Aortic Coarctation-induced Hypertension Research Articles

Redox Regulating Protein APE1/Ref-1 Expression is Increased in Abdominal Aortic Coarctation-induced Hypertension Rats

❙ABSTRACT❙ Background: Aim of study is designed to investigate whether apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) expression is changed in abdominal aortic coarctation models. Methods: Male Sprague–Dawley rats were randomly assigned with abdominal aortic coarctation, repaired group, sham, and control groups. Endothelial function was assessed with endothelium-dependent relaxations. Detection of superoxide anion and lipid peroxidation was performed by lucigenin chemiluminescence and thiobarbituric acid-reactive substances assay. APE1/Ref-1 expression was measured with Western blot and immunohistochemistry. Results: In anesthetized condition, the abdominal aortic coarctation rats showed hypertension as systolic/diastolic arterial pressure of 171/114 mm Hg, compared with 114/94 mm Hg of control. Endothelium-dependent relaxations were significantly impaired in the aortic coarctation which was recovered in 1 week after coarctation repair. Superoxide production and lipid peroxidation were elevated in aortic coarctation rats. In immunohistochemistry, APE1/Ref-1 expressions were increased at aorta and kidney in aortic coarctation rats. Increased APE1/Ref-1 expression in aorta was recovered by repair of coarctation. Conclusions: Taken together, it suggests that APE1/Ref-1 expression was increased in aortic coarctation-induced hypertensive rats, suggesting a biomarker for hypertension. Impaired endothelium dependent relaxation in the aortic coarctation can be modulated by repair of coarctation or the modulation of blood pressure. (J Korean Soc Hypertens 2012;18(3):126-135)

Effect of inter-renal aortic coarctation-induced hypertension on function and expression of vascular α1A- and α1D-adrenoceptors

We investigated the effect of inter-renal aortic coarctation on the function and expression of vascular α(1A)- and α(1D)-adrenoceptors and plasma angiotensin II (ATII) in rats. Male Wistar rats, either sham operated (SO), or with aortic coarctation for 7 (AC7) and 14days (AC14) were used for agonist-induced pressor responses in vehicle (physiological saline)- and antagonist-treated anesthetized animals, immunoblot analysis (α(1A)- and α(1D)-adrenoceptor in aorta and caudal arteries), and immunoassay (plasma ATII). The α(1D)-adrenoceptor antagonist, BMY-7378 (BMY) blocked noradrenaline-induced responses in the order SO> AC7≫ AC14; in contrast, the α(1A)-adrenoceptor antagonist RS-100329 (RS), produced a marginal shift to the right of the dose-response curve to noradrenaline, along with a strong decrease of the maximum pressor effect in the order SO> AC7= AC14. The potency of the α(1A)-adrenoceptor agonist A-61603 increased in rats with AC14, and responses were inhibited by RS in the order AC14> AC7> SO. In aorta, α(1D)-adrenoceptor protein increased in AC7 and decreased in AC14; α(1A)-adrenoreceptor protein increased in the caudal artery of AC7 and returned to control values in AC14. Plasma ATII increased in AC7 and AC14, compared with SO rats. These results suggest an early and direct relationship between ATII and α(1D)-adrenoreceptors in the development of hypertension in this experimental model.

Indomethacin enhances reactivity to vasopressin in normotensive and hypertensive rats, while PGE2 receptor blockade only attenuates reactivity in normotensive rats.

