Intermittent hypoxia as a means to improve aerobic capacity in type 2 diabetes.

Physical inactivity and a low maximal aerobic capacity (VO2max) strongly predict morbidity and mortality in patients with type 2 diabetes (T2D). Patients with T2D have a reduced VO2max when compared with healthy individuals of similar age, weight, and physical activity levels, and this lower aerobic capacity is usually attributed to a reduced oxygen delivery to the working muscles. The oxygen carrying capacity of the blood, as well as increases in cardiac output and blood flow, contribute to the delivery of oxygen to the active muscles during exercise. Hemoglobin mass (Hb mass), a key determinant of oxygen carrying capacity, is suggested to be reduced in patients with T2D following the observation of a lower blood volume (BV) in combination with normal hematocrit levels in this population. Therefore, a lower Hb mass, in addition to a reported lower BV and impaired cardiovascular response to exercise, likely contributes to the reduced oxygen delivery and VO2max in patients with T2D. While exercise training increases Hb mass, BV, and consequently VO2max, the majority of patients with T2D are not physically active, highlighting the need for alternative methods to improve VO2max in this population. Exposure to hypoxia triggers the release of erythropoietin, the hormone regulating red blood cell production, which increases Hb mass and consequently BV. Exposure to mild intermittent hypoxia (IH), characterized by few and short episodes of hypoxia at a fraction of inspired oxygen ranging between 10 and 14% interspersed with cycles of normoxia, increased red blood cell volume, Hb mass, and plasma volume in patients with coronary artery disease or chronic obstructive pulmonary disease, which resulted in an improved VO2max in both populations. We hypothesize that 12 exposures to mild IH over a period of 4weeks will increase Hb mass, BV, cardiac function, and VO2max in patients with T2D. Therefore, exposures to mild IH may increase oxygen delivery and VO2max without the need to perform exercise in patients with T2D.

Optimizing a canine survival model of orthotopic lung transplantation.

INTRODUCTION: While acute models of orthotopic lung transplantation have been described in dogs, the technical considerations of developing a survival model in this species have not been elaborated. Herein, we describe optimization of a canine survival model of orthotopic lung transplantation. METHODS: Protocols of orthotopic left lung transplantation and single lung ventilation were established in acute experiments (n=9). Four dogs, serving as controls, received autologous, orthotopic lung transplants. Allogeneic transplants were performed in 16 DLA-identical and 16 DLA-mismatched unrelated recipient dogs. Selective right lung ventilation was utilized in all animals. A Malecot tube was left in the pleural space connected to a Heimlich valve for up to 24 hours. To date, animals have been followed up to 24 months by chest radiography, pulmonary function tests, bronchoscopy with lavage, and open biopsies. RESULTS: Long-term survival was achieved in 34/36 animals. Two recipients died intraoperatively secondary to cardiac arrest. All animals were extubated on the operating table, and in all cases the chest tube was removed within 24 hours. Major complications included thrombosis of the pulmonary artery and subcritical stenosis of bronchial anastamosis. One recipient underwent successful treatment of a small bowel intussusception. CONCLUSIONS: We report our experience in developing a survival canine model of orthotopic single lung transplantation. While short-term survival following canine lung transplantation is achievable, we report particular considerations that facilitate animal comfort, early extubation, and lung reexpansion in the immediate postoperative period, further optimizing use of this species for experimental modeling of long-term complications after lung transplantation.

Nonoperative management of pediatric blunt hepatic trauma.

