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Background Mechanical arterial recanalization is increasingly used to treat acute ischemic stroke. Known to inflict vascular injury, it might affect pro-thrombotic character and healing patterns. Stent-retriever thrombectomy (SR) and direct aspiration (DA) are both used for acute recanalization and not only lead to endothelial denudation, but also to platelet activation and local formation of microthrombi, potentially adding to the risk of distal embolization. Purpose We aimed to quantify and characterize endovascular damage, microthrombus formation, and vascular healing following SR and DA in a swine model of arterial thrombo-embolic occlusion. Methods Aged autologous thrombi, created under flow, were used to occlude swine extracranial arteries for two hours to mimic a thrombo-embolic occlusion. Arteries were randomized to SR, DA, or control (C). Injury was assessed acutely (SR n=8; DA n=7; C n=4), and at 3 days follow-up (SR n=8; DA n=7; C n=4) using Evans Blue (EB) dye-exclusion-testing to quantify injury, expressed as %EB-area in the treated area. Scanning electron microscopy (SEM) was used to characterize vascular injury and presence of microthrombi ( Results Regression analysis for EB-area (ANOVA p Conclusions Stent-retrievers induce more endothelial damage than direct aspiration. Both treatments yield microthrombi, platelet activation and leukocyte adhesion. After three days, the endothelium is significantly, but only partially recovered. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): We acknowledge the support of the Netherlands Cardiovascular Research Initiative which is supported by the Dutch Heart Foundation (CVON2015-01: CONTRAST), the support of the Brain Foundation Netherlands (HA2015.01.06), and the support of Health∼Holland, Top Sector Life Sciences & Health (LSHM17016), Stryker, Medtronic and Cerenovus. The collaboration project is additionally financed by the Ministry of Economic Affairs by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships.

Background: DM remains a risk factor for poor outcome after stent-implantation, but little is known if and how DM affects the vascular response to BVS. Aim: The aim of our study was to examine coronary responses to bioresorbable vascular scaffolds (BVS) in swine with and without diabetes mellitus fed a ‘fast-food’ diet (FF-DM and FF-NDM, respectively) by sequential optical coherence tomography (OCT)-imaging and histology. Methods: Fifteen male swine were evaluated. Eight received streptozotocin-injection to induce DM. After 9 months (M), 32 single BVS were implanted in epicardial arteries with a stent to artery (S/A)-ratio of 1.1:1 under quantitative coronary angiography (QCA) and OCT guidance. Lumen, scaffold, neointimal coverage and composition were assessed by QCA, OCT and near-infrared spectroscopy (NIRS) pre- and/or post-procedure, at 3M and 6M. Additionally, polarization-sensitive (PS)-OCT was performed in 7 swine at 6M. After sacrifice at 3M and 6M, histology and polymer degradation analysis were performed. Results: Late lumen loss was high (~60%) within the first 3M after BVS-implantation (P 0.20). Neointimal coverage was highly heterogeneous in all swine (DM vs. NDM P>0.05), with focal lipid accumulation, irregular collagen distribution and neointimal calcification. Likewise, polymer mass loss was low (~2% at 3M, ~5% at 6M;P>0.20) and not associated with DM or inflammation. Conclusion: Scaffold coverage showed signs of neo-atherosclerosis in all FF-DM and FF-NDM swine, scaffold polymer was preserved and the vascular response to BVS was not influenced by diabetes.

Experimental disease models have enhanced our understanding of the pathogenesis of atherosclerosis development. For example, insight has been gained into the role of the endothelium, lipids, platelets and inflammation, as well as into potential diagnostic and therapeutic interventions. Moreover, transgenic and knock-out technologies have become a widespread approach and this is a growing field to assess the role of individual genes in vascular biology and pathology. However, atherosclerosis is most of all a multifactorial disease, influenced by a multitude of environmental factors. Therefore, it is important to also study non-transgenic animal models that closely resemble the human situation with atherosclerotic lesions at anatomical locations that mimic the clinical manifestation of the disease, e.g. coronary artery disease (CAD). Although no model completely mimics human atherosclerosis, much can be learned from existing models in the study of this disease, also with respect to the development of new interventions. Here, we describe the most relevant animal models of atherosclerosis, while focusing on CAD development and the use of coronary diagnostic and therapeutic interventions. In addition, we show examples of features of a large animal model of CAD including pictures of invasive coronary imaging.

