Prolonged angiotensin II antagonism in spontaneously hypertensive rats. Hemodynamic and biochemical consequences.

Bunkenburg, B; Schnell, C; Baum, Hans-Peter; Cumin, Frédéric; Wood, Jeanette M.

doi:10.1161/01.hyp.18.3.278

Cited by 97 publications

(52 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For comparison, we also performed experiments using AngII-infused rats. Increased AngII signaling is implicated in the development of hypertension in SHRs (10). We used an immunofluorescence approach to establish the level of sarcolemmal PKC␣ translocation (i.e., activation) in SHR and AngII-infused cells.…”

Section: Pkc␣ Is Required For Increased Persistent Ca 2؉ Sparklets Dumentioning

confidence: 99%

“…(i) LTCC function is increased in hypertensive arterial smooth muscle (3,4). (ii) The vasoconstrictor angiotensin II (AngII), an activator of PKC, is a likely contributor to vascular dysfunction in human (9) and model hypertension (10). Accordingly, AngII-converting enzyme inhibitors and AngII receptor antagonists are used extensively for the treatment of hypertension in humans.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The control of Ca ²⁺ influx and NFATc3 signaling in arterial smooth muscle during hypertension

Nieves‐Cintrón

Amberg

Navedo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

100

127

View full text Add to dashboard Cite

Many excitable cells express L-type Ca 2؉ channels (LTCCs), which participate in physiological and pathophysiological processes ranging from memory, secretion, and contraction to epilepsy, heart failure, and hypertension. Clusters of LTCCs can operate in a PKC␣-dependent, high open probability mode that generates sites of sustained Ca 2؉ influx called ''persistent Ca 2؉ sparklets.'' Although increased LTCC activity is necessary for the development of vascular dysfunction during hypertension, the mechanisms leading to increased LTCC function are unclear. Here, we tested the hypothesis that increased PKC␣ and persistent Ca 2؉ sparklet activity contributes to arterial dysfunction during hypertension. We found that PKC␣ and persistent Ca 2؉ sparklet activity is indeed increased in arterial myocytes during hypertension. Furthermore, in human arterial myocytes, PKC␣-dependent persistent Ca 2؉ sparklets activated the prohypertensive calcineurin/NFATc3 signaling cascade. These events culminated in three hallmark signs of hypertensionassociated vascular dysfunction: increased Ca 2؉ entry, elevated arterial [Ca 2؉ ]i, and enhanced myogenic tone. Consistent with these observations, we show that PKC␣ ablation is protective against the development of angiotensin II-induced hypertension. These data support a model in which persistent Ca 2؉ sparklets, PKC␣, and calcineurin form a subcellular signaling triad controlling NFATc3-dependent gene expression, arterial function, and blood pressure. Because of the ubiquity of these proteins, this model may represent a general signaling pathway controlling gene expression and cellular function.angiotensin II ͉ myogenic tone ͉ sparklets ͉ transcription factors ͉ voltage-gated calcium channels A rterial tone is elevated during hypertension, increasing the probability of stroke, coronary artery disease, cardiac hypertrophy, and renal failure (1, 2). Although the etiology of arterial dysfunction during hypertension is unclear, multiple studies suggest that increased L-type Ca 2ϩ channel (LTCC) activity in arterial smooth muscle is a major contributor to this pathological change (3, 4). However, the mechanisms and functional implications of increased Ca 2ϩ influx via LTCCs remain unclear.In normotensive arterial smooth muscle, the opening of LTCCs produces local elevations in [Ca 2ϩ ] i called ''Ca 2ϩ sparklets'' (5, 6). Two modes of Ca 2ϩ sparklet activity have been identified (6-8). Low-activity Ca 2ϩ sparklets are produced by brief random openings of LTCCs that result in limited Ca 2ϩ influx. In contrast, long openings of LTCCs associated with PKC␣ produce high activity, persistent Ca 2ϩ sparklets that create regions of sustained Ca 2ϩ influx. Low-and high-activity, persistent Ca 2ϩ sparklets are produced by the opening of a single or a small cluster of LTCCs. PKC␣ is required for persistent, but not for low-activity, Ca 2ϩ sparklets. Under physiological conditions, Ca 2ϩ entry and global [Ca 2ϩ ] i and, thus, contraction are regulated by low-activity and PKC␣-dependent persistent Ca 2ϩ...

show abstract

Section: Pkc␣ Is Required For Increased Persistent Ca 2؉ Sparklets Dumentioning

confidence: 99%

mentioning

confidence: 99%

The control of Ca ²⁺ influx and NFATc3 signaling in arterial smooth muscle during hypertension

Nieves‐Cintrón

Amberg

Navedo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

100

127

View full text Add to dashboard Cite

show abstract

“…5 With rats under halothane anesthesia, a catheter was inserted via a femoral artery into the aorta of all rats for the measurement of mean arterial pressure and for blood sampling. A catheter was also implanted into a femoral vein in rats that received intravenous infusions.…”

Section: Surgical Proceduresmentioning

confidence: 99%

“…Mean arterial BP and heart rates were measured continuously via the aortic catheter with an on-line computerized system as described in detail previously. 5 The conscious rats were freely moving throughout the recording periods. One value of each parameter was recorded every 2 minutes, and data were averaged over the time periods of interest.…”

Section: Measurement Of Blood Pressure and Heart Ratementioning

confidence: 99%

Kidney is an important target for the antihypertensive action of an angiotensin II receptor antagonist in spontaneously hypertensive rats.

