Functional role of alpha-calcitonin gene-related peptide in the regulation of the cardiovascular system.

It remains unknown whether the extent of vasoactive response to exogenous calcitonin gene-related peptide (CGRP) varies among different regional vascular beds. It is also unclear whether endogenous CGRP plays a functional role in regulating basal vascular activity. To address these two issues, experiments were conducted in 27 anesthetized rats instrumented with a carotid flow probe and catheters in a jugular vein, left ventricle (LV), and femoral artery, and in 6 conscious dogs, chronically instrumented with LV pressure gauge, aortic and atrial catheters, and ascending aortic, coronary, carotid, and renal flow probes. In both species, administration of human alpha-CGRP (0.1-0.5 microg/kg, i.v.) induced a dose-dependent peripheral vasodilation that was completely abolished by pretreatment with alpha-CGRP[8-37] (30 microg/kg/min, i.v.), a competitive antagonist of CGRP receptors. Regional blood flow measured by the radioactive microsphere technique in rats showed that the alpha-CGRP (0.3 microg/kg, i.v.)-induced increase in blood flow was greater (p < 0.05) in the heart (+53 +/- 16%) than in the brain (+14 +/- 6%). In the presence of beta-adrenergic receptor blockade with propranolol, however, the increases in blood flow in these two vascular beds were identical. In conscious dogs, alpha-CGRP (0.3 microg/kg, i.v.) produced similar increases in coronary (+24 +/- 6%), carotid (+26 +/- 3%), and renal (+26 +/- 6%) blood flow, which were different from the patterns induced by other vasodilators; at an equivalent level of reduction in mean arterial pressure and total peripheral resistance, alpha-CGRP increased coronary and carotid blood flow significantly less (p < 0.05) than adenosine or nitroprusside. Unlike alpha-CGRP, adenosine and nitroprusside, as expected, induced pronounced differential blood flow changes in these vascular beds. Neither systemic hemodynamics nor regional blood flow distribution was altered by the administration of a pharmacological blocking dose of alpha-CGRP[8-37] in the two species. Thus, we conclude that endogenous alpha-CGRP does not play an important role in cardiovascular regulation under normal, resting conditions, although exogenous alpha-CGRP induces a marked, comparable vasorelaxation in different regional vascular beds.     

Antiarrhythmic efficacy of combined I(Ks) and beta-adrenergic receptor blockade

Suppression of malignant ventricular arrhythmias by selective blockade of the cardiac slowly activating delayed rectifier current (I(Ks)) has been demonstrated with the benzodiazepine L-768673 [(R)-2-(2,4-trifluoromethyl-phenyl)-N-[2-oxo-5-phenyl-1-(2,2,2-trifluoro-ethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide] in canine models of recent and healed myocardial infarction. The present study extends the initial antiarrhythmic assessment of I(Ks) blockade by demonstrating prevention of ischemic malignant arrhythmias in dogs with recent (8.0 +/- 0.4 days) anterior myocardial infarction with the coadministration of a subeffective dose of L-768673 and a subeffective, minimally beta-adrenergic blocking dose of timolol. Administered individually, neither 0.3 microg/kg i.v. L-768673 nor 1.0 microg/kg i.v. timolol prevented the induction of ventricular tachyarrhythmia (VT) by programmed ventricular stimulation (PVS) or the development of malignant ventricular arrhythmia in response to acute coronary artery thrombosis. In contrast, coadministration of 0.3 microg/kg i.v. L-768673 + 1.0 microg/kg i.v. timolol suppressed the induction of VT by PVS (8/10, 80% rendered noninducible versus 1/10, 10% noninducible in vehicle group; p < 0.01) and prevented the development of acute ischemic lethal arrhythmias (3/10, 30% incidence versus 8/10, 80% incidence in vehicle group; p < 0.05). Concomitant administration of low-dose L-768673 + timolol produced modest increases in QTc and paced QT intervals (4.5 +/- 1.2 and 5.5 +/- 1.4%; both p < 0.01), increases in noninfarct zone relative and effective refractory periods (7.0 +/- 1.7 and 12.3 +/- 3.0%; both p < 0.01), and lesser increases in infarct zone relative and effective refractory periods (5.3 +/- 1.6 and 5.8 +/- 1.4%; both p < 0.01). These findings suggest that concomitant low-dose I(Ks) and beta-adrenergic blockade may constitute a potential pharmacologic strategy for prevention of malignant ischemic ventricular arrhythmias.     

Assessment of coronary flow reserve by adenosine transthoracic echocardiography: validation with intracoronary Doppler.

