Circulation In Conscious Dogs Research Articles

CVT3146, a novel A2A receptor agonist, selectively dilates the coronary circulation in conscious dogs

CVT3146, a novel A2A receptor agonist, selectively dilates the coronary circulation in conscious dogs

Nitric oxide and oxygen utilization: exercise, heart failure and diabetes.

In addition to regulating vascular tone, there is increasing evidence for the involvement of NO in the modulation of oxygen consumption. Our in-vitro studies indicated that exogenous and endogenous NO reduces the consumption of oxygen in isolated canine skeletal and cardiac muscle, which is probably related to its direct effect on mitochondria, i.e. cytochrome oxidase. In resting, conscious dogs, the blockade of NO synthesis results in an increase in total oxygen consumption. During exercise, there is a significant increase in the release of NO from the coronary circulation in conscious dogs, and there are greater increases in total oxygen consumption, and oxygen consumption in skeletal muscle and in the heart when NO synthesis is blocked. Our results suggest that NO plays a role in matching blood flow to tissue metabolism at rest and during exercise. The modulation of the consumption of O2 by endogenous NO in skeletal or cardiac muscle is blunted after the development of heart failure or diabetes. After heart failure, the heart switches from fatty acid to glucose metabolism, suggesting that NO also plays a role in the regulation of metabolism in the heart.

Interaction between prostacyclin and nitric oxide in the reflex control of the coronary circulation in conscious dogs

Interaction between prostacyclin and nitric oxide in the reflex control of the coronary circulation in conscious dogs

Interaction between prostacyclin and nitric oxide in the reflex control of the coronary circulation in conscious dogs

Our goal was to determine the role of nitric oxide (NO) on the coronary vasodilation induced by prostacyclin (PGI2) in conscious dogs. Dogs were chronically instrumented for the measurements of coronary blood flow (CBF), left ventricular pressure (LVP), mean arterial pressure (MAP) and heart rate (HR). Intravenous injections of PGI2 caused dose-dependent increases in CBF, and decreases in MAP and late diastolic coronary resistance (LDCR). For instance, CBF increased by 128 +/- 19% (P < 0.05) from 30 +/- 3.5 ml/min and LDCR decreased by 73 +/- 3% (P < 0.05) from 2.57 +/- 0.20 mmHg/ml/min following injection of PGI2 (1.0 microgram/kg). After infusion of nitro-L-arginine (NLA, 35 mg/kg) intravenously, the coronary vasodilation induced by PGI2 was partially attenuated. PGI2 (1.0 microgram/kg) increased CBF by 55 +/- 15% from 33 +/- 5.3 ml/min and decreased LDCR by 42 +/- 9% (both P < 0.05, compared with before NLA) from 3.29 +/- 0.39 mmHg/ml/min. Infusion of L-arginine (100 mg/kg) reversed the action of NLA. For example, PGI2 (1.0 microgram/kg) increased CBF by 115 +/- 15% from 36 +/- 6 ml/min and decreased LDCR by 68 +/- 3% from 3.02 +/- 0.36 mmHg/ml/min (both P > 0.05, compared with before NLA). Atropine (0.1 mg/kg) partially attenuated the coronary vasodilation induced by PGI2 the magnitude of which was almost identical to that by NLA. NLA or atropine also blunted the coronary vasodilation induced by acetylcholine, while the coronary vasodilation induced by nitroglycerin was not affected by NLA. Our results indicate that the coronary vasodilation induced by PGI2 was partially attenuated by NLA or atropine, suggesting that the coronary vasodilation induced by PGI2 is due to two components: a reflex parasympathetic cholinergic vasodilation mediated by NO and a direct action of PGI2.

Restraining effects of captopril on sympathetic excitatory responses in dogs: a spectral analysis approach.

