Effects of ischemic preconditioning on myocardial perfusion, function, and microvascular regulation.

BACKGROUND: Ischemic preconditioning (PC) has been advocated as a method to preserve myocardial function and perfusion during minimally invasive direct coronary bypass (MIDCAB). We examined the effects of PC on indexes of myocardial function, perfusion, and endothelial and beta-adrenergic coronary regulation after 30 minutes of ischemia and 60 minutes of reperfusion (IR). METHODS AND RESULTS: Five groups of pigs were studied: (1) PC-IR: PC by 3 cycles of 5-minute left anterior descending coronary artery occlusion (CO) and 5-minute reperfusion (Rep) + 30 minutes of CO + 60 minutes of Rep; (2) IR alone: 30 minutes of CO + 60 minutes of Rep; (3) PC alone; (4) PC-IR-glibenclamide (GLIB): PC-IR + infusion of GLIB; (5) control: noninstrumented. Reactivity (in vitro) of coronary arterioles (70 to 150 microns) from the myocardial area at risk was examined with video microscopy. beta-Adrenergic microvascular relaxations to isoproterenol, forskolin, and 8-bromo-cAMP were significantly reduced after IR alone (P < 0.05 versus control, 2-way ANOVA). PC before IR restored these responses to normal (P < 0.05 PC-IR versus IR alone), and GLIB abolished this effect of PC. Subepicardial endothelium-dependent microvascular relaxation to ADP was significantly reduced after IR alone (P < 0.01 versus control) but was preserved in both the PC-IR and PC-IR-GLIB groups (P < 0.05 versus IR alone). The response of vessels to ADP from the subendocardium was significantly reduced in all groups compared with the control response (all P < 0.05 versus control). Nitroprusside elicited a similar response in vessels from all groups. PC before IR did not affect the reduced myocardial percent segmental shortening or left ventricular maximal dP/dt, did not affect myocardial perfusion in the subepicardium or subendocardium, and did not change expression of the inducible or the constitutively expressed isoforms of nitric oxide synthase. CONCLUSIONS: PC before IR preserves beta-adrenergic signal transduction in coronary smooth muscle through a KATP channel mechanism, whereas PC preserves endothelium-dependent relaxation in the subepicardium through a mechanism not related to KATP channels or the enhanced expression of nitric oxide synthase. Nevertheless, PC does not improve short-term myocardial function or baseline myocardial perfusion after IR. Thus, the short-term beneficial role of PC in myocardial protection during MIDCAB may be limited.

Low-dose dopexamine's effect on lung and gut function after CPB in a sheep model.

OBJECTIVE: The lung injury regularly associated with cardiopulmonary bypass (CPB) may be linked to gut mucosal dysfunction occurring as the result of mucosal ischemia associated with nonpulsatile CPB. To examine this possibility we postulated that the weak-beta 2 agonist dopexamine would improve gut mucosal blood flow, thereby decreasing gut and lung dysfunction seen after CPB in sheep. METHODS: Anesthetized sheep had 2 h of hypothermic (24 degrees C), nonpulsatile CPB, and 60 min of cold, blood cardioplegic arrest. After warming they were separated from CPB for 2 h of reperfusion. Before and during CPB, dopexamine at 2 micrograms/kg/min (n = 7) or saline (n = 7) were infused in a blinded fashion. Hemodynamic parameters were measured. Biatrial thromboxane B2 levels were obtained. Mesenteric arterial flow (QSMA), mucosal flow (Qmuc), FD-4 clearance (ClFD-4), and tonometric pHi were measured at baseline and 30-min intervals on, and after, CPB. RESULTS: After CPB, similar reductions in MAP were seen (P < 0.05 vs. baseline), but heart rate and the mean pulmonary vascular resistance were significantly increased in the dopexamine animals (P < 0.05 vs. placebo). Plasma thromboxane was similarly increased in both groups after CPB (P < 0.05 vs. baseline), returning to baseline 1 h after CPB. The Qsma was not altered, but a statistically significant decrease in Qmuc and pHi occurred in both groups (P < 0.05 vs. baseline). In both groups FD-4 clearance reached a peak 30 min after CPB (P < 0.05; dopexamine vs. baseline). After 2 h neither of these changes returned to control levels. CONCLUSIONS: In this ovine model, gut mucosal ischemia and increased permeability occur with hypothermic CPB, but dopexamine administration during CPB, compared to placebo, neither ameliorates these intestinal derangements nor reduces post-CPB lung pathophysiology.

Vascular endothelial growth factor/vascular permeability factor produces nitric oxide-dependent hypotension. Evidence for a maintenance role in quiescent adult endothelium.

