Restriction of placental and fetal growth in sheep alters fetal blood pressure responses to angiotensin II and captopril.
(17/7785)
1. We have measured arterial blood pressure between 115 and 145 days gestation in normally grown fetal sheep (control group; n = 16) and in fetal sheep in which growth was restricted by experimental restriction of placental growth and development (PR group; n = 13). There was no significant difference in the mean gestational arterial blood pressure between the PR (42.7 +/- 2.6 mmHg) and control groups (37.7 +/- 2.3 mmHg). Mean arterial blood pressure and arterial PO2 were significantly correlated in control animals (r = 0.53, P < 0.05, n = 16), but not in the PR group. 2. There were no changes in mean arterial blood pressure in either the PR or control groups in response to captopril (7.5 microg captopril min-1; PR group n = 7, control group n = 6) between 115 and 125 days gestation. After 135 days gestation, there was a significant decrease (P < 0.05) in the fetal arterial blood pressure in the PR group but not in the control group during the captopril infusion (15 microg captopril min-1; PR group n = 7, control group n = 6). 3. There was a significant effect (F = 14.75; P < 0.001) of increasing doses of angiotensin II on fetal diastolic blood pressure in the PR and control groups. The effects of angiotensin II were different (F = 8.67; P < 0.05) in the PR and control groups at both gestational age ranges. 4. These data indicate that arterial blood pressure may be maintained by different mechanisms in growth restricted fetuses and normally grown counterparts and suggests a role for the fetal renin-angiotensin system in the maintenance of blood pressure in growth restricted fetuses. (+info)
Angiotensin II-induced constrictions are masked by bovine retinal vessels.
(18/7785)
PURPOSE: To unmask the vasoconstricting effect of angiotensin II (Ang II) on retinal smooth muscle by studying its interaction with endothelium-derived paracrine substances. This study focused specifically on determining the changes in vascular diameter and the release of endothelial-derived vasodilators, nitric oxide (NO) and prostaglandin (PG) I2, from isolated retinal microvessels. METHODS: Bovine retinal central artery and vein were cannulated, and arterioles and venules were perfused with oxygenated/heparinized physiological salt solution at 37 degrees C. This ex vivo perfused retinal microcirculation model was used to observe the contractile effects of Ang II on arterioles and venules of different diameters. The NO and PGI2 synthase inhibitors, 1-NOARG and flurbiprofen, respectively, were used to unmask Ang II vasoconstriction; the changes in vascular diameters were then measured. Enzyme immunoassays were used to measure the release of cGMP (an index of NO release) and 6-keto-PG-F1alpha (a stable metabolite of PGI2) from isolated bovine retinal vessels. RESULTS: Topically applied Ang II (10(-10) M to 10(-4) M) caused significant (P < 0.05) arteriolar and venular constrictions in a dose-dependent manner, with the smallest retinal arterioles (7+/-0.2 microm luminal diameter) and venules (12+/-2 microm luminal diameter) significantly more sensitive than larger vessels. After the inhibition of endogenous NO and PGI2 synthesis by 1-NOARG and flurbiprofen, respectively, the vasoconstriction effects of Ang II became more pronounced. Again, the smallest vessels tested were significantly more sensitive, and synthesis of endothelial-derived relaxing factor (EDRF), therefore, may be most important in these vessels. Vasoactive doses of Ang II (10(-10) M to 10(-4) M) caused a dose-dependent increase in the release of NO and PGI2 from isolated bovine retinal vessels, indicating that the increase in EDRF may nullify direct Ang II-induced vasoconstriction. Interestingly, intraluminal administration of Ang II caused only vasodilation. CONCLUSIONS: This study demonstrates that the retinal vascular endothelium acts as a buffer against the vasoconstricting agent Ang II via release of vasodilators NO and PGI2, and the vasoconstriction effects due to Ang II are most prominent in the smallest diameter vessels. (+info)
Sympathetic nervous system activity and alpha-adrenergic responsiveness in older hypertensive humans.