Previously, we reported that in female (F) rats 17‐β‐estradiol and aortic coarctation‐induced hypertension (ACIH) increase release of thromboxane (TXA2) and prostacyclin from mesenteric arterioles (MA), and that constrictor responses of aorta to vasopressin (VP) are reduced ~40% by TP receptor antagonist SQ 29,548 (SQ). Thus, the roles of TXA2 and PGE2 in constrictor responses to VP were studied in MA. F Sprague‐Dawley rats (14–16 wks age) underwent ACIH (hypertensive; HT) or sham (normotensive; NT). Rats were sacrificed 12–14 days post‐ACIH and reactivity to VP was measured in MA (150–200 μm dia.) using isometric myography. Data are means ± S.E. (n = 4–5 rats/group). Maximal contractile responses of MA to VP did not differ between NT (9.97 ± 0.75 mN/mm) and HT (11.77 ± 1.40). SQ (40 μM) did not alter responses in NT (9.16 ± 1.53) or HT (12.69 ± 1.77). In separate rats, maximal responses to VP did not differ between NT and HT. AH6809, a PGE2 receptor blocker (EP1, 2, 3) reduced maximal responses of MA from NT (8.95 ± 0.36 vs. 10.24 ± 0.63) but not HT (9.73 ± 0.81 vs. 9.36 ± 0.61). Indomethacin (non‐specific COX inhibitor; 10 μM) increased contractions to VP in NT and HT (11.74 ± 0.84 and 12.75 ± 0.79, respectively). While TXA2 potentiates constrictor responses of aorta to VP, the role of TXA2 in reactivity of MA to VP is less certain. However, it appears that PGE2 may also play a role in modulating MA responses to VP in NT rats. (NIH:HL‐080402)

Increased hypothalamic angiotensin-(1–7) levels in rats with aortic coarctation-induced hypertension

Since angiotensin (Ang) (1–7) injected into the brain blocked Ang II pressor actions in rats made hypertensive by aortic coarctation (CH), we examined systemic and tissue angiotensin peptide levels, specifically concentrating on the hypothalamic Ang-(1–7) levels. Plasma, heart and kidney isolated from CH rats showed increased levels of Ang I, Ang II and Ang-(1–7) compared with the normotensive group, with Ang II being the predominant peptide in heart and kidney. In the hypothalamus, equimolar amounts of Ang II and Ang-(1–7) were found in the sham group, whereas only Ang-(1–7) levels increased in CH rats. We conclude that aortic coarctation activates systemic and tissue renin–angiotensin system. The increased central levels of Ang-(1–7) in the CH rats suggest a potential mitigating role of this peptide in central control of the hypertensive process.

Selective Estrogen Receptor Agonists Enhance Blood Pressure and Vascular Reactivity to Vasopressin in Aortic Coarctation‐Induced Hypertensive Female Rats

Estrogen receptor (ER)α and ERβ may enhance vasoconstriction to arginine vasopressin (VP) via different pathways. Therefore, mean arterial pressure (MAP) was measured in normotension (NT) and in aortic coarctation-induced hypertension (HT) in female Sprague-Dawley rats (14–16 wks) that were intact (INT), ovariectomized (OVX) or OVX+treated with ER-selective agonists 2,3-bis(4-hydroxy-phenyl)-propionitrile (DPN, ERβ)or 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT, ERα), 100μg/rat/day (13–16 days). Reactivity to VP was measured in mesenteric arterioles (MA, 200μ dia.) using isometric myography. Data are means ± S.E. (n=3–8 rats). During the acute phase of HT (day 10), OVX (150±9 mmHg) reduced MAP compared to INT (193±7). Treatment of OVX with DPN (187±9 mmHg) increased MAP more than with PPT (172±5); MAP of NT controls was lower (125±5). In NT MA, maximal response to VP was increased by PPT (4.79±0.67 mN) but unchanged by DPN (3.18±0.46) compared to INT (3.43±0.67). HT enhanced MA response to VP in PPT (6.07±1.13) to a greater extent than DPN (3.11±0.07). In HT MA,simvastatin (inhibitor of Ca2+ release from sarcoplasmic reticulum, SR) reduced maximal response to VP in both PPT and DPN (1.54±0.54 vs. 0.87±0.06). These data suggest that: ERβ enhances MAP to greater extent than ERα in HT, while vascular reactivity to VP is enhanced by ERα; the vascular actions of ER may involve enhanced release of SR Ca2+. (NIH: HL-080402).