In vitro studies suggest that vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) may stimulate release of nitric oxide (NO) from endothelial cells. To investigate the hemodynamic consequences of recombinant VEGF/VPF administered in vivo, recombinant human VEGF/VPF was administered as a bolus dose of 500 micrograms to anesthetized (n = 6) or conscious (n = 5) New Zealand White rabbits, as well as anesthetized rabbits with diet-induced hypercholesterolemia (HC; n = 7). Anesthetized Yorkshire farm pigs (no specific dietary pretreatment) were studied before and after receiving 500 micrograms intravenous (IV; n = 5) or intracoronary (IC; n = 5) VEGF/VPF. In anesthetized, normal rabbits, mean arterial pressure (MAP) fell by 20.5 +/- 1.4% (P < .05 versus baseline) within 3 minutes after IV VEGF/VPF. Pretreatment with N omega-nitro-L-arginine caused a significant inhibition of VEGF/VPF-induced hypotension. In conscious, normal rabbits, VEGF/VPF produced a consistent though lesser reduction in MAP. The fall in MAP induced by VEGF/VPF in anesthetized, HC rabbits (21.5 +/- 2.5% from baseline) was no different from that observed in normal anesthetized rabbits. In pigs, both IV and IC administration of VEGF/VPF produced a prompt reduction in MAP. Heart rate increased, while cardiac output, stroke volume, left atrial pressure, and total peripheral resistance all declined to a similar, statistically significant degree in both IV and IC groups. Epicardial echocardiography disclosed neither global nor segmental wall motion abnormalities in response to VEGF/VPF. We conclude that (1) VEGF/VPF-stimulated release of NO, previously suggested in vitro, occurs in vivo; (2) this finding suggests that functional VEGF/VPF receptors are present on quiescent adult endothelium, consistent with a maintenance function for VEGF/VPF, which may include regulation of NO; and (3) the preserved response of HC rabbits suggests that endothelial cell receptors for VEGF/VPF are spared in the setting of hypercholesterolemia.

Comparative effects of continuous warm blood and intermittent cold blood cardioplegia on coronary reactivity.

BACKGROUND: Cardioplegia is known to affect coronary vascular reactivity. We examined the effects of intermittent cold and continuous warm blood cardioplegia on beta-adrenoceptor-mediated, adenosine triphosphate-sensitive K+ (K+ATP)-channel-mediated, and endothelium-dependent relaxation and on the myogenic tone of coronary arterioles. METHODS: Pigs were placed on cardiopulmonary bypass. Hearts were arrested for 1 hour with a cold blood cardioplegic solution administered intermittently (n = 12; iCB-CP) or with a warm blood cardioplegic solution delivered continuously (n = 12; cWB-CP). Selected hearts (n = 6 in each group) were then reperfused for 1 hour. In vitro relaxation responses of precontracted microvessels (50 to 160 microns) were studied in a pressurized no-flow state. RESULTS: Relaxation in response to isoproterenol (beta-adrenergic agonist) was similar after iCB-CP and cWB-CP, whereas forskolin (adenylate cyclase activator)-induced relaxation was impaired more after iCB-CP than after cWB-CP. After reperfusion the respective responses were similar. Both iCB-CP and cWB-CP preserved receptor-mediated, endothelium-dependent relaxation in response to adenosine, 5'-diphosphate; non-receptor-mediated endothelium-dependent relaxation in response to A23187; endothelium-independent cyclic guanosine monophosphate-mediated relaxation in response to sodium nitroprusside, and K+ATP-channel-mediated relaxation. Relaxations in response to 8-bromo-cyclic guanosine monophosphate (a cyclic guanosine monophosphate-dependent protein kinase activator) and to 8-bromo-cyclic adenosine monophosphate (a cyclic adenosine monophosphate-dependent protein kinase activator) were impaired after iCB-CP alone and after reperfusion, whereas the respective responses were not affected after cWB-CP. Myogenic tone was decreased similarly after iCB-CP and cWB-CP but was not further altered after reperfusion. Cardiac function was similar after iCB-CP and cWB-CP. CONCLUSIONS: These results suggest that cWB-CP is similar to iCB-CP in its ability to preserve endothelium-dependent relaxation and K+ATP-channel function. The superior preservation of beta-adrenergic-cyclic adenosine monophosphate-mediated coronary responses after cWB-CP is brief and associated with minimal improvement of myocardial function and myogenic tone.

Effects of magnesium cardioplegia on regulation of the porcine coronary circulation.