(19/7785)
We have previously demonstrated in normotensive humans an age-associated increase in sympathetic nervous system (SNS) activity combined with appropriate downregulation of alpha-adrenergic responsiveness. Impaired downregulation of alpha-adrenergic responsiveness, despite a comparable level of SNS activity, could contribute to higher blood pressure in older hypertensive humans. We measured arterial plasma norepinephrine (NE) levels and the extravascular NE release rate (NE2) derived from [3H]NE kinetics (to assess systemic SNS activity), and platelet and forearm arterial adrenergic responsiveness in 20 normotensive (N) and in 24 hypertensive (H), otherwise healthy, older subjects (60-75 yr). Although plasma NE levels were similar (N 357 +/- 27 vs. H 322 +/- 22 pg/ml; P = 0.37), NE2 tended to be greater in the hypertensive group (H 2.23 +/- 0.21 vs. N 1.64 +/- 0.20 microgram. min-1. m-2; P = 0. 11), and the NE metabolic clearance rate was greater (H 1,100 +/- 30 vs. N 900 +/- 50 ml/m2; P = 0.004). In the hypertensive group, there was a greater alpha-agonist-mediated inhibition of platelet membrane adenylyl cyclase activity and a NE- but not ANG II-mediated decrease in forearm blood flow. Compared with normotensive subjects, in older hypertensive subjects 1) NE metabolic clearance rate is increased, 2) systemic SNS activity tends to be increased, and 3) arterial and platelet alpha-adrenergic responsiveness is enhanced. These results suggest that heightened SNS activity coupled with enhanced alpha-adrenergic responsiveness may contribute to elevated blood pressure in older hypertensive humans. (+info)
Proapoptotic effects of ANG II in human coronary artery endothelial cells: role of AT1 receptor and PKC activation.
(20/7785)
Anoxia-reoxygenation, tumor necrosis factor-alpha (TNF-alpha), and angiotensin II (ANG II) have been shown to induce apoptosis in myocytes. However, the role of these mediators in causing apoptosis of human coronary artery endothelial cells (HCAEC) is not known. This study was designed to examine the interaction of these mediators in induction of apoptosis in HCAEC. Cultured HCAEC were exposed to anoxia-reoxygenation, TNF-alpha, and ANG II. TNF-alpha enhanced apoptosis of HCAEC (determined by DNA nick-end labeling in situ and DNA laddering) caused by anoxia-reoxygenation. ANG II increased apoptosis beyond that caused by anoxia-reoxygenation and TNF-alpha. Apoptosis caused by ANG II was reduced by losartan, a specific ANG II type 1 receptor (AT1R) blocker, whereas PD-123,177, a specific ANG II type 2 receptor blocker, under identical conditions had minimal effect. The proapoptotic effects of ANG II were associated with the activation of protein kinase C (PKC). The importance of PKC activation as a signal transduction mechanism became evident in experiments wherein treatment of HCAEC with a specific inhibitor of PKC activation decreased ANG II-mediated apoptosis. Thus AT1R activation appears to be responsible for apoptosis caused by ANG II in HCAEC, and AT1R activation-mediated apoptosis involves activation of PKC. (+info)
Resetting of exaggerated tubuloglomerular feedback activity in acutely volume-expanded young SHR.
(21/7785)
One purpose of the present study was to evaluate the ability of 7-wk-old spontaneously hypertensive rats (SHR) to reset tubuloglomerular feedback (TGF) activity in response to acute volume expansion (VE). Second, we evaluated the contribution of ANG II, via its action on AT1 receptors, to TGF control of glomerular function during VE. TGF was assessed by micropuncture methods and proximal tubular stop-flow pressure (SFP) determinations in SHR, Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD). During euvolemia SHR exhibited enhanced TGF activity. In the same animals acute VE was achieved by infusion of saline (5 ml. h-1. 100 g body wt-1). VE led to resetting of TGF in all three strains. Maximal SFP responses, elicited by a 30-40 nl/min loop of Henle perfusion rate, decreased from 19 to 12 mmHg in SHR and, on average, from 11 to 5 mmHg in WKY and SD (P < 0.001). Tubular flow rate producing a half-maximal response (turning point) shifted to higher flow rates during VE, from 12 to 14 nl/min in SHR and from 15 to 19 nl/min in WKY. Administration of the AT1 receptor blocker candesartan (0.05 mg/kg iv) during sustained VE decreased TGF-mediated reductions in SFP in SHR and slightly increased the turning point in WKY. Nevertheless, other parameters of TGF activity were unaffected by AT1 receptor blockade. In conclusion, young SHR possess the ability to reset TGF activity in response to VE to a degree similar to compensatory adjustments in WKY. However, TGF remains enhanced in SHR during VE. ANG II and its action on AT1 receptors are in part responsible for the exaggerated SFP responses in young SHR during VE. (+info)
Inhibitory effects of nifedipine on DNA and protein synthesis in cultured cardiac nonmyocytes of neonatal rats.
