Comparative hemodynamic effects of periodic obstructive and simulated central apneas in sedated pigs

Chen, Ling, and Steven M. Scharf. Comparativehemodynamic effects of periodic obstructive and simulated centralapneas in sedated pigs. J. Appl.Physiol. 83(2): 485-494, 1997.It has beenspeculated that because of increased left ventricular (LV) afterload,decreased intrathoracic pressure (ITP) is responsible for decreasedcardiac output (CO) in obstructive sleep apnea. If this were true, thenobstructive apnea (OA) should have a greater effect on CO than wouldcentral apnea (CA). To assess the importance of decreasedITP during OA, we studied seven preinstrumented sedated pigs with OAand simulated CA that were matched for blood gases and apneaperiodicities (with 15- or 30-s apnea duration). Compared with OA, CAwith 30-s apnea duration produced comparable decreases in heart rate(from baseline to end apnea: OA, 106.6 ± 4.8 to 93.4 ± 4.4 beats/min, P < 0.01; and CA, 111.1 ± 6.2 to 94.0 ± 5.2 beats/min,P < 0.01) and comparable increasesin LV end-diastolic pressure and LV end-diastolic myocardial segmentlength but greater increases in mean arterial pressure (97.1 ± 3.7 to 107.7 ± 4.3 Torr, P < 0.05;and 97.3 ± 4.8 to 119.3 ± 7.4 Torr,P < 0.01) and systemic vascularresistance (2,577 ± 224 to 3,346 ± 400 dyn · s · cm⁵,P < 0.01; and 2,738 ± 294 to5,111 ± 1,181 dyn · s · cm⁵,P < 0.01) and greater decreases inCO (3.18 ± 0.31 to 2.74 ± 0.26 l/min,P < 0.05; and 3.07 ± 0.38 to2.30 ± 0.36 l/min, P < 0.01) andstroke volume (32.2 ± 2.9 to 25.9 ± 2.4 ml,P < 0.05; and 31.5 ± 1.9 to 19.8 ± 3.1 ml, P < 0.01). Only CA increased LV end-systolic myocardialsegment length. Similar findings were observed with 15-s apneaduration. We conclude that CA produced greater depression of CO andgreater changes of afterload-related LV dysfunction than did OA.Therefore, decreased ITP was not the dominant factor determining LVfunction with apneas.

     

Hemodynamic effects of periodic obstructive apneas in sedated pigs with congestive heart failure.

Because of similar physiological changes such as increased left ventricular (LV) afterload and sympathetic tone, an exaggerated depression in cardiac output (CO) could be expected in patients with coexisting obstructive sleep apnea and congestive heart failure (CHF). To determine cardiovascular effects and mechanisms of periodic obstructive apnea in the presence of CHF, 11 sedated and chronically instrumented pigs with CHF (rapid pacing) were tested with upper airway occlusion under room air breathing (RA), O(2) breathing (O2), and room air breathing after hexamethonium (Hex). All conditions led to large negative swings in intrathoracic pressure (-30 to -39 Torr) and hypercapnia (PCO(2) approximately 60 Torr), and RA and Hex also caused hypoxia (to approximately 42 Torr). Relative to baseline, RA increased mean arterial pressure (from 97.5 +/- 5.0 to 107.3 +/- 5.7 Torr, P < 0.01), systemic vascular resistance, LV end-diastolic pressure, and LV end-systolic length while it decreased CO (from 2.17 +/- 0.27 to 1.52 +/- 0.31 l/min, P < 0.01), stroke volume (SV; from 23.5 +/- 2.4 to 16.0 +/- 4.0 ml, P < 0.01), and LV end-diastolic length (LVEDL). O2 and Hex decreased mean arterial pressure [from 102.3 +/- 4.1 to 16.0 +/- 4.0 Torr (P < 0.01) with O2 and from 86.0 +/- 8.5 to 78.1 +/- 8.7 Torr (P < 0.05) with Hex] and blunted the reduction in CO [from 2.09 +/- 0.15 to 1.78 +/- 0.18 l/ml for O2 and from 2.91 +/- 0.43 to 2.50 +/- 0.35 l/ml for Hex (both P < 0.05)] and SV. However, the reduction in LVEDL and LV end-diastolic pressure was the same as with RA. There was no change in systemic vascular resistance and LVEDL during O2 and Hex relative to baseline. In the CHF pigs during apnea, there was an exaggerated reduction in CO and SV relative to our previously published data from normal sedated pigs under similar conditions. The primary difference between CHF (present study) and the normal animals is that, in addition to increased LV afterload, there was a decrease in LV preload in CHF contributing to SV depression not seen in normal animals. The decrease in LV preload during apneas in CHF may be related to effects of ventricular interdependence.     

