Baoxue Yuan

Brain ‘Ouabain’ Mediates Sympathetic Hyperactivity in Congestive Heart Failure

In congestive heart failure (CHF), endogenous compounds with ouabainlike activity (OLA) may contribute to the maintenance of the circulatory homeostasis by peripheral as well as central effects. In the present study, we assessed changes in peripheral (plasma and left ventricle) and central (pituitary, hypothalamus, pons, and cortex) OLA in two animal models of CHF and determined whether brain OLA mediates sympathetic hyperactivity in CHF. Cardiomyopathic hamsters with their controls were studied at 9 months of age for tissue OLA. Rats were studied 4 weeks after acute coronary artery ligation for tissue OLA and sympathetic activity. In both models, left ventricular end-diastolic pressure was markedly increased. CHF was associated with significant increases in both plasma and tissue OLA in both models. In the brain, the most marked (twofold to threefold) increases occurred in the hypothalamus. In vitro, all OLA measured could be blocked by antibody Fab fragments (Digibind). Conscious rats with CHF showed elevated plasma catecholamines and enhanced responses of mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) to air stress and to intracerebroventricular (ICV) injection of the alpha 2-adrenergic receptor agonist guanabenz compared with sham-operated rats. ICV administration of the Fab fragments did not change resting RSNA or responses to air stress at 1 hour. However, 18 hours after injection of the Fab fragments, resting RSNA levels had significantly decreased compared with the control values, and plasma catecholamine levels had decreased to control values.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary-sodium-induced cardiac remodeling in spontaneously hypertensive rat versus Wistar-Kyoto rat.

Objective To study the effects of short-term and long-term high sodium intake on cardiac mass and design in sodium-sensitive spontaneously hypertensive rats versus sodium-resistant Wistar–Kyoto rats. Methods Young spontaneously hypertensive rats and Wistar–Kyoto rats were randomly allocated to control diet, 2 or 8% dietary sodium for 2–12 weeks and changes in resting hemodynamics, cardiac angiotensin II level, sympathetic activity and cardiac structure evaluated. Sympathetic activity was assessed by measuring levels of plasma catecholamines, responses of blood pressure to ganglionic blockade, and rates of cardiac turnover of norepinephrine. Results High sodium intake for 4 weeks increased left ventricle weight of Wistar–Kyoto rats aged 4 weeks (by 11 and 25% for 2 and 8% NaCl diets, respectively). This hypertrophic response was temporary, however, had already diminished after 6 weeks, and was absent after 12 weeks of a high sodium intake. However, after prolonged exposure concentric remodeling occurred (i.e. left ventricle wall thickness: radius ratio increased with no change in left ventricle mass). High sodium intake did not affect resting blood pressure, cardiac index, cardiac angiotensin II level, and general sympathetic activity of Wistar–Kyoto rats. Short-term high sodium intake did not increase left ventricle mass of young spontaneously hypertensive rats, unless sodium intake was so high (8% NaCl) that blood pressure and general sympathetic activity increased, too. However, a prolonged moderate (2%) increase in sodium intake also caused concentric remodeling in spontaneously hypertensive rats without increasing left ventricle mass, blood pressure, cardiac index, and general and cardiac sympathetic activities. Conclusions The blood pressure in young Wistar–Kyoto rats is sodium-insensitive but the heart structure is sodium-sensitive and high dietary sodium intake causes an early hypertrophic response, and then concentric remodeling. In contrast, hypertrophic response appears to occur after the response of blood pressure in spontaneously hypertensive rats, whereas the remodeling is similar to that in Wistar–Kyoto rats.

Effects of enalapril versus losartan on regression of volume overload-induced cardiac hypertrophy in rats.