(22/7785)
AIM: To observe the inhibitory effects of nifedipine (Nif) on cardiac nonmyocytes growth and proliferation. METHODS: Using nonmyocytes in culture as a model, [3H]thymidine and [3H]leucine incorporation were measured. RESULTS: There was a significant decrease in cell number and in total cellular protein after 72-h exposure to Nif 1 mumol.L-1 in the presence of angiotensin II (Ang II). A 48-h exposure to 1, 10, 100, 1000 nmol.L-1 of Ang II caused a 19%, 35%, 46%, 48% increase in protein synthesis and 27%, 46%, 56%, 57% increase in DNA synthesis. Nif 1, 3, and 10 mumol.L-1 were able to reduce the Ang II 100 nmol.L-1-induced increase of protein synthesis and DNA synthesis. CONCLUSION: Nif had a direct inhibitory action on the growth of nonmyocytes, which was related to the regression of cardical hypertrophy. (+info)
Angiotensin II-stimulated nitric oxide release from porcine pulmonary endothelium is mediated by angiotensin IV.
(23/7785)
In this study, a nitric oxide (NO) sensor was used to examine the ability of angiotensin II (AngII), AngIV, and bradykinin (Bk) to stimulate NO release from porcine pulmonary artery (PPAE) and porcine aortic endothelial (PAE) cells and to explore the mechanism of the AngII-stimulated NO release. Physiologic concentrations of AngII, but not Bk, caused release of NO from PPAE cells. In contrast, Bk, but not AngII, stimulated NO release from PAE cells. AngIII-stimulated NO release from PPAE cells required extracellular L-arginine and was inhibited by L-nitro-arginine methyl ester. AT1 and AT2 receptor inhibition had no affect on AngII-mediated NO release or activation of NO synthase (NOS). AngIV, an AngII metabolite with binding sites that are pharmacologically distinct from the classic AngII receptors, stimulated considerably greater NO release and greater endothelial-type constitutive NOS activity than the same amount of AngII. The AngIV receptor antagonist, divalinal AngIV, blocked both AngII- and AngIV-mediated NO release as well as NOS activation. The results demonstrate that AngIV and the AngIV receptor are responsible, at least in part, for AngII-stimulated NO release and the associated endothelium-dependent vasorelaxation. Furthermore, these results suggest that differences exist in both AngII- and Bk-mediated NO release between PPAE and PAE cells, which may reflect important differences in response to these hormones between vascular beds. (+info)
Renal function in high-output heart failure in rats: role of endogenous natriuretic peptides.
(24/7785)
The physiologic and pathophysiologic importance of natriuretic peptides (NP) has been imperfectly defined. The diminished renal responses to exogenous atrial NP in heart failure have led to the perception that the endogenous NP system might be less effective and thus contribute to renal sodium retention in heart failure. This study tests the hypothesis that in experimental heart failure, the renal responses to an acute volume load are still dependent on the NP system. The specific antagonist HS-142-1 was used to block the effects of NP in a model of high-output heart failure induced by an aortocaval shunt. Plasma cGMP levels and renal cGMP excretion were significantly lower in shunted and sham-operated rats receiving HS-142-1, compared with vehicle-treated controls, indicating effective blockade of guanylate cyclase-coupled receptors. Baseline sodium excretion and urine flow rate were lower in HS-142-1-treated sham-operated rats (15.2+/-1.1 microl/min versus 27.5+/-3.1 microl/min with vehicle, P < 0.001) and in HS-142-1-treated shunted rats (8.1+/-1.3 microl/min versus 19.9+/-2.3 microl/min with vehicle, P < 0.001). After an acute volume load, the diuretic and natriuretic responses were attenuated by HS-142-1 in control and shunted rats. The renal responses were reduced by HS-142-1 to a significantly greater extent in shunted rats than in control rats. HS-142-1 did not induce any significant systemic hemodynamic changes in either group, nor did it alter renal blood flow. However, the GFR in HS-142-1-treated shunted rats was lower than that in vehicle-treated shunted rats, both at baseline (0.6+/-0.3 ml/min versus 2.1+/-0.4 ml/min with vehicle, P < 0.05) and after an acute volume load (1.2+/-0.4 ml/min versus 2.6+/-0.4 ml/min with vehicle, P = 0.01), whereas no such effect was observed in control rats. These data indicate that the maintenance of basal renal function and the responses to acute volume loading are dependent on the NP system. The NP seem to be of particular importance for the maintenance of GFR in this model of experimental heart failure. These observations provide new insights into the importance of the renal NP system in heart failure. (+info)