OBJECTIVE: Data on the accuracy of transthoracic echocardiographic (TTE) analysis of coronary flow reserve are scarce. We compared coronary flow reserve measurements assessed using TTE with those achieved using the gold standard of intracoronary Doppler. METHODS: Twenty-one patients admitted for elective coronary angioplasty to the circumflex or left anterior descending (LAD) coronary artery underwent TTE immediately before angioplasty, both at rest and during intravenous administration of adenosine 140 microg/kg/min. Transthoracic images of distal LAD coronary diameter and coronary flow were obtained in 14 patients (66%). These patients then underwent intracoronary Doppler analysis of coronary flow reserve in the distal LAD coronary artery. In 1 patient with a proximal LAD artery lesion, the narrowing could not be crossed with the Doppler guidewire. Paired data on coronary flow reserve were therefore available in 13 patients. RESULTS: Patients were aged 61.7 +/- 8.3 years. Ten were men. Body mass index was 26.3 +/- 4.6 kg/m(2). Resting distal LAD artery blood flow was 18.4 +/- 9.0 mL/min assessed by TTE versus 17.6 +/- 8.1 mL/min by intracoronary Doppler. Hyperemic flow was 36.3 +/- 23.4 versus 33.1 +/- 19.2 mL/min, respectively. Coronary flow reserve was therefore 1.89 +/- 0.66 by TTE compared with 1.83 +/- 0.62 by intracoronary Doppler. Limits of agreement for coronary flow reserve were -0.28 to +0.44, well within boundaries of clinical acceptability. CONCLUSION: Transthoracic echocardiography is capable of providing accurate data on coronary flow reserve in the distal LAD coronary artery. As a truly noninvasive modality, this technique offers advantages over traditional invasive procedures.     

Effects of vasopressin on left anterior descending coronary artery blood flow during extremely low cardiac output

Because of the possibility of vasopressin-mediated coronary vasospasm, this study was designed to assess effects of vasopressin compared to saline placebo on left anterior descending (LAD) coronary artery blood flow. Twelve anaesthetized domestic swine were prepared for LAD coronary artery blood flow measurement with ultrasonic flow probes, using cardiopulmonary by-pass adjusted to 10% of the prearrest cardiac output. This 10% value approximates that reported for cardiac output during conventional closed-chest CPR. After 4 min of untreated ventricular fibrillation, and 3 min of cardiopulmonary by-pass blood flow, 12 pigs were randomly assigned to receive intravenously, every 5 min, either vasopressin (0.4, 0.4, and 0.8 U/kg; n = 6) or saline placebo (n = 6). The mean +/- S.D. LAD coronary artery blood flow in the vasopressin and placebo pigs was comparable before cardiac arrest, and during cardiopulmonary by-pass low flow; but increased significantly (P < 0.05) 90 s after each of three vasopressin injections compared to placebo (78 +/- 1 versus 42 +/- 2 ml/min; 62 +/- 2 versus 36 +/- 1 ml/min; and 54 +/- 1 versus 27 +/- 1 ml/min), respectively. Coronary vascular resistance decreased significantly (P < 0.05 ) 90 s after each of three vasopressin and placebo injections. In this model, repeated bolus administration of vasopressin, given during simulated extremely low cardiac output improved LAD coronary artery blood flow to prearrest levels without affecting coronary vascular resistance. Conclusions: during extremely low blood flow using cardiopulmonary by-pass, vasopressin improves LAD coronary artery blood flow without affecting coronary vascular resistance.     

Improved left ventricular function and reduced necrosis after myocardial ischemia/reperfusion in rabbits treated with ranolazine, an inhibitor of the late sodium channel

Ranolazine is an inhibitor of the late sodium current and, via this mechanism, decreases sodium-dependent intracellular calcium overload during ischemia and reperfusion. Ranolazine reduces angina, but there is little information on its effects in acute myocardial infarction. The aim of this study was to test the effects of ranolazine on left ventricular (LV) function and myocardial infarct size after ischemia/reperfusion in rabbits. Ten minutes before coronary artery occlusion (CAO), anesthetized rabbits were assigned to vehicle (n=15) or ranolazine (2 mg/kg i.v. bolus plus 60 microg/kg/min i.v. infusion; n=15). Hearts received 60 min of CAO and 3 h of reperfusion. CAO caused LV dysfunction associated with necrosis. However, at the end of reperfusion, rabbits treated with ranolazine had better global LV ejection fraction (0.42+/-0.02 versus 0.33+/-0.02; p<0.007) and stroke volume (1.05+/-0.08 versus 0.78+/-0.07 ml; p<0.01) compared with vehicle. The fraction of the LV wall that was akinetic or dyskinetic was significantly less in the ranolazine group at 0.23+/-0.03 versus 0.34+/-0.03 in vehicle-treated group; p<0.02. The ischemic risk region was similar in both groups; however, infarct size was significantly smaller in the treated group (44+/-5 versus 57+/-4% vehicle; p<0.04). There were no significant differences among groups in heart rate, arterial pressure, LV end-diastolic pressure, or maximum-positive or -negative first time derivative of LV pressure (dP/dt). In conclusion, the results of this study show that ranolazine provides protection during acute myocardial infarction in this rabbit model of ischemia/reperfusion. Ranolazine treatment led to better ejection fraction, stroke volume and less wall motion abnormality after reperfusion, and less myocardial necrosis.     