Ischaemic postconditioning (IPOC) is an intervention in which brief, intermittent periods of reocclusion at the onset of reperfusion (i.e. stuttering reperfusion) protect myocardium from lethal reperfusion injury. The mechanism underlying the cardioprotective effects of IPOC is incompletely understood. However, it is perceived that IPOC begins with specific cell-surface receptors responsible for activating a number of signalling pathways, many of which appear to converge at the mitochondrial level. IPOC has been demonstrated both in animal models and in patients with acute myocardial infarction (AMI) in small proof-of-concept trials. This intervention offers the possibility of further limiting infarct size in patients undergoing primary percutaneous coronary intervention (PCI). Here, we provide a brief overview of the concept of IPOC and the mechanisms underlying this phenomenon. (Neth Heart J 2010;18:389-93.).

Whole blood is a non-Newtonian fluid, which means that its viscosity depends on shear rate. At low shear, blood cells aggregate, which induces a sharp increase in viscosity, whereas at higher shear blood cells disaggregate, deform and align in the direction of flow. Other important determinants of blood viscosity are the haematocrit, the presence of macro-molecules in the medium, temperature and, especially at high shear, the deformability of red blood cells. At the sites of severe atherosclerotic obstructions or at vasospastic locations, when change of vessel diameter is limited, blood viscosity contributes to stenotic resistance thereby jeopardising tissue perfusion. However, blood viscosity plays its most important role in the microcirculation where it contributes significantly to peripheral resistance and may cause sludging in the postcapillary venules. Apart from the direct haemodynamic significance, an increase in blood viscosity at low shear by red blood cell aggregation is also associated with increased thrombotic risk, as has been demonstrated in atrial fibrillation. Furthermore, as increased red blood cell aggregation is a reflection of inflammation, hyperviscosity has been shown to be a marker of inflammatory activity. Thus, because of its potential role in haemodynamics, thrombosis and inflammation, determination of whole blood viscosity could provide useful information for diagnostics and therapy of (cardio)vascular disease.

Intracoronary Fourier-Domain optical coherence tomography (FD-OCT) enables imaging of the coronary artery within 2-4 seconds, a so far unparalleled speed. Despite such fast data acquisition, cardiac and respiratory motion can cause artefacts due to longitudinal displacement of the catheter within the artery. We studied the influence of longitudinal FD-OCT catheter displacement on serial global lumen and scaffold area measurements in coronary arteries of swine that received PLLA-based bioresorbable scaffolds. In 10 swine, 20 scaffolds (18 x 3.0 mm) were randomly implanted in two epicardial coronary arteries. Serial FD-OCT imaging was performed immediately after implantation (T1) and at 3 (T2) and 6 months (T3) follow-up. Two methods for the selection of OCT cross-sections were compared. Method A did not take into account longitudinal displacement of the FD-OCT catheter. Method B accounted for longitudinal displacement of the FD-OCT catheter. Fifty-one OCT pullbacks of 17 scaffolds were serially analyzed. The measured scaffold length differed between time points, up to one fourth of the total scaffold length, indicating the presence of longitudinal catheter displacement. Between method A and B, low error was demonstrated for mean area measurements. Correlations between measurements were high: R-2 ranged from 0.91 to 0.99 for all mean area measurements at all time points. Considerable longitudinal displacement of the FD-OCT catheter was observed, diminishing the number of truly anatomically matching cross-sections in serial investigations. Global OCT dimensions such as mean lumen and scaffold area were not significantly affected by this displacement. Accurate co-registration of cross-sections, however, is mandatory when specific regions, e.g. jailed side branch ostia, are analyzed.