This study was planned to clarify the effects of captopril administration on the autonomic control of the circulation in conscious dogs and in dynamic conditions using spectral analysis of R-R interval and systolic arterial pressure (SAP) variabilities. Changes in sympathovagal balance modulating the sinoatrial (SA) node were inferred, respectively, from the low (LFR-R)- and high-frequency (HFR-R) components of R-R variability; LFSAP furnished a marker of sympathetic vasomotor control. Increases in sympathetic activity were induced by three different experimental maneuvers [bilateral carotid occlusion (BCO), coronary artery occlusion (CAO), and dynamic exercise] capable of increasing sympathetic outflow to the SA node and to the vessels. Studies were performed both before and after intravenous captopril administration. During BCO, only LFSAP increased from 4.3 +/- 1.5 to 19.7 +/- 4.1 mmHg2; during CAO, both LFR-R and LFSAP increased, respectively, from 3 +/- 1 to 21 +/- 2 normalized units (nu) and from 4.1 +/- 1.3 to 7.2 +/- 1.5 mmHg2. Dynamic exercise at 2 and 4 km/h progressively raised LFR-R from 8 +/- 2 to 58 +/- 7 and 75 +/- 5 nu, respectively; LFSAP showed a parallel trend increasing from 2.5 +/- 0.7 to 8.04 +/- 1.9 and 12.7 +/- 2.2 mmHg2. In all experimental conditions, captopril significantly (P < 0.05) blunted the increase of LFSAP. A restraining effect on LFR-R was apparent only with CAO. Spectral analysis of cardiovascular variabilities indicates that, in the conscious dog, acute captopril administration has an important inhibitory effect on cardiac sympathetic excitatory mechanisms as well as on sympathetic vasomotor control.

Defective endothelium-mediated control of coronary circulation in conscious dogs after heart failure

The goal of this study was to determine whether coronary endothelial function was altered after pacing-induced heart failure in conscious dogs. Fourteen mongrel dogs were chronically instrumented for measurements of systemic hemodynamics, left circumflex coronary artery diameter (CD) and blood flow, and for left ventricular pacing for 4 wk. Heart failure developed during this pacing regimen and was characterized by a significant reduction in arterial pressure, an increase in left atrial pressure, a resting tachycardia, a depression of left ventricular dP/dt to isoproterenol injection, a significant reduction of the slope of the end-systolic pressure-diameter relationship, and all of the characteristic clinical signs. During heart failure, the dilation of CD after release of a brief coronary artery occlusion, acetylcholine, and arachidonic acid was attenuated, whereas prostaglandin (PG) I2- and nitroglycerin-induced dilations of CD were unchanged. The coronary blood flow responses to occlusion, acetylcholine, and nitroglycerin were depressed, but not to PG. Large coronary arteries and microvessels were isolated from normal and failing hearts. Both isolated large coronary arteries and microvessels from failing hearts produced significantly less nitrite, the immediate metabolite of nitric oxide in aqueous solution, than those of normal hearts. Thus endothelium-mediated control of the coronary circulation was depressed during heart failure. A decrease in the production of nitric oxide-endothelium-derived relaxing factor was most likely responsible for this depression.

Pulmonary vascular beta-adrenoreceptor activity in conscious dogs after left lung autotransplantation

