RESUMEN
The adenine nucleotide hypothesis postulates that the ATP released from red blood cells is broken down to ADP and AMP in coronary capillaries and that ATP, ADP, and AMP act on purinergic receptors on the surface of capillary endothelial cells. Purinergic receptor activation initiates a retrograde conducted vasodilator signal to the upstream arteriole that controls coronary blood flow in a negative feedback manner. A previous study (M. Farias 3rd, M. W. Gorman, M. V. Savage, and E. O. Feigl, Am J Physiol Heart Circ Physiol 288: H1586-H1590, 2005) demonstrated that coronary venous plasma ATP concentration increased during exercise and correlated with coronary blood flow. The present experiments test the adenine nucleotide hypothesis by examining the balance between oxygen delivery (via coronary blood flow) and myocardial oxygen consumption during exercise before and after purinergic receptor blockade. Dogs (n = 7) were chronically instrumented with catheters in the aorta and coronary sinus and a flow transducer around the circumflex coronary artery. During control treadmill exercise, myocardial oxygen consumption increased and the balance between oxygen delivery and myocardial oxygen consumption fell as indicated by a declining coronary venous oxygen tension. Blockade of P1 and P2Y(1) purinergic receptors combined with inhibition of nitric oxide synthesis significantly decreased the balance between oxygen delivery and myocardial oxygen consumption compared with control. The results support the hypothesis that ATP and its breakdown products ADP and AMP are part of a negative feedback control mechanism that matches coronary blood flow to myocardial oxygen consumption at rest and during exercise.
Asunto(s)
Nucleótidos de Adenina/metabolismo , Circulación Coronaria , Vasos Coronarios/metabolismo , Miocardio/metabolismo , Esfuerzo Físico , Receptores Purinérgicos P1/metabolismo , Receptores Purinérgicos P2Y1/metabolismo , Adenosina Difosfato/metabolismo , Adenosina Monofosfato/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Circulación Coronaria/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Perros , Inhibidores Enzimáticos/farmacología , Retroalimentación Fisiológica , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Oxígeno/sangre , Consumo de Oxígeno , Antagonistas de Receptores Purinérgicos P1/farmacología , Antagonistas del Receptor Purinérgico P2Y/farmacología , Receptores Purinérgicos P1/efectos de los fármacos , Receptores Purinérgicos P2Y1/efectos de los fármacos , Flujo Sanguíneo RegionalRESUMEN
It was previously shown that red blood cells release ATP when blood oxygen tension decreases. ATP acts on microvascular endothelial cells to produce a retrograde conducted vasodilation (presumably via gap junctions) to the upstream arteriole. These observations form the basis for an ATP hypothesis of local metabolic control of coronary blood flow due to vasodilation in microvascular units where myocardial oxygen extraction is high. Dogs (n = 10) were instrumented with catheters in the aorta and coronary sinus, and a flow transducer was placed around the circumflex coronary artery. Arterial and coronary venous plasma ATP concentrations were measured at rest and during three levels of treadmill exercise by using a luciferin-luciferase assay. During exercise, myocardial oxygen consumption increased approximately 3.2-fold, coronary blood flow increased approximately 2.7-fold, and coronary venous oxygen tension decreased from 19 to 12.9 mmHg. Coronary venous plasma ATP concentration increased significantly from 31.1 to 51.2 nM (P < 0.01) during exercise. Coronary blood flow increased linearly with coronary venous ATP concentration (P < 0.01). Coronary venous-arterial plasma ATP concentration difference increased significantly during exercise (P < 0.05). The data support the hypothesis that ATP is one of the factors controlling coronary blood flow during exercise.
Asunto(s)
Adenosina Trifosfato/sangre , Circulación Coronaria/fisiología , Esfuerzo Físico/fisiología , Animales , Perros , Eritrocitos/metabolismo , Hemoglobinas/metabolismo , Oxígeno/sangre , Venas/metabolismoRESUMEN
The role of P1 receptors and P2Y1 receptors in coronary vasodilator responses to adenine nucleotides was examined in the isolated guinea pig heart. Bolus arterial injections of nucleotides were made in hearts perfused at constant pressure. Peak increase in flow was measured before and after addition of purinoceptor antagonists. Both the P1 receptor antagonist 8-(p-sulfophenyl)theophylline and adenosine deaminase inhibited adenosine vasodilation. AMP-induced vasodilation was inhibited by P1 receptor blockade but not by adenosine deaminase or by the selective P2Y1 antagonist N6-methyl-2'-deoxyadenosine 3',5'-bisphosphate (MRS 2179). ADP-induced vasodilation was moderately inhibited by P1 receptor blockade and greatly inhibited by combined P1 and P2Y1 blockade. ATP-induced vasodilation was antagonized by P1 blockade but not by adenosine deaminase. Addition of P2Y1 blockade to P1 blockade shifted the ATP dose-response curve further rightward. It is concluded that in this preparation ATP-induced vasodilation results primarily from AMP stimulation of P1 receptors, with a smaller component from ATP or ADP acting on P2Y1 receptors. ADP-induced vasodilation is largely due to P2Y1 receptors, with a smaller contribution by AMP or adenosine acting via P1 receptors. AMP responses are mediated solely by P1 receptors. Adenosine contributes very little to vasodilation resulting from bolus intracoronary injections of ATP, ADP, or AMP.
Asunto(s)
Nucleótidos de Adenina/farmacología , Adenosina Difosfato/análogos & derivados , Circulación Coronaria/efectos de los fármacos , Teofilina/análogos & derivados , Vasodilatación/efectos de los fármacos , Adenosina Difosfato/farmacología , Adenosina Monofosfato/farmacología , Adenosina Trifosfato/farmacología , Animales , Cobayas , Masculino , Antagonistas de Receptores Purinérgicos P1 , Antagonistas del Receptor Purinérgico P2 , Receptores Purinérgicos P1/metabolismo , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y1 , Teofilina/farmacologíaRESUMEN
OBJECTIVE: We tested a theoretical stress model cross-sectionally and prospectively that examined whether relationships of chronic stress, psychophysiology, and coronary heart disease (CHD) varied in older adult men (N = 47), older adult women not using hormone replacement therapy (HRT) (N = 64), and older adult women using HRT (N = 41). METHOD: Structural equations examined relationships of CHD with 1) chronic stress (caring for a spouse with Alzheimer's disease and patient functioning), 2) vulnerability (anger and hostility), 3) social resources (supports), 4) psychological distress (burden, sleep problems, and low uplifts), 5) poor health habits (high-caloric, high-fat diet and limited exercise), and 6) the metabolic syndrome (MS) (blood pressure, obesity, insulin, glucose, and lipids). RESULTS: Caregiver men had a greater prevalence of CHD (13/24) than did noncaregiver men (6/23) (p <.05) 27 to 30 months after study entry. This was influenced by pathways from caregiving to distress, distress to the MS, and the MS to CHD. In men, poor health habits predicted the MS 15 to 18 months later, and the MS predicted new CHD cases over 27 to 30 months. In women, no "caregiving-CHD" relationship occurred; however, 15 to 18 months after study entry women not using HRT showed "distress-MS" and "MS-CHD" relationships. In women using HRT, associations did not occur among distress, the MS, and CHD, but poor health habits and the MS were related. CONCLUSIONS: In older men, pathways occurred from chronic stress to distress to the metabolic syndrome, which in turn predicted CHD. Older women not using HRT showed fewer pathways than men; however, over time, distress, the MS, and CHD were related. No psychophysiological pathways occurred in older women using HRT.