Maria Caterina Fattaccio

Early Blockade of Bradykinin B2-Receptors Alters the Adult Cardiovascular Phenotype in Rats

We evaluated whether long-term inhibition of bradykinin B2-receptors by the long-acting antagonist Hoe 140 (D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin) affects the blood pressure of normotensive rats. Neither Hoe 140 (at 75 nmol/d for 8 weeks) nor its vehicle altered systolic pressure of adult rats on a normal or high sodium intake. In further experiments, pairs of Hoe 140-treated rats were mated and their offspring maintained on Hoe 140 and a normal sodium diet. Controls were given vehicle instead of Hoe 140. At 9 weeks of age, rats given Hoe 140 during prenatal and postnatal phases of life showed greater systolic pressures, heart rates, and body weights than controls (122 +/- 1 versus 113 +/- 1 mm Hg, 444 +/- 6 versus 395 +/- 8 beats per minute, 258 +/- 7 versus 213 +/- 3 g, respectively, P < .01), whereas urinary creatinine excretion was reduced (1.13 +/- 0.05 versus 1.36 +/- 0.04 mumol/100 g body wt in controls, P < .05). The difference in blood pressure (confirmed by direct intra-arterial measurement) persisted after 20 days of dietary sodium loading, whereas it was nullified by sodium restriction. In additional experiments, the offspring of untreated rats received Hoe 140 or vehicle from 2 days to 11 weeks of age. At this stage, systolic pressure and body weight were significantly greater in Hoe 140-treated rats compared with controls, and heart rate was similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic inhibition of bradykinin B2-receptors enhances the slow vasopressor response to angiotensin II.

The contribution of endogenous kinins in the regulation of blood pressure of angiotensin-treated rats was evaluated using the new bradykinin B2-receptor antagonist Hoe 140 (D-Arg,[Hyp3,Thi5,D-Tic7, Oic8]-bradykinin). Chronic infusion of Hoe 140 at 75 nmol/d (a dose able to inhibit the vasodepressor effect of an intra-aortic bolus injection of 0.85 nmol/kg bradykinin) did not alter systolic blood pressure (tail-cuff plethysmography). Chronic infusion of angiotensin II (Ang II) induced a dose-related increase in systolic blood pressure and plasma Ang II levels. The vasopressor effect of 40 or 100 nmol/d Ang II was enhanced in rats given chronic infusion of Hoe 140 (by 12 and 14 mm Hg, respectively), whereas the increase in plasma Ang II levels remained unaltered. Furthermore, a low nonpressor dose of Ang II (20 nmol/d) was then able to increase blood pressure during chronic blockade of bradykinin receptors by Hoe 140 (from 126 +/- 3 to 137 +/- 3 mm Hg, P < .05). Combined infusion of 20 nmol Ang II and Hoe 140 did not alter the urinary excretion of sodium and water despite the fact that blood pressure was increased. Potentiation of the pressure effect of Ang II by Hoe 140 was confirmed by direct measurement of mean blood pressure (125 +/- 2 versus 108 +/- 2 mm Hg at 20 nmol, 123 +/- 2 versus 110 +/- 2 mm Hg at 40 nmol, and 139 +/- 2 versus 125 +/- 3 mm Hg at 100 nmol Ang II, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic kinin receptor blockade induces hypertension in deoxycorticosterone-treated rats.