Mechanisms of acute cardiovascular response to periodic apneas in sedated pigs.

This study was designed to evaluate the importance of sympathoadrenal activation in the acute cardiovascular response to apneas and the role of hypoxemia in this response. In addition, we evaluated the contribution of the vagus nerve to apnea responses after chemical sympathectomy. In six pigs preinstrumented with an electromagnetic flow probe and five nonpreinstrumented pigs, effects of periodic nonobstructive apneas were tested under the following six conditions: room air breathing, 100% O2 supplementation, both repeated after administration of hexamethonium (Hex), and both repeated again after bilateral vagotomy in addition to Hex. With room air apneas, during the apnea cycle, there were increases in mean arterial pressure (MAP; from baseline of 108 +/- 4 to 124 +/- 6 Torr, P < 0.01), plasma norepinephrine (from 681 +/- 99 to 1,825 +/- 578 pg/ml, P < 0.05), and epinephrine (from 191 +/- 67 to 1,245 +/- 685 pg/ml, P < 0.05) but decreases in cardiac output (CO; from 3.3 +/- 0.6 to 2.4 +/- 0.3 l/min, P < 0.01) and cervical sympathetic nerve activity. With O2 supplementation relative to baseline, apneas were associated with small increases in MAP (from 112 +/- 4 to 118 +/- 3 Torr, P < 0.01) and norepinephrine (from 675 +/- 97 to 861 +/- 170 pg/ml, P < 0.05). After Hex, apneas with room air were associated with small increases in MAP (from 103 +/- 6 to 109 +/- 6 Torr, P < 0.05) and epinephrine (from 136 +/- 45 to 666 +/- 467 pg/ml, P < 0.05) and decreases in CO (from 3.6 +/- 0.4 to 3.2 +/- 0. 5 l/min, P < 0.05). After Hex, apneas with O2 supplementation were associated with decreased MAP (from 107 +/- 5 to 100 +/- 5 Torr, P < 0.05) and no other changes. After vagotomy + Hex, with room air and O2 supplementation, apneas were associated with decreased MAP (from 98 +/- 6 to 76 +/- 7 and from 103 +/- 7 to 95 +/- 6 Torr, respectively, both P < 0.01) but increased CO [from 2.7 +/- 0.3 to 3. 2 +/- 0.4 l/min (P < 0.05) and from 2.4 +/- 0.2 to 2.7 +/- 0.2 l/min (P < 0.01), respectively]. We conclude that sympathoadrenal activation is the major pressor mechanism during apneas. Cervical sympathetic nerve activity does not reflect overall sympathoadrenal activity during apneas. Hypoxemia is an important but not the sole trigger factor for sympathoadrenal activation. There is an important vagally mediated reflex that contributes to the pressor response to apneas.     

Effects of vagotomy on cardiovascular response to periodic apneas in sedated pigs.

