CO(2) by approximately 25% below control. The CO(2) reserve was estimated during non-rapid eye movement (NREM) sleep. The apnea threshold was determined, both with and without Indo, in NREM sleep, in a random order using a ventilator in pressure support mode to gradually reduce Pa(CO(2)) until apnea occurred. results: Indo significantly reduced the CO(2) reserve required to produce apnea from 6.3 +/- 0.5 to 4.4 +/- 0.7 mmHg (P = 0.01) and increased the slope of the ventilation decrease in response to hypocapnic inhibition below eupnea (control vs. Indo: 1.06 +/- 0.10 vs. 1.61 +/- 0.27 l x min(-1) x mmHg(-1), P < 0.05). We conclude that reductions in the normal cerebral vascular response to hypocapnia will increase the susceptibility to apneas and breathing instability during sleep.

Topics: Adolescent; Adult; Blood Flow Velocity; Brain; Carbon Dioxide; Cardiovascular Agents; Cerebrovascular Circulation; Female; Humans; Hypercapnia; Indomethacin; Male; Pulmonary Ventilation; Sleep Apnea Syndromes; Young Adult

We hypothesize that inhibitory effects exist between prostanoids and nitric oxide (NO) in their contributions to cerebral circulation. Piglets (1-4 days old) were divided into three chronically treated (6-8 days) groups: control piglets, piglets treated with indomethacin (75 mg/day), and piglets treated with N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 mg x kg(-1) x day(-1)). Pial arterioles dilated in response to hypercapnia similarly among the three groups (41 +/- 4, 40 +/- 6, and 45 +/- 11%). Cerebrospinal fluid cAMP increased in control piglets, while cGMP increased in indomethacin-treated piglets. L-NAME, but not 7-nitroindazole, inhibited the response to hypercapnia only in indomethacin-treated piglets (40 +/- 6 vs. 17 +/- 5%). Topical sodium nitroprusside or iloprost restored dilation in response to hypercapnia. Similar results were obtained when the dilator was bradykinin. Pial arterioles of control and L-NAME-treated piglets constricted in response to ACh (-24 +/- 3%). However, those of indomethacin-treated piglets dilated in response to ACh (15 +/- 2%). This dilation was inhibited by L-NAME. NO synthase activity, but not endothelial NO synthase expression, increased after chronic indomethacin treatment. These data suggest that chronic inhibition of cyclooxygenase can increase the contribution of NO to cerebrovascular circulatory control in piglets.

Topics: Acetylcholine; Animals; Animals, Newborn; Bradykinin; Cardiovascular Agents; Cells, Cultured; Cerebrovascular Circulation; Cyclic AMP; Cyclic GMP; Cyclooxygenase Inhibitors; Endothelium, Vascular; Enzyme Inhibitors; Hypercapnia; Indazoles; Indomethacin; Microcirculation; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Pia Mater; Swine; Vasodilator Agents

Specific cerebrovascular dilatory responses in newborn piglets are entirely prostanoid dependent, but require both nitric oxide (NO) and prostanoids in juveniles. We examined endothelial dependency and mechanisms of NO- and prostanoid-mediated cerebrovascular responses in anesthetized newborn and juvenile pigs implanted with closed cranial windows. Light/dye endothelial injury inhibited newborn and juvenile hypercapnic and bradykinin (BK) responses and inhibited dilation to acetylcholine in juveniles. Iloprost and NO act permissively in restoring light/dye inhibited newborn and juvenile responses, respectively. Differences in sensitivity to iloprost and sodium nitroprusside were not observed. Juvenile (not newborn) hypercapnic and BK cerebrovascular responses were sensitive to soluble guanylyl cyclase inhibition. Pial arteriolar diameter and cortical production of prostacyclin, cAMP, and cGMP in response to BK were measured under control conditions, after treatment with indomethacin and/or N(omega)-nitro-L-arginine methyl ester (L-NAME). Indomethacin inhibited BK responses in newborns. Juvenile responses were inhibited by L-NAME, and mildly by indomethacin. Cortical 6-keto-PGF(1 alpha), cAMP, and cGMP increased in response to BK in both age groups. Newborn cerebrovascular responses are largely NO independent, but NO becomes more important with maturation.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Age Factors; Animals; Animals, Newborn; Arterioles; Bradykinin; Cardiotonic Agents; Cardiovascular Agents; Cerebrovascular Circulation; Cyclic AMP; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Epoprostenol; Female; Hypercapnia; Iloprost; Indomethacin; Isoproterenol; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroprusside; Pia Mater; Swine; Vasodilation; Vasodilator Agents