Micropuncture and/or morphologic studies were performed in seven groups of uninephrectomized (UNX) adult male Munich-Wistar rats. Control groups 1, 3, and 6 received standard (24% protein) chow and tap water. Groups 2, 4, and 5 received weekly injections of desoxycorticosterone pivilate (DOC) and 1% saline for drinking, groups 2 and 4 were fed standard chow, and Group 5 a diet containing 6% protein. Group 7 received DOC, salt, and standard chow for 3 wk followed by withdrawal of DOC and salt for an additional 6 wk. 10-14 d after UNX, groups 1 and 2 exhibited similar single nephron glomerular filtration rates (SNGFR) and initial glomerular plasma flow rates (QA). Group 2 had higher mean arterial pressure (AP) and glomerular capillary hydraulic pressure (PGC) than group 1. 3-4 wk after UNX, group 4 exhibited further elevations in AP and PGC as compared with groups 2 and 3. SNGFR and QA were similar in groups 3 and 4, but these average values were greater than typical for normal rats. Group 4 also demonstrated increased urinary protein excretion. Morphologic evaluation of glomeruli in groups 2 and 4 revealed mesangial expansion and focal intraglomerular hemorrhage whereas glomeruli of groups 1 and 3 were essentially normal. Values for AP and PGC in group 5 were not different than group 3 but significantly lower than group 4. QA and SNGFR were lower in group 5 (low protein) than in groups 3 and 4. Furthermore, proteinuria and glomerular structural lesions were abolished in group 5. Morphologic studies performed in groups 6 and 7 showed that early DOC-SALT lesions progress to focal glomerular sclerosis. These studies suggest that continued elevations in glomerular capillary flows and pressures predispose to glomerular injury in this model of systemic arterial hypertension.

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Hemodynamic basis for glomerular injury in rats with desoxycorticosterone-salt hypertension.

Mechanisms of action of various hormones and vasoactive substances on glomerular ultrafiltration in the rat.

To characterize the hemodynamic events responsible for alterations in renal function during administration of atrial natriuretic peptide, we studied the systemic, renal, and glomerular circulatory effects of intravenous rANP[126-149], administered as a 4 micrograms/kg prime and 0.5 microgram/kg per minute continuous infusion in anesthetized, euvolemic rats. With this protocol, a small decline in mean systemic arterial blood pressure occurred in the context of markedly enhanced urinary sodium excretion, hemoconcentration, and reduced left ventricular end-diastolic pressure and +dP/dt. However, despite a significant decrement in renal vascular resistance, total peripheral resistance remained constant, thereby denoting a preferential renal vasodilatory effect of this peptide in vivo. Whole kidney and single nephron GFR increased by approximately 20%, while effective renal and glomerular plasma flow rates remained stable, resulting in a substantial rise in filtration fraction. Of all the parameters potentially capable of augmenting single nephron GFR, only glomerular capillary hydraulic pressure increased significantly and therefore accounted entirely for the hyperfiltration observed during ANP infusion. This rise in glomerular capillary pressure, in turn, resulted from afferent arteriolar vasodilatation and concurrent efferent arteriolar vasoconstriction, findings that proved independent of both endogenous angiotensin II activity and ANP-induced reductions in renal perfusion pressure. These renal hemodynamic effects are unique when compared with actions of previously studied renal vasodilatory agents.

Renal and systemic hemodynamic effects of synthetic atrial natriuretic peptide in the anesthetized rat.

Reversal of renal cortical actions of angiotensin II by verapamil and manganese.

Histamine covalently bound to glutaraldehyde-activated ferritin was prepared as either monomers or as small aggregates of approximately 0.05 to 0.15 micrometer Diam, suitable for electron microscopic detection of histamine cellular binding sites. The histamine-ferritin conjugates (MF) maintain the histamine capability to induce the opening of endothelial junctions in venules. To investigate the distribution of histamine receptors in the vascular endothelium, monomers or aggregates of MF were perfused in situ (mice), and various vascular beds, particularly that of the diaphragm, were fixed and processed for electron microscopy. The conjugate was preferentially bound on restricted areas of luminal endothelial cell plasmalemma especially in regions rich in filaments, and near the junctions between endothelial cells. The density of histamine binding sites was characteristically high in venules; it occurred to a much lesser extent in arterioles, veins, and muscular arteries whereas capillaries and aorta showed the lowest values. A similar distribution was obtained after perfusion of H1 or H2 receptor agonists coupled to ferritin (2-pyridylethylamine-ferritin [PF], or 4-methylhistamine-ferritin [MF], respectively). The binding specificity was assessed through control experiments with either native or activated ferritin or by competition with histamine. The findings suggest that histamine receptors are largely represented in the cell membrane of the vascular endothelium, particularly in venules. Experiments using specific H1 and H2 receptor agonists (PF and MF) and antagonists (mepyramine and cimetidine) indicate that the venular endothelium contains mainly H2 receptors.

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Histamine receptors of the microvascular endothelium revealed in situ with a histamine-ferritin conjugate: characteristic high-affinity binding sites in venules.

We made direct measurements of pregiomerular, glomerular, and postglomerular pressures and flows before and during intra-aortic infusion of a mildly vasodepressor dose of histamine in 20 Munich-Wistar rats. As with whole kidney GFR, single nephron (SN) GFR remained unchanged during histamine infusion, despite significant mean increases in total renal and glomerular plasma flow (QA) rates, as well as in mean glomerular capillary hydraulic pressure (Pec)- These hemodynamic changes were accompanied by proportionately greater reductions in afferent than in efferent arteriolar resistances. A declinein the glomerular capillary ultrafiltration coefficient, Kr, served to offset the increases in QA and PGC. thus accounting for the near-constancy of SNGFR and GFR. Infusion of diphenhydramine, but not metiamide, largely prevented these histamine-induced changes in the glomerular microcirculation, indicating that, in the Munich-Wistar rat, the action of histamine on the glomerulus is channeled largely through an Hi-receptor system. Fractional clearances of uncharged dextrans with molecular radii of 20-42 A, measured in a separate group of five rats, were unaffected by histamine infusion. Using a hydrodynamic theory describing transport of macromolecules through an isoporous membrane, we showed that histamine did not affect glomerular pore size but did produce a major reduction in the ratio of pore area:pore length, a measure of pore density. Taken in conjunction with the finding of a histamine-induced decline in Kr, the results with dextrans suggest that the fall in K0 is due largely to a functional reduction in total filtration surface area. Ore Res 45: 737- 745, 1979

B M Brenner

Papers

Mechanisms of action of hisamine and histamine antagonists on the glomerular microcirculation in the rat.