There are few studies investigating the influence of vagally mediated reflexes on the cardiovascular response to apneas. In 12 sedated preinstrumented pigs, we studied the effects of vagotomy during apneas, controlling for apnea periodicity and thoracic mechanical effects. Nonobstructive apneas were produced by paralyzing and mechanically ventilating the animals, then turning the ventilator off and on every 30 s. Before vagotomy, relative to baseline, apnea caused increased mean arterial pressure (MAP; +19 +/- 25%, P < 0.05), systemic vascular resistance (SVR; +33 +/- 16%, P < 0.0005), and heart rate (HR; +5 +/- 6%, P < 0.05) and decreased cardiac output (CO) and stroke volume (SV; -16 +/- 10% P < 0.001). After vagotomy, no significant change occurred in MAP, SVR, and SV during apneas, but CO and HR increased relative to baseline. HR was always greater ( approximately 14%, P < 0.01) during the interapneic interval compared with during apnea. We conclude that vagally mediated reflexes are important mediators of the apneic pressor response. HR increases after apnea termination are related, at least in part, to nonvagally mediated reflexes.     

Effects of aortic nerve on hemodynamic response to obstructive apnea in sedated pigs.

In this study we test the hypothesis that aortic nerve traffic is responsible for the pressor response to periodic apneas. In nine intubated, sedated chronically instrumented pigs, periodic obstructive apneas were caused by occlusion of the endotracheal tube for 30 s, followed by spontaneous breathing for 30 s. This was done under control (C) conditions, after section of the aortic nerve (ANS), and after bilateral cervical vagotomy (Vagot). Blood-gas tensions and airway pressure changed similarly under all conditions: PO(2) decreased to 50-60 Torr, PCO(2) increased to approximately 55 Torr, and airway pressure decreased by 40-50 mmHg during apnea. With C, mean arterial pressure (MAP) increased from 111 +/- 4 mmHg at baseline to 120 +/- 5 mmHg at late apnea (P < 0.01). After ANS and Vagot, there was no change in MAP with apneas compared with baseline. Relative to baseline, cardiac output and stroke volume decreased with C but not with ANS or Vagot during apneas. Increased MAP was due to increased systemic vascular resistance. Heart rate behaved similarly with C and ANS, being greater at early interapnea than late apnea. With Vagot, heart rate increased throughout the apnea-interapnea cycle relative to baseline. We conclude that, in sedated pigs, aortic nerve traffic mediates the increase in MAP and systemic vascular resistance observed during periodic apneas. Increase in MAP is responsible for decreased cardiac output and stroke volume. Additional vagal reflexes, most likely parasympathetic efferents, are responsible for interacting with sympathetic excitatory influences in modulating heart rate.     

Systemic hemodynamics affecting cardiac output during hypocapnic and hypercapnic hypoxia

Systemic hemodynamic adjustments involved in the control of cardiac output (CO) were examined in chronically instrumented unanesthetized sheep inhaling gas mixtures resulting in hypocapnic hypoxia (H) [arterial pH (pHa) = 7.53, arterial partial pressure of O2 (Pao2) = 30 Torr, arterial partial pressure of CO2 (Paco2) = 29 Torr] or hypercapnic hypoxia (HCH) (pHa = 7.14, Pao2 = 34 Torr, Paco2 = 72 Torr) for 1 h. H (n = 7) and HCH (n = 6) resulted in 26% and 61% increases in CO, respectively, and mean systemic arterial pressure rose to a greater extent during HCH. Both H and HCH resulted in increased blood flow (microsphere method) to the peripheral systemic circulation including the brain, heart, diaphragm, and nonrespiratory skeletal muscle (the latter blood flow increased 120% during H and 380% during HCH). Gastrointestinal and renal blood flow remained unchanged during H and HCH. Transit time of green dye from the pulmonary artery to regional veins in the hindlimb and intestine was 5.0 and 8.2 s, respectively, during base-line conditions and remained unchanged with HCH. During HCH, regional O2 consumption increased 274% for the hindlimb and decreased 39% for the intestine. Total catecholamines rose 250% during H and 3,700% during HCH. During hypocapnic and hypercapnic hypoxia, CO is augmented in part by systemic hemodynamic adjustments that include a redistribution of blood flow and a translocation of blood volume to the fast transit time peripheral systemic circuit. The sympathetic nervous system may play an important role in mediating these systemic hemodynamic adjustments.     