The role of serotonin (5HT2) receptor blockade in myocardial reperfusion injury: effects of LY53857 in a canine model of myocardial infarction.

The potential protective effects of serotonin receptor antagonism during the process of acute myocardial infarction were studied in anesthetized male dogs, which were subjected to a 90-min left circumflex coronary artery occlusion followed by 5 h of reperfusion. Either vehicle (0.9% NaCl) or the serotonin (5HT2) receptor antagonist LY53857 was infused i.v. at a dose of 0.5 mg/kg, followed by a constant infusion of 2 mg/kg/min beginning 5 min before left circumflex coronary artery occlusion and continuing throughout the duration of the ischemia and subsequent reperfusion. Verification of functional 5HT2 receptor antagonism in the circulating blood of the LY53857-treated dogs was monitored throughout the experiments by periodic assessment of ex vivo platelet reactivity to exogenous serotonin. After 5 h of reperfusion, the hearts were excised and analyzed utilizing histochemical staining with triphenyltetrazolium, which demarcates myocardial infarct size and anatomical area of myocardium at risk of infarction. There was not a significant reduction of infarct size with LY53857 treatment: control infarct/area at risk = 38.6 +/- 4.7%, n = 9 LY53857 infarct/area at risk = 33.4 +/- 3.8%, n = 6. Similarly, when myocardial infarct size was analyzed as a function of myocardial collateral blood flow, there were no significant effects of drug treatment on the relationship between collateral blood flow and infarct size. The effects of 5HT on neutrophil activation were determined by measuring the potential ability of 5HT to enhance the chemotactic peptide-induced production of superoxide. 5HT did not activate human neutrophils in vitro and LY53857 had no effect on neutrophil superoxide production.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intramyocardial gene therapy with naked DNA encoding vascular endothelial growth factor improves collateral flow to ischemic myocardium

Both VEGF protein and VEGF DNA in combination with an adenoviral vector have been shown to enhance collateral formation in a porcine model of chronic myocardial ischemia. We sought to determine whether direct intramyocardial injection of naked DNA encoding for VEGF could similarly improve myocardial perfusion. Initially, 23 nonischemic pigs received either 200 microg of plasmid DNA encoding beta-galactosidase (pCMVbeta, n = 11) or 500 microg of phVEGF165 (n = 12) into four separate sites in the myocardium via a small anterolateral thoracotomy incision in the fourth intercostal space. Two additional groups of pigs received an intramyocardial injection of either phVEGF165 (n = 6) or pCMVbeta (n = 7) 3 to 4 weeks after implantation of an ameroid constrictor around the left circumflex coronary artery. The injections caused no change in heart rate or blood pressure, and no ventricular arrhythmias or histologic evidence of inflammation. VEGF protein was detected by Western blot in VEGF-treated animals, with the strongest bands closest to the injection site. Plasma VEGF concentration (ELISA) increased from 3+/-2 to 27+/-13 pg/ml (p = 0.035) by day 4 after treatment. No increase in VEGF protein was noted in pCMVbeta-treated animals whereas these did stain positive for beta-Gal. Resting myocardial blood flow (colored microspheres) was significantly reduced in the ischemic versus nonischemic territory in control animals (1.07+/-0.05 versus 1.32+/-0.05; p < 0.05) but not VEGF-treated pigs (1.32+/-0.24 versus 1.13+/-0.12; p = NS). Maximal vasodilatation with adenosine significantly increased flow to the ischemic region in VEGF-treated pigs (2.16+/-0.57 versus 1.32+/-0.24; p < 0.05) but not controls (1.31+/-0.05 versus 1.17+/-0.06;p = NS). Collateral filling of the occluded circumflex artery improved in five of six VEGF-treated pigs (mean change in Rentrop score, +1.5). We conclude that direct intramyocardial transfection phVEGF165 is safe and capable of producing sufficient VEGF protein to enhance collateral formation and myocardial perfusion. This approach may offer an alternative therapy for patients with intractable myocardial ischemia not amenable to PTCA or CABG.     

Anti-ischemic and vasorelaxant effects of the new benzazepine calcium channel blocker SQ 31,765