In view of the remarkable decrease of the relative heart weight (HW) and the relative blood volume in growing pigs, we investigated whether HW, cardiac output (CO), and stroke volume (SV) of modern growing pigs are proportional to BW, as predicted by allometric scaling laws: HW (or CO or SV) = a·BW(b), in which a and b are constants, and constant b is a multiple of 0.25 (quarter-power scaling law). Specifically, we tested the hypothesis that both HW and CO scale with BW to the power of 0.75 (HW or CO = a·BW(0.75)) and SV scales with BW to the power of 1.00 (SV = a·BW(1.0)). For this purpose, 2 groups of pigs (group 1, consisting of 157 pigs of 50 ± 1 kg; group 2, consisting of 45 pigs of 268 ± 18 kg) were surgically instrumented with a flow probe or a thermodilution dilution catheter, under open-chest anesthetized conditions to measure CO and SV, after which HW was determined. The 95% confidence intervals of power-coefficient b for HW were 0.74 to 0.80, encompassing the predicted value of 0.75, suggesting that HW increased proportionally with BW, as predicted by the allometric scaling laws. In contrast, the 95% confidence intervals of power-coefficient b for CO and SV as measured with flow probes were 0.40 to 0.56 and 0.39 to 0.61, respectively, and values obtained with the thermodilution technique were 0.34 to 0.53 and 0.40 to 0.62, respectively. Thus, the 95% confidence limits failed to encompass the predicted values of b for CO and SV of 0.75 and 1.0, respectively. In conclusion, although adult breeding sows display normal heart growth, cardiac performance appears to be disproportionately low for BW. This raises concern regarding the health status of adult breeding sows.

During the last decade transplantation of cells into the heart has emerged as a novel therapy for the prevention and treatment of heart failure. Although various cell types have been used, most experience has been obtained with the progenitor cells of skeletal muscle, also called myoblasts, and a wide array of bone marrow-derived cell types. The first preclinical studies demonstrated an improvement in global and regional heart function that was attributed mainly to a direct contractile effect of the transplanted cells. Furthermore, it was suggested that multiple cell types are able to form true cardiomyocytes and truly ‘regenerate’ the myocardium. More recent studies have questioned these early findings. Other mechanisms such as paracrine effects on the infarct and remote myocardium, a reduction in adverse remodelling and improvement of mechanical properties of the infarct tissue likely play a more important role. On the basis of encouraging preclinical studies, multiple early-phase clinical trials and several randomised controlled trials have been conducted that have demonstrated the feasibility, safety and potential efficacy of this novel therapy in humans. This review summarises the available evidence on cardiac cell transplantation and provides an outlook on future preclinical and clinical research that has to fill in the remaining gaps. (Neth Heart J 2008; 16:88-95.)

The consistently high level of myocardial oxygen extraction requires tight control of coronary blood flow, because an increase in myocardial oxygen demand, as occurs during exercise, cannot be obtained by a further increase in oxygen extraction. Consequently, adequate control of coronary vascular resistance is critical. Coronary resistance vessel tone is the result of a myriad of vasodilator and vasoconstrictor influences, which are exerted by the myocardium, endothelium and neurohumoral status. Unraveling of the integrative mechanisms controlling metabolic vasodilation has been difficult, more than likely due to the redundancy design of vasomotor control. In contrast to the traditional view that myocardial ischemia produced by a coronary artery stenosis causes maximal microvascular dilation, more recent studies have shown that the coronary microvessels retain some degree of vasodilator reserve during ischemia and remain responsive to vasoconstrictor stimuli. These observations raise the question of whether pharmacologic vasodilators acting at the microvascular level might be therapeutically useful. The critical property of effective vasodilator therapy requires selective dilation of small arteries, while avoiding coronary steal by not interfering with metabolic vasoregulation at the level of the arterioles.

1. It is unknown how cardiac stimulation by Ca(2+) sensitization modulates the cardiovascular response to exercise when left ventricular (LV) function is chronically depressed following a myocardial infarction. We therefore investigated the effects of EMD 57033 at rest and during exercise and compared these to those of the mixed Ca(2+)-sensitizer/phosphodiesterase-III inhibitor pimobendan. 2. Pigs were chronically instrumented for measurement of cardiovascular performance. At the time of instrumentation, infarction was produced by coronary artery ligation (MI, n=12). Studies in MI were performed in the awake state, 2 - 3 weeks after infarction. 3. MI were characterized by a lower resting cardiac output (18%), stroke volume (30%) and LVdP/dt(max) (18%), and a doubling of LV end-diastolic pressure, compared to normal pigs (N, n=13). 4. In 11 resting MI, intravenous EMD 57033 (0.2 - 0.8 mg kg(-1) min(-1)) increased LVdP/dt(max) (57+/-5%) and stroke volume (26+/-6%) with no effect on heart rate, LV filling pressure, and myocardial O(2)-consumption, similar to N. 5. In MI, the effects of EMD 57033 (0.4 mg kg(-1) min(-1), IV) on stroke volume and LVdP/dt(max) were maintained during treadmill exercise up to 85% of maximal heart rate, while heart rate was lower compared to control exercise (all P0.05). In contrast, the effects of EMD57033 gradually waned in N at increasing intensity of exercise. 6. Compared to N, the cardiostimulatory effects of pimobendan (20 microg kg(-1) min(-1), IV) were blunted in MI both at rest and during exercise compared to N. 7. In conclusion, the positive inotropic actions of the Ca(2+) sensitizer EMD 57033 are unmitigated in resting and exercising MI compared to N, while those of the mixed Ca(2+)-sensitizer/phosphodiesterase-III inhibitor pimobendan are blunted.