1 The contribution of endogenous kinins to the regulation of blood pressure and renal function of Wistar rats was evaluated by use of the new B2‐receptor antagonist, Hoe 140, (d‐Arg[Hyp3,Thi5,d‐Tic7,Oic8]‐bradykinin). 2 Neither Hoe 140 (4 μg h−1 s.c, for 6 weeks), nor vehicle altered systolic blood pressure (SBP, tail‐cuff plethysmography) or renal function in rats, under normal conditions. 3 Chronic administration of deoxycorticosterone (DOC, 25 mg kg−1 s.c., weekly) increased SBP slightly only after 6 weeks (from 124 ± 2 to 133 ± 3 mmHg, P < 0.05). An earlier and greater rise in SBP (P < 0.01) occurred when DOC was combined with chronic infusion of Hoe 140 (from 125 ± 1 to 154 ± 3, P < 0.01). The hypertensive effect of Hoe 140 was confirmed by direct measurement of mean blood pressure (143 ± 2 vs 122 ± 2 mmHg in controls, P < 0.01). 4 DOC caused an initial fall, followed by a transitory increase in urinary volume and sodium excretion; thereafter, both parameters returned to baseline. The initial antidiuretic and antinatriuretic effects were enhanced by Hoe 140 (P < 0.05). 5 Urinary prostaglandin E2 excretion was increased by DOC (from 106 ±3 to 153 ±4 ng 24 h−1, P < 0.01) and this effect was prevented by Hoe 140 (from 95 ± 3 to 104 ± 3 ng 24 h−1, NS). By contrast, the high urinary vasopressin excretion and suppressed plasma renin activity found in DOC‐treated rats were not altered by Hoe 140. 6 These data suggest that endogenous kinins play an important role in the regulation of arterial blood pressure under conditions of mineralocorticoid excess.

Bradykinin B2-receptor blockade facilitates deoxycorticosterone-salt hypertension.

The contribution of endogenous kinins to the regulation of blood pressure, urinary volume, and renal sodium excretion was evaluated in Wistar rats on high sodium intake by using the new bradykinin receptor antagonist Hoe 140 (D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin). Neither Hoe 140 (3 nmol/hr s.c. for 4 weeks) nor its vehicle altered systolic blood pressure (tail-cuff plethysmography) or renal function in rats given saline solution (0.15 mol/L NaCl) to drink ad libitum. Four-week administration of deoxycorticosterone (DOC), combined with high sodium intake and uninephrectomy, increased systolic blood pressure from 127 +/- 3 to 160 +/- 3 mm Hg (p < 0.01). When long-term infusion of Hoe 140 was combined with DOC, high sodium intake, and uninephrectomy, systolic blood pressure rose from 127 +/- 3 to 175 +/- 3 mm Hg (p < 0.01). The hypertensive effect was greater in the Hoe 140 group (48 +/- 4 versus 33 +/- 3 mm Hg in controls, p < 0.05). This difference was confirmed by direct measurement of mean blood pressure (Hoe 140 group, 154 +/- 4 mm Hg; vehicle group, 139 +/- 4 mm Hg; p < 0.05). The antagonist blunted the increase in urinary volume induced by salt load and DOC in uninephrectomized rats, whereas it did not alter the increase in urinary sodium excretion. These results suggest that endogenous kinins do not play a major role in the regulation of normal blood pressure in sodium-loaded rats, whereas they may attenuate the hypertensive effect induced by long-term administration of mineralocorticoids and salt in uninephrectomized rats.

Prevention by blockade of angiotensin subtype1-receptors of the development of genetic hypertension but not its heritability.

1 We determined whether early inhibition of angiotensin II subtype1 (AT1) receptors by the newly synthesized nonpeptidic antagonist, A‐81988, can attenuate the development of hypertension in spontaneously hypertensive rats (SHR) and if the altered blood pressure phenotype can be passed on to the subsequent generation, not exposed to the antagonist. 2 Pairs of SHR were mated while drinking tap water or A‐81988 in tap water, and the progeny was maintained on the parental regimen until 14 weeks of age. At this stage, A‐81988‐treated rats showed lower systolic blood pressure and body weight values (136 ±5 versus 185 ±4 mmHg and 247 ±4 versus 283±4 g in controls, P<0.01), while heart rate was similar. In addition, mean blood pressure was reduced (101 ±7 versus 170 ±7 mmHg in controls, P < 0.01), and the pressor responses to intravenous or intracerebroventricular angiotensin II were inhibited by 27 and 59%, respectively. Heart/body weight ratio was smaller in A‐81988‐treated rats (3.2±0.1 versus 3.8±0.1 in controls, P<0.01). 3 The antihypertensive and antihypertrophic effect of A‐81988 persisted in rats removed from therapy for 7 weeks (systolic blood pressure: 173 ±4 versus 220 ±4 mmHg, heart/body weight ratio: 3.4 ±0.1 versus 4.1 ±0.1 in controls at 21 weeks of age, P < 0.01 for both comparisons), whereas the cardiovascular hypertensive phenotype was fully expressed in the subsequent generation that was maintained without treatment. 4 These results indicate that chronic blockade of angiotensin AT1‐receptors attenuates the development of hypertension in SHR but it does not prevent the transmission of hypertension to the following generation. Thus, heritability of the SHRs hypertensive trait is not affected by pharmacological manipulation of the cardiovascular phenotype.