The anti-ischemic effects of SQ 31,765 or its relatively inactive enantiomer SQ 32,189 (to test for effects not related to calcium channel blockade) were determined in a model of stable angina. Anesthetized dogs were given saline (n = 6), SQ 31,765 (n = 6; 0.2 mg/kg) or SQ 32,189 (n = 6; 0.2 mg/kg) i.v. 10 min before ischemia. The effect on pacing-induced ST-segment elevation (pacing + left anterior descending coronary artery stenosis) and myocardial blood flow were determined. SQ 31,765 reduced ST-elevation (P less than .05) compared to saline at 10, 40 and 70 min after infusion (5.9 +/- 1.4 and 12.0 +/- 1.4 mV, respectively, at 70 min). SQ 32,189, which is a 10-fold less potent calcium channel blocker in coronary arteries, did not affect ST-elevation (11.8 +/- 2.1 mV). Left anterior descending coronary artery stenosis during atrial pacing resulted in a significant reduction in subendocardial flow in all groups before drug infusion (41 +/- 7, 44 +/- 7 and 35 +/- 9 ml/min/100 g for saline, SQ 31,765 and SQ 32,189, respectively) and treatment with SQ 31,765 did not affect this flow. SQ 32,189 further reduced subendocardial blood flow such that it was significantly lower compared to saline. To test for any partial agonist activity, Bay k 8644 and SQ 32,189 were tested as constrictors of porcine coronary strips in vitro. Bay k 8644 induced appreciable force whereas SQ 32,189 did not. However, the vasorelaxant potency of SQ 32,189 was decreased under hypoxic conditions. Thus, SQ 31,765 can reduce the severity of ischemia in a manner which is independent of changes in myocardial blood flow or hemodynamic alterations.     

Apolipoprotein A-IMilano and 1-palmitoyl-2-oleoyl phosphatidylcholine complex (ETC-216) protects the in vivo rabbit heart from regional ischemia-reperfusion injury

Ex vivo studies demonstrated that a synthetic high-density lipoprotein (HDL) comprised of a complex of recombinant apolipoprotein A-IMilano and 1-palmitoyl-2-oleoyl phosphatidylcholine protects the isolated rabbit heart from reperfusion injury. Therefore, we sought to determine whether a pharmaceutical preparation of this complex, ETC-216, was cardioprotective in an in vivo model of left anterior descending artery (LAD) occlusion and reperfusion. Initially, ETC-216 (100 mg/kg) was tested in acute (one-treatment) and chronic (two-treatment) i.v. administrations. ETC-216-treated rabbits developed smaller infarcts expressed as percentage of area at risk (p <0.01) compared with vehicle treatments. No differences were noted between chronic and acute administration. Therefore, ETC-216 (10, 3, or 1 mg/kg) or equivalent vehicle volumes were acutely infused. Compared with vehicle, ETC-216 reduced infarct size as a percentage of the area at risk at 10 (p <0.0005) and 3 mg/kg (p <0.05). No significant differences occurred at 1 mg/kg. To determine whether ETC-216 could protect the heart after initiation of ischemia, the synthetic HDL (10 mg/kg) was infused intravenously beginning 5 min before the end of 30 min of LAD occlusion. Infarct size as percentage of the area at risk was 31.6 +/- 3.0 (ETC-216) versus 49.5 +/- 2.5 (vehicle) (p <0.001), and as percentage of left ventricle was 19.7 +/- 1.6 (ETC-216) versus 34.1 +/- 2.3 (vehicle) (p <0.0005). Electron microscopy demonstrated that ETC-216 prevented irreversible cardiac damage as assessed by mitochondrial granulation and sarcomere contraction band formation. These findings suggest ETC-216 reduces reperfusion injury and may have utility for coronary artery revascularization procedures.     

Antagonism of leukotriene B4 receptors does not limit canine myocardial infarct size

Injection of leukotriene (LT)B4 (0.1-3 micrograms/kg i.v.) in normal anesthetized dogs produced dose-related leukopenia that was accompanied by arterial hypotension and tachycardia at higher tested doses. LTD4 (0.1-3 micrograms/kg i.v.), in contrast, increased arterial blood pressure, lowered cardiac rate and produced little change in arterial blood leukocyte count. Continuous infusion of LY255283 [(1-(5-ethyl-2-hydroxy-4-(6-methyl-6-(1H-tetrazol-5-yl)- heptyloxy)phenyl)ethanone] (0.33 mg/kg/min i.v.), a selective LTB4 receptor antagonist, resulted in near complete inhibition of leukopenic, hypotensive and tachycardic responses to LTB4 (3 micrograms/kg i.v.) challenge over a 6-hr test period. Persistent antagonism of canine LTB4 receptors was associated with high circulating levels of LY255283 that were bound extensively to plasma proteins. In subsequent experiments, myocardial infarct size was measured following 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion in control dogs infused with vehicle, and in dogs receiving LY255283 (0.33 mg/kg/min i.v.). Drug and vehicle were infused continuously beginning 15 min before coronary artery occlusion. LY255283 treatment essentially did not alter base-line cardiovascular parameters or myocardial oxygen demand when alterations were compared to time-related changes observed in control dogs. LY255283 infusion also did not alter the degree of myocardial ischemia or the intensity and duration of cardiac arrhythmias associated with coronary artery occlusion and reperfusion. Resultant infarct sizes were 43 +/- 5% of the left ventricle placed at risk in control dogs and 32 +/- 5% in dogs given LY255283; this difference was not statistically significant. The extent of left ventricle placed at risk was similar between groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of delayed preconditioning on myocardial regional contractility during repeated episodes of low-flow ischaemia in anaesthetized dogs: possible role of nitric oxide