Catecholamines and regional hemodynamics during isovolemic hemodilution in anesthetized pigs.

The effects of stepwise isovolemic hemodilution on systemic and regional hemodynamics, oxygen flux, and circulating catecholamines were studied in six pigs anesthetized with midazolam and fentanyl. Reduction of the hematocrit from 28 to 9% resulted in doubling of the cardiac output, mainly due to an increase in stroke volume. Regional blood flows, measured using the radioactive microsphere technique, showed an increase in blood flow to all organs except liver (hepatic artery fraction) and adrenals, with a redistribution of cardiac output in favor of heart and brain (increase in blood flow 420 and 170%, respectively). Oxygen flux to most organs did not decrease until hematocrit decreased to 9%, while total body oxygen consumption was well maintained. Left ventricular oxygen consumption increased, but because left ventricular blood flow also increased, left ventricular extraction ratio did not increase. Circulating catecholamines did not play any role in these regulatory mechanisms.     

Systemic and regional hemodynamics in conscious rats during 24-hour antiorthostatic posture

The systemic and regional hemodynamics during antiorthostatic hypokinesia were studied in male Wistar rats using the radioactive microsphere technique. The animals were hanged up by the tail with the head tilted down (30 degrees) and were able to exercise using only front limbs. Twenty four hours long exposure to antiorthostasis induced significant changes in systemic hemodynamics as well as in regional blood flow in skeletal muscles, spleen, liver and pancreas. Antiorthostasis induced blood flow changes in lungs, heart and brain were less pronounced.     

Systemic and regional hemodynamics during audiogenic convulsions in rats genetically epilepsy-prone]

Changes in systemic and regional hemodynamic during sound-induced convulsions were measured with microsphere technique in genetically epilepsy-prone rats of Krushinsky-Molodkina (KM-rats) strain. Blood pressure increased from 103 till 178 mm Hg and cardiac index rose from 27.3 till 49.3 ml/min/100 g b. w. during convulsions. Blood flow was increased in the brain and in the heart by 140-700%, whereas in most of internal organs it was decreased by 40-94%.     

Repetitive apneas induce periodic hypertension in normal subjects through hypoxia.

Periodic increases in blood pressure (BP) can occur in the sleep apnea syndrome (SAS) during recurrent apneas. To investigate the mechanisms causing this periodic hypertension, we simulated SAS by imposing a matching breathing pattern on seven healthy awake male volunteers. Continuous finger arterial BP, electrocardiogram, arterial O2 saturation (SaO2), end-tidal CO2, and tidal volume were measured. The role of hypoxia was studied by comparing apneas during depletion of O2 in the spirometer with those during 100% O2 breathing. In all subjects, BP periodically reached values greater than 150/95 mmHg in the hypoxic series. During the hyperoxic apnea series, however, BP remained stable. End-apneic mean BP was shown to be inversely correlated to SaO2 in six subjects in the SaO2 range from 60 to 100%. Although the hypoxic BP pattern closely mimicked that in SAS, the heart rate pattern in four of our subjects remained distinct from that in patients. Atropine could not prevent large BP swings in the hypoxic series. We conclude that SaO2 is a major determinant of periodic hypertension in recurrent apneas. Its effect probably results from chemoreflex modulation of peripheral resistance.     

Mixed and obstructive apneas are related to ventilatory oscillations in premature infants