Decreases in the expression of CGRP and galanin mRNA in central and peripheral neurons related to the control of blood pressure following experimental hypertension in rats

Calcitonin gene-related peptide (αCGRP) and galanin (GAL) are peptides known to participate in central mechanisms of blood pressure control. Nonetheless, variations in the synthesis of the peptides in response to a hypertensive challenge are not well described, specially using a model, which allows acute and chronic analyses. In this study, we have employed in situ hybridization to analyse changes in mRNA expression of αCGRP and GAL in the nucleus tractus solitarii (NTS), hypothalamic paraventricular nucleus (PVN) as well as petrosal and nodose ganglia after aortic coarctation-induced hypertension in rats. Acute (2 h) and chronic (3 and 7 days) analyses were performed in order to evaluate the involvement of both peptides in different periods of hypertension. The analysis of relative mRNA levels showed significant differences between sham-operated and aortic coarcted hypertensive rats. αCGRP mRNA expression was decreased 2 h (40%) and 3 days (42%) in nodose and petrosal ganglia, respectively, after coarctation. No changes in CGRP mRNA signal were seen in the NTS and PVN in the analysed periods. GAL mRNA expression was decreased in the NTS (19%) and PVN (55%), 3 and 7 days, respectively, after coarctation-induced hypertension. No changes in GAL mRNA expression were observed in petrosal and nodose ganglia following aortic coarctation. Data suggest that αCGRP and GAL may participate in the mechanisms involved in the establishment/maintenance of hypertension induced by aortic coarctation. Acute changes might be involved with the adaptation to the hypertensive state, while changes at the chronic phase might be related to counteraction of hypertension.

Enhanced nitric oxide inactivation in aortic coarctation-induced hypertension

Abdominal aortic coarctation above the renal arteries leads to severe hypertension (HTN) above the stenotic site. We have recently shown marked up-regulations of endothelial nitric oxide synthase (eNOS) in heart and thoracic aorta and of neuronal NOS (nNOS) in the brain of rats with severe aortic coarctation above the renal arteries. We hypothesize that the presence of severe regional HTN in the face of marked up-regulation of NO system may be partly due to enhanced NO inactivation by reactive oxygen species (ROS) leading to functional NO deficiency. Tissue nitrotyrosine (which is the footprint of NO interaction with ROS) was determined by Western blot in sham-operated control and aortic-banded (above renal arteries) rats three weeks postoperatively. Intra-arterial pressure and tissue nitrotyrosine (Western blot) were measured. The banded group showed a marked rise in arterial pressure measured directly through a carotid cannula (203 +/- 9 vs. 131 +/- 2 mm Hg, P < 0.01). Compared with the sham-operated controls, the banded animals exhibited significant increases in nitrotyrosine abundance in the heart, brain, and the aorta segment above the stricture. In contrast, nitrotyrosine abundance was unchanged in the abdominal aorta segment below the stricture wherein blood pressure was not elevated. Coarctation-induced HTN is associated with increased nitrotyrosine abundance in all tissues exposed to high arterial pressure, denoting enhanced ROS-mediated inactivation and sequestration of NO in these sites. This can, in part, account for severe regional HTN in this model. The normality of nitrotyrosine abundance in the abdominal aorta wherein blood pressure is not elevated points to the role of baromechanical factors as opposed to circulating humoral factors that were necessarily similar in both segments.

Expression of myogenic constrictor tone in the aorta of hypertensive rats.