The purpose of this study was to examine the effect of operative versus nonoperative management of blunt hepatic trauma in children including transfusion practices. We reviewed the experience at our American College of Surgeons-verified Level I trauma center with pediatric commitment over a 5-year period. Children < or = 16 years of age suffering blunt liver injury as documented on admission CT scan were included in the study. Liver injuries identified on CT scan were classified according to the American Association for the Surgery of Trauma's Organ Injury Scaling system. All data are presented as mean +/- standard error. One case of pediatric liver trauma not identified on CT was excluded (prehospital cardiopulmonary resuscitation). Twenty-seven patients were included [age 9.3 +/- 1.0 years (range 3-16)]. Mechanisms of injury included motor vehicle crash (14), pedestrian struck by motor vehicle (7), bicycle crash (4), fall from height (1), and pedestrian struck by falling object (1). Trauma Score was 11.5 +/- 0.3. Distribution of Liver Injury Grade was as follows: grade I, 13; grade II, 9; grade III, 3; grade IV, 2; and grade V, 0. All five patients who underwent operative management had multiple organ injuries; three had concomitant splenic injury requiring operative repair; the remaining two had small bowel injury requiring repair. Hepatorrhaphy did not correlate with severity of liver injury: grade I, n = 1; II, n = 2; III, n = 1; and IV, n = 1. Three operated patients received blood transfusions. Twenty-two patients were managed with nonoperative treatment, of these only one required blood transfusion. No patients in the study died, three were transferred to subacute rehabilitation, one was transferred to another hospital, and 23 were discharged home. Our findings indicate that a majority of children with blunt hepatic injury as documented on CT scan can be managed with nonoperative treatment, and few require blood transfusions. Patients with multiple organ injury including simultaneous splenic injury are likely ideally managed through operative exploration and repair, whereas those with isolated liver injuries can be successfully managed nonoperatively.

Surgical residents' knowledge of injury prevention principles.

BACKGROUND: Injury prevention is not routinely taught in medical school or surgical residency curricula. Because of the integral role surgeons play in the diagnosis and treatment of trauma, we sought to determine the knowledge base of injury prevention concepts of surgical residents training in a state's level 1 trauma centers. METHODS: A written survey was given to general surgery residents at our state's three level 1 trauma centers. Twenty-one questions related to injury prevention were asked in addition to demographic data. Basic concepts of injury prevention, statistical knowledge of injury patterns, and knowledge of intentional violence were tested. RESULTS: Sixty-two residents completed the survey. Only 9 respondents reported prior formal instruction in injury prevention. Overall performance was (mean +/- SD) 10.6 +/- 2.5 of 31 possible points, for a mean average score of 34% correct answers. Postgraduate year level, prior medical school instruction in injury prevention or months of experience on a trauma service did not correlate with improved scores. Specific question performance ranged from 2% to 82% correct responses. Questions regarding domestic violence (60%), risk of burns (65%), and incidence of trauma deaths (82%) were answered correctly most often, while injury prevention theory questions, such as components of the Injury Prevention Triangle (5%), definition of YPLL (2%), and annual cost attributable to injury (19%) were least often answered correctly. CONCLUSIONS: These data indicate that general surgery residents are poorly educated regarding basic concepts of injury prevention. Importantly, a majority of respondents (69%) felt formal instruction in injury prevention should be included in their surgical residency curriculum.

'Spontaneous' neonatal gastric perforation: is it really spontaneous?

BACKGROUND/PURPOSE: Most historical reports have described gastric perforation in the neonatal population as "spontaneous." More recently, several variables, including prematurity and nasal ventilation, have been implicated as contributing factors. The authors sought to analyze the etiology, course, and outcome of newborns with spontaneous gastric perforation from one institution over a 16-year period. METHODS: The authors reviewed retrospectively the charts of all infants who underwent operation or had perforation of the stomach diagnosed in the newborn period. RESULTS: Among more than 84,000 live births, 7 newborns were identified with perforation of the stomach. Four had coexisting gastrointestinal lesions (2 necrotizing enterocolitis, 1 undiagnosed tracheoesophageal fistula, 1 meconium plug), and 1 received nasal continuous positive airway pressure (CPAP). In only 2 cases were no other gastrointestinal lesions or other presumed contributing factors (nasal CPAP) present, and thus, only 2 cases could be classified as "spontaneous." Mortality rate was 57%. Three of the patients were premature, all of whom died. CONCLUSIONS: Whereas in the older literature, most cases of gastric perforation were considered spontaneous, and were full term, the authors' review of 7 cases over a 16-year period leads us to question the cause as spontaneous. The authors found that prematurity and concomitant gastrointestinal lesions were associated with gastric perforation in the neonate and that few cases truly are spontaneous. The authors suggest that when gastric perforation occurs in neonates, a contributing cause should be sought.