A kallikrein-like enzyme in the aorta of normotensive and hypertensive rats.

We evaluated whether vascular kallikrein is altered in rats with genetic or experimental hypertension. Group 1 was infused intraperitoneally with angiotensin II (Ang II) or vehicle for 4 weeks; group 2 was injected subcutaneously with deoxycorticosterone (75 mumol/kg once a week) or vehicle for 4 weeks; group 3 consisted of uninephrectomized rats on high sodium intake given deoxycorticosterone or vehicle; and group 4 consisted of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Active and total kallikrein activity was measured in abdominal aortic homogenates using an amidolytic assay. Ang II increased systolic blood pressure at a dose of 400 nmol/kg per day (146 +/- 6 versus 123 +/- 3 mm Hg in controls, P < .01) but not at 80 nmol/kg per day. Deoxycorticosterone did not increase blood pressure except in uninephrectomized rats on high salt (173 +/- 6 versus 135 +/- 4 mm Hg in controls, P < .01). Blood pressure averaged 194 +/- 2 mm Hg in SHR and 123 +/- 3 mm Hg in WKY rats. Vascular kallikrein was similar in rats given Ang II or vehicle. In deoxycorticosterone-treated rats total kallikrein was higher than in controls (9.2 +/- 0.8 versus 3.5 +/- 0.1 pkat/mg protein, P < .05), whereas active kallikrein did not differ (0.09 +/- 0.04 versus 0.09 +/- 0.03 pkat/mg protein, P = NS). A similar pattern was observed in uninephrectomized deoxycorticosterone-treated rats (active, 0.09 +/- 0.03 versus 0.10 +/- 0.04, P = NS; total, 7.4 +/- 0.7 versus 4.1 +/- 0.2 pkat/mg protein, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Kinin Blockade on the Blood Pressure of Salt-Loaded Pregnant Rats

We evaluated whether chronic inhibition of bradykinin B2 receptors by the long-acting antagonist D-Arg, [Hyp3, Thi5,D-Tic7,Oic8]-bradykinin (Hoe 140) affects blood pressure of salt-loaded pregnant rats. Pairs of rats fed a high sodium diet (0.84 mmol sodium per gram chow) were mated at 14 weeks of age. Infusion of vehicle or Hoe 140 (300 nmol/d per kilogram body weight) was performed throughout each dams pregnancy by use of an Alzet osmotic pump implanted in the abdominal cavity. In both groups, no significant change in systolic pressure (tail-cuff plethysmography) or renal blood flow (Doppler flow-meter) was observed from that in the unmated state to that at midterm pregnancy. In the control group, systolic pressure decreased at the 21st day of pregnancy (from 126 +/- 2 to 97 +/- 2 mm Hg, P < .01), and renal blood flow increased (from 6.1 +/- 0.1 to 7.5 +/- 0.2 kHz, P < .01). These changes were nullified by the administration of Hoe 140 (systolic pressure changing from 124 +/- 2 to 118 +/- 4 mm Hg, P = NS; renal blood flow changing from 6.3 +/- 0.2 to 6.2 +/- 0.1 kHz, P = NS). In the group given Hoe 140, placental weight was greater (0.50 +/- 0.01 versus 0.43 +/- 0.01 g in controls, P < .01) and the fetal/placental weight ratio was reduced (4.53 +/- 0.09 versus 5.31 +/- 0.17 in controls, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)