The effect of cardiac pacing on repeated low-flow ischaemia-induced changes in regional myocardial segmental contractility, and the role in these changes of nitric oxide, were investigated in anaesthetized dogs. Dogs were instrumented for cardiac pacing (pacing electrode in the right ventricle). Dogs were paced (four times for 5 min; pacing rate 220 beats.min(-1)) 24 h prior to the repeated ischaemic insults. Controls were instrumented, but not paced. After 24 h, the dogs were re-anaesthetized with pentobarbitone and subjected to four 20 min low-flow ischaemia and reperfusion cycles, by constricting the left anterior descending coronary artery (LAD) to achieve an approx. 50% reduction in resting coronary blood flow. In some dogs (both control and paced), N (G)-nitro-L-arginine methyl ester (L-NAME; a non-selective inhibitor of nitric oxide synthase) was infused into a side-branch of the LAD 10 min prior to the first ischaemia/reperfusion cycle. Regional contractile function was measured by ultrasonic microcrystals in the ischaemic and normal regions of the left ventricular wall supplied from the LAD and left circumflex coronary artery respectively, and expressed as percentage changes in segmental shortening (%SS). In some dogs, myocardial tissue blood flow (coloured microspheres) and lactate production (local coronary venous sampling) were measured; samples were also taken for histological analysis. In control dogs, the regional %SS was progressively reduced within the ischaemic segment during the four repeated occlusions (by 40+/-6, 59+/-6, 68+/-6, 70+/-6% during occlusions 1-4 respectively). These reductions were more pronounced, especially during the first two cycles (68+/-6, 68+/-6, 67+/-6, 67+/-6%, respectively), when the dogs had been previously subjected to cardiac pacing. In both paced and control dogs, these changes in contractile function were L-NAME-sensitive. Thus, in the presence of L-NAME, changes in regional segmental shortening in control dogs were 37+/-8, 40+/-8, 37+/-8, 42+/-11% and in the paced dogs 46+/-6, 45+/-7, 45+/-8, 45+/-7% respectively, during the four consecutive occlusions. There were no significant differences in tissue blood flow or in lactate production between the groups, and no structural changes indicative of infarction. These results show that the myocardium rapidly adapts to re-occurring acute ischaemia by reducing contractility within the ischaemic segment and, thereby, metabolic demand. Furthermore, cardiac pacing 24 h prior to these ischaemic challenges induces a similar adaptive response, a form of 'delayed preconditioning'. Since both the acute and delayed adaptation were L-NAME-sensitive, we suggest that this adaptation involves nitric oxide.     

The nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) increases free radical generation and degrades left ventricular function after myocardial ischemia-reperfusion

BACKGROUND: During reperfusion of ischemic myocardium nitric oxide (NO) reacts with superoxide radicals to form cardiotoxic peroxynitrite, which causes lipid peroxidation. Our hypothesis was that infusion of a NO donor S-nitroso-N-acetylpenicillamine (SNAP) during ischemia-reperfusion would exacerbate the oxidative damage to the myocardium by increased formation of nitrogen radicals. METHODS AND RESULTS: In 19 open-chest dogs, left anterior descending (LAD) coronary occlusion (15 min)-reperfusion (15 min) sequences were created. Using electron paramagnetic resonance (EPR), we monitored the coronary sinus concentration of ascorbate free radical (Ascz*-), a measure of free radical generation (total oxidative flux). Seven control dogs (Group 1) received intravenous saline infusion during occlusion-reperfusion, while 12 dogs received SNAP infusion (Group 2: 2.5 microg/min per kg SNAP, and Group 3: 5 microg/min per kg SNAP). Left ventricular fractional area shortening was determined by echocardiography. Dogs in Group 3 receiving a high dose of SNAP (5 microg/min per kg) demonstrated a higher Ascz*- concentration increase than the control group. Percent fractional area shortening in Group 1 declined from 77+/-4.0 (baseline) to 54+/-9.0% during ischemia (P<0.05), and then fully recovered to 74+/-3.7% with reperfusion. In the SNAP-treated dogs, the percent fractional area shortening during reperfusion was significantly lower than baseline in Group 2 (55+/-3.9 vs. baseline 74+/-4.4%, P<0.05) and in Group 3 (49+/-5.0 vs. baseline 71+/-4.5%, P<0.01). In five additional dogs, nitrotyrosine immunohistochemistry showed heavy staining of the ischemic-reperfused myocardium. CONCLUSIONS: The NO donor SNAP increased free radical concentration and exacerbated myocardial oxidative damage after ischemia-reperfusion.     