Down regulation of myocardial beta1-adrenoceptor signal transduction system in pacing-induced failure in dogs with aortic stenosis-induced left ventricular hypertrophy.

We recently demonstrated that rapid ventricular pacing caused cardiac failure (Failure) in dogs with aortic stenosis-induced left ventricular hypertrophy (Hypertrophy) and isoproterenol caused no significant increases in function, O2 consumption and intracellular cyclic AMP level in the failing hypertrophied hearts. We tested the hypothesis that alterations in the beta1-adrenoceptor-signal transduction pathway would correlate with the reduced functional and metabolic responses to beta-adrenergic stimulation during the transition from the compensated hypertrophy to failure. Pressure overload-induced left ventricular hypertrophy was created using aortic valve plication in 10 dogs over a 6-month period. Five months after aortic valve plication, congestive heart failure was induced in 5 dogs by rapid ventricular pacing at 240 bpm for 4 weeks. The density of myocardial beta1-adrenoceptors (fmoles/mg membrane protein; fmoles/g wet tissue) was significantly reduced in the Failure dogs (176+/-19; 755+/-136) when compared to those of the Control (344+/-51; 1,551+/-203) and the Hypertrophy (298+/-33; 1,721+/-162) dogs. The receptor affinities were not significantly different among all groups. There was a small but significant decrease in the percentage of beta1-adrenoceptors of the failing hypertrophied hearts (62+/-3%) when compared to that of the hypertrophied hearts (77+/-5%). The basal myocardial adenylyl cyclase activity (pmoles/mg protein/min) was significantly lower in the Failure dogs (45+/-4) than in the Control (116+/-14) and Hypertrophy (86+/-6) dogs. The forskolin (0.1 mM)-stimulated adenylyl cyclase activity was also significantly lower in the Failure dogs (158+/-17) than in the Control dogs (296+/-35) and slightly lower than in the Hypertrophy dogs (215+/-10). There were no significant differences in low Km cyclic AMP-phosphodiesterase activities among all groups. We conclude that down regulation of beta1-adrenoceptors and reduced adenylyl cyclase activities contribute to the decreases in myocardial functions and beta-adrenergic responses in the failing hypertrophied hearts induced by rapid ventricular pacing.

Effects of beta-adrenoceptor stimulation on pacing-induced failure of dog hypertrophic hearts.

1. We tested the hypothesis that the transition to pacing-induced failure in hypertrophic hearts would result in reduced functional and metabolic responses to beta-adrenoceptor stimulation. 2. Isoproterenol (ISO; 0.1 microg/kg per min) was infused into a coronary artery in five anaesthetized open-chest control, five aortic stenosis-induced left ventricular hypertrophy (LVH) and five LVH pacing-induced failure dogs. 3. In both control and LVH dogs, but not in failure dogs, ISO significantly increased local regional work (1,923+/-665 vs 2,656+/-715, 1,185+/-286 vs 1,906+/-562 and 835+/-106 vs 849+/-216g.mm/min, respectively), force (11.1+/-1.4 vs 16.9+/-2.6, 8.6+/-1.5 vs 13.7+/-2.3 and 12.2+/-1.1 vs 11.0+/-1.8g, respectively) and myocardial O2 consumption (7.3+/-2.0 vs 10.0+/-1.5, 8.2+/-1.6 vs 11.6+/-2.6 and 4.4+/-1.5 vs 5.5+/-1.8 mL O2/min per 100 g, respectively). 4. Isoproterenol also significantly increased cAMP in control and LVH dogs (474+/-67 vs 600+/-91 and 473+/-34 vs 619+/-53 pmol/g, respectively). In heart failure, cAMP was significantly lower and there was no significant increase in cAMP in response to ISO (245+/-43 vs 314+/-40pmol/g, respectively). 5. We conclude that there were no significant myocardial functional, O2 consumption or cAMP responses to ISO after the transition from hypertrophy to cardiac failure.

