You-Tang Shen

Catecholamine stimulation is associated with impaired myocardial O2 utilization in heart failure

OBJECTIVESnTo investigate the effect of alpha,beta(1) and beta(2) adrenergic receptor (AR) stimulation on coronary hemodynamics, myocardial oxygen consumption (M(v)O(2)) and metabolic substrate preference in advanced dilated cardiomyopathy (DCM).nnnMETHODSnWe studied 19 conscious, instrumented dogs with pacing-induced DCM. We evaluated systemic, coronary hemodynamics and M(v)O(2) in response to norepinephrine (NOR, 0.05-0.4 microg/kg per min), dobutamine (DOB, 1-10 microg/kg per min), phenylephrine (PHE, 1-5 microg/kg per min) and isoproterenol (ISO, 0.05-0.4 microg/kg per min) alone or in the presence of metoprolol (ISO+MET). Experiments were conducted in control state and in advanced DCM, 4-5 weeks after the initiation of pacing.nnnRESULTSnContractile responses (LV dP/dt) to catecholamines were desensitized and accompanied by a parallel decrease in heart rate-adjusted myocardial O(2) consumption (M(v)O(2/beat)), when alpha(PHE) or beta(1) (DOB) or both alpha/beta(1) (NOR) AR were stimulated in DCM. This was due to impaired transmyocardial (Ao-Cs) O(2) extraction rather than limitations in CBF responses. There was an associated shift in myocardial metabolism, evidenced by an increased preference for glycolytic substrates (Respiratory Quotient) following administration of any of these three adrenergic agonists in DCM. Combined beta(1)/beta(2) stimulation with ISO or beta(2)-AR stimulation (ISO+MET) in DCM resulted in greater M(v)O(2/beat), [(Ao-Cs) O(2)] extraction, and decreases in myocardial RQ consistent with a shift toward oxidation of FFA.nnnCONCLUSIONSnThe impairment in contractile responses to dobutamine and norepinephrine in DCM is associated with impaired myocardial O(2) extraction, and a shift toward a preference for glycolysis. A different myocardial metabolic pattern suggestive of increased oxidation of FFA with increased myocardial O(2) extraction was observed in the presence of combined beta(1)/beta(2) stimulation with isoproterenol or beta(2) stimulation (ISO+MET). These data suggest that beta(2)-AR stimulation in DCM shifts substrate preference toward FFA oxidation associated with greater M(v)O(2) requirements. These findings identify a putative metabolic effect of beta(2) -AR in DCM that may be deleterious.

Effects of inhibition of α-CGRP receptors on cardiac and peripheral vascular dynamics in conscious dogs with chronic heart failure

Whether endogenous calcitonin gene-related peptide (CGRP) plays a role in heart failure is unclear. Seven dogs were instrumented with left ventricular (LV) pressure gauges, pacers, coronary occluder and aortic, atrial, and coronary sinus catheters. Hemodynamic recordings and response to &agr;-CGRP challenge were obtained for baseline in the conscious state. Rapid pacing (240 beats/min) was then initiated. The coronary artery was occluded for 90 minutes followed by reperfusion after 2 weeks of pacing. After 6 weeks of pacing, LV pressure (−11 ± 6%), LV dP/dt (−53 ± 5%), and mean arterial pressure (−15 ± 4%) decreased (P < 0.01), while left atrial pressure (+19 ± 3 mm Hg from 7 ± 1 mm Hg) and heart rate (+53 ± 16%) increased (P < 0.01). Infusion of the &agr;-CGRP receptor antagonist &agr;-CGRP[8-37] (30 &mgr;g/kg/min, iv), which blocked the exogenous &agr;-CGRP challenge, did not affect any of these indices. Regional blood flow, as measured by the microsphere technique, in the nonischemic myocardium, as well as cerebral and renal vasculatures were unaltered during the infusion of &agr;-CGRP[8-37]. Plasma concentrations of CGRP from both arterial and coronary sinus samples were unchanged after 6 weeks of pacing as compared with control. Thus, we conclude that endogenous &agr;-CGRP does not appear to play a major role in the regulation of cardiac and peripheral vascular dynamics in the late stage of heart failure.