We investigated the effect of intraluminal pressure or stretch on the development of tone in the descending thoracic aorta from rats with aortic coarctation-induced hypertension of 7-14 days duration. Increments of pressure >100 mmHg decreased the diameter of thoracic aortas from hypertensive but not from normotensive rats. The pressure-induced constriction was not demonstrable in vessels superfused with calcium-free buffer. Stretched rings of aorta from hypertensive rats exhibited a calcium-dependent constrictor tone accompanied by elevated calcium influx that varied in relation to the degree of stretch. Blockers of L-type calcium channels and inhibitors of protein kinase C reduced both basal tone and calcium influx in aortic rings of hypertensive rats. Hence, the thoracic aorta of hypertensive rats expresses a pressure- and stretch-activated constrictor mechanism that relies on increased calcium influx through L-type calcium channels via a protein kinase C-regulated pathway. The expression of such a constrictor mechanism is suggestive of acquired myogenic behavior.

Regional inactivation and sequestration of nitric oxide (NO) as nitrotyrosine in aortic coarctation-induced hypertension (HTN)

Regional inactivation and sequestration of nitric oxide (NO) as nitrotyrosine in aortic coarctation-induced hypertension (HTN)

LIPOXYGENASE-DEPENDENT MECHANISMS IN HYPERTENSION

This study was designed to examine the contribution of lipoxygenase products to mechanisms of vascular contraction and elevated blood pressure in rats with aortic coarctation-induced hypertension. In cytosolic fractions of aortae taken from hypertensive rats, 12-lipoxygenase protein was increased as compared to normotensive controls. Aortic rings from hypertensive, but not from normotensive rats, exhibited a basal tone which was reduced 74±12 and 71±22%, respectively, by the lipoxygenase inhibitors cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC,10−5 mol/L) and 5,8,11-eicosatriynoic acid (ETI, 10−5 mol/L). CDC (8mg/kg sc) did not affect the blood pressure of normotensive rats but decreased that of hypertensive rats from 182±6 to 151±10 mm Hg. The blood pressure lowering effect of CDC was blunted in hypertensive rats pretreated with indomethacin or antibodies against 5,6-dihydro-prostaglandin I2. These data suggest contribution of lipoxygenase-derived products to mechanisms underlying aortic smooth muscle basal tone and elevated blood pressure in rats with aortic coarctation-induced hypertension. The vasodepressor effect of CDC depends on a mechanism involving vasodilatory prostaglandins.

Effect of ACE inhibitor on DOCA-salt- and aortic coarctation-induced hypertension in mice: do kinin B2 receptors play a role?

Kinins have been shown to play an important role in the cardioprotective effect of ACE inhibitors (ACEi) during heart failure and ischemia-reperfusion. However, it is controversial as to whether kinins oppose the hypertensinogenic effect of deoxycorticosterone acetate plus salt (DOCA-salt) or aortic coarctation and whether they mediate both chronic antihypertensive and cardiac antihypertrophic effects of ACEi in hypertension. Using normal 129/SvEvTac mice and mice lacking the bradykinin B2 receptor gene (B2-KO), we investigated whether (1) the hypertensinogenic effect of DOCA-salt or aortic coarctation is enhanced in B2-KO mice and (2) the chronic antihypertensive and antihypertrophic effects of an ACEi (ramipril, 4 mg. kg-1. d-1) are mediated by B2 receptors in aortic coarctation (6 weeks)- and DOCA-salt (4 weeks)-induced hypertension. Before surgery, there was no difference between 129/SvEvTac and B2-KO mice in terms of blood pressure and heart weight, suggesting that kinins are not essential to maintaining normal blood pressure. DOCA-salt (volume expansion) or aortic coarctation (renin-dependent) induced similar hypertension and left ventricular hypertrophy (LVH) in 129/SvEvTac and B2-KO mice, suggesting that kinins do not play an essential role in the development of DOCA-salt- or aortic coarctation-induced hypertension. We found that B2 receptors mediate only the early (1 week) but not the late phase (4 weeks) of the chronic hypotensive effect of ACEi in DOCA-salt hypertension. On the other hand, chronic ACE inhibition prevented the development of hypertension and LVH in both 129/SvEvTac and B2-KO mice given DOCA-salt or subjected to aortic coarctation, suggesting that kinins do not participate in the chronic antihypertensive and antihypertrophic effects of ACEi in these 2 models of hypertension. Thus, in mice, kinins acting via B2 receptors do not participate in (1) maintenance of normal basal blood pressure, (2) establishment and maintenance of hypertension induced by DOCA-salt or aortic coarctation, and (3) chronic antihypertensive and cardiac antihypertrophic effects of ACEi in DOCA-salt and aortic coarctation hypertension.

