Role of adenosine in the regulation of coronary blood flow in swine at rest and during treadmill exercise

A pivotal role for adenosine in the regulation of coronary blood flow is still controversial. Consequently, we investigated its role in the regulation of coronary vasomotor tone in swine at rest and during graded treadmill exercise. During exercise, myocardial O2 consumption increased from 167 +/- 18 micromol/min at rest to 399 +/- 27 micromol/min at 5 km/h (P </= 0.05), which was paralleled by an increase in O2 delivery, so that myocardial O2 extraction (76 +/- 1 and 78 +/- 1% at rest and 5 km/h, respectively) and coronary venous PO2 (24.5 +/- 1.0 and 22.8 +/- 0.3 mmHg at rest and 5 km/h, respectively) remained unchanged. After adenosine receptor blockade with 8-phenyltheophylline (5 mg/kg iv), the relation between myocardial O2 consumption and coronary vascular resistance was shifted toward higher resistance, whereas myocardial O2 extraction rose to 81 +/- 1 and 83 +/- 1% at rest and 5 km/h and coronary venous PO2 fell to 19.2 +/- 0.8 and 18.9 +/- 0.8 mmHg at rest and 5 km/h, respectively (all P </= 0.05). Thus, although adenosine is not mandatory for the exercise-induced coronary vasodilation, it exerts a vasodilator influence on the coronary resistance vessels in swine at rest and during exercise

Role of K(ATP)(+) channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine

The role of ATP-sensitive K(+) (K(ATP)(+)) channels in vasomotor tone regulation during metabolic stimulation is incompletely understood. Consequently, we studied the contribution of K(ATP)(+) channels to vasomotor tone regulation in the systemic, pulmonary, and coronary vascular bed in nine treadmill-exercising swine. Exercise up to 85% of maximum heart rat

Angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade prevent cardiac remodeling in pigs after myocardial infarction: role of tissue angiotensin II

BACKGROUND: The mechanisms behind the beneficial effects of renin-angiotensin system blockade after myocardial infarction (MI) are not fully elucidated but may include interference with tissue angiotensin II (Ang II). METHODS AND RESULTS: Forty-nine pigs underwent coronary artery ligation or sham operation and were studied up to 6 weeks. To determine coronary angiotensin I (Ang I) to Ang II conversion and to distinguish plasma-derived Ang II from locally synthesized Ang II, (125)I-labeled and endogenous Ang I and II were measured in plasma and in infarcted and noninfarcted left ventricle (LV) during (125)I-Ang I infusion. Ang II type 1 (AT(1)) receptor-mediated uptake of circulating (125)I-Ang II was increased at 1 and 3 weeks in noninfarcted LV, and this uptake was the main cause of the transient elevation in Ang II levels in the noninfarcted LV at 1 week. Ang II levels and AT(1) receptor-mediated uptake of circulating Ang II were reduced in the infarct area at all time points. Coronary Ang I to Ang II conversion was unaffected by MI. Captopril and the AT(1) receptor antagonist eprosartan attenuated postinfarct remodeling, although both drugs increased cardiac Ang II production. Captopril blocked coronary conversion by >80% and normalized Ang II uptake in the noninfarcted LV. Eprosartan did not affect coronary conversion and blocked cardiac Ang II uptake by >90%. CONCLUSIONS: Both circulating and locally generated Ang II contribute to remodeling after MI. The rise in tissue Ang II production during angiotensin-converting enzyme inhibition and AT(1) receptor blockade suggests that the antihypertrophic effects of these drugs result not only from diminished AT(1) receptor stimulation but also from increased stimulation of growth-inhibitory Ang II type 2 receptors

Systemic, pulmonary and coronary haemodynamic actions of the novel dopamine receptor agonist in awake pigs at rest and during treadmill exercise Z1046