Effects of the prototype serotonin 5-HT1B/1D receptor agonist sumatriptan and the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP8-37 on myocardial reactive hyperemic response in conscious dogs

The triptans, serotonin 5-HT(1B/1D) receptor agonists exemplified by sumatriptan, are a mainstay migraine therapy but have class labeling contraindicating their use in patients with coronary artery disease. Triptans constrict human coronary artery in vitro, and there are case reports of myocardial infarction in patients using sumatriptan. However, preclinical studies with sumatriptan in normal dogs have failed to demonstrate effects on resting coronary flow. Calcitonin gene-related peptide (CGRP) receptor antagonism, exemplified by the prototype CGRP receptor antagonist peptide CGRP(8-37), is a new antimigraine mechanism which also has been reported to have no effect on coronary flow in normal, non-stressed animals. The goal of the present studies was to compare the effects of sumatriptan (10microg/kg/min i.v.) and CGRP(8-37) (30microg/kg/min i.v.) on systemic and coronary hemodynamics in conscious dogs under resting conditions and during myocardial reactive hyperemia following a brief 15s of coronary artery occlusion. Neither CGRP(8-37) nor sumatriptan affected resting coronary flow. However, whereas CGRP(8-37) had no effect on myocardial reactive hyperemic response, sumatriptan reduced peak reactive hyperemic coronary artery blood flow (baseline vs treatment: 75.4+/-12.7 vs 60.0+/-10.3ml/min, P<0.05), reactive hyperemic flow (16.7+/-5.2 vs 11.6+/-3.3ml, P<0.05) and the repayment of coronary blood flow debt following coronary artery occlusion (484+/-76 vs 369+/-57%, P<0.05), indicating an impairment in coronary blood flow reserve. The positive control nitric oxide synthase inhibitor L-NNA (30mg/kg/30min i.v.) likewise significantly attenuated myocardial reactive hyperemic response. These findings provide evidence for a differentiation between CGRP receptor antagonism and triptan effects on coronary vascular function.

A novel heart failure model induced by sequential coronary artery occlusions and tachycardiac stress in awake pigs

A heart failure model was developed using conscious pigs subjected to serial myocardial infarctions followed by intermittent rapid ventricular pacing. Aortic and atrial catheters, left ventricular (LV) pressure gauge, LV dimension crystals, ascending aortic flow probe, pacing leads, and two coronary artery occluders were implanted in 15 pigs. The initial distal left circumflex coronary artery (LCX) occlusion produced a modest infarct, i.e., 18 ± 3% of LV, and the second proximal LCX occlusion, performed 48 h later, enlarged the infarct to 33 ± 2% of the LV with only modest changes in LV function. Thereafter, the pigs were subjected to ventricular pacing at 220 beats/min, which was maintained for 7 days and terminated for 3 days. This pacing cycle was repeated two more times and resulted in significantly impaired LV function and systemic hemodynamics. For example, after the second cycle of pacing, LV rate of pressure change (dP/d t, -41 ± 4% from 2,778 ± 112 mmHg/s), velocity of circumferential fiber shortening ( V cf: -53 ± 6% from 1.1 ± 0.1 s-1), and cardiac index (CI: -42 ± 5% from 122 ± 4 ml ⋅ min-1 ⋅ kg-1) were reduced significantly, whereas LV end-diastolic diameter (EDD: +34 ± 6% from 39 ± 2 mm), total peripheral resistance (TPR: +75 ± 16% from 0.79 ± 0.05 U), and mean left atrial pressure (LAP) (+21 ± 1 mmHg from 5 ± 1 mmHg) were increased significantly. Importantly, 3 wk after cessation of the final pacing cycle, LV dP/d t (-40 ± 5%), V cf(-48 ± 9%), and CI (-30 ± 4%) remained depressed, whereas LV EDD (+39 ± 5%), TPR (+43 ± 9%), and LAP (+13 ± 4 mmHg) were still increased. In contrast, hemodynamic impairment in six conscious pigs subjected to pacing only did not persist when pacing was terminated. Thus this model could provide a unique opportunity to study both the effects of preclinical therapeutic interventions and the mechanisms involved in the development of heart failure.A heart failure model was developed using conscious pigs subjected to serial myocardial infarctions followed by intermittent rapid ventricular pacing. Aortic and atrial catheters, left ventricular (LV) pressure gauge, LV dimension crystals, ascending aortic flow probe, pacing leads, and two coronary artery occluders were implanted in 15 pigs. The initial distal left circumflex coronary artery (LCX) occlusion produced a modest infarct, i.e., 18 +/- 3% of LV, and the second proximal LCX occlusion, performed 48 h later, enlarged the infarct to 33 +/- 2% of the LV with only modest changes in LV function. Thereafter, the pigs were subjected to ventricular pacing at 220 beats/min, which was maintained for 7 days and terminated for 3 days. This pacing cycle was repeated two more times and resulted in significantly impaired LV function and systemic hemodynamics. For example, after the second cycle of pacing, LV rate of pressure change (dP/dt, -41 +/- 4% from 2,778 +/- 112 mmHg/s), velocity of circumferential fiber shortening (V(cf): -53 +/- 6% from 1.1 +/- 0.1 s(-1)), and cardiac index (CI: -42 +/- 5% from 122 +/- 4 ml. min(-1). kg(-1)) were reduced significantly, whereas LV end-diastolic diameter (EDD: +34 +/- 6% from 39 +/- 2 mm), total peripheral resistance (TPR: +75 +/- 16% from 0.79 +/- 0.05 U), and mean left atrial pressure (LAP) (+21 +/- 1 mmHg from 5 +/- 1 mmHg) were increased significantly. Importantly, 3 wk after cessation of the final pacing cycle, LV dP/dt (-40 +/- 5%), V(cf) (-48 +/- 9%), and CI (-30 +/- 4%) remained depressed, whereas LV EDD (+39 +/- 5%), TPR (+43 +/- 9%), and LAP (+13 +/- 4 mmHg) were still increased. In contrast, hemodynamic impairment in six conscious pigs subjected to pacing only did not persist when pacing was terminated. Thus this model could provide a unique opportunity to study both the effects of preclinical therapeutic interventions and the mechanisms involved in the development of heart failure.