The role of nitric oxide in angiotensin II-induced renal vasoconstriction in renovascular hypertension.

To evaluate the contribution of nitric oxide to the regulation of angiotensin II-induced renal vasoconstriction in normotensive rats and in rats with aortic coarctation-induced hypertension. We evaluated the renal vascular reactivity of nonischemic kidney to angiotensin II with and without nitric oxide synthesis inhibitor (NG-nitro-L-arginine methyl ester) in the isolated perfused kidney. The nitrite concentration in renal perfusate of nonischemic kidney was measured as an index of nitric oxide released and the activity of nitric oxide synthase in renal tissue was determined by production of [3H]-L-citrulline. The perfusion of NG-nitro-L-arginine methyl ester potentiated angiotensin II-induced renal vasoconstriction in normotensive rats but had no effect on hypertensive rats. The release of nitrites in kidneys from hypertensive rats was lower than that in kidneys from normotensive rats. The activity of renal nitric oxide synthase was less in the hypertensive rats than it was in the normotensive rats. Nitric oxide counteracts the vasoconstrictor effect of angiotensin II in normotensive rats, whereas this protective mechanism is impaired in hypertensive rats. This impairment potentiates effect of angiotensin II on vascular resistance, thereby contributing to the development of high blood pressure.

Involvement of Nitric Oxide and Potassium Channels in the Reduction of Basal Tone Produced by Blockade of Thromboxane A2/Prostaglandin H2/ Receptors in Aortic Rings Of Hypertensive Rats

This study was designed to investigate involvement of potassium channels in the action of nitric oxide facilitating reduction of basal tone by thromboxane A2/prostaglandin H2receptor blockade with ifetroban in rings of thoracic aorta taken from rats with aortic coarctation-induced hypertension. Ifetroban-induced reduction of basal tone in aortic rings without drug pretreatment was attenuated (P<0.05) in rings pretreated with the nitric oxide synthesis inhibitor Nω-nitro-L-arginine methyl ester (L-NAME; 3 × 10<-4mol/L; 0.55±0.09 g versus 0.23±0.07 g). The vasorelaxing effect of ifetroban also was decreased (P<0.05) in preparations pretreated with a potassium channel blocker, either tetraethylammonium (TEA; 10-2mol/L) or 4-aminopyridine (4-AP; 3 × 10-3mol/L). Ifetroban-induced reduction of basal tone was not attenuated in preparations pretreated first with L-NAME and then with sodium nitroprusside (SNP; 6±1 nmol/L) to compensate for the loss of endogenous nitric oxide. However, the facilitatory effect of SNP on ifetroban-induced relaxation of aortic rings pretreated with L-NAME alone was not demonstrable in rings pretreated with L-NAME plus TEA or 4-AP. These observations suggest that a mechanism involving nitric oxide and potassium channels facilitates the reduction in basal tone produced by ifetroban in aortic rings of rats with aortic coarctation-induced hypertension

Vascular responsiveness to nitric oxide synthesis inhibition in hypertensive rats.