The role of nonhemodynamic cardiac trophic mechanisms differs not only between different models of cardiac hypertrophy but also within the same model for development versus maintenance of cardiac hypertrophy. Our previous studies pointed to a major role for the renin-angiotensin system (RAS) as a cardiac trophic stimulus in the remodeling of the heart in response to volume overload by aortocaval shunt or minoxidil treatment. Methds and ResultsIn the present study, we evaluated the effects of blockade of the RAS by the angiotensin-converting enzyme inhibitor enalapril and the angiotensin II receptor blocker losartan on left ventricular (LV) and right ventricular mass and LV dilation in relation to changes in central hemodynamics during the maintenance of minoxidil and aortocaval shunt-induced cardiac hypertrophy. Both blockers similarly decreased LV end-diastolic pressure (LVEDP) and LV peak systolic pressure, whereas cardiac output remained unchanged in both models of volume overload. This suggests a major contribution of improved LV performance and decreased afterload to the decrease in cardiac preload by the two blockers rather than decreased venous return. Both blockers reversed LV hypertrophy in parallel to their effects on LVEDP in both models of volume overload. In minoxidil-treated rats, the extent of reversal in LV mass and dilation by the two blockers was similar to “spontaneous regression” after discontinuation of minoxidil treatment. ConclusionsThese results indicate that in contrast to the development phase of cardiac hypertrophy, the RAS does not contribute to the maintenance of volume overload-induced cardiac hypertrophy in these two models via direct cardiac trophic effects. The RAS, however, maintains cardiac hypertrophy indirectly by contributing to the persistence of high filling pressures.

Changes in cardiac ANG II postmyocardial infarction in rats: effects of nephrectomy and ACE inhibitors

We evaluated in rats the time course of changes in cardiac versus plasma ANG I and II postmyocardial infarction (MI) and the effects of nephrectomy and angiotensin-converting enzyme (ACE) inhibitors on the early changes post-MI. Acute coronary artery ligation was induced in conscious rats using the two-stage model, and plasma and cardiac tissue were obtained shortly (6 h, 1 and 3 days) and chronically (1, 4, and 8-9 wk) after MI. In an additional group of rats, bilateral nephrectomy was performed 18 h before the coronary artery ligation, and samples were obtained at 6 h post-MI. Furthermore, in two additional groups of rats, treatment with enalapril and quinapril was started 3 days before the ligation, and samples were obtained at 1 or 3 days post-MI. In these groups of rats, plasma and left ventricular (LV) (infarct and infarct free) ANG I and II were measured by RIA after separation on HPLC. In control rats, plasma ANG I and II showed a clear increase at 6 h post-MI but subsequently only minor increases were observed. In contrast, LV ANG II showed major increases at 6 h and 1 day post-MI, which had returned to normal by 3 days in the infarct-free LV and after 1(-2) wk in the infarct LV. LV ANG I showed a more gradual increase and remained elevated in the infarct up to 8-9 wk. Nephrectomy preceding the MI lowered ANG I and II in plasma but enhanced their increases in the heart at 6 h post-MI. Both ACE inhibitors decreased plasma ANG II associated with large increases in plasma ANG I. They also inhibited the increases in LV ANG II in both the infarct and infarct-free LV at 1 and 3 days post-MI with however no significant increase in LV ANG I. In conclusion, induction of a MI in conscious rats leads to rapid and marked, but only short-lived, increases in cardiac tissue ANG II in both the infarct and infarct-free parts of the LV. Pretreatment with ACE inhibitors, but not nephrectomy, blocks this increase. Local production appears to play a major role in the increases in cardiac ANG II post-MI.We evaluated in rats the time course of changes in cardiac versus plasma ANG I and II postmyocardial infarction (MI) and the effects of nephrectomy and angiotensin-converting enzyme (ACE) inhibitors on the early changes post-MI. Acute coronary artery ligation was induced in conscious rats using the two-stage model, and plasma and cardiac tissue were obtained shortly (6 h, 1 and 3 days) and chronically (1, 4, and 8-9 wk) after MI. In an additional group of rats, bilateral nephrectomy was performed 18 h before the coronary artery ligation, and samples were obtained at 6 h post-MI. Furthermore, in two additional groups of rats, treatment with enalapril and quinapril was started 3 days before the ligation, and samples were obtained at 1 or 3 days post-MI. In these groups of rats, plasma and left ventricular (LV) (infarct and infarct free) ANG I and II were measured by RIA after separation on HPLC. In control rats, plasma ANG I and II showed a clear increase at 6 h post-MI but subsequently only minor increases were observed. In contrast, LV ANG II showed major increases at 6 h and 1 day post-MI, which had returned to normal by 3 days in the infarct-free LV and after 1(-2) wk in the infarct LV. LV ANG I showed a more gradual increase and remained elevated in the infarct up to 8-9 wk. Nephrectomy preceding the MI lowered ANG I and II in plasma but enhanced their increases in the heart at 6 h post-MI. Both ACE inhibitors decreased plasma ANG II associated with large increases in plasma ANG I. They also inhibited the increases in LV ANG II in both the infarct and infarct-free LV at 1 and 3 days post-MI with however no significant increase in LV ANG I. In conclusion, induction of a MI in conscious rats leads to rapid and marked, but only short-lived, increases in cardiac tissue ANG II in both the infarct and infarct-free parts of the LV. Pretreatment with ACE inhibitors, but not nephrectomy, blocks this increase. Local production appears to play a major role in the increases in cardiac ANG II post-MI.