Since the phenomenon of ischemic preconditioning was first described some 15 years ago, interest in strategies aimed at reducing infarct size has increased. During the past 10 years, investigations into the mechanism of ischemic preconditioning have clearly demonstrated the cardioprotective effect of K+ATP channel opening. Thus, K+ATP channel activation has been shown to be involved in cardioprotection by a variety of stimuli, including a brief period of complete ischemia (classical ischemic preconditioning) or a partial coronary artery occlusion. In addition, ischemia in remote organs and nonischemic stimuli in the heart such as ventricular pacing, stretch, and heat stress also confer protection via K+ATP channel activation. Pharmacological agents that open K+ATP channels reduce infarct size, but K+ATP channel opening must occur prior to or early during the sustained infarct-producing coronary artery occlusion, while the degree and memory of cardioprotection are less than those produced by classical ischemic preconditioning. Although the exact mechanism by which K+ATP channel activation protects is still incompletely understood, recent studies indicate a role for the mitochondrial K+ATP channels. Before K+ATP channel opening can be employed in patients at increased risk of developing myocardial infarction (e.g., unstable angina), it is mandatory to determine whether tolerance (tachyphylaxia) occurs with repeated administration of K+ATP channel openers in a fashion similar to what occurs with ischemic preconditioning.

1. Ca(2+) sensitizers enhance systolic function, but may impair relaxation in vitro; these effects may differ in stunned and normal myocardium. We therefore studied the effect of EMD 57033 on systolic and diastolic function of normal and stunned porcine myocardium in vivo. 2. Myocardial stunning by 15 min coronary occlusion and 30 min reperfusion abolished systolic shortening (SS) (baseline 13+/-1%) and decreased end-systolic elastance (E(es)) from 67+/-7 to 47+/-5 mmHg mm(-1) (both P0.05). Maximum rate of fall of myocardial elastance (dE/dt(min)) decreased from -850+/-100 to -320+/-30 mmHg mm(-1) s(-1), while the time constant tau(e) of the decay of elastance increased from 58+/-3 to 68+/-6 ms (both P0.05). End-diastolic elastance (E(ed)) was unchanged although the zero pressure intercept (L(0,ed)) had increased. 3. In the stunned region, EMD 57033 (0.2 mg kg(-1) min(-1) for 60 min, i.v., n=7) increased SS to 19+/-2%, E(es) to 287+/-40 mmHg mm(-1), dE/dt(min) to -3630+/-640 mmHg mm(-1) s(-1) and decreased tau(e) to 50+/-3 ms, while E(ed) remained unchanged. In the normal region, 4. EMD 57033 increased SS from 14+/-2 to 18+/-3%, E(es) from 59+/-4 to 263+/-23 mmHg mm(-1), dE/dt(min) from -480+/-70 to -2280+/-700 mmHg mm(-1) s(-1) and decreased tau(e) from 91+/-12 to 61+/-3 ms (all P0.05), while E(ed) remained unchanged. These responses were minimally affected by adrenoceptor blockade (n=7). Vehicle (n=7) had no effect on either region. EMD 57033 increased cardiac output (up to 27+/-8%) and LVdP/dt(max) (86+/-19%). Mean aortic pressure decreased (19+/-7%) due to systemic vasodilation that was not amenable to blockade of adrenoceptors or NO synthesis. 5. In conclusion, EMD 57033 restored systolic and diastolic function of stunned myocardium, and produced similar improvements in systolic and diastolic function in normal myocardium.

