Changes in myocardial capillary diffusion capacity during infusion of vasoactive drugs

The present study investigated how variations in coronary vascular resistance and metabolic demand affected myocardial capillary diffusion capacity. Hearts from Wistar rats were perfused with Krebs-Henseleit-albumin buffer in a Langendorff preparation, where heart rate (HR), contractility (dP/dt_max) and myocardial oxygen consumption (MVO₂) were recorded continuously. Myocardial capillary diffusion capacity was measured as the permeability surface area product (PS) for Cr-EDTA and vitamin B₁₂ by the single injection colorimetric indicator dilution method. After base-line recordings without drugs, angiotensin II + arginine-vasopressin was infused, which increased coronary vascular resistance by 90%, stimulated HR by 11%, decreased dP/dt_max by 21% and reduced MVO₂ by 4%. PS_Cr-EDTA and PS_B12, decreased by 24 and 27%, respectively, leaving the ratio PS_Cr-EDTA/PS_B12 unchanged indicating unaltered capillary permeability. Moreover, the reductions in MVO₂ and PS correlated significantly. During vasodilation: (1) nitroprusside-NA stimulated HR by 7% and decreased dP/dt_max by 14%; (2) adenosine reduced dP/dt_max by 37% and decreased MVO₂ by 9%; and (3) isoproterenol increased HR, dP/dt_max and MVO₂ by 53, 76 and 9%, respectively. However, all three vasodilators reduced PS_Cr-EDTA and PS_B12 in parallel by 7–25% leaving PS_Cr-EDTA/PS_B12 unchanged. Thus, maximal estimated diffusion capacities were obtained during spontaneous coronary vascular tone, most likely reflecting maximal capillary recruitment in the Krebs-Henseleit-albumin perfused heart. The derecruiting effects of the vasoconstrictors were partly overridden by metabolic factors, while the reductions of PS after vasodilation more likely were due to increased heterogeneity in coronary flow.     

Reduced permselectivity in isolated perfused rat kidneys following small elevations of glomerular capillary pressure

A modified rat kidney preparation was used to explore how changes in hydrostatic pressure affect the permselective properties of the glomerular capillary bed. Th? maximally vasodilated kidneys of 18 rats were perfused with albumin solutions (16.7 g ^-1) at different flow rates and hence arterial pressures (P_A). One kidney in each rat was exposed to pressure elevations with the other kidney serving as a control perfused at constant P_A of about 100 mmHg. Both the vascular resistance to flow and the glomerular filtration rate (GFR 34.6 ± 2.9 ml min¹ 100 g^_1) were similar in the two kidneys at equal P_A and remained constant throughout the experiment. The ratio of albumin clearance over GFR (Θ) was initially around 0.4% at constant P_A and gradually increased during 1.5 h to reach 0.7% at the end of the experiment. A direct increase of P_A from 100 to 200 mmHg for 15 min resulted in a calculated increase of the effective glomerular filtration pressure gradient of 10–15 mmHg and in a two-fold increase ofΘ when measured at an identical P_A of 100 mmHg. Albumin clearance was almost fully normalized within 20 min similar to that observed in e.g. skeletal muscle. However, the glomerular capillary barrier seemed to be far more sensitive to elevations of hydrostatic pressure than other capillary walls which require capillary pressure increments of 60 mmHg in order to induce similar reversible changes in permeability. Therefore, we conclude that an elevated P_G:c per se induces changes of glomerular permselectivity, which may have important pathophysiological implications during conditions of proteinuria.     

Structurally reduced distensibility of cardiovascular ‘low-pressure’ compartments in primary hypertension,as studied in spontaneously hypertensive rats (SHR)

Adult male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) were compared to explore to what extent venous ‘unstressed’ volume, compliance and wall distensibility are structurally altered in primary hypertension. The perfused, maximally vasodilated hindquarters and the entire, completely relaxed cardiovascular system during cardiac arrest were used for comparisons of ‘initial’ volumes and pressure-volume characteristics of the respective low-pressure compartments. In both preparations SHR and WKY showed identical ‘unstressed’ venous volumes, computed by extrapolation to zero pressure from initial volumes and the nearly linear pressure-volume relationships, while venous compliance (Δ/ΔP) was in each case about 20% reduced in SHR. Consequently, the structurally determined wall distensibility of the low-pressure compartment, calculated as the square root of volume compliance/unstressed (or initial) volume, was significantly reduced in SHR; about 10%. Such venous ‘structural resetting’ has important hemodynamic consequences, not least because it reinforces increase of venous return and cardiac filling pressure in SHR, caused by given sympathetic activations. Evidently, not only resistance, cardiac and barostat functions but also the venous capacitance function are structurally reset early in primary hypertension, implying a redesign of the entire cardiovascular system to operate at a higher pressure equilibrium.     

Effect of pre-treatment with desferrioxamine and mannitol on radical production and kidney function after ischaemia-reperfusion. A study on rabbit kidneys

The effects of pre-treatment with mannitol and the iron chelator desferrioxamine on oxygen radical formation and glomerular and tubular function after ischaemia in the rabbit kidney were studied. Radicals were measured with ESR and spin trapping. At reperfusion after 60 min of renal ischaemia there was a significant increase in the production of free radicals in the venous effluent from the kidney. Administration of either mannitol or desferrioxamine given before ischaemia and before recirculation reduced the radical production significantly. The iron chelator appeared to be more effective. Glomerular function measured 48 h after reperfusion was significantly better after pretreatment with desferrioxamine and mannitol compared with mannitol alone. Tubular function did not differ between the two pre-treatment groups.     