Sodium-induced cardiac hypertrophy. Cardiac sympathetic activity versus volume load.

To investigate the possible contributions of cardiac volume overload and cardiac sympathetic hyperactivity in the effects of sodium on cardiac mass, we evaluated the effects of treatment with saline (1%) and deoxycorticosterone acetate + saline (DOCA/saline) for 10 days and 3 and 6 weeks on ventricular anatomy and intracardiac pressures. Sympathetic activity in the heart and other tissues was assessed at 10 days and 3 weeks by catecholamine turnover rates and tyrosine hydroxylase activity. Both saline and DOCA/saline produced concentric left ventricular (LV) hypertrophy. Right ventricular weight showed only small increases. Saline treatment did not affect LV end-systolic pressure, whereas DOCA/saline caused a moderate increase (to 159 mm Hg). Right atrial pressure was not affected by either treatment, whereas LV end-diastolic pressure increased but only after the development of LV hypertrophy. Both saline and DOCA/saline decreased LV norepinephrine concentration; only DOCA/saline decreased norepinephrine content per LV. However, neither treatment altered the norepinephrine turnover rate constant, the absolute turnover rate, or the tyrosine hydroxylase activity. The results demonstrate that increased saline intake or DOCA/saline produces concentric LV hypertrophy without any increase in blood pressure in the case of saline and with increases in LV filling pressure following rather than preceding the appearance of LV hypertrophy. The lack of an increase in LV norepinephrine turnover and tyrosine hydroxylase activity suggests that the hypertrophy is not mediated through increased cardiac neuronal sympathetic activity.

Prevention of Hypertension by Irbesartan in Dahl S Rats Relates to Central Angiotensin II Type 1 Receptor Blockade