The Effect of Melatonin on Hemodynamics, Blood Flow, and Myocardial Infarct Size in a Rabbit Model of Ischemia-Reperfusion

BACKGROUND: Melatonin, a hormone, has gained popularity and is being used by millions for a variety of indications. There are few data on its safety or its effects on hemodynamics and coronary blood flow. Also, studies have confirmed that melatonin is a potent antioxidant. Therefore, it may be capable of scavenging free radicals during the reperfusion phase after a heart attack. This study evaluates the safety of melatonin with regard to its cardiovascular effects and tests the hypothesis that melatonin might be protective in the setting of ischemia-reperfusion and reduce myocardial infarct size. METHODS AND RESULTS: Anesthetized rabbits were treated with melatonin (n = 8, 10 mg/kg, intravenously) 10 minutes before coronary artery occlusion (CAO) and again 15 minutes before reperfusion. Control rabbits received vehicle (n = 8). All rabbits underwent 30 minutes of occlusion and 3 hour reperfusion. Both before and during CAO, melatonin did not alter heart rate compared with control (185 +/- 7 beats/min v 181 +/- 7 before; and 179 +/- 5 v 181 +/- 9 during, respectively, P = NS) or blood pressure (70 +/- 4 mmHg v 66 +/- 6 before and 59 +/- 4 v 58 +/- 5 during, respectively, P = NS). Regional myocardial blood flow (RMBF) was similar before CAO in the melatonin group (1.18 +/- 0.17 mL/min/g) versus the control group (1.15 +/- 0.10 mL/min/g). Infarct size, expressed as a fraction of ischemic risk zone, was similar in the melatonin (0.29 +/- 0.03) and control groups (0.29 +/- 0.06, P = NS). At a higher dose of 50 mg/kg in treated (n = 7) versus control (n = 7) rabbits, melatonin treatment did not alter heart rate (204 +/- 14 in melatonin group v 181 +/- 5 in controls, P = NS) or blood pressure (80 +/- 11 in melatonin v 66 +/- 7 in controls, P = NS) when compared with control. Melatonin at this dose also did not affect infarct size, 0.38 +/- 0.06, when compared with control, 0.34 +/- 0.07, P = NS. CONCLUSION: Melatonin's effects on hemodynamics and coronary blood flow were neutral, and it did not exacerbate myocardial ischemia or necrosis in this model. Melatonin appears to be a safe drug with no apparent effects on the cardiovascular system in this model.     

Spontaneous gasping produces carotid blood flow during untreated cardiac arrest

We have shown previously that arginine vasopressin (AVP) given during sinus rhythm increases mean arterial blood pressure (MAP) and left anterior descending (LAD) coronary artery cross sectional area. AVP was assumed to result in vasodilatation via activation of the endothelial nitric oxide system. The purpose of the present study was to assess the effects of AVP before and after NO-inhibition. Nine domestic pigs were instrumented for measurement of haemodynamic variables using micromanometer-tipped catheters, and measurement of LAD coronary artery cross sectional area employing intravascular ultrasound (IVUS). Haemodynamic variables, LAD coronary artery cross sectional area and cardiac output were measured at baseline, 90 s and 5, 15, and 30 min after AVP (0.4 U kg (-1) IV) before and after blockade of nitric oxide synthase with N(G)-nitro L-arginine methyl ester (L-NAME). Compared with baseline, AVP significantly increased MAP after 90 s (89+/-4 versus 160+/-5 mm Hg), increased LAD coronary artery cross sectional area (11.3+/-1 versus 11.8+/-1 mm(2)) and decreased cardiac index (138+/-6 versus 53+/-6 mL/min kg(-1)). After blockade of nitric oxide synthase, AVP significantly increased MAP after 90 s (135+/-4 versus 151+/-3 mm Hg), increased LAD coronary artery cross sectional area (8.7+/-1 versus 8.9+/-1 mm(2)), and significantly decreased cardiac index (95+/-6 versus 29+/-4 mL/min kg (-1)). IMPLICATIONS: During sinus rhythm, AVP increased MAP and LAD coronary artery cross sectional area, but decreased cardiac index.     

Effects of hydralazine on regional blood flow in conscious dogs

This study was designed to assess the effects of hydralazine administered p.o. on regional circulation, including the carotid, coronary and renal arteries. Hydralazine in doses of 0.5, 1 and 5 mg/kg (p.o., n = 5) increased coronary blood flow by 9 +/- 4, 15 +/- 4 and 18 +/- 3 ml/min (P less than .05), respectively, and renal blood flow by 17 +/- 7, 26 +/- 12, 36 +/- 10 ml/min (P less than .05), respectively, but had no effects on carotid blood flow in conscious, normotensive dogs. The increase in coronary blood flow was correlated linearly with the rate pressure product (r = 0.581, P less than .05). After ganglionic blockade using chlorisondamine (2 mg/kg i.v.), hydralazine in a dose of 1 mg/kg (p.o., n = 4) increased renal blood flow by 45 +/- 6 ml/min (P less than .05), whereas mean arterial pressure, cardiac output, heart rate and coronary blood flow remained essentially unchanged. The increase in renal blood flow produced by hydralazine (1 mg/kg p.o., n = 6) was prevented by pretreatment with a cyclooxygenase inhibitor, indomethacin (2 mg/kg, i.v.). In vitro, hydralazine failed to relax segments of carotid, coronary and renal arteries. Our data indicate that hydralazine is a direct and preferential renal vasodilator. It produces an indirect coronary vasodilation related to an increase in myocardial oxygen demand. Its effect on renal circulation appears to be dependent on the prostaglandin system and is related mainly to a relaxation of arteriolar resistant vessels.     

