1 Fibrosis leads to chronic impairment of cardiac and renal function and thus reversal of existing ®brosis may improve function and survival. This project has determined whether pirfenidone, a new anti®brotic compound, and spironolactone, an aldosterone antagonist, reverse both deposition of the major extracellular matrix proteins, collagen and ®bronectin, and functional changes in the streptozotocin(STZ)-diabetic rat. 2 Streptozotocin (65 mg kg 71 i.v.)-treated rats given pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone; approximately 200 mg kg 71 day 71 as 0.2 ± 2g 1 71 drinking water) or spironolactone (50 mg kg 71 day 71 s.c.) for 4 weeks starting 4 weeks after STZ showed no attenuation of the increased blood glucose concentrations and increased food and water intakes which characterize diabetes in this model. 3 STZ-treatment increased perivascular and interstitial collagen deposition in the left ventricle and kidney, and surrounding the aorta. Cardiac, renal and plasma ®bronectin concentrations increased in STZ-diabetic rats. Passive diastolic sti ness increased in isolated hearts from STZ-diabetic rats. Both pirfenidone and spironolactone treatment attenuated these increases without normalizing the decreased +dP/dt max of STZ-diabetic hearts. 4 Left ventricular papillary muscles from STZ-treated rats showed decreased maximal positive inotropic responses to noradrenaline, EMD 57033 (calcium sensitizer) and calcium chloride; this was not reversed by pirfenidone or spironolactone treatment. STZ-treatment transiently decreased GFR and urine¯ow rates in isolated perfused kidneys; pirfenidone but not spironolactone prevented the return to control values. 5 Thus, short-term pirfenidone and spironolactone treatment reversed cardiac and renal ®brosis and attenuated the increased diastolic sti ness without normalizing cardiac contractility or renal function in STZ-diabetic rats.

SUMMARYThe effect ofa converting-enzyme inhibitor (captopril) was studied in nine conscious dehydrated Merino ewes. Captopril (4 mg I.V. over 40 min) caused significant decreases in mean arterial blood pressure (M.A.B.P.), renal vascular resistance (R.V.R.) and filtration fraction, and increases in urine flow (V), sodium excretion, glomerular filtration rate (G.F.R.), renal plasma flow, solute clearance (Cosm), solute-free water reabsorption (TC,H,O) and plasma renin activity (P.R.A.).None of these effects was observed when captopril was similarly administered to sheep pretreated with angiotensin II (AII) receptor blocker, l-sarcosine-8-isoleucine-AII (sarileucin). It is concluded that the effects of captopril were probably not due to bradykinin potentiation but rather to decreased levels of circulating AlI. The effect of sarileucin itself was complex. It effectively blocked the pressor response to administered AII, but it also had an AII-like effect indicated by a rise in R.V.R., and decreases in V, G.F.R., Cosm and Tc, H,O. This apparent mixture of All agonist and antagonist properties probably accounts for the absence of any change in M.A.B.P. or P.R.A. during sarileucin administration.

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Summary: This study has compared renal function in deoxycorticosterone (DOCA)‐salt hypertensive Wistar rats (uninephrectomy followed by administration of DOCA 25 mg subcutaneously every fourth day and 1% NaCl in the drinking water) with various control rats using the isolated perfused kidney preparation. The systolic blood pressure of DOCA‐salt hypertensive rats was 180 ± 10 mmHg (uninephrectomy controls: 136 ± 9 mmHg) while normalization of calcium intake (DOCA‐Ca rats, 1% CaCl2 in water) attenuated this increase (systolic blood pressure, 146 ± 5 mmHg). Renal mass corrected for body weight increased by 25% after uninephrectomy, 55% in uninephrectomized rats given NaCl, 152% in DOCA‐salt rats and 147% in DOCA‐Ca rats. At a renal perfusion pressure of 135 mmHg, isolated perfused kidneys from DOCA‐salt rats showed decreases of 48% in glomerular filtration rate and 69% in sodium excretion with an increase of 44% in renal vascular resistance compared with uninephrectomized rats. There were no significant differences in renal function between DOCA‐salt and DOCA‐Ca rats. Histological assessment of renal pathology showed proximal tubular hypertrophy and hyperplasia, marked focal distal tubular atrophy, interstitial fibrosis and glomerular hypercellularity in DOCA rats compared with UNX rats. Lesions were less obvious in UNX‐salt or DOCA‐Ca rats. The lack of direct correlation between alterations in function and pathology may be explained by the compensatory effect of remaining healthy or hypertrophied nephrons. Thus, the DOCA‐salt model of hypertension in rats is associated with marked structural kidney damage and severely decreased kidney function. Marked attenuation of systemic hypertension by normalizing calcium intake in DOCA‐salt rats did not prevent impairment of kidney function.

We examined the effect of acutely lowering the colloid osmotic pressure by removing plasma (36.2 ± 3.1 ml/kg) and replacing it with Hartmann’s solution (93.0 ± 8.2 ml/kg) in 6 conscious merino sheep. The colloid osmotic pressure was reduced significantly (p < 0.05) from 20.3 ± 0.9 to 8.5 ± 2.5 mm Hg 0 h after plasmapheresis and to 15.2 ± 0.8 mm Hg 20 h after treatment. The filtration fraction increased from 0.16 ± 0.02 to 0.27 ± 0.02 at 0 h (p < 0.05 vs. control) and to 0.20 ± 0.02 at 20 h after treatment (p < 0.05 vs. control). At 0 h after plasmapheresis there was an increase in both sodium excretion from 187 ± 69 to 459 ± 82 µmol · min^-1(p < 0.05) and in fractional sodium excretion from 1.6 ± 0.4 to 4.4 ± 1.0% (p < 0.05). The results are consistent with the hypothesis that acute alteration of Starling forces produce clinically significant effects on both glomerular filtration and tubular reabsorption.