1993

Self Cite

View full text Add to dashboard Cite

Inhibitors of the renin-angiotensin system lower blood pressure of spontaneously hypertensive rats, although plasma renin is not elevated. To test the hypothesis that the actions of angiotensin II within the kidney may contribute to the high blood pressure in spontaneously hypertensive rats, we infused valsartan, a subtype 1 angiotensin II receptor antagonist, via the suprarenal artery into the right kidney of conscious, freely moving, unilaterally nephrectomized (left) spontaneously hypertensive rats (12 to 14 weeks old). Valsartan (03 mg/kg per day for 48 hours) lowered blood pressure (change in blood pressure, -7 ± 3 , -1 9 ± 4 , and -2 6 ± 4 mm Hg, n = l l , at 12, 24, and 48 hours) after intrarenal administration but had no significant effect on blood pressure after intravenous administration (change in blood pressure, 1±5, -3 ± 4 , and 10±5 mm Hg, n=l, at 12, 24, and 48 hours). Infusion of vehicle (0.9% saline) intrarenally had no significant effect on blood pressure (change in blood pressure, 2±5, -1 ± 6 , and 0±7 mm Hg, n = l l , at 12, 24, and 48 hours). The maximum fall in blood pressure reached after intrarenal administration of this dose of valsartan was similar to the maximum fall induced after intravenous administration of higher doses (change in blood pressure, -1 4 ± 5 , -27±4, and -3 2 ± 5 mm Hg, n=7, at 12,24, and 48 hours after 3 mg/kg per day i.v.). Thus, endogenous angiotensin II acting within the kidney appears to play an important role in the maintenance of high blood pressure in spontaneously hypertensive rats. Renal function studies have shown that renal hemodynamic abnormalities may be involved in the initiation of hypertension in SHR. Young SHR (4 to 6 weeks) are moderately hypertensive and have a reduced glomerular filtration rate and renal blood flow and an increased renal vascular resistance compared with the normotensive Wistar-Kyoto control strain. 2 -3 Moreover, an exaggerated salt and water retention has been detected in young SHR. 2 As the hypertension develops, renal hemodynamic abnormalities become normalized (after 12 to 14 weeks of age). The low renal blood flow and glomerular filtration rate in young SHR may be a stimulus for BP to increase and return renal perfusion to normal. SHR have a normal to low plasma renin activity 4 -5 and have not generally been considered to be a renindependent model of hypertension. 6 However, the antihypertensive efficacy of renin inhibitors, 7 angiotensin converting enzyme (ACE) inhibitors, 7 " 9 and angiotensin II (Ang II) receptor antagonists 510 in SHR implicates an involvement of the renin-angiotensin system in the pathogenesis of hypertension in this animal model. Treatment of SHR with an ACE inhibitor normalizes glomerular filtration rate, renal blood flow, renal vascular resistance, and BP, 9 suggesting a role for Ang II in both the renal hemodynamic abnormalities and development of hypertension. The observation that the antihypertensive response induced by renin inhibition, ACE inhibition, or Ang II receptor antagonism in SHR is abol...

show abstract

“…2 Since the angiotensin AT 2 receptor is not blocked by losartan, it should be expected that the functions mediated via this receptor might be enhanced during angiotensin AT 1 receptor blockade. When the angiotensin AT 1 receptor is blocked, plasma and tissue renin and angiotensins increase markedly; 6 angiotensin II may act on angiotensin AT 2 receptors which could have an opposite effect such as vasodilation. Thus, one could predict that during footshock-stress, increased levels of angiotensin II would bind to unblocked angiotensin AT 2 receptors leading to a vasodepressor response.…”

Section: Introductionmentioning

confidence: 99%

Role of bradykinins and nitric oxide in the AT2 receptor-mediated hypotension

et al. 2000

View full text Add to dashboard Cite

Footshocks increases mean arterial pressure and heart rate. Systemic or intracerebroventricular (IVT) administration of losartan, a specific angiotensin AT 1 receptor antagonist, not only inhibited the pressor response to footshocks but resulted in vasodepression. Peripheral or IVT administration of PD 123319, a specific angiotensin AT 2 receptor antagonist, did not alter the haemodynamic response to footshocks. However, simultaneous blockade of angiotensin AT 1 and AT 2 receptors by combined systemic or central administration of losartan and PD 12319, eliminated the vasodepressor response to footshocks unmasked in losartan pretreated rats. Our data suggest that activation of peripheral or brain angiotensin AT 2 receptor mediated the vasodepressor response to footshocks in the presence

show abstract

Prolonged angiotensin II antagonism in spontaneously hypertensive rats. Hemodynamic and biochemical consequences.

Cited by 97 publications

References 23 publications

The control of Ca ²⁺ influx and NFATc3 signaling in arterial smooth muscle during hypertension

The control of Ca ²⁺ influx and NFATc3 signaling in arterial smooth muscle during hypertension

Kidney is an important target for the antihypertensive action of an angiotensin II receptor antagonist in spontaneously hypertensive rats.

Role of bradykinins and nitric oxide in the AT2 receptor-mediated hypotension

Contact Info

Product

Resources

About

Prolonged angiotensin II antagonism in spontaneously hypertensive rats. Hemodynamic and biochemical consequences.

Cited by 97 publications

References 23 publications

The control of Ca 2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension

The control of Ca 2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension

Kidney is an important target for the antihypertensive action of an angiotensin II receptor antagonist in spontaneously hypertensive rats.

Role of bradykinins and nitric oxide in the AT2 receptor-mediated hypotension

Contact Info

Product

Resources

About

The control of Ca ²⁺ influx and NFATc3 signaling in arterial smooth muscle during hypertension

The control of Ca ²⁺ influx and NFATc3 signaling in arterial smooth muscle during hypertension