We contrasted in normotensive and hypertensive rats the effect of inhibition of nitric oxide synthesis on isometric tension development by aortic rings bathed in Krebs' bicarbonate buffer. NG-Nitro-L-arginine methyl ester (L-NAME) (3 x 10(-4) mol/L) increased tension (82 +/- 11% of the response to 120 mmol/L potassium chloride) in rings of thoracic aorta taken from hypertensive rats 7 to 14 days after aortic coarctation, whereas rings of abdominal aorta from below the coarctation were unresponsive, as were rings of thoracic aorta from rats with deoxycorticosterone-salt-induced hypertension and from the corresponding normotensive controls of either model of hypertension. The contractile response to L-NAME in aortic rings of rats with aortic coarctation was reversed by L-arginine (1 mmol/L), attenuated by removal of the endothelium, and blunted by the protein kinase C inhibitor staurosporine but was unaffected by inhibition of cyclooxygenase, scavengers of superoxide anion, or blockade of receptors for angiotensin, norepinephrine, serotonin, or endothelin. In additional experiments we contrasted the effect of L-NAME (10 mg/kg IV) on the blood pressure of sham-operated rats and rats with aortic coarctation after pretreatment of animals in both groups with DuP 753 (30 mg/kg IV) to achieve blood pressure equalization. The pressor response to L-NAME was twofold greater in rats with aortic coarctation than in sham-operated controls. That pressor and aortic constrictor responsiveness to L-NAME are increased after aortic coarctation suggests that a mechanism of vasodilation, mediated by nitric oxide, is preferentially manifested in rats with aortic coarctation-induced hypertension.

Expression of prostaglandin H2-mediated mechanism of vascular contraction in hypertensive rats. Relation to lipoxygenase and prostacyclin synthase activities.

We tested the hypothesis that a prostanoid-mediated mechanism of vascular contraction is expressed in rats with aortic coarctation-induced hypertension. Rings of descending thoracic aorta taken from normotensive and hypertensive rats were contrasted in terms of constrictor responsiveness to arachidonic acid (AA), AA-induced release of eicosanoids, and ability to convert exogenous prostaglandin (PG) H2 to PGI2. AA (10(-8) to 10(-5) mol/L) increased isometric tension in aortic rings (bathed in Krebs' bicarbonate buffer) of hypertensive but not normotensive rats. AA (10(-5) mol/L) also elicited the release of PGI2, PGE2, thromboxane (TX) A2, and monohydroxyeicosatetraenoic acids (HETEs); this release from the aortic rings of hypertensive rats exceeded the corresponding release from the aortic rings of normotensive rats. However, the rate of conversion of exogenous PGH2 to PGI2 by aortic rings of hypertensive rats was < 50% the rate of conversion by aortic rings of normotensive rats. The constrictor effect of AA in aortic rings of hypertensive rats was abolished by an inhibitor of cyclooxygenase (indomethacin, 10 mumol/L) and a blocker of TXA2-PGH2 receptors (SQ29548, 1 mumol/L) but was not affected by an inhibitor of TXA2 synthesis (CGS13080, 10 mumol/L), suggesting mediation by PGH2. The lipoxygenase inhibitor baicalein (75 mumol/L) also attenuated the constrictor effect of AA in aortic rings of hypertensive rats while decreasing the associated release of HETEs and correcting the impairment in the conversion of PGH2 to PGI2.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostanoid-mediated vascular contraction in normotensive and hypertensive rats

We investigated the role of prostanoids in the constrictor effect of calcium ionophore A23187, endothelin-1 and vasopressin in rings of thoracic aorta obtained from normotensive rats and rats with aortic coarctation-induced hypertension. Isometric tension was measured in aortic rings bathed in buffer with and without indomethacin (10 μM), CGS13080 (10 μM) or SQ29548 (1 μM) to inhibit cyclooxygenase and thromboxane synthase and to block TxA 2-PGH 2 receptors, respectively. Increases in tension elicited by A23187 and vasopressin in aortic rings from hypertensive rats exceeded responses in rings from normotensive rats. A23187-induced contractions were virtually abolished by indomethacin and SQ29548, and slightly attenuated by CGS13080. These agents also attenuated the contractions elicited by endothelin but not by vasopressin. According to these data, a prostanoid(s) agonist for TxA 2-PGH 2 receptors contributes to the constrictor effect of A23187 in aortic rings of hypertensive rats, and of endothelin in aortic rings of normotensive and hypertensive rats. Moreover, the expression of prostanoid-mediated contractions as it pertains to the aortic response to A23187 is greatly increased in hypertensive rats.