1. In view of the potential therapeutic application of specific dopamine receptor agonists in the treatment of hypertension and left ventricular dysfunction, we investigated the cardiovascular actions of the novel mixed D1/D2 dopamine receptor agonist Z1046 in awake pigs at rest and during treadmill exercise. 2. Thirteen swine were chronically instrumented under sterile conditions for measurement of systemic, pulmonary, and coronary haemodynamics. Regional blood flows were determined with the radioactive microsphere technique. 3. Z1046 (1, 10, 100 μg kg-1, i.v.) produced dose-dependent reductions in central aortic blood pressure (up to 27 ± 3%, P ≤ 0.05) in awake resting pigs which was accompanied by only minimal reflex activation of the sympathetic nervous system. The hypotensive response was principally the result of peripheral vasodilatation (system vascular resistance decreased up to 35 ± 4%, P ≤ 0.05), which was located in the cerebral, coronary, renal, mesenteric, adrenal, splenic and skeletal muscular vascular beds (vascular resistance decreased up to 30-40% after the highest dose in these beds). Only in the cerebral and mesenteric bed was the vasodilatation sufficiently large to overcome the decrease in blood pressure and result in an increased blood flow; the vasodilatation in the coronary bed was most likely due to autoregulation as neither coronary blood flow nor myocardial oxygen demand were changed significantly by Z1046. The systemic vasodilatation that was caused by the highest i.v. dose (100 μg kg-1) was accompanied by transient and minor increases in heart rate (15 ± 5%, P ≤ 0.05) and cardiac output (15 ± 5%, P ≤ 0.05) whereas after 10 μg kg-1, i.v., a slight decrease in cardiac output also contributed to the hypotension. Z1046 had no effect on pulmonary vascular resistance. 4. The systemic vasodilator responses to Z1046 (100 μg kg-1, i.v.) were sustained during treadmill exercise (2-4 km h-1 which produced heart rates of up to 233 ± 10 beats min-1), but with increasing treadmill speed attenuation of the exercise-induced increase in heart rate (-11 ± 3%, P ≤ 0.05) and hence cardiac output (-10 ± 3%, P ≤ 0.05) (as stroke volume was not altered by Z1046) contributed significantly to a lower aortic blood pressure (-20 ± 3%, P ≤ 0.05). Z1046 had no effect on pulmonary vascular resistance during exercise. 5. Oral administration of Z1046 (0.5, 1.5 mg kg-1) produced a fall in central aortic blood pressure (up to 15 ± 3%, P ≤ 0.05), which developed gradually during the first 90 min and lasted up to 4 h after administration, again with negligible changes in heart rate and LVdP/dt(max). 6. Neither non-selective α- and β-adrenoceptor blockade, nor selective α2-adrenoceptor blockade altered the vasodilator actions of Z1046, but non-selective α- and β-adrenoceptor blockade abolished the cardiac responses to dopamine receptor stimulation, suggesting that its cardiac actions were principally caused by D2-receptor-mediated inhibition of catecholamine release, whereas the vasodilator response was probably the result of vascular D1-receptor stimulation. 7. In conclusion, the novel dopamine receptor agonist Z1046 is an effective blood pressure lowering agent that elicits minimal reflex activation of the sympathetic nervous system in awake resting pigs. Systemic vasodilatation was not affected by combined α- and β-adrenoceptor blockade, which is consistent with a predominantly D1 receptor-dependent vasodilator mechanism. The hypotensive effect is maintained during treadmill exercise during which systemic vasodilatation and a lower cardiac output both contribute to the blood pressure lowering actions of Z1046. The cardiovascular profile of this orally active compound warrants further investigation of this class of drugs in experimental and clinical hypertension.</p

Systemic, pulmonary and coronary haemodynamic actions of the novel dopamine receptor agonist in awake pigs at rest and during treadmill exercise Z1046