Platelet Glycoprotein IIb/IIIa Receptor Inhibitor Preserves Coronary Flow Reserve During Progressive Coronary Arteriostenosis in Swine

Thrombosis resulting from blood platelet aggregation via glycoprotein (GP) IIb/IIIa receptor activation triggers the local release of vasoactive substances. Therefore, inhibition of these receptors could affect coronary vasoactive function during thrombotic coronary arteriostenosis. Twenty pigs were instrumented with an aortic catheter and with hydraulic occluders and flow probes on both the left anterior descending (LAD) and the left circumflex (LCx) coronary arteries. One of these 2 coronary arteries was repeatedly injured by external clamping for 15-second periods at 30-minute intervals while the pigs were given either a GP IIb/IIIa receptor inhibitor (L-739,758) (n=5), heparin (n=5), aspirin (n=3), or saline (n=7). There were no baseline differences between the 4 groups in mean arterial pressure, resting coronary blood flow (CBF), or reactive hyperemic response (RHR), which was induced by brief coronary artery occlusion and expressed as flow debt repayment. After multiple injuries, resting CBF had decreased by 95±2% (ie, nearly complete coronary artery occlusion) at 15±4 minutes in the control group, whereas in the heparin-, aspirin-, and GP IIb/IIIa inhibitor–treated groups, resting CBF had decreased by only 21±7% at 18±3 minutes, 15±3% at 18±5 minutes, and 15±7% at 21±4 minutes, respectively, suggesting that heparin, aspirin, and the GP IIb/IIIa inhibitor each prevented injury-induced coronary artery occlusion. After the initial injury, the RHR was progressively reduced in the control and heparin- and aspirin-treated groups but not in the GP IIb/IIIa inhibitor–treated group. At a comparable level of resting CBF (≈15% below baseline), the RHR was reduced more in the control (−56±9%), heparin-treated (−49±9%), and aspirin-treated (−61±12) groups (P <0.05) than in the GP IIb/IIIa inhibitor–treated group (−26±6%). When the resting CBF had decreased by ≈35%, the RHR still was reduced significantly more (P <0.01) in the heparin-treated group (−64±9%) than in the GP IIb/IIIa inhibitor–treated group (−21±6%). In a separate group of control pigs (n=4) subjected to 2 injuries, coronary perfusion pressure distal to the injury site was reduced by 14±1 mm Hg from the arterial pressure, and the RHR was 20±6%. When the distal coronary perfusion pressure was reduced similarly (−14±1 mm Hg) in a separate group of GP IIb/IIIa inhibitor–treated pigs (n=4) by 2 injuries and the use of a hydraulic occluder, the RHR was 130±16% (P <0.01 versus control). Our data demonstrate for the first time that a platelet GP IIb/IIIa receptor inhibitor can preserve the distal coronary vasodilatory response during progressive coronary arteriostenosis.

