Effects of long acting calcium channel blocker (CCB) and hydralazine on insulin sensitivity in spontaneously hypertensive rats (SHR).

Kushiro, Toshio; Asagami, Tomoko; Takahashi, Atsuhiko; Furukawa, LN; Saitoh, Fumio; Hino, Tohru; Kurumatani, Hitoshi; Otsuka, Yuji; Osada, Tsugio; Nagao, Keisuke; Kanmatsuse, Katsuo

doi:10.1016/0895-7061(95)97633-3

Cited by 6 publications

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“…26 Similarly in SHR, long-term treatment with amlodipine or manidipine lowered plasma norepinephrine, whereas hydralazine caused a further increase. 27 The extent of such central effects with peripheral (oral or IV infusion) treatment is likely related to the degree of lipophilicity, which determines the speed and extent of the crossing of the blood-brain barrier. However, in humans 13 and rats, 6 after the peripheral administration of fast-acting dihydropyridines, rapid decreases in BP by arterial vasodilation are associated with increases in sympathetic activity, suggesting that excitatory baroreflex-mediated responses in sympathetic activity prevail.…”

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Sympathoinhibition by Central and Peripheral Infusion of Nifedipine in Spontaneously Hypertensive Rats

2000

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Abstract-The present study assessed whether central mechanisms may contribute to the hypotensive effect of the calcium channel blocker nifedipine. In conscious, spontaneously hypertensive rats (SHR) on a high-salt diet, hemodynamic (mean arterial pressure [MAP] and heart rate) and sympathetic (renal sympathetic nerve activity) responses to low, central, intracerebroventricular infusion rates (25 g ⅐ kg Ϫ1 ⅐ h Ϫ1 for 2 hours) and peripheral intravenous rates (50 g ⅐ kg Ϫ1 ⅐ h Ϫ1 for 3 hours and then 100 g ⅐ kg Ϫ1 ⅐ h Ϫ1 for 2 hours) of nifedipine were evaluated. The distribution of nifedipine in the blood and tissues was assessed at the end of the infusions. Nifedipine significantly inhibited renal sympathetic nerve activity and lowered MAP in SHR beginning 30 minutes after the start of the intracerebroventricular infusion. The decrease of MAP by intravenous infusion began at 60 minutes and was more profound with 100 g ⅐ kg Ϫ1 ⅐ h Ϫ1. Inhibition of sympathetic activity preceded and then paralleled the decrease in blood pressure; it occurred earlier with central (15 to 30 minutes) than with peripheral (30 to 60 minutes) infusion. Intravenous infusion resulted in concentrations of nifedipine in brain structures (brain stem, midbrain, and cortex) that were 30% to 40% of those in the heart, kidneys, and liver. From the hemodynamic and sympathetic responses and the distribution of nifedipine into the central nervous system, we conclude that the peripheral infusion of nifedipine at relatively low rates may evoke a hypotensive response in SHR, not only via peripheral mechanisms, but also through central mechanisms, which will lead to an inhibition of sympathetic outflow and, therefore, a lowering of blood pressure.

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Sympathoinhibition by Central and Peripheral Infusion of Nifedipine in Spontaneously Hypertensive Rats

2000

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“…20 Similarly, in SHR, chronic treatment with amlodipine or manidipine lowered plasma norepinephrine, whereas hydralazine caused a further increase. 21 Such decreases in peripheral parameters of sympathetic activity may, at least in part, relate to central effects of the dihydropyridines. The extent of such central effects with oral treatment is likely related to the degree of lipophilicity, which would determine speed and extent of crossing of the blood-brain barrier.…”

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Sympathoinhibitory Effects of Central Nifedipine in Spontaneously Hypertensive Rats on High Versus Regular Sodium Intake