1. In view of the potential therapeutic application of specific dopamine receptor agonists in the treatment of hypertension and left ventricular dysfunction, we investigated the cardiovascular actions of the novel mixed D1/D2 dopamine receptor agonist Z1046 in awake pigs at rest and during treadmill exercise. 2. Thirteen swine were chronically instrumented under sterile conditions for measurement of systemic, pulmonary, and coronary haemodynamics. Regional blood flows were determined with the radioactive microsphere technique. 3. Z1046 (1, 10, 100 μg kg-1, i.v.) produced dose-dependent reductions in central aortic blood pressure (up to 27 ± 3%, P ≤ 0.05) in awake resting pigs which was accompanied by only minimal reflex activation of the sympathetic nervous system. The hypotensive response was principally the result of peripheral vasodilatation (system vascular resistance decreased up to 35 ± 4%, P ≤ 0.05), which was located in the cerebral, coronary, renal, mesenteric, adrenal, splenic and skeletal muscular vascular beds (vascular resistance decreased up to 30-40% after the highest dose in these beds). Only in the cerebral and mesenteric bed was the vasodilatation sufficiently large to overcome the decrease in blood pressure and result in an increased blood flow; the vasodilatation in the coronary bed was most likely due to autoregulation as neither coronary blood flow nor myocardial oxygen demand were changed significantly by Z1046. The systemic vasodilatation that was caused by the highest i.v. dose (100 μg kg-1) was accompanied by transient and minor increases in heart rate (15 ± 5%, P ≤ 0.05) and cardiac output (15 ± 5%, P ≤ 0.05) whereas after 10 μg kg-1, i.v., a slight decrease in cardiac output also contributed to the hypotension. Z1046 had no effect on pulmonary vascular resistance. 4. The systemic vasodilator responses to Z1046 (100 μg kg-1, i.v.) were sustained during treadmill exercise (2-4 km h-1 which produced heart rates of up to 233 ± 10 beats min-1), but with increasing treadmill speed attenuation of the exercise-induced increase in heart rate (-11 ± 3%, P ≤ 0.05) and hence cardiac output (-10 ± 3%, P ≤ 0.05) (as stroke volume was not altered by Z1046) contributed significantly to a lower aortic blood pressure (-20 ± 3%, P ≤ 0.05). Z1046 had no effect on pulmonary vascular resistance during exercise. 5. Oral administration of Z1046 (0.5, 1.5 mg kg-1) produced a fall in central aortic blood pressure (up to 15 ± 3%, P ≤ 0.05), which developed gradually during the first 90 min and lasted up to 4 h after administration, again with negligible changes in heart rate and LVdP/dt(max). 6. Neither non-selective α- and β-adrenoceptor blockade, nor selective α2-adrenoceptor blockade altered the vasodilator actions of Z1046, but non-selective α- and β-adrenoceptor blockade abolished the cardiac responses to dopamine receptor stimulation, suggesting that its cardiac actions were principally caused by D2-receptor-mediated inhibition of catecholamine release, whereas the vasodilator response was probably the result of vascular D1-receptor stimulation. 7. In conclusion, the novel dopamine receptor agonist Z1046 is an effective blood pressure lowering agent that elicits minimal reflex activation of the sympathetic nervous system in awake resting pigs. Systemic vasodilatation was not affected by combined α- and β-adrenoceptor blockade, which is consistent with a predominantly D1 receptor-dependent vasodilator mechanism. The hypotensive effect is maintained during treadmill exercise during which systemic vasodilatation and a lower cardiac output both contribute to the blood pressure lowering actions of Z1046. The cardiovascular profile of this orally active compound warrants further investigation of this class of drugs in experimental and clinical hypertension.</p

Changing perspectives on the internationalization of R&D and innovation by multinational enterprises: a review of the literature

Internationalization of R&D and innovation by Multinational Enterprises (MNEs) has undergone a gradual and comprehensive change in perspective over the past 50 years. From sporadic works in the late 1950s and in the 1960s, it became a systematically analysed topic in the 1970s, starting with pioneering reports and “foundation texts”. Our review unfolds the theoretical and empirical evolution of the literature from dyadic interpretations of centralization versus decentralization of R&D by MNEs to more comprehensive frameworks, wherein established MNEs from Advanced Economies still play a pivotal role, but new players and places also emerge in the global generation and diffusion of knowledge. Hence views of R&D internationalization increasingly rely on concepts, ideas and methods from IB and other related disciplines such as industrial organization, international economics and economic geography. Two main findings are highlighted. First, scholarly research pays an increasing attention to the network-like characteristics of international R&D activities. Second, different streams of literature have emphasized the role of location- specific factors in R&D internationalization. The increasing emphasis on these aspects has created new research opportunities in some key areas, including inter alia: cross-border knowledge sourcing strategies, changes in the geography of R&D and innovation, and the international fragmentation of production and R&D activities