Cyclic GMP attenuates cyclic AMP-stimulated inotropy and oxygen consumption in control and hypertrophic hearts.

We tested the hypothesis that increasing myocardial cyclic GMP would attenuate cyclic AMP induced positive inotropy and O2 consumption, in part, through changes in cyclic AMP and that renal hypertension-induced cardiac hypertrophy (HYP) would alter this relationship. Anesthetized, open chest rabbits (N = 48) were divided into four groups of control (CON) and HYP animals which received vehicle (VEH), isoproterenol 10(-6)M (ISO), 3-morpholinosyndnonimine 10(-4)M, (SIN-1), or a combination of ISO+SIN-1. Coronary blood flow (microspheres) and O2 extraction (microspectrophotometry) were used to determine O2 consumption in both subepicardium (EPI) and subendocardium (ENDO). Left ventricular change in wall thickness (%) was increased significantly by ISO in both CON (16 +/- 4 to 31 +/- 6) and HYP (17 +/- 2 to 24 +/- 3). Percent change in wall thickness was similar in the CON, SIN-1, and ISO+SIN-1 groups. Myocardial O2 consumption (ml O2/min/100 g) was increased by ISO in CON (10.3 +/- 1.0 to 13.6 +/- 2.0 EPI; 10.9 +/- 1.0 17.1 +/- 1.7 ENDO) and HYP (8.2 +/- 1.4 to 12.3 +/- 2.2 EPI; 6.6 +/- 1.4 to 14.8 +/- 1.8 ENDO). Oxygen consumption was unaffected by SIN-1 in CON and HYP animals. ISO+SIN-1 caused attenuated ISO-induced increases in O2 consumption in CON in EPI and ENDO, and in EPI in HYP. Cyclic GMP (pmol/g) was unchanged by ISO in CON and HYP, and increased by SIN-1 in CON (8.1 +/- 1.3 to 19.2 +/- 2.3 EPI) and HYP (9.1 +/- 1.5 to 12.8 +/- 2.0 EPI). Cyclic GMP remained elevated with ISO+SIN-1 in both groups. Cyclic AMP (pmol/g) was increased significantly by ISO in CON (496 +/- 43 to 725 +/- 106 EPI; 534 +/- 44 to 756 +/- 148 ENDO) and insignificantly in HYP (435 +/- 50 to 566 +/- 35 EPI; 497 +/- 51 to 583 +/- 47 ENDO). Cyclic AMP levels were unaffected by SIN-1 in either group. Isoproterenol induced increases in cyclic AMP were blunted by ISO+SIN-1 in CON (496 +/- 43 to 537 +/- 59 EPI) and not affected in HYP. The current study demonstrated attenuation of cyclic AMP mediated increased inotropy and O2 consumption by increasing cyclic GMP, which appeared, in part, related to cyclic GMP-induced reduction in cyclic AMP. This effect of cyclic GMP on cyclic AMP was not observed in myocardial hypertrophy.

Nitroprusside attenuates myocardial stunning through reduced contractile delay and time.

