Blockade of the renin-angiotensin system by inhibition of angiotensin-converting enzyme (ACE) is beneficial for the treatment of hypertension and congestive heart failure. However, it is unclear how complete the blockade by ACE inhibitors is and if there is continuing angiotensin II (Ang II) formation during chronic treatment with ACE inhibitors. Indeed chymase, a serine protease, which is able to form angiotensin II from angiotensin I (Ang I) and cannot be blocked by ACE inhibitors, has been shown to be present in human heart. The goal of the present study was to evaluate the extent of renin-angiotensin system blockade and the Ang II-forming pathways in cardiac tissue of patients chronically treated with ACE inhibitors or in patients without ACE inhibition therapy. Our studies indicate an incomplete ACE inhibition in human heart tissue after chronic ACE inhibitor therapy. Moreover, ACE contributes only a small portion to the total Ang I conversion, as shown in biochemical studies in ventricular and coronary homogenates or functionally as Ang I contractions in isolated rings of coronary arteries. A serine protease was responsible for the majority of Ang II production in both the membrane preparation and Ang I-induced contractions of isolated coronary arteries. In humans, the serine protease pathway is likely to play an important role in cardiac Ang II formation. Thus, drugs such as renin inhibitors and Ang II receptor blockers might be able to induce a more complete blockade of the renin-angiotensin system, providing a more efficacious therapy.
The pattern of radiographic enhancement in cases of brain abscess has been extensively studied, but the magnitude of blood-brain barrier (BBB) damage that accompanies enhancement has not. The question of whether BBB permeability increases continuously as a cerebritis evolves into an abscess was studied. The tracers 3H-labeled aminoisobutyric acid and 14C-labeled butanol were used in a rat Staphylococcus aureus cerebritis model to measure simultaneously BBB permeability and blood flow. The rats were examined at 1, 2, 3, 5, or 7 days after inoculation, and tissue samples were collected from the cerebritis site and uninoculated regions. Permeability of the BBB in the cerebritis region increased to five times the normal values by 72 hours after inoculation, then reached a plateau. The plasma volume in the cerebritis region increased to six times greater than the normal value at 72 hours, then remained unchanged. Uninoculated brain in both ipsilateral and contralateral hemispheres showed no significant changes. Cerebral blood flow was not substantially altered at the inoculated or uninoculated sites. In this model, incidence of BBB damage rises rapidly, reaches a plateau, and does not continue to increase despite the ongoing evolution of a cerebritis into an abscess. The BBB damage is accompanied by an increase in the regional plasma volume, a novel finding that has not been previously reported in central nervous system inflammation. These results suggest that the vascular events contributing to brain edema formation become established early in the cerebritis phase and imply that control of the host's inflammatory response is important in the management of cerebritis-associated brain edema.
The term "hibernating" myocardium has been applied to chronic left ventricular dysfunction without angina or ischemic electrocardiographic changes in patients with coronary artery disease that is reversed by therapy that increases myocardial blood flow. To investigate the relation between coronary blood flow and ventricular function experimentally, graded reductions in coronary artery pressure were produced in isolated perfused rat hearts as contractile performance (peak systolic pressure and its first derivative [dP/dt]) and metabolic variables were measured using phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy. As coronary pressure and flow were reduced, significant reductions in myocardial oxygen consumption and contractile performance were observed, which returned to control levels when coronary artery pressure and flow were restored to baseline values. Two phases of metabolic abnormality were observed. With modest reductions in coronary perfusion, proportionate reductions in myocardial oxygen consumption and contractile behavior were accompanied by a slight reduction in creatine phosphate but no significant lactate production. With greater reductions in coronary artery pressure and flow, creatine phosphate decreased more, adenosine triphosphate levels and myocardial pH decreased significantly and myocardial lactate production increased. The balanced reductions in myocardial contractility and oxygen consumption without metabolic abnormalities traditionally associated with "ischemia" observed in the first phase provides evidence in normal hearts for resetting of the myocardial contractile behavior and oxygen consumption in the presence of reduced coronary flow (that is, hibernating myocardium). The data suggest that reductions in adenosine diphosphate and the index of the reduced form of nicotinamide adenine dinucleotide (NADH) (lactate formation) do not explain the coupling between coronary artery pressure and flow and myocardial oxygen consumption as contractile performance decreases.
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