Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats.

Fibrosis leads to chronic impairment of cardiac and renal function and thus reversal of existing fibrosis may improve function and survival. This project has determined whether pirfenidone, a new antifibrotic compound, and spironolactone, an aldosterone antagonist, reverse both deposition of the major extracellular matrix proteins, collagen and fibronectin, and functional changes in the streptozotocin(STZ)-diabetic rat. Streptozotocin (65 mg kg(-1) i.v.)-treated rats given pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone; approximately 200 mg kg(-1) day(-1) as 0.2 - 2g 1(-1) drinking water) or spironolactone (50 mg kg(-1) day(-1) 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. STZ-treatment increased perivascular and interstitial collagen deposition in the left ventricle and kidney, and surrounding the aorta. Cardiac, renal and plasma fibronectin concentrations increased in STZ-diabetic rats. Passive diastolic stiffness 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. 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 flow rates in isolated perfused kidneys; pirfenidone but not spironolactone prevented the return to control values. Thus, short-term pirfenidone and spironolactone treatment reversed cardiac and renal fibrosis and attenuated the increased diastolic stiffness without normalizing cardiac contractility or renal function in STZ-diabetic rats.

Reversal of cardiac fibrosis in deoxycorticosterone acetate-salt hypertensive rats by inhibition of the renin-angiotensin system.

Fibrosis impairs cardiac function. This project has determined the expression and deposition of collagens and fibronectin and cardiac function in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat after inhibition of the renin-angiotensin system. DOCA-salt hypertension was induced in 8-wk-old male Wistar rats by uninephrectomy and administration of DOCA (25 mg every fourth day, subcutaneously) and 1% NaCl in the drinking water for 4 wk. Starting 2 wk after surgery, rats were given either oral captopril (100 mg/kg), oral candesartan cilexetil (2 mg/kg), or subcutaneous spironolactone (50 mg/kg) daily for 2 wk (reversal protocol). DOCA-salt rats failed to gain weight with markedly increased water intake and decreased food intake; drug treatment did not alter these parameters. Systolic BP increased from 116+/-5 mmHg in uninephrectomized rats to 179+/-7 mmHg in DOCA-salt rats and was not decreased by treatment (captopril 172+/-1 mmHg; candesartan 187+/-2 mmHg; spironolactone 178+/-3 mmHg). Captopril, candesartan, and spironolactone reversed the increased collagen I mRNA in DOCA-salt rats; only candesartan reversed the increased collagen III mRNA. Collagen IV mRNA was unchanged in DOCA-salt rats and following treatment. Total fibronectin mRNA increased without changing the proportion of fibronectin mRNA as the fetal isoforms EIIIA and EIIIB. Captopril, candesartan, and spironolactone reversed the increased deposition of perivascular and interstitial collagen in DOCA-salt rats; the increased cardiac fibronectin deposition was reversed by candesartan and spironolactone. Captopril, candesartan, and spironolactone also attenuated or reversed the increased diastolic stiffness and the increased dP/dt but not the increased rate-pressure products in DOCA-salt rat hearts. Thus, inhibition of the renin-angiotensin system reverses cardiac fibrosis in DOCA-salt rats and returns some indices of myocardial function to normal.

[Dietetic-hygienic measures in the control of arterial hypertension in obese females]. / Dijetetsko-higijenske mere u suzbijanju arterijske hipertenzije gojaznih osoba zenskog pola.

Since the evidence to data suggest that some obese person respond well to non-pharmacological measures, the aim of this study was to examine the extent of body weight reduction necessary to reduce blood pressure to normal values. A group of 250 obese women with hypertension (blood pressure measurements over 160/95) and an overweight of at least 20 per cent excess of ideal weight was included in the study. The patients were advised to take well balanced low-calorie (about 1000 kcal/day) diet containing 66 g proteins, 140 g carbohydrates, 13 g fat and 0.5 g salt. They were advised to increase daily physical activities. Low-calorie diets were used to decrease body weight in groups of patients with changed of unchanged antihypertensive drug therapy, also. Decrease in body weight resulted in significant decrease in blood pressure; over two-thirds of complaint patients achieve normal blood pressure with a loss of only 5-10 per cent of their weight excess even if at this point they were still overweight. In the group receiving no drug therapy 78 per cent reached normal blood pressure, 76 per cent in the patients whose antihypertensive treatment had to be modified during the study and 63 per cent in the group receiving unchanged drug therapy. It was concluded that weight reduction program (diet and physical activity) can be a possible approach to treat hypertension without drugs and patients can attain normotension long before achieving the ideal weight.

Doppler flow velocity in assessment of peripheral arterial disease in the lower limbs.

In 74 patients with the chronic obliterative arterial disease of the lower limbs, the systolic perfusion pressure and the ankle systolic pressure index were measured using CW-Doppler ultrasound on the dorsalis pedis and posterior tibial arteries. At the same time Doppler flow velocity recordings were made at the femoral, popliteal and pedal levels. Peak foreward velocity and peak reverse velocity were measured directly from the tracing, while blood acceleration and deceleration as well as the acceleration/deceleration index were calculated using simple arithmetics. Patients with obliterative arterial disease had a significantly lower systolic pressure and ankle systolic pressure index in both pedal arteries than healthy volunteers constituting the control group. Peak forward velocity, acceleration and deceleration had a great accuracy in evaluating the peripheral circulatory status in affected persons, while peak reverse velocity and the acceleration/deceleration index were reproducible only at the high femoral level. Doppler velocity tracings appeared to be as useful in evaluating the peripheral arterial circulation as the previously used systolic perfusion pressure and ankle systolic pressure index.