We hypothesized that myocardial stunning would be reversed through increased cyclic GMP caused by nitroprusside, and that this would be accomplished through a decreased proportion of regional work during diastole. Hearts were instrumented to measure left ventricular pressure, and regional myocardial mechanics were recorded using a miniature force transducer and ultrasonic dimension crystals in eight open-chest anesthetized dogs. Following baseline (CON), the left anterior descending coronary artery (LAD) was occluded for 15 min, followed by a 30-min recovery (STUN). Then intracoronary LAD infusion of sodium nitroprusside (NP) (4 microg/kg/ min) was begun. The time delay (msec) to regional shortening increased significantly from 18+/-13 to 73+/-13 following stunning, but was reduced to 49+/-18 by NP. Total regional work (g*mm/min) at baseline (1368+/-401 CON) was unchanged with stunning (1320+/-333 STUN), but reduced (961+/-240) following NP. Time to peak force development (msec) increased significantly with stunning from 284+/-13 (CON) to 333+/-11 (STUN), but was reduced to 269+/-12 following NP. The percentage work during systole was reduced from 96%+/-2% (CON) to 77%+/-7% (STUN), but returned to 98%+/-1% with NP. Regional O2 consumption was unaffected by either treatment. Cyclic GMP was unchanged by stunning (2.9+/-0.3-2.9+/-0.4 pmol/g) but increased significantly with NP (4.6+/-0.6). These data indicated that regional myocardial stunning could be attenuated by nitroprusside, which increased cyclic GMP, decreased contractile delay, increased the proportion of work done during systole, and reduced time of shortening.

Pacing-induced cardiac failure of hypertrophic hearts: effects of cyclic GMP reduction.

BACKGROUND: We tested the hypothesis that pacing-induced cardiac failure of hypertrophic hearts would reduce the functional and metabolic responses of these hearts to guanylate cyclase inhibition and this was associated with alterations in cyclic GMP. MATERIALS AND METHODS: Methylene blue (MB, 2 mg/kg/min, guanylate cyclase inhibitor) was infused into the left anterior descending coronary artery in 5 control, 5 left ventricular hypertrophy (LVH), and 5 LVH pacing-induced failure dogs. Regional myocardial work was calculated as the integrated product of force and segment shortening and regional myocardial O(2) consumption (VO(2)) from coronary blood flow and O(2) extraction measurements. Cyclic GMP was determined by radioimmunoassay. RESULTS: MB increased regional work (635 +/- 169 vs 1649 +/- 500, 781 +/- 184 vs 1569 +/- 203 g * mm/min) and VO(2) (8.3 +/- 1.4 vs 10.9 +/- 1.4, 7.3 +/- 0.7 vs 9.1 +/- 0.7 ml O(2)/min/100 g) in both control and LVH dogs but not in failure dogs (536 +/- 234 vs 623 +/- 193, 3.6 +/- 1.1 vs 4.7 +/- 1.9). MB also decreased cyclic GMP in control dogs (1170 +/- 142 vs 812 +/- 105 pmol/g). LVH dogs had elevated baseline cyclic GMP (5875 +/- 949) compared to control dogs but also demonstrated decreased cyclic GMP in response to MB (2820 +/- 372). In failure dogs, basal cyclic GMP was also elevated (4650 +/- 613) compared to control dogs but there was a lack of response to MB (3670 +/- 640). CONCLUSIONS: We conclude that the myocardial function, VO(2) and cyclic GMP responses to methylene blue are diminished in the transition from hypertrophy to cardiac failure.

Myocardial effects of cyclic AMP phosphodiesterase inhibition are dampened in thyroxine-induced cardiac hypertrophy.