Role of endothelium-derived prostanoid in angiotensin-induced vasoconstriction.

To test the hypothesis that prostanoids contribute to angiotensin II-induced vascular contraction, we compared the effect of angiotensin II on isometric tension development by rings of descending thoracic aorta bathed in Krebs' bicarbonate buffer with and without indomethacin (10 microM) to inhibit cyclooxygenase, CGS13080 (10 microM) to inhibit thromboxane A2 synthesis, or SQ29548 (1 microM) to block thromboxane A2/prostaglandin endoperoxide receptors. The comparisons were made in rings of aorta taken from normotensive rats and from rats with aortic coarctation-induced hypertension at 12 days and 90-113 days after coarctation. These rings released thromboxane B2, which was found to be endothelium dependent, increased in hypertensive rats, and stimulated by angiotensin II (10(-6) M) in normotensive rats and in hypertensive rats at 12 days after coarctation. The angiotensin II (10(-6) to 10(-5)M)-induced contraction of aortic rings was increased by about 30% at 12 days after coarctation and decreased at 90-113 days after coarctation. Removal of the endothelium increased the contractile effect of angiotensin II (10(-6) M) in aortic rings of normotensive rats and hypertensive rats at 90-113 days after coarctation but decreased the effect in aortic rings of hypertensive rats at 12 days after coarctation. In rats at 12 days after coarctation, the angiotensin II (10(-6) M)-induced contraction of aortic rings with endothelium was attenuated by indomethacin and SQ29548 but not by CGS13080. These data suggest that a prostanoid-mediated and endothelium-dependent mechanism of vasoconstriction contributes to the constrictor effect of angiotensin II in aortic rings of rats in the early phase of aortic coarctation-induced hypertension.

Role of prostanoids in renin-dependent and renin-independent hypertension.

We investigated the role of prostanoid-mediated pressor mechanisms in setting the level of blood pressure in renin-dependent and renin-independent models of hypertension in unanesthetized rats. Intravenous administration of a blocker of thromboxane A2/prostaglandin endoperoxide receptors, SQ29548 (2 mg/kg bolus injection plus 2 mg/kg/hr for 3 hours), reduced from 162 +/- 4 to 144 +/- 5 mm Hg (p less than 0.05) the blood pressure of rats with aortic coarctation-induced hypertension at 7-14 days after coarctation when plasma renin activity is greatly increased. In contrast, treatment with SQ29548 was without effect on the blood pressure of either normotensive or hypertensive rats (i.e., aortic coarctation-induced hypertension at 90-113 days after coarctation, deoxycorticosterone-salt-induced hypertension) having normal or depressed values of plasma renin activity. The blood pressure-lowering effect of SQ29548 in the early phase of aortic coarctation-induced hypertension was positively correlated with the prevailing plasma renin activity and could not be demonstrated in hypertensive rats pretreated with indomethacin. We attribute the hypotensive effect of SQ29548 to interference with pressor mechanisms that depend on activation of thromboxane A2/prostaglandin endoperoxide receptors and suggest that such prostanoid-mediated mechanisms are operational and contribute to an increase in blood pressure in angiotensin-dependent forms of hypertension. Also prostanoid-mediated vasodepressor mechanisms are operational in the early phase of aortic coarctation-induced hypertension since the blood pressure of rats pretreated with SQ29548 was increased by the subsequent administration of indomethacin. Accordingly, the blood pressure of rats with aortic coarctation-induced hypertension is influenced by the interplay of prostanoid-mediated pressor and vasodepressor mechanisms.