Our objective was to determine whether chronic denervation associated with left lung autotransplantation (LLA) results in an alteration in sympathetic beta-adrenoreceptor regulation of the pulmonary circulation in conscious dogs. Continuous left pulmonary vascular pressure-flow (LPQ) plots were generated in conscious dogs 2-4 wk post-LLA and in sham-operated control conscious dogs. We tested the hypothesis that endogenous sympathetic beta-adrenoreceptor activation via circulating catecholamines acted to attenuate the chronic increase in pulmonary vascular resistance post-LLA. Administration of the sympathetic beta-adrenoreceptor antagonist propranolol had no significant effect on the LPQ relationship post-LLA. We also tested the hypothesis that pulmonary vascular reactivity to sympathetic beta-adrenoreceptor activation would be increased post-LLA. The thromboxane analogue U-46619 was used to acutely preconstrict (P < 0.01) the pulmonary circulation in control dogs; this preconstriction shifted the LPQ relationship to the same position measured post-LLA. Under these conditions, cumulative doses of the beta-adrenoreceptor agonist isoproterenol caused pulmonary vasodilation (P < 0.01) in the control group but had no effect post-LLA. However, after acute preconstriction with U-46619, the pulmonary vasodilator response (P < 0.01) to isoproterenol post-LLA was not significantly different from that in the control group. These differential responses to isoproterenol with and without acute preconstriction indicate that a significant component of the chronic increase in pulmonary vascular resistance post-LLA is mediated by passive nonvasoactive mechanisms. Moreover, sympathetic beta-adrenoreceptor reactivity of the pulmonary circulation is not enhanced by chronic denervation resulting from the LLA procedure.

P-462 - Effects of CD-832, a new calcium antagonist, on coronary circulation in conscious dogs

P-462 - Effects of CD-832, a new calcium antagonist, on coronary circulation in conscious dogs

Effects of Nitroglycerin and Diltiazem on Well-Developed Coronary Collateral Circulation in Conscious Dogs

The purpose of the present study was to compare the effects of nitroglycerin and diltiazem on coronary collateral circulation. Studies were conducted in 8 conscious dogs instrumented for the measurement of left circumflex coronary artery (LCCA) flow, subendocardial segment lengths in areas perfused by the LCCA, and left anterior descending coronary artery (LAD). Brief, repeated LCCA occlusions sufficiently developed collateral vessels for the resting metabolic requirement in the LCCA region. One week following the cessation of repeated LCCA occlusions, two-minute coronary occlusions with and without drug pretreatment were performed on separate days. The ischemic responses to coronary occlusions were not altered by diltiazem (50 micrograms/kg, IV), but nitroglycerin (5 micrograms/kg, IV) attenuated myocardial ischemia definitely. The authors conclude that nitroglycerin produces greater effects than diltiazem in attenuating myocardial ischemia in the collateral dependent zone when effects of each drug on systemic and coronary circulation were minimized by pretreatment with small doses.

Effects of atrial natriuretic peptide on water and NaCl absorption across the intestine

Previous studies have demonstrated that atrial natriuretic peptide (ANP) causes natriuresis and diuresis. However, it is not established whether ANP also alters fluid and electrolyte balance via actions on intestinal absorption of water and sodium chloride. Therefore, the purpose of the present study was to investigate the effects of ANP on water and NaCl absorption across the intestine. First, we determined that ANP was taken up from the intestinal circulation in conscious dogs. During the intravenous infusion of ANP (0.3 microgram.kg-1.min-1), 27.4% of the ANP delivered to the intestinal vascular bed were removed from the circulation at that vascular bed, whereas only 1% of the ANP delivered to the hepatic circulation was removed at the hepatic vascular bed. Second, we determined the effects of the ANP infusion on splanchnic circulation in conscious dogs. ANP decreased hepatic arterial blood flow by 14%, portal venous blood flow by 16%, total hepatic blood flow by 15%, and cardiac output by 14%. Finally, we studied the effects of ANP on intestinal absorption of water and NaCl. ANP suppressed net absorption of water by 61%, Na+ by 43%, and Cl- by 42% across the jejunum but not the ileum. These results suggest that ANP modulates water and NaCl homeostasis across the jejunum but not across the ileum.