We tested the hypothesis that the increase in myocardial O2 consumption (MVO2) and myocardial wall thickening in response to milrinone would not be limited by thyroxine (T4)-induced (0.5 mg/kg for 16 days) cardiac hypertrophy. Anesthetized open-chest New Zealand white rabbits were divided into four groups: control vehicle (CV, n = 5), control milrinone (CM, n = 8), T4 vehicle (T4V, n = 7), and T4 milrinone (T4M, n = 9). Vehicle or milrinone (10(-3) M) were topically applied to the left ventricular epicardium for 15 min. Coronary blood flow (radioactive microspheres) and O2 extraction (microspectrophotometry) were used to determine O2 consumption. Cyclic AMP levels were determined by radioimmunoassay. T4 increased the heart weight to body weight ratio from 2.6 +/- 0.1 to 3.1 +/- 0.1 (g/kg). T4 rabbits had significantly higher baseline heart rates, blood pressures, and dP/dtmax and both subepicardial (EPI) and subendocardial (ENDO) blood flows. Topical application of milrinone did not have significant hemodynamic effects in either group. Baseline cyclic AMP levels (pmol/g) in the EPI and ENDO myocytes were comparable between control and T4 rabbits (CVEPI = 599 +/- 34, CVENDO = 532 +/- 26, T4VEPI = 656 +/- 42, T4VENDO = 657 +/- 17). Milrinone increased cyclic AMP in all groups although the increases were less in the T4 rabbits (CMEPI = 742 +/- 115, CMENDO = 698 +/- 101, T4MEPI = 742 +/- 103, T4MENDO = 690 +/- 55). Baseline MVO2 (ml O2/min/100 g) was significantly higher in T4 rabbits than controls (T4VEPI = 17.7 +/- 3.5 vs CVEPI = 8.5 +/- 1.5, T4VENDO = 17.2 +/- 3.2 vs CVENDO = 9.2 +/- 1.5). Significant increases in MVO2 were noted with the addition of milrinone in control (CMEPI = 14.8 +/- 3.0, CMENDO = 13.5 +/- 1.6) and T4 (T4MEPI = 25.5 +/- 3.4, T4MENDO = 22.0 +/- 3.3) rabbits; however, the percentage increase in MVO2 was significantly greater in controls (CEPI = 73%, CENDO = 47%) than T4 (T4,EPI = 44%, T4,ENDO = 28%). Thus, although the cyclic AMP phosphodiesterase activity was comparable between T4 rabbit hearts and controls, the metabolic effects and cyclic AMP effects of milrinone were dampened in this form of hypertrophy.

Positive functional effects of milrinone and methylene blue are not additive in control and hypertrophic canine hearts.

This study was designed to test whether increased inotropy caused by raising intracellular cAMP would add to the positive inotropy caused by reducing cGMP and whether this relationship was affected by experimental hypertrophy. We used open chest anesthetized dogs with left ventricular hypertrophy (LVH) induced by valvular aortic stenosis and age matched controls (CON). Hearts were instrumented to measure local segment shortening, force, and regional work. Milrinone (MIL), a selective cyclic AMP-phosphodiesterase inhibitor, and methylene blue (MB), a guanylate cyclase inhibitor, were used to alter cAMP and cGMP levels. Ten CON and 11 LVH animals were randomly assigned to receive first either MIL (1 microg/kg/min) or MB (2 mg/kg/min) intracoronary (i.c.) infusion. After 10 min, simultaneous i.c. infusion of the other agent was begun. MIL increased regional minute work (g x mm/min) in both CON (1311 +/- 207 to 2072 +/- 285) and LVH (1052 +/- 136 to 1371 +/- 351) hearts. MB did not increase work significantly, but did increase contractile force. MIL + MB increased work from baseline; however, the combination did not increase work more than either agent alone (1961 +/- 510 CON; 1390 +/- 285 LVH). Myocardial cAMP levels (pmol/g) were significantly increased by MIL in both CON (329 +/- 53 to 437 +/- 13) and LVH hearts (351 +/- 67 to 538 +/- 32), and the addition of MB further raised cAMP (879 +/- 115 CON; 741 +/- 96 LVH). MB resulted in decreased myocardial cGMP (pmol/g) (3.20 +/- 0.61 to 2.16 +/- 0.92 CON; 5.21 +/- 1.15 to 2.46 +/- 0.56 LVH), while MIL increased cGMP (3.20 +/- 0.61 to 6.24 +/- 1.79 CON; 5.21 +/- 1.15 to 6.53 +/- 0.41 LVH). Both MIL and MB caused increases in O2 consumption, with MIL + MB together increasing O2 consumption further. The current findings demonstrate a potentiation of cAMP production in the presence of MIL + MB above either agent alone, but this did not lead to potentiation of positive functional effects. High levels of cGMP caused by milrinone may have limited the positive functional effects of cAMP.