In our previous study of 14 premature infants, apnea occurred at the minimum phase of ventilatory oscillations. The apneas corresponded to cessation of airflow at the nose and mouth and were not distinguished as central, mixed, or obstructive. Changes in heart rate associated with the apneas were not identified. To determine whether ventilatory pattern characteristics might predict either the type of apnea or heart rate changes during the apnea, we analyzed measurements of chest wall movement and heart rate that were made during the earlier studies. Chest wall movement measured by magnetometers was compared with airflow measured with a face mask and pneumotachograph. Tidal volume, breath duration, and ventilation were calculated on a breath-by-breath basis, converted to time-axis data strings, and filtered with a comb of zero phase shift digital band-pass filters to detect breathing patterns. Of 182 apneas greater than or equal to 3 s duration, 55% were central, 31% were mixed, and 14% were obstructive. All three types of apnea were related to ventilatory oscillations. Multiple linear and logistic regressions showed that an apnea was more likely to be obstructive when it was long and when the underlying ventilatory oscillation was due primarily to an oscillation in breath duration. Multiple linear and logistic regressions showed that decreases in heart rate were related primarily to the duration of apnea and secondarily to the characteristics of the underlying breathing patterns.     

Distraction osteogenesis for obstructive apneas in patients with congenital craniofacial malformations

Infants with congenital craniofacial malformations often have associated severe mandibular hypoplasia causing obstruction of the hypopharynx by retroposition of the base of the tongue into the posterior pharyngeal airway. Management depends on the severity of the airway obstruction. Most cases can be managed by prone positioning until the infant outgrows the problem at 3 to 6 months of age. In more critical cases, monitoring of oxygen saturation, temporary placement of a nasopharyngeal tube, and placement of an endotracheal tube will be useful procedures. Tracheotomy is an effective method for more severe cases, but longstanding tracheotomies result in high morbidity and occasional mortality. Mandibular distraction was performed in seven patients, ranging in age from 1 to 18 months, with critical obstructive apnea secondary to mandibular hypoplasia characterized by an apnea/hypopnea index greater than 20 apneas per hour and oxygen saturation below 80 percent. Two patients were tracheotomized previously. Mandibular lengthening, from 16 to 25 mm on the left side and from 10 to 22 mm on the right, was achieved in 21 to 25 days. Improvement of airway obstruction parameters was measured on polysomnograms and lateral cephalograms. Mandibular lengthening by gradual distraction is a successful method for young patients with severe mandibular hypoplasia causing critical obstructive apneas. Avoidance of tracheotomy or early decannulation in previously tracheotomized patients is a great advantage for patients with congenital craniofacial malformation.     

Stroke volume and cardiac output decrease at termination of obstructive apneas.

Patients with obstructive sleep apnea (OSA) experience repetitive nocturnal oscillations of systemic arterial pressure that occur in association with changes in respiration and changes in sleep state. To investigate cardiac function during the cycle of obstruction (apnea) and resumption of ventilation (recovery), we continuously measured left ventricular stroke volume (LVSV) and mean arterial blood pressure (MAP) during non-rapid-eye-movement sleep in six males with severe OSA (apnea/hypopnea index > or = 30 events/h associated with oxygen saturation < 82%). LVSV was assessed continuously using an ambulatory ventricular function monitor (VEST; Capintec). The apnea-recovery cycle was divided into three phases: 1) early apnea (EA), 2) late apnea (LA), and 3) recovery (Rec). In all subjects recovery was associated with an abrupt decrease in LVSV [54.0 +/- 14.5 (SD) ml] compared with either EA (91.4 +/- 14.7 ml; P < 0.001) or LA (77.1 +/- 15.2 ml; P < 0.005). Although heart rate increased with recovery, the increase was not sufficient to compensate for the decrease in LVSV so that cardiac output (CO) fell (EA: 6,247 +/- 739 ml/min; LA: 5,741 +/- 1,094 ml/min; Rec: 4,601 +/- 1,249 ml/min; EA vs. Rec, P < 0.01; LA vs. Rec, P < 0.025). Recovery was also associated with a significant increase in MAP. We speculate that such abrupt decreases in LVSV and CO at apnea termination, occurring coincident with the nadir of oxygen saturation, may further compromise tissue oxygen delivery.     

Spleen and cardiovascular function during short apneas in divers.