AVP-induced pulmonary vasodilation during specific V1 receptor block in conscious dogs

Our objectives were 1) to determine whether exogenously administered arginine vasopressin (AVP) can exert a vasoactive influence on the pulmonary circulation of conscious dogs during specific vasopressinergic-1 (V1) receptor block, and 2) to assess the extent to which the pulmonary vascular response to AVP during V1 receptor block is mediated by either sympathetic beta-adrenergic or cholinergic receptor activation or by cyclooxygenase pathway activation. Multipoint pulmonary vascular pressure-cardiac index (P/Q) plots were constructed during normoxia in conscious dogs by stepwise constriction of the thoracic inferior vena cava to reduce Q. In dogs pretreated with a specific V1 receptor antagonist [d(CH2)5 AVP, 10 micrograms/kg iv], AVP infusion (7.6 ng.kg-1 X min-1 iv) increased (P less than 0.01) Q from 139 +/- 6 to 175 +/- 8 ml.min-1 X kg-1, and decreased (P less than 0.01) the pulmonary vascular pressure gradient (pulmonary arterial pressure-pulmonary capillary wedge pressure: PAP-PCWP) over the entire range of Q studied (140 to 80 ml.min-1 X kg-1). This pulmonary vasodilator response to AVP during V1 block was also observed following sympathetic beta-adrenergic block alone, following combined sympathetic beta-adrenergic and cholinergic block, and following cyclooxygenase pathway inhibition. Thus exogenous administration of AVP during specific V1 receptor block results in active, nonflow-dependent pulmonary vasodilation. This pulmonary vasodilator response is not mediated by reflex activation of sympathetic beta-adrenergic or cholinergic receptors or by metabolites of the cyclooxygenase pathway over a broad range of Q.

Vascular sensitivity to prostaglandin I2 and urinary excretion of 6-keto-prostaglandin F1 alpha in conscious dogs.

A method is described for measuring the urinary excretion of 6-keto-prostaglandin F1 alpha, the stable hydrolysis product of prostaglandin I2, by stable isotope dilution gas chromatography-mass spectrometry. Three different doses of prostaglandin I2 were infused intravenously into conscious dogs and the effects on systemic and renal haemodynamics and urinary sodium excretion were observed. The two highest infusion rates of prostaglandin I2 (15 and 30 ng min-1 kg-1 body weight) induced significant decreases in systematic blood pressure and dose-related increases in sodium excretion, but no change in renal haemodynamics. There was a linear relationship between urinary excretion of 6-keto-prostaglandin F1 alpha and the rate of infusion of prostaglandin I2. The calculated basal rate of entry of prostaglandin I2 into the systematic circulation in conscious dogs is 4 ng min-1 kg-1 body weight, which is substantially higher than that previously reported in man.

Pulmonary vascular responses to angiotensin II and captopril in conscious dogs

Our objectives were to investigate the extent to which angiotensin II (ANG II) and converting-enzyme inhibition (CEI) exert a direct vasoactive influence on the pulmonary circulation of conscious dogs. Multipoint pulmonary vascular pressure-cardiac index (P/Q) plots were constructed during normoxia in conscious dogs by stepwise constriction of the thoracic inferior vena cava to reduce Q. The effects of ANG II infusion (60 ng X kg-1 X min-1, iv) and CEI with captopril (1 mg/kg plus 1 mg X kg-1 X h-1, iv) on pulmonary vascular P/Q plots were assessed first with the conscious dogs intact and again after combined administration of pharmacological antagonists to block sympathetic alpha- and beta-adrenergic, cholinergic, and arginine vasopressin receptors. In intact dogs, ANG II increased (P less than 0.01) the pulmonary vascular pressure gradient (pulmonary arterial pressure-pulmonary capillary wedge pressure, PAP-PCWP) over the entire range of Q studied (60-120 ml X min-1 X kg-1). Conversely, CEI decreased (P less than 0.05) PAP-PCWP at each level of Q. After administration of the autonomic nervous system and arginine vasopressin receptor antagonists, ANG II again increased (P less than 0.01) and CEI decreased (P less than 0.01) PAP-PCWP over the entire range of Q studied. Thus exogenous administration of ANG II results in active, nonflow-dependent constriction of the pulmonary circulation, and this effect is not dependent on the autonomic nervous system or increased circulating levels of arginine vasopressin.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of selected drugs and myocardial infarction on the disappearance of creatine kinase from the circulation in conscious dogs.