Increased O2 consumption and positive inotropy caused by cyclic GMP reduction are not altered after L-type calcium channel blockade.

We tested the hypothesis that increased O2 consumption and inotropy after reduction of myocardial cyclic guanosine monophosphate (cGMP) are mediated through L-type calcium channels. Anesthetized, open-chest New Zealand white rabbits were divided into four groups. Hearts were exposed to control vehicle (n = 8); LY83583 (LY, 10(-3) mol/l, guanylate cyclase inhibitor, (n = 9); nifedipine (nif, 10(-4) mol/l, L-type calcium channel blocker, n = 8), or nif+LY (n = 6). Vehicle or compound was applied topically to the epicardium for 15 min. Subepicardial (EPI) blood flow increased (from 213 +/- 22 to 323 +/- 24 ml/ min/100 g) in the presence of LY, as did subendocardial (ENDO) blood flow (from 238 +/- 20 to 333 +/- 38 ml/min/ 100 g). O2 consumption increased in the presence of LY:18.0 +/- 1.0 (EPI) and 17.0 +/- 0.6 (ENDO) ml O2/min/100 g as compared with 9.5 +/- 2.0 (EPI) and 10.6 +/- 2.5 (ENDO) in the control group. The increase in O2 consumption with LY was undiminished in the presence of nif (nif+LY group 21.0 +/- 3.0 ml O2/min/100 g EPI and 22.1 +/- 3.8 ENDO). Nif alone decreased left ventricular dP/dtmax from (2,762 +/- 197 to 2,413 +/- 316 mm Hg/s) and maximal rate of change in wall thickness (dW/dtmax from 13.5 +/- 2.0 to 9.5 +/- 0.8 mm/s), while percent change of wall thickness (from 21.3 +/- 3.3 to 31.3 +/- 7.2) and dW/dtmax (from 13.3 +/- 3.0 to 15.3 +/- 2.3 mm/s) increased in the nif+LY group. Thus, the positive O2 consumption and inotropic effects of decreasing cGMP were undiminished by nif. These results suggest that the cGMP reduction induced increases in O2 consumption and that inotropy may not be mediated through L-type calcium channels.

Positive inotropy due to lowering cyclic GMP is also mediated by increases in cyclic AMP in control and hypertrophic hearts.

The aim of the current study was to determine if lowering myocardial cyclic GMP by guanylate cyclase inhibition would add independently to the positive inotropic effects caused by raising cyclic AMP and if these effects are modified in left ventricular hypertrophy (LVH) produced by aortic valve plication. Isoproterenol (ISO) (0.1 mg x kg(-1) x min(-1)) was infused into a branch of the left anterior descending coronary artery of seven control and eight hypertrophy open-chest anesthetized dogs. After 10 min, simultaneous infusion of methylene blue (MB) (2 mg x kg(-1) x min(-1)) was initiated at the same site. Hypertrophy increased heart weight and heart weight/body weight ratio. While both drugs increased left ventricular dP/dt(max), no additional global effects were observed in either group. Changes in regional variables followed the same pattern in both groups, i.e., ISO produced an increase that was enhanced by the addition of MB. ISO increased segment shortening, with a significant change in the control group. ISO increased regional force in both groups. The addition of MB increased force above ISO levels, with a significant change in the LVH group. ISO increased regional minute work (g x mm x min(-1)) (control, 1779 +/- 428 to 2541 +/- 500; LVH, 1157 +/- 253 to 1839 +/- 404) and O2 consumption. MB further increased regional work (control, 2993 +/- 952; LVH, 2416 +/- 853) and O2 consumption. ISO raised cyclic AMP (pmoles x g(-1)) (control, 468 +/- 41 to 580 +/- 84; LVH, 445 +/- 43 to 562 +/- 71) and had no effect on cyclic GMP (pmoles x g(-1)) (control, baseline 3.27 +/- 0.22, ISO 2.87 +/- 0.23; LVH, baseline 6.84 +/- 1.12, ISO 5.66 +/- 0.54). The addition of MB lowered cyclic GMP (control, 2.41 +/- 0.26; LVH, 3.68 +/- 0.35), but also increased cyclic AMP (control, 1021 +/- 121; LVH, 1107 +/- 134). Similar results were observed in control hearts using a specific soluble guanylate cyclase inhibitor (ODQ) in terms of changes in local work, O2 consumption, and cyclic nucleotides. Thus, at least part of the positive inotropic response to lowering cyclic GMP was mediated by changes in cyclic AMP in the current model. This was true in both control and LVH animals, although baseline cyclic GMP levels were higher, and a larger reduction in cyclic GMP was observed with MB in the LVH group.