We investigated the spleen volume changes as related to the cardiovascular responses during short-duration apneas at rest. We used dynamic ultrasound splenic imaging and noninvasive photoplethysmographic cardiovascular measurements before, during, and after 15-20 s apneas in seven trained divers. The role of baroreflex was studied by intravenous bolus of vasodilating drug trinitrosan during tidal breathing. The role of lung volume was studied by comparing the apneas at near-maximal lung volume with apneas after inhaling tidal volume, with and without cold forehead stimulation. In apneas at near maximal lung volume, a 20% reduction in splenic volume (P = 0.03) was observed as early as 3 s after the onset of breath holding. Around that time the heart rate increased, the mean arterial pressure abruptly decreased from 89.6 to 66.7 mmHg (P = 0.02), and cardiac output decreased, on account of reduction in stroke volume. Intravenous application of trinitrosan resulted in approximately 6-mmHg decrement in mean arterial pressure, while the splenic volume decreased for approximately 13%. In apneas at low lung volume, the early splenic contraction was also observed, 10% without and 12% with cold forehead stimulation, although the mean arterial pressure did not change or even increased, respectively. In conclusion, the spleen contraction is present at the beginning of apnea, accentuated by cold forehead stimulation. At large, but not small, lung volume, this initial contraction is probably facilitated by downloaded baroreflex in conditions of decreased blood pressure and cardiac output.     

CO(2) homeostasis during periodic breathing in obstructive sleep apnea.

The contribution of apnea to chronic hypercapnia in obstructive sleep apnea (OSA) has not been clarified. Using a model (D. M. Rapoport, R. G. Norman, and R. M. Goldring. J. Appl. Physiol. 75: 2302-2309, 1993), we previously illustrated failure of CO(2) homeostasis during periodic breathing resulting from temporal dissociation between ventilation and perfusion ("temporal V/Q mismatch"). This study measures acute kinetics of CO(2) during periodic breathing and addresses interapnea ventilatory compensation for maintenance of CO(2) homeostasis in 11 patients with OSA during daytime sleep (37-171 min). Ventilation and expiratory CO(2) and O(2) fractions were measured on a breath-by-breath basis by means of a tight-fitting full facemask. Calculations included CO(2) excretion, metabolic CO(2) production, and CO(2) balance (metabolic CO(2) production - exhaled CO(2)). CO(2) balance was tabulated for each apnea/hypopnea event-interevent cycle and as a cumulative value during sleep. Cumulative CO(2) balance varied (-3,570 to +1,388 ml). Positive cumulative CO(2) balance occurred in the absence of overall hypoventilation during sleep. For each cycle, positive CO(2) balance occurred despite increased interevent ventilation to rates as high as 45 l/min. This failure of CO(2) homeostasis was dependent on the event-to-interevent duration ratio. The results demonstrate that 1) periodic breathing provides a mechanism for acute hypercapnia in OSA, 2) acute hypercapnia during periodic breathing may occur without a decrease in average minute ventilation, supporting the presence of temporal V/Q mismatch, as predicted from our model, and 3) compensation for CO(2) accumulation during apnea/hypopnea may be limited by the duration of the interevent interval. The relationship of this acute hypercapnia to sustained chronic hypercapnia in OSA remains to be further explored.     

Systemic oxygen extraction during incremental exercise in patients with severe chronic obstructive pulmonary disease