Coronary vascular responses to short-term cocaine administration in conscious baboons compared with dogs☆

OBJECTIVESnCardiovascular complications of cocaine use represent an important clinical problem, yet the mechanisms by which cocaine predisposes to myocardial ischemia are poorly understood.nnnBACKGROUNDnThe effects of cocaine on the coronary circulation have been studied extensively in experimental animal models, but have failed to recapitulate the clinical findings reported in humans who use cocaine.nnnMETHODSnWe studied 12 conscious, chronically instrumented dogs and 5 conscious, chronically instrumented baboons to determine whether there were important species differences in the response to cocaine.nnnRESULTSnComparable doses of intravenous cocaine caused similar increases in left ventricular systolic, diastolic and mean arterial pressure in the two species. However, the peak coronary blood flow response in baboons (+8 +/- 3 from 47 +/- 6 ml/min) was less compared with dogs (+15 +/- 4 from 41 +/- 4 ml/min), while the coronary vascular resistance response was greater in baboons (+0.60 +/- 0.09 from 1.94 +/- 0.09 mm Hg/ml/mm) compared with dogs (+0.35 +/- 0.09 from 2.24 +/- 0.10 mm Hg/ml/min). Although myocardial oxygen consumption responses were similar between species, there was a significant difference (p < 0.05) in oxygen delivery between baboons (+164 +/- 47 from 705 +/- 59 ml of oxygen per minute) and dogs (+397 +/-51 from 656 +/- 33 ml of oxygen per minute) that was attributable to a significant (p < 0.05) increase in hemoglobin concentration in dogs (+2.1 +/- 0.5 g/dl) that was not observed in baboons. Consequently, cocaine caused a significant increase in myocardial oxygen extraction and decreased coronary sinus pH in baboons, but not dogs.nnnCONCLUSIONSnCocaine caused greater coronary vasoconstriction and greater requirements for oxygen extraction in baboons compared with dogs.

Chronic therapy with an ETA/B receptor antagonist in conscious dogs during progression of congestive heart failure intracellular Ca2+ regulation and nitric oxide mediated coronary relaxation

BACKGROUNDnAlthough it is known that endothelin (ET-1) is elevated in heart failure (HF), it remains unclear if chronic ET(A/B) receptor antagonism affects the progression of HF, particularly by affecting coronary vasoactivity and left ventricular (LV) diastolic function.nnnMETHODSnWe examined the effects of an ET(A/B) receptor antagonist, L-753,037 (oral bid for 6 weeks, n=7), and vehicle (n=8) in conscious dogs with previously implanted aortic, coronary sinus and left atrial catheters, LV pressure gauge, aortic flow probe, LV dimension crystals and pacers.nnnRESULTSnBaseline hemodynamics were similar in the two groups. During the development of rapid pacing-induced HF, treatment with the ET(A/B) antagonist significantly reduced total peripheral resistance and increased cardiac output compared to vehicle. After 2 weeks of pacing, LV diastolic function (tau) was improved (P<0.05) in the ET(A/B) antagonist group (+6+/-2 ms) compared to the vehicle group (+12+/-2 ms). In addition, ET(A/B) antagonist treatment attenuated the increase in mean left atrial pressure and LV end-diastolic pressure that occurred during heart failure in vehicle-treated animals. However, LV systolic function (LV dP/dt, fractional shortening and Vcfc) neither at rest nor in response to dobutamine was altered by ET(A/B) antagonist treatment. Also, ET(A/B) antagonist treatment did not affect the progressive increases in LV dimension. After 6 weeks of pacing, maximal Ca(2+) transport in isolated cardiac sarcoplasmic reticulum (SR) was reduced (P<0.02) in the vehicle-treated compared to the ET(A/B) antagonist-treated dogs (1.34+/-0.09 vs. 1.60+/-0.06 micromol/mg/min, respectively). The improvement in SR function in the ET(A/B) antagonist-treated dogs was associated with a significant attenuation of the reduction in protein expression of SERCA2a and calsequestrin observed in the vehicle-treated dogs. Coronary arteries isolated from the dogs treated with the ET(A/B) antagonist exhibited enhanced (P<0.01) coronary endothelium-dependent relaxation compared to the vehicle group, while coronary responses to an NO donor were identical in the two groups. Plasma NO levels in the coronary sinus during the late stage of HF were higher (P<0.05) in the ET(A/B) antagonist group (40+/-2 microM) compared to the vehicle group (18+/-2 microM).nnnCONCLUSIONSnWe conclude that in conscious dogs during the development of HF induced by rapid pacing, chronic inhibition of ET(A/B) receptors does not affect resting myocardial contractile function nor reserve, but reduces vascular resistance and improves LV diastolic function. After 6 weeks of pacing, the reduction in intracellular Ca(2+) regulation by the SR is also attenuated, and endothelium-dependent coronary relaxation is improved, which appears to be related to the preservation of coronary NO levels.