Estimates of infarct size based on serial plasma creatine kinase (CK) changes have been made utilising the disappearance rate of CK from blood (kd) as one parameter. This study was performed to evaluate the effects on CK disappearance of myocardial infarction per se and selected drugs often used in the management of patients with myocardial infarction. Fifty-six conscious dogs were studied. Canine myocardial CK was isolated and radioactively labelled. Experiments were performed with intravenous injections of unlabelled CK or with radioactively labelled material. After injection, plasma CK activity declined monoexponentially (r = -0.95, n = 30) exceeding the rate of CK disappearance in vitro in whole blood or plasma. Three successive daily determinations of kd differed by less than or equal to 10% in the same dog (n = 5). Removal of radioactively labelled protein from plasma paralleled disappearance of plasma CK enzyme activity for several hours after i.v. injection of 14C-CK (n = 5). Myocardial infarction after occlusion of the left anterior descending coronary artery altered kd by less than 10% (n = 5) estimated after i.v. injection of 14C-CK. Administration of large doses of Nembutal (30 mg-kg-1), morphine (2 mg-kg-1), or Valium (1 mg-kg-1) decreased kd markedly (n = 17), but low doses of morphine (0-2 mg-kg-1) or Valium (0-1 mg-kg-1) did not substantially diminish kd. Thus, enzymatic estimates of infarct size are not likely to be influenced by changes in kd occurring during myocardial infarction. However, modification of estimates may be required when pharmacological interventions are employed, capable of altering CK disappearance.

Hemodynamic evidence of the development of coronary collateral circulation in conscious dogs.

Since 1964, we have addressed ourselves to the problem of the rate of development of collateral circulation following coronary occlusion in the conscious dog preparation. Four different experimental approaches have been used, all of which have essentially involved the effects of gradual circumflex branch occlusion on collateral development. An attempt will be made to summarize the earlier experiments and to give in more detail the salient features of more recent experiments.KeywordsCoronary OcclusionReactive HyperemiaCollateral Blood FlowElectromagnetic FlowmeterCoronary PressureThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

A comparison of the cardiovascular actions of four adrenergic β-receptor blocking agents in resting, conscious dogs

The present study was undertaken to investigate the effect of blockade of adrenergic β-receptors on resting hemodynamics in conscious dogs. Contrary to the findings in anesthetized animals, in which the activity of the autonomic nervous system is markedly altered, propranolol and MJ 1999 had little effect on heart rate, cardiac output, and left ventricular work. These two drugs were also equipotent in blocking the cardiovascular effects induced by isoprenaline. H 56 28 and I.C.I. 50172 have been shown to possess intrinsic sympathomimetic activity; in the present experiments H 56 28 also increased heart rate and decreased total peripheral resistance. I.C.I. 50172 did not alter the systemic hemodynamics in conscious dogs. H 56 28 had comparable activity to propranolol and MJ 1999 in blocking the response to isoprenaline, while I.C.I. 50172 was less potent. In contrast with the earlier observations that β-receptor blocking agents markedly decrease coronary flow in anesthetized animals, propranolol, MJ 1999, and H 56 28 had practically no effect on resting coronary circulation in conscious dogs. All three drugs increased coronary resistance and were almost equipotent in blocking the effect of isoprenaline on coronary hemodynamics. I.C.I. 50172 had a biphasic dose-dependent effect: the coronary flow was increased by the smallest dose and decreased after the largest one. This compound had no effect on late diastolic resistance and was less potent than the other three drugs in antagonizing the coronary changes induced by isoprenaline. The present observations indicate that β-receptor blocking agents have little effect on the coronary circulation and systemic hemodynamics, and suggest that it could be misleading to extrapolate the findings in anesthetized dogs to man.

Effect of controlled coronary occlusion on collateral circulation in conscious dogs.

Effect of controlled coronary occlusion on collateral circulation in conscious dogs.