1. To date no study has described the cardiovascular effects of increased myofilament Ca2+ responsiveness in awake animals both under resting conditions and during treadmill exercise. In the present study we therefore investigated the systemic, pulmonary and coronary haemodynamic actions of the Ca2+ sensitizer EMD 57033 in 16 chronically instrumented awake pigs at rest and during treadmill exercise, and compared these to the haemodynamic actions of the Ca2+ sensitizer/phosphodiesterase inhibitor pimobendan. 2. Under resting conditions EMD 57033 (0.2, 0.4 and 0.8 mg kg(-1) min(-1), i.v.) produced dose-dependent increases in LVdP/dt(max) (up to 65+/-17% (mean+/-s.e.mean), Por = 0.05) and stroke volume (up to 20+/-3%, Por = 0.05), with an increase in heart rate only after the highest dose (22+/-5%, Por = 0.05), while mean aortic blood pressure and LVdP/dt(min) were not altered. EMD 57033 had also no effect on pulmonary vascular resistance, but produced dose-dependent decreases in systemic vascular resistance (32+/-4%, Por = 0.05), and coronary vascular resistance (44+/-2%, Por = 0.05). These effects were essentially unchanged when animals were pretreated with non-selective beta-adrenoceptor blockade, indicating that phosphodiesterase inhibition did not contribute to the positive inotropic actions of EMD 57033. 3. During exercise at 2, 3, and 4 km h(-1), the positive inotropic actions of EMD 57033 gradually waned at higher levels of exercise. This may have been caused by the exercise-induced increase in beta-adrenergic activity, because after pretreatment with propranolol the positive inotropic actions of EMD 57033 were preserved at all levels of exercise. In contrast, the positive inotropic and chronotropic effects of pimobendan were amplified during exercise, but were abolished (at rest) or markedly attenuated (during exercise) after pretreatment with propranolol. 4. The responses to EMD 57033 during exercise after combined alpha- and beta-adrenergic receptor blockade were not different from those after beta-adrenergic receptor blockade alone, indicating that the positive inotropic actions of EMD 57033 were not mediated via or did not depend on intact alpha-adrenergic receptor activity. 5. In conclusion, EMD 57033 increases left ventricular myocardial contractility in awake pigs. During exercise this effect is partially offset by the increased beta-adrenergic activity, with no effect of alpha-adrenergic activity, suggesting that EMD 57033 may be most effective in patients with severe loss of beta-adrenergic responsiveness.

Dopamine receptor agonists can be useful in the treatment of hypertension or heart failure. Consequently, the present study investigated the hemodynamic profile of the novel dopamine D1/D2 receptor agonist Z1046 in open-chest, pentobarbital-anesthetized swine. Z1046 was administered in a dose of 10 micrograms/kg (n = 9) or 100 micrograms/kg (n = 8), which was injected over 1 minute; hemodynamic responses were studied for 90 minutes after administration. Both doses of Z1046 produced sustained decreases in mean aortic blood pressure (15-20%). The hypotension produced by the lower dose was principally due to a decrease in cardiac output, as the trend toward a lower systemic vascular resistance failed to reach levels of statistical significance. Conversely, the decrease in mean arterial blood pressure produced by the higher dose of Z1046 was mainly due to a decrease in systemic vascular resistance (up to 17%), as the trend toward a decrease in cardiac output at 60 and 90 minutes after administration was not different from the changes in the saline-treated group. Heart rate decreased slightly with both doses of Z1046. Z1046 decreased left ventricular myocardial blood flow (up to 28 +/- 9%, p0.05) in parallel with the decrease in myocardial oxygen consumption (up to 24 +/- 7%, p0.05), with no change in the transmural distribution of myocardial blood. Z1046 in a dose of 10 micrograms/kg did not produce significant vasodilation of regional vascular beds, but in a dose of 100 micrograms/kg produced vasodilator responses in the small intestine (34 +/- 2% decrease in vascular resistance), spleen (43 +/- 7%), and kidneys (22 +/- 3% all p0.05 vs. baseline). In conclusion, Z1046 produced systemic hypotension with negligible reflex activation of sympathetic tone.

In conscious pigs, arteriovenous anastomoses (AVAs) are in a constricted state so that < 5% of intra-atrially injected radioactive (15-microns-diam) microspheres are shunted to the lungs. Many of the anesthetic regimens frequently used in cardiovascular research dilate AVAs, thereby greatly increasing the percentage of microspheres reaching the lungs. This may seriously limit extrapolation of results obtained under anesthesia to the conscious state. We now describe that anesthesia with a combination of fentanyl and thiopental preserves the tone of AVAs, maintaining shunting under 4% of cardiac output. Furthermore, we studied in the carotid circulation of this model whether norepinephrine or 5-hydroxy-tryptamine (5-HT), both contained in perivascular nerves, is responsible for this tone. Consecutive antagonism of alpha 1-, alpha 2-, 5-HT1, and 5-HT2 receptors was obtained by sequential injection of prazosin, phentolamine, ketanserin, and methiothepin. Prazosin increased AVA blood flow, partly at the expense of extracerebral tissue blood flow, but preserved cerebral blood flow. None of the other antagonists had any additional significant effect. Therefore, in this model the tone in AVAs seems to be maintained by sympathetic norepinephrine-containing nerves via alpha 1-adrenoceptors.