Hypertension in Dahl S rats on high-salt intake is in general considered a model of “low-renin hypertension,” unresponsive to treatment with blockers of the renin-angiotensin system. However, direct central administration of an angiotensin II type 1 (AT1) receptor blocker prevents both the sympathoexcitation and hypertension caused by high-salt intake in Dahl S rats. In the present study, we tested the hypothesis that chronic peripheral administration of an AT1 receptor blocker inhibits the salt-induced hypertension relative to the extent of central AT1 receptor blockade that is induced. Dahl S rats received a high-salt (1370 &mgr;mol Na+/g) or regular (101 &mgr;mol Na+/g) diet from 4 to 8 weeks of age. In 3 different sets of experiments, Dahl S on high salt were randomized to intracerebroventricular (ICV) treatment with control infusion versus irbesartan at 50 or 250 &mgr;g · kg−1 · d−1, oral treatment with control versus irbesartan at 125 or 500 mg · kg−1 · d−1 once daily by gavage, or subcutaneous treatment with control versus irbesartan at 50 or 150 mg · kg−1 · d−1 by once daily injection. At 8 weeks of age, MAP was measured in conscious rats at rest and in response to angiotensin II ICV or IV. On high-salt intake, Dahl S developed the anticipated marked increase in MAP to ≈160 mm Hg. Irbesartan ICV did not affect pressor responses to angiotensin II IV, but irbesartan administered subcutaneously or by gavage markedly inhibited these responses. Irbesartan ICV or by gavage partially inhibited pressor responses to angiotensin II ICV and the development of hypertension. Irbesartan subcutaneously at the higher dose more completely inhibited pressor responses to angiotensin II ICV and fully prevented the salt-induced hypertension. The degree of central but not peripheral AT1 receptor blockade parallels the antihypertensive effect of irbesartan, indicating that inhibition of the brain renin-angiotensin system can contribute to a significant extent to the therapeutic effectiveness of AT1 receptor blockers such as irbesartan when administered in sufficiently high doses to cause central AT1 receptor blockade.

Arterial hypertrophy and pressor responsiveness during development of hypertension in spontaneously hypertensive rats.

Background In contrast to studies in isolated blood vessels, results from whole-animal studies are ambiguous regarding differences in pressor responsiveness between spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, possibly related to the measurement of blood pressure instead of total peripheral resistance (TPR) and to differences in compensatory mechanisms. Objective and design We evaluated responses of blood pressure and TPR to two doses of the αl-agonist phenylephrine during the development of hypertension and cardiovascular hypertrophy in SHR aged 8–26 weeks compared with age-matched WKY rats before and after ganglionic blockade. At 16 weeks of age more-complete dose-response curves to the αl-agonist methoxamine were also constructed. Results Over the age range studied, the SHR developed marked hypertension, related to a significant rise in TPR, and concomitantly significant cardiac hypertrophy, as well as hypertrophy of the mesenteric arterial bed. The blood pressure responses to phenylephrine were diminished in the SHR compared with the WKY rats at all ages studied, but this effect was significant only in the absence of ganglionic blockade. TPR responses were significantly less in the SHR than in the WKY rats, both with and without concomitant ganglionic blockade. In contrast, both blood pressure and TPR responses to low doses, but not higher doses, of methoxamine were enhanced in the SHR compared with the WKY rats. Conclusion These results indicate that the development of hypertension in SHR in vivo is associated with variable changes in blood pressure and TPR responses to al-receptor stimulation, depending on the αl-agonist employed.

Mortality After Coronary Artery Occlusion in Different Models of Cardiac Hypertrophy in Rats

Chronic treatment with minoxidil induces cardiac trophic and sympathetic responses, which may increase the propensity for lethal arrhythmias. To test this hypothesis, acute coronary artery occlusion was performed in conscious normotensive rats treated for 2 or 5 weeks with minoxidil with the use of a 2-stage approach to cause a myocardial infarction. For comparison, rats with aortocaval (A-V) shunts and spontaneously hypertensive rats (SHR) were studied. Minoxidil increased left ventricular and right ventricular weights by 15% to 20%, and the A-V shunt increased these weights by 30% to 40%. In SHR, left ventricular weight was increased by 50%, and right ventricular weight was increased by 25%. In rats treated with minoxidil for 5 weeks, coronary artery occlusion caused a rapid and marked mortality, and 4 hours after myocardial infarction, only 18% of these rats were alive versus 61% of the control rats. In rats with the A-V shunt, coronary artery occlusion was also associated with increased mortality, and after 6 hours, 33% were still alive compared with 59% of the control rats. In contrast, SHR with marked hypertension and cardiac hypertrophy showed only a minor increase in mortality (survival rates were 53% versus 60% in SHR versus Wistar-Kyoto rats, respectively). Mortality was preceded by high arrhythmia scores, and ventricular fibrillation was the cause of death. Discontinuation of minoxidil for 1 week, sympathetic blockade with nadolol or clonidine, or blockade of the renin-angiotensin system with enalapril or losartan did not improve minoxidil-induced excess mortality. We conclude that ventricular stretch and other mechanisms (eg, cardiac vagal activity) in rats appear to be more potent than hypertension-induced left ventricular hypertrophy in predisposing for lethal arrhythmias in the setting of acute ischemia.