Inhibition of adenosine deaminase and administration of adenosine increase hypoxia induced ventricular ectopy.

Eighteen anesthetized, instrumented beagles (both genders, 10.4 +/- 0.5 kg) were used to investigate the effects of administered adenosine (n = 6), erythro-9-(2-hydroxy, 3-nonyl)adenine (EHNA), a potent inhibitor of endogenous adenosine deaminase (n = 6), and saline (n = 6), on the incidence of ventricular arrhythmias caused by systemic hypoxia (5% O2, 95% N2, PaO2 = 21 +/- 3 mmHg). After dogs were instrumented and monitored variables were in the steady-state, the above compounds were infused continuously into the cannulated left anterior descending (LAD) coronary artery for three minutes before, and throughout a four-minute period of hypoxia. After approximately 4 min of hypoxia the rates of ventricular ectopy [(total beats-normal beats)/total beats x 100 = % ectopy] were 73 +/- 9%, 73 +/- 11%, and 35 +/- 8% for the three groups, respectively. The percent ectopy of the adenosine- and EHNA-treated dogs was significantly greater (p < 0.05) than that for the saline-treated controls. These findings suggest that adenosine contributes to the ventricular arrhythmias of experimental systemic hypoxia.

Adenosine deaminase and BW A1433U attenuate hypoxia-induced ventricular ectopy.

Twenty-six beagles of either sex, weighing 10.4 +/- 0.3 kg, were used to investigate the role of adenosine in the genesis of ventricular arrhythmias during systemic hypoxia. After instrumentation dogs were randomly assigned to one of four treatment groups: 14 dogs were pretreated before hypoxia with adenosine deaminase (n = 7, group I) or its vehicle (n = 7, group II) while 12 other dogs were pretreated with the A1 selective adenosine receptor antagonist BW A1433U (n = 6, group III) or its vehicle (n = 6, group IV). Each dog was exposed to a 3-min period of hypoxic ventilation [3% O2-5% CO2-92% N2; PO2 in arterial blood 96 +/- 3 Torr (before hypoxia), 21 +/- 1 Torr (during hypoxia)]. The percentages of ventricular ectopic beats (19) experienced in the four groups after 3 min of hypoxia were 21 +/- 10% (group I, P < 0.05 relative to group II), 50 +/- 2% (group II), 15 +/- 8% (group III, P < 0.05 relative to group IV), and 42 +/- 7% (group IV). Ventricular bigeminy, the most prominent arrhythmia seen in this study, was significantly reduced by adenosine deaminase and BW A1433U. No significant differences in other monitored cardiovascular variables were seen between adenosine deaminase and BW A1433U treatment groups and their corresponding vehicles. These findings implicate endogenous adenosine as an arrhythmogenic mediator during hypoxia and point to a mechanism involving the A1 adenosine receptor.