Contrasting effects of verapamil and nifedipine on pH of ischemic myocardium in the dog

It remains unknown whether the actions of verapamil to depress and nifedipine to enhance contractile function of ischemic myocardium influence the degree of myocardial ischemic injury. Thus, we measured intramyocardial pH using fiberoptic pH probes in 43 anesthetized open-chest dogs pretreated for 30 min with verapamil, or nifedipine in doses that decreased aortic pressure 10 to 15 mm Hg before ligation of the left anterior descending coronary artery for 15 min. Drugs were continued during the 15-min ischemic period until the animals were euthanized without reperfusion: verapamil, 10-20 micrograms/kg/min and nifedipine, 2 to 4 micrograms/kg/min i.v. Verapamil-treated dogs showed higher pH of ischemic subendocardium after 15 min ischemia (6.75 +/- 0.07) than did the nifedipine (6.48 +/- 0.04) or placebo (6.43 +/- 0.05) groups, even if the animals were paced (6.71 +/- 0.11) to prevent the negative chronotropic effect of verapamil (P less than 0.01). Neither verapamil nor nifedipine changed collateral myocardial blood flow from 0.10 +/- 0.02 in the subendocardium and 0.17 +/- 0.03 ml/min/g in the subepicardium. Left ventricular function estimated by left ventricular dp/dt was depressed 15% by verapamil and enhanced 26% by nifedipine. Thus, verapamil, but not nifedipine, relieves acidosis of ischemic myocardium after acute coronary occlusion in doses that sustain a 10 to 15 mm Hg decrease in aortic pressure. Nifedipine, in doses that produced the same 10 to 15 mm Hg decrease in mean aortic pressure, did not increase intramyocardial pH, as it enhanced contractile function, estimated by left ventricular dp/dt.(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of coronary flow reserve with transthoracic Doppler echocardiography: comparison among adenosine, standard-dose dipyridamole, and high-dose dipyridamole.

Coronary flow reserve (CFR), defined as a ratio of hyperemic-to-basal coronary flow velocity, provides important information about the functional aspect of coronary circulation. However, it usually is determined by invasive methods during catheterization. Recent studies have shown that transthoracic Doppler echocardiography (TTDE) may be useful in the measurement of coronary flow velocity in the distal portion of the left anterior descending coronary artery (LAD). The vasodilators used for hyperemia are adenosine and dipyridamole. However, the coronary vasodilative response and systemic hemodynamic effects of the two agents have not been directly compared with TTDE. We assessed blood flow velocity and vascular resistance in the distal LAD by TTDE during an intravenous 2-minute adenosine infusion (140 microg/kg/min) and low- (0.56 mg/kg) and high-dose dipyridamole (0. 84 mg/kg) infusion in 25 patients with patent LAD. Coronary flow velocity was successfully recorded in 20 patients (80%) during baseline and the consecutive vasodilator-infusion period. Compared with low-dose dipyridamole, adenosine infusion induced a higher CFR (3.7 +/- 0.87 vs 2.73 +/- 0.65; P <.05) and a lower coronary resistance index (0.31 +/- 0.04 vs 0.35 +/- 0.08; P <.05). But by increasing the dipyridamole dose to 0.84 mg/kg, the values of the CFR and coronary resistance index became comparable to those of adenosine infusion (2.85 +/- 0.78 vs 3.03 +/- 0.7, P = not significant [NS]; 0.33 +/- 0.04 vs 0.32 +/- 0.09, P = NS; respectively). We conclude that adenosine seems to be a favorable vasodilator for the measurement of CFR with TTDE.     

Revised resuscitation guidelines: adrenaline versus adrenaline/vasopressin in a pig model of cardiopulmonary resuscitation--a randomised, controlled trial