We compared the effect of hypermagnesium and hyperkalemic crystalloid cardioplegia on beta-adrenoceptor-mediated and endothelium-dependent relaxation and myogenic responses of coronary arterioles. Pigs were placed on cardiopulmonary bypass. Hearts were arrested with cold hypermagnesium (25 mM Mg2+, hyper-Mg, n = 12) or hyperkalemic (25 mM K+, hyper-K, n = 12) crystalloid cardioplegia for 1 hr. Hearts of selected pigs (n = 6 in each group) were then reperfused for 1 hr. In vitro relaxation responses of acetylcholine-pre-contracted arterioles were studied in a pressurized no-flow state with video-microscopy. Relaxation of pre-contracted coronary microvessels (70-150 microns) to isoproterenol (beta-adrenergic agonist) and forskolin (adenylate cyclase activator) was preserved after cardioplegia using a hyper-Mg solution. In contrast, responses were impaired to isoproterenol [P < 0.01 (two-factor ANOVA) vs. controls, n = 6] and forskolin (P < 0.01) after hyper-K cardioplegia. After 1 hr of reperfusion, relaxation responses to isoproterenol and forskolin were partially recovered. Hyper-Mg cardioplegia and post-cardioplegic reperfusion did not affect receptor-mediated endothelium-dependent relaxation to ADP, non-receptor-mediated endothelium-dependent relaxation to A23187, and endothelium-independent relaxation to nitroprusside. However, responses to ADP (P < 0.01) and A23187 (P < 0.05) were selectively impaired after hyper-K cardioplegia. Myogenic contraction was impaired after either hyper-Mg or hyper-K cardioplegia. Left ventricular systolic pressure, coronary blood flow, and +dP/dt were similar after hyper-Mg or hyper-K cardioplegia. These results suggest that hyper-Mg cardioplegia is superior to hyper-K cardioplegia in terms of preserving beta-adrenoceptor-mediated and endothelium-dependent regulation of the coronary microcirculation, yet it has minimal if any additional beneficial effect on preserving myogenic responses or myocardial contractile function.

Insulin resistance: a common factor in the triad of dyslipidemia, hypertension, and coronary artery disease?

In addition to the goal of controlling elevated blood pressure in patients with hypertension improving Dyslipidemia associated with insulin resistance may be an important element in preventing coronary artery disease. Antihypertensive treatment may differ based on the pathophysiology present. It appears that the evidence that supports the development of lipid abnormalities in patients who have insulin resistance is growing. In such patients the morbidity and mortality associated with coronary artery disease may be significantly decreased by selecting agents with favourable metabolic consequences.

VEGF improves myocardial blood flow but produces EDRF-mediated hypotension in porcine hearts.

Several recent studies have demonstrated the potential for improving myocardial perfusion by the continuous administration of angiogenic growth factors. Studies in our laboratory have shown that a single intraarterial or intravenous bolus of the endothelial cell specific mitogen vascular endothelial growth factor (VEGF) can significantly improve perfusion in a rabbit ischemic limb model. To test the efficacy of this therapeutic approach in chronic myocardial ischemia, 18 Yorkshire pigs underwent a left thoracotomy followed by placement of an ameroid constrictor around the proximal circumflex coronary artery. Gradual occlusion of the artery (26 +/- 4 days) was accompanied by identifiable hypokinesis of the posterolateral wall of the left ventricle (2D echo). Thirty days postoperatively, rhVEGF(165) (2 mg; n = 8) or saline (n = 10) was administered directly into the left coronary ostium. Postadenosine myocardial perfusion studies using colored microspheres 30 days later demonstrated superior blood flow in the ischemic zone of the VEGF-treated hearts (ischemic/normal ratio 1.09 vs 0.97, P < 0.05) compared with those receiving saline injection. Four of eight VEGF-treated animals succumbed, however, to severe hypotension following VEGF administration. Therefore 500 micrograms of VEGF were administered intracoronary to five normal pigs. A significant drop in mean arterial pressure (-44.4 +/- 3.2%, P < 0.05 vs baseline) and peripheral resistance (-13.2 +/- 4.5%, P < 0.05 vs baseline) was accompanied by increased heart rate. IV administration of N(omega)-nitro-L-arginine (L-NNA), an EDRF inhibitor, restored blood pressure to baseline. We conclude that a single intracoronary bolus of VEGF is capable of significantly augmenting flow to collateral-dependent ischemic myocardium. The associated hypotension appears to be EDRF-mediated. Further studies are needed to define the best dose and route of administration of VEGF for the treatment of coronary insufficiency.