Blockade of AT1 receptors and Na+/H+exchanger and LV dysfunction after myocardial infarction in rats

Mechanical stretch, ANG II, and α1-receptor stimulation may contribute to cardiac remodeling after myocardial infarction (MI). Each of these mechanisms involves different signaling pathways for the cellular hypertrophic response. All three also activate the Na+/H+exchanger. In the present study we evaluated the hypothesis that activation of the Na+/H+exchanger is involved in parallel with other signaling mechanisms for ANG II. Three days before coronary artery ligation, rats were randomly allocated to no treatment or treatment with amiloride, losartan, or amiloride and losartan in combination. Four weeks after coronary artery ligation, left ventricular (LV) function was assessed from in vivo resting cardiac pressures, hemodynamic responses to cardiac volume and pressure load, and cardiac remodeling by in vitro pressure-volume curves and LV and right ventricle (RV) weight. Amiloride and losartan given alone to a similar extent attenuated the shift of the pressure-volume curve to the right. This effect was significantly more pronounced with amiloride and losartan in combination. Each drug alone to a minor extent improved LV responses to pressure and volume load. However, with amiloride and losartan in combination, close-to-normal responses to pressure and volume load were observed. Losartan and amiloride alone had only a small effect on development of RV hypertrophy after MI but in combination completely prevented the RV hypertrophy. Amiloride and losartan appear to be complementary in prevention of cardiac remodeling and LV dysfunction after MI. This finding suggests that, besides ANG II, other mechanisms activating the Na+/H+exchanger contribute to cardiac remodeling after MI.

Dietary sodium restriction and pressor responsiveness to tyramine in spontaneously hypertensive rats.

OBJECTIVE To determine in vivo whether in young spontaneously hypertensive rats (SHR) dietary sodium restriction decreases adrenergic transmitter release from the sympathetic nerve terminal. DESIGN Dietary sodium restriction was initiated in young and mature SHR and Wistar-Kyoto (WKY) rats, and subsequently changes in pressor responsiveness to norepinephrine and to the indirectly acting sympathomimetic tyramine were determined in relation to their effects upon plasma catecholamines. RESULTS In young SHR sodium restriction for 3-6 weeks prevented the development of hypertension, whereas in mature SHR sodium restriction did not affect blood pressure. Sodium restriction caused modest decreases in pressor responsiveness to the exogenous alpha-agonist, not different in young and mature SHR compared with WKY rats. In contrast, sodium restriction markedly inhibited pressor-responses to tyramine in young SHR and WKY rats, but not at all in mature rats. Tyramine increased plasma norepinephrine 5-10-fold. However, sodium restriction did not affect this response. The pressor response to tyramine was related to increases in total peripheral resistance, with minimal changes in cardiac output, and could be blocked by alpha 1-receptor blockade in rats on either control or low-sodium diets. CONCLUSIONS These results show that sodium restriction causes only a small decrease in the pressor response to norepinephrine, but a more marked inhibition of the pressor response to tyramine in young SHR and WKY rats without affecting the plasma norepinephrine response to tyramine. These results suggest that dietary sodium can indeed affect presynaptic functions in vivo, but that plasma norepinephrine responses to tyramine may not reflect changes in arterial norepinephrine release, or that sodium restriction affects a co-transmitter rather than norepinephrine release per se.