To determine if decreased systemic oxygen (O₂) extraction contributes to the exercise limit in severe chronic obstructive pulmonary disease (COPD), 40 consecutive incremental cycle ergometer exercise tests performed by such patients, from which a “log-log” lactate threshold (LT) was identified, were compared to those of 8 patients with left ventricular failure (LVF) and 10 normal controls. Pulmonary gas exchange and minute ventilation were measured continuously and arterial blood gas tensions, pH, and lactate concentrations were sampled each minute. Cardiac output (Q˙ _c) was measured by first-pass radionuclide ventriculography. The systemic O₂ extraction ratio (O₂ER) was calculated as arterial − mixed venous O₂ content difference (C _aO₂ − C _vO₂)/C _aO₂. Peak exercise O₂ uptake (V˙O_2peak) was markedly reduced in both COPD and LVF [41 (3) and 42 (3)% predicted, respectively], compared to controls [89 (2)% predicted, P < 0.0001 for each]. Similarly, the LT occurred at a low percentage of predicted maximal oxygen consumption in both COPD and LVF [25 (2) and 27 (3)%] compared to normals [46 (3)%, P < 0.0001 for each]. The systemic O₂ER at peak exercise was severely reduced in COPD [0.36 (0.02)] compared to the other groups [P < 0.0001 for each], for whom it was nearly identical [0.58 (0.03) vs 0.63 (0.04), LVF vs control, P > 0.05]. In the COPD group, an early LT correlated with reduced systemic O₂ER at peak exercise (r = 0.64, P < 0.0001), but not with any index of systemic O₂ delivery. These data suggest that lactic acidemia during exercise in patients with severe COPD is better related to abnormal systemic O₂ extraction than to its delivery and contributes to the exercise limit. Accepted: 10 March 1998     

Enhanced cAMP-induced nitric oxide-dependent coronary dilation during myocardial stunning in conscious pigs

The goal of the current study was to determine the effects of cAMP-mediated coronary reactivity in conscious pigs with stunned myocardium induced by 1.5 h coronary stenosis (CS) and 12 h coronary artery reperfusion (CAR). Domestic swine (n = 5) were chronically instrumented with a coronary artery blood flow (CBF) probe, hydraulic occluder, left ventricular pressure gauge, wall-thickening crystals in the ischemic and nonischemic zones, and a coronary sinus catheter. The hydraulic occluder was inflated to induce a CS with a stable 38 +/- 1% reduction in CBF for 1.5 h. Before flow reduction and during CAR, cAMP-induced coronary vasodilation was investigated by forskolin (20 nmol. kg(-1). min(-1)). Enhanced CBF responses [+62 +/- 9%, P < 0.05, compared with pre-CS (+37 +/- 3%)] were observed for forskolin at 12 h after CAR as well as for bradykinin and reactive hyperemia. With the use of a similar protocol during systemic nitric oxide (NO) synthase inhibition with N(omega)-nitro-L-arginine (30 mg. kg(-1). day(-1) for 3 days), the enhanced CBF responses to forskolin, bradykinin, and reactive hyperemia were not observed after CS. Isolated microvessel preparations from pigs (n = 8) also demonstrated enhanced NO production to direct stimulation of adenylyl cyclase with forskolin (+71 +/- 12%) or NKH-477 (+60 +/- 10%) and administration of 8-bromo-cAMP (+74 +/- 13%), which were abolished by protein kinase A or NO synthase inhibition. These data indicate that cAMP stimulation elicits direct coronary vasodilation and that this action is amplified in the presence of sustained myocardial stunning after recovery from CS. This enhanced cAMP coronary vasodilation is mediated by an NO mechanism that may be involved in myocardial protection from ischemic injury.     

Systemic inflammation and mortality in chronic obstructive pulmonary disease

Cardiovascular diseases and cancer (especially lung cancer) are leading causes of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Some have implicated systemic inflammation, which is commonly observed in COPD, as the potential mechanistic bridge between COPD and these disorders. This concept has been supported by animal studies especially in rabbits, which have clearly demonstrated the effect of local lung inflammation on systemic inflammation and on the progression of atherosclerosis and by cross-sectional population-based studies, which have shown a significant relationship between systemic inflammation, as measured by circulating C-reactive protein (CRP) and the risk of cardiovascular diseases in COPD patients. These data have been further extended by a recent study that has elucidated the temporal nature of the relationship between systemic inflammation and the risk of cardiovascular events and cancer in COPD patients. This study showed that baseline CRP levels predicted the incidence of cardiovascular events and cancer-specific mortality over 7 to 8 years of follow-up. CRP levels also predicted all-cause mortality. Collectively, these data indicate that systemic inflammation may play an important role in mediating the extra-pulmonary complications of COPD. Systemic inflammation may contribute substantially to the overall morbidity and mortality of COPD patients.