Importance of molecular charge for the passage of endogenous macromolecules across continuous capillary walls,studied by serum clearance of Lactate Dehydrogenase (LDH) isoenzymes

Electrostatic capillary barrier characteristics was studied in the isolated maximally vasodilated rat hindquarter by use of a modified “tissue uptake” technique (Rippe et al. 1979). The hindquarters were artificially perfused with oxygenated horse serum at isogravimetry. As tracers two isoenzymes of lactate dehydrogenase (LDH) were used, having indentical size (41 Å, M_w? 140000) but with differing molecular charge and labelled with two separable isotopes. LDH-H₄ (¹²⁵I) is negatively charged and LDH-M₄ (¹³¹I) slightly positive, at physiological pH. The negatively charged protein LDH-H₄ was more retarded in its transcapillary passage than LDH-M₄. Net clearance of H₄ was 0.0242±0.0045 ml/min × 100 g and that of M₄ was 0.0748±0.0092 ml/min × 100 g (n= 11, p<0.001). This difference is suggested to be due to an interaction of the polyanionic tracer with a barrier of negative molecular charge, most effective at the small pore equivalent. Clearance data for H₄ and for albumin (Rippe et al. 1979) are compatible with an equivalent large pore radius of 520 Å. Neither vesicular transport (Palade 1953) nor the impact of fibre pore matrix (Michel 1980) is considered to be involved in the transcapillary passage of proteins. Negatively charged proteins probably pass through the large pore equivalent exclusively, while neutral macromolecules also utilize part of the small pore equivalent, for their transcapillary passage.     

Analysis of the pressure-flow characteristics of isolated perfused rat kidneys with inhibited tubular reabsorption

The renal hemodynamics were studied in an isolated perfused rat kidney model modified for investigations of the glomerular permeability characteristics. The tubular reabsorptive activity was inhibited by perfusion at low temperature (8 ^oC) in the presence of furosemide and nitroprusside resulting in a dramatic increase in the filtered load of fluid and solute reaching the tubules and hence in tubular pressure. The glomerular filtration rate (GFR), arterial pressure (P_A) aid needle pressure (intrarenal tissue pressure, P_iR) were continuously recorded and the glomerular hydrostatic pressure was estimated by an arterial occlusion technique. The pre- to postglomerular resistance ratio was calculated from the pressure vs. GFR relationships for two perfusates having differing oncotic pressures (π= 5.5 and 77 = 20 mmHg), from which estimations of glomerular hydrostatic pressures (P_GC) were concomitantly made. Thus, increases in An could be exactly counterbalanced by equally large increases in P_ac for any given GFR, the needle and Bowman's capsule pressures being dependent on GFR but not on plasma colloid oncotic pressure. The experimental interventions resulted in a pronounced elevation of P_iR as compared with in vivo conditions, while the P_GC values were in a normal range, resulting in reduced glomerular filtration pressures. Furthermore, the clearance of albumin varied with the oncotic pressure in agreement with the notion of heteroporosity.     

T Cell Subsets and T Cell Function in Cartilage-Hair Hypoplasia

Cartilage hair hypoplasia is a rare autosomal recessive form of short-limbed dwarfism associated with a cellular immunodeficiency. In eight patients, the authors studied the presence of T cell subsets and in vitro T cell function in order to address the basis for the immunological disorder. Both the proliferative response to phytohaemagglutinin (PHA) and the PHA-induced IL2 production were 60% lower compared with controls ( P   =  0.007 and 0.005, respectively). The impaired proliferative response could not be restored by addition of IL-2. This result is in accordance with a decrease in the percentage of activated T cells expressing the p 55 subunit of the IL-2 receptor complex (CD25). The results define more precisely that T cells from cartilage hair hypoplasia patients are defective in the transition from the G₀ to the G₁ phase of the cell cycle. Furthermore, the data demonstrate that several CHH patients show a reduced proportion of CD45RA⁺'naive' T cells. However, the in vitro impairment of T cell function cannot solely be explained by imbalance between 'naive' and 'memory' T cells. Although CHH patients with a history of recurrent respiratory tract infections showed the most aberrant in vitro immune parameters, a clear relationship between clinical data and in vitro parameters could not be established for the whole patient group.     

Immunoglobulin G, A, and M Light Chain Ratios in some Humoral Immunological Disorders

The total kappa/lambda immunoglobulin light chain ratio and the kappa/lambda ratios within each of the serum immunoglobulin classes G, A, and M were measured in thirteen patients with humoral immunological disorders. Of those patients, eight had common variable immunodeficiency whereas five patients had other forms of humoral immunological deficiencies. Eleven patients had abnormal antibody response in vivo. All but three of the thirteen patients had clearly abnormal light chain ratios in one or more of the immunoglobulin classes. We conclude that humoral immunological disorders, usually characterized by abnormal heavy chain production and a disturbed antibody response, may frequently have a concomitant abnormal synthesis of the light chains resulting in an abnormal kappa/lambda light chain ratio.