Coronary flow reserve has been shown to be abnormally low in several models of left ventricular hypertrophy induced by long-standing pressure overload. Because the presence of hypertrophy is a risk factor for the development of subendocardial ischaemia and sudden death, efforts to restore alterations in flow reserve may prove beneficial. In the following review, we discuss potential mechanisms which might contribute to this abnormal vasodilator capacity in the hypertrophied heart, with particular emphasis on how chronic therapy may potentially reverse such abnormalities. In addition, we report how the acute administration of various classes of pharmacological agents can alter measurements of coronary flow reserve, as observed in our anaesthetised swine model. Such factors must be considered before interpreting any changes in coronary flow reserve in models of hypertrophy following chronic administration of drugs.

The acute systemic hemodynamic effects of the calcium antagonist nisoldipine and the pyridazinone-derivative pimobendan, a phosphodiesterase inhibitor with vasodilating as well as positive inotropic properties, were studied in conscious pigs with chronic heart failure. Left ventricular (LV) dysfunction, manifested by a 25% decrease in cardiac output (CO), a 35% increase in systemic vascular resistance (SVR), and a doubling of the left ventricular filling pressure, was induced by a proximal ligation of the left circumflex coronary artery. Two to three weeks after myocardial infarction, cumulative 10-min infusions of either nisoldipine (0.05, 0.1, 0.25, and 0.5 micrograms/kg/min), pimobendan (2.5, 5, 12.5, and 25 micrograms/kg/min) or the solvents were administered. Infusion of the solvents did not affect any of the hemodynamic variables. Both nisoldipine and pimobendan normalized CO and exhibited a similar cardiac profile [systemic vasodilatation, reduction in left ventricular filling pressure, and an increase in heart rate (HR)] except for the significantly (p less than 0.05) larger increase in LVdP/dtmax with pimobendan (85%) than with nisoldipine (45%). In animals with heart failure, lower doses of both nisoldipine (twice) and pimobendan (four times) were needed to elicit a 30% reduction in SVR than in animals with normal pump function. For both drugs, the slope of the line describing the vasodilatory and positive inotropic properties shifted more in favor of the vasodilatory actions during heart failure (p less than 0.05). We conclude that in swine with chronic LV dysfunction nisoldipine, despite its lack of inotropic properties, appeared to improve ventricular function to the same extent as the primary positive inotropic agent pimobendan.

The potent systemic and coronary vasodilatory properties of nisoldipine have been demonstrated in several studies in patients with cardiovascular disease. The increase in cardiac output results from enhancements of both stroke volume and heart rate, while coronary blood supply increases in excess of demand. There is evidence that nisoldipine favourably affects several indicators of myocardial ischemia during exercise such as time to onset of anginal complaints and ST segment changes. Furthermore, in patients with elevated left ventricular filling pressures and reduced cardiac pump function the drug tends to normalize these parameters, thus opening new avenues for the treatment of patients with heart failure. The effect of nisoldipine on the incidence of ventricular arrhythmias has not yet been studied in patients, but experimental evidence shows an antifibrillatory activity at doses which may, however, not be clinically applicable. Finally, in healthy men, nisoldipine partially inhibits platelet aggregation. This, together with a potential antiatherosclerotic effect, could be of additional benefit to patients with coronary artery disease.