BACKGROUND: Synergistic effects of adrenaline (epinephrine) and vasopressin may be beneficial during cardiopulmonary resuscitation. However, it is unknown whether either adrenaline alone or an alternating administration of adrenaline and vasopressin is better for restoring vital organ perfusion following basic life support (BLS) according to the revised algorithm with a compression-to-ventilation (c/v) ratio of 30:2. MATERIAL AND METHODS: After 4min of ventricular fibrillation, and 6min of BLS with a c/v ratio of 30:2, 16 pigs were randomised to receive either 45microg/kg adrenaline, or alternating 45microg/kg adrenaline and 0.4U/kg vasopressin, respectively. RESULTS: Coronary perfusion pressure (mean+/-S.D.) 20 and 25min after cardiac arrest was 7+/-4 and 5+/-3mm Hg after adrenaline, and 25+/-2 and 14+/-3mm Hg after adrenaline/vasopressin (p<0.001 and <0.01 versus adrenaline), respectively. Cerebral perfusion pressure was 23+/-7 and 19+/-9mm Hg after adrenaline, and 40+/-10 and 33+/-7mm Hg after adrenaline/vasopressin (p<0.001 and <0.01 versus adrenaline), and cerebral blood flow was 30+/-10 and 27+/-11% of baseline after adrenaline, and 65+/-40 and 50+/-31% of baseline after adrenaline/vasopressin (p<0.05 versus adrenaline), respectively. Return of spontaneous circulation (ROSC) did not differ significantly between the adrenaline group (0/8) and the adrenaline/vasopressin group (3/8). CONCLUSION: Adrenaline/vasopressin resulted in higher coronary and cerebral perfusion pressures, and cerebral blood flow, while ROSC was comparable.     

Quantification of the spectrum of changes in regional myocardial function during acute ischemia in closed chest pigs: an ultrasonic strain rate and strain study.

The objectives of this study were to define the spectrum of regional myocardial function changes during acute ischemia in closed chest animals by using newly developed ultrasonic strain rate and strain indexes derived from regional color Doppler myocardial imaging (CDMI) velocity data. Myocardial ischemia was induced in 18 pigs either with acute total 20-second occlusions (group 1, n = 12) or graded hypoperfusion (40 to 0 mL/min, group 2, n = 6) of the circumflex coronary artery. In addition, a dobutamine challenge (5 to 10 microg/kg per minute) was performed during sustained subtotal ischemia (10 mL/min) in group 2. CDMI acquisitions with parasternal views monitored the myocardial posterior wall function. Regional radial strain rate and strain (epsilon(r)) were measured for systole, isovolumic relaxation, early diastole, and atrial filling, respectively. During total and graded ischemia, epsilon(r) profiles were consistently modified, showing a delayed onset and a decrease in regional systolic thickening as well as increased postsystolic thickening. Radial strain rate and epsilon(r) indexes decreased consistently during systole and early diastole and increased during isovolumic relaxation. End-systolic epsilon(r) could differentiate total ischemia from severe hypoperfusion (10 mL/min), decreasing from 32% +/- 8% to 16% +/- 5% (versus 60% +/- 10% at baseline). During dobutamine infusion (10 microg/kg per minute), end-systolic epsilon(r) tended to decrease from 27% +/- 5% to 18% +/- 11%, whereas postsystolic thickening increased by 2-fold (P <.05). The combined analysis of regional deformation characteristics and global cardiac event timing derived from CDMI data can identify and quantify regional function changes induced by experimental acute ischemia in closed chest pigs. This would appear to be a potentially promising new noninvasive approach to the clinical evaluation of ischemia-induced changes in segmental myocardial function.     

Nitric oxide inhibition intensifies the depressant effect of cocaine on the left ventricular function in anaesthetized pigs

Myocardial ischaemia and left ventricular dysfunction have been described in cocaine users. Whether nitric oxide (NO) inhibition may potentiate the effects of cocaine on coronary circulation and ventricular function is still unknown. In order to test this hypothesis, 38 pentobarbital-anaesthetized pigs were instrumented for systolic blood pressure, coronary blood flow, left ventricular dp/dt, cardiac output, left ventricular end-diastolic and end-systolic lengths and shortening fraction. The pigs were randomized into three groups: control group: i.v. saline (n = 5); group 1: i.v. cocaine, 10 mg kg-1 over 20 min (n = 17); group 2: the same doses of cocaine 30 min after i.c. L-NAME 20 microg/kg min-1 infusion (n = 16). In order to know whether the observed effects were specific of NO inhibition, in five pigs i.c. L-arginine was simultaneously infused with L-NAME, in five pigs i.c. NTG, an endothelial-independent vasodilator, was simultaneously infused with L-NAME before cocaine was administered, and in nine additional pigs the proximal left anterior descending (LAD) flow was reduced to around 20% of the basal value by means of a mechanical occluder before cocaine was administered. Cocaine i.v did not change the coronary blood flow, while it induced a significant reduction in cardiac output, left ventricular dp/dt and shortening fraction (15 +/- 4-8 +/- 4%, P < 0.05). When cocaine was administered after L-NAME infused i.c. during 30 min, a significantly more severe reduction of the shortening fraction (12 +/- 3-4 +/- 2%, P < 0.0001) was induced; this effect was abolished by simultaneous perfusion of L-arginine i.c. NTG. The results when cocaine was administered after the 20% LAD flow reduction by mechanical occluder did not differ from those of cocaine alone. NO inhibition intensifies the cocaine-induced left ventricular dysfunction.