The effects of the benzimidazole-pyridazinone pimobendan (UD-CG 115 BS) on systemic haemodynamics, myocardial performance and the distribution of cardiac output were studied in open-chest anaesthetized pigs. After intravenous bolus injections (0.1-0.5 mg X kg-1, n = 7) increases in heart rate (up to 37%), LVdP/dtmax (up to 54%) and decreases in systemic vascular resistance (up to 33%) and left ventricular filling pressure (up to 50%) were observed, while cardiac output was unchanged. Vasodilation occurred in nearly all regional vascular beds, but was most pronounced in the adrenals (200%), followed by stomach (150%), small intestines (130%), heart (125%) and brain (110%). O2-consumption was not affected in spite of the increases in heart rate and myocardial inotropy. To evaluate the direct effects on the myocardial, pimobendan was also infused (1-5 micrograms X kg-1 X min-1, n = 7) directly into the left anterior descending coronary artery. In addition to a marked vasodilation of the coronary bed (140%), also a lowering of the left ventricular filling pressure (up to 20%) and cardiac output (15%) was observed, but no changes in regional myocardial function, LVdP/dtmax and systemic vascular resistance occurred. Immediately after intracoronary bolus injections (1 mg X kg-1, n = 4), vasodilation of the coronary vessels was apparent, but myocardial contractility was not affected. This may explain that cyclic AMP content, determined in biopsies excised 30 s after injection, was unaltered. It may be concluded that pimobendan exerts actions on the cardiovascular system which may be useful in the treatment of heart failure.

Studies using electromagnetic flowmeters and radioactive labeled microspheres (15 +/- 1 micron) have revealed that about 80% of the total common carotid artery blood flow in young domestic pigs (12-14 weeks) is shunted through arteriovenous anastomoses (AVAs). To investigate the influence of the sympathetic nervous system we measured the distribution of carotid blood flow before and after cervical sympathetic nerve stimulation (2-16 Hz), intracarotid infusions of noradrenaline (0.025-0.2 micrograms X kg-1 X min-1) or intracarotid bolus injections of noradrenaline (0.3 and 1.0 micrograms X kg-1) and clonidine (1 and 5 micrograms X kg-1). The first two interventions did not exert any effect, but bolus injections of noradrenaline and clonidine, achieving high local concentrations temporarily, caused a short-lasting decrease in AVA-flow, which was attenuated by phentolamine (1 mg X kg-1). It is concluded that the sympathetic nervous system in the carotid vascular bed of young Yorkshire pigs is poorly developed.

We studied the cardiovascular profile of the new cardioselective beta-adrenoceptor antagonist bisoprolol in the conscious pig and compared this profile with that of propranolol. Acute i.v. administration of bisoprolol (16-1024 micrograms.kg-1) did not affect mean arterial blood pressure but caused dose-related decreases in cardiac output (from 8 to 17%; p less than 0.05) due to a negative chronotropic action (heart rate reduction ranging from 9 to 21%; p less than 0.05) as stroke volume was unaffected. Max LVdP/dt decreased (ranging from 18 to 27%; p less than 0.05) while left ventricular end-diastolic blood pressure (from 8.6 +/- 0.6 to 15 +/- 0.2 mmHg; p less than 0.05) and systemic vascular resistance (from 8 to 18%; p less than 0.05) increased. Propranolol in a dose-range from 25-300 micrograms.kg-1 produced strikingly similar changes. Bisoprolol was more effective in antagonizing the isoproterenol-induced responses of max LVdP/dt than those on either heart rate or diastolic arterial blood pressure, whereas propranolol caused equi-effective inhibitions of the responses of heart rate and max LVdP/dt. However, with propranolol also the inhibition of the diastolic arterial blood pressure was less marked than for the other parameters. Propranolol proved to be the more potent beta-adrenoceptor antagonist, as the isoproterenol dose ratios of all 3 parameters during beta-adrenoceptors blockade with propranolol exceeded those obtained with bisoprolol.

Severe meningococcal disease is characterized by: a high load of specific endotoxin, capillary leakage and coagulation disorders. We studied the possible age-related differences in global hemodynamic and regional blood flow responses to different dosages (1 and 10 microg/kg body weight) of rough meningococcal endotoxin in young (8 kg) and older piglets (40 kg). Animals were chronically instrumented and studied in the awake state. The response to plasma infusion (30 mL/kg in 30 min) was evaluated after placebo and endotoxin infusion. The clinical picture was similar in all groups. The mortality was 0/8, 3/8,1/8, 4/9 in young-low, young-high, old-low, and old-high dose respectively. Most important findings were that cardiac index (CI) decreased in the young animals after endotoxin infusion, while it was well preserved in the older animals; in the older animals the systemic vascular resistance dropped 20%, while in the younger ones there was no change in resistance. Conductance to the kidneys, intestines, and spleen decreased significantly more in the young animals, while the increase in conductance and flow to the liver was higher in the old animals; subsequent volume loading resulted only partly in a recovery of the hemodynamic parameters, but failed to improve oxygen delivery.