Huang¹,

Leenen²

1999

Hypertension

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Abstract-The putative central sympathoinhibitory actions of the dihydropyridine calcium antagonist nifedipine and the effect of dietary sodium on these actions were investigated in spontaneously hypertensive rats (SHR). Regular or high dietary salt was administered from 4 to 8 weeks of age. At 8 weeks, blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity were recorded in conscious rats at rest as well as in response to intravenous (50 g/kg) and intracerebroventricular (5 and 50 g/kg) injections of nifedipine and intracerebroventricular injections of vehicle. Resting mean arterial pressure was higher in SHR on high versus regular salt (159Ϯ3 versus 135Ϯ4 mm Hg; PϽ0.05). Nifedipine administered intracerebroventricularly decreased BP as well as renal sympathetic nerve activity and HR in a dose-related manner. The responses reached their peak at 3 to 5 minutes and lasted Ϸ30 minutes. Peak decreases in BP, renal sympathetic nerve activity, and HR in response to both doses of nifedipine were significantly larger in SHR on high versus regular salt. Nifedipine administered intravenously also decreased BP but, in contrast, caused (reflex) increases in renal sympathetic nerve activity and HR. On both diets, intracerebroventricular vehicle did not affect mean arterial pressure, renal sympathetic nerve activity, or HR. These data indicate that in contrast to its peripheral vasodilator effect, centrally administered nifedipine may decrease sympathetic outflow and therefore BP and HR. The enhanced sympathoinhibitory and depressor responses to nifedipine in SHR on high versus regular salt suggest that the sympathetic hyperactivity induced by high salt intake is dependent on neuronal calcium influx via L-type channels. (Hypertension. 1999;33:32-35.)Key Words: nifedipine Ⅲ dihydropyridines Ⅲ nervous system, sympathetic Ⅲ hypertension Ⅲ rats, inbred SHR Ⅲ sodium, dietary A n increase in Ca 2ϩ influx triggers a variety of cellular functions, such as increased cardiac and smooth muscle contractility, endocrine gland secretion, and neurotransmitter release. 1 Dihydropyridines such as nifedipine inhibit Ca 2ϩ influx through voltage-sensitive calcium channels. 2 The effects of calcium antagonists on sympathetic activity have thus far been related mainly to reflex responses after rapid lowering of blood pressure (BP) induced by rapidly acting calcium antagonists 3 and perhaps presynaptic effects. 4 Although receptors for calcium antagonists 5 as well as calcium antagonist-sensitive calcium channels 6 have been demonstrated in the brain, little is known regarding direct central effects of Ca 2ϩ antagonists on sympathetic activity and central control of circulation.In vitro, dihydropyridine-sensitive Ca 2ϩ channels exist in rat hypothalamus. 6 The stimulus-induced high-frequency activity in brain cells is carried by L-type but not T-type Ca 2ϩ channels, 7 and a dihydropyridine such as nifedipine is a potent L-but not T-type channel antagonist. 8 Although centrally administered calcium antagonists have been reported ...

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Relevance of 24 H blood pressure profile and sympathetic activity for outcome on short- versus long-acting 1,4-dihydropyridines

Ruzicka

1996

American Journal of Hypertension

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Short-acting formulations of nifedipine-like 1,4-dihydropyridines cause clearly less regression of left ventricular hypertrophy (LVH) than anticipated from their antihypertensive effect. Moreover, these compounds increase the risk of cardiac death and myocardial reinfarction in patients with coronary artery disease (CAD) not on concomitant beta-blocker therapy. Increased sympathetic activity is one of the non-pressure-related risk factors for LVH and atherosclerosis in hypertensives. In addition, increased sympathetic tone may precipitate clinical events in subclinical or stable CAD. Intermittent increases in sympathetic activity persist during chronic treatment with those 1,4-dihydropyridines that have a poor peak/trough ratio with a rapid fall of BP and deactivation of the arterial baroreflex. On the other hand, these intermittent increases in sympathetic activity do not occur for formulations and compounds with a gradual and sustained antihypertensive effect over the dosing interval. Such long-acting 1,4-dihydropyridines cause regression of LVH as anticipated from their antihypertensive effect, and are similar to angiotensin converting enzyme inhibitors. In contrast to short-acting 1,4-dihydropyridines, long-acting 1,4-dihydropyridines appear not to be detrimental for patients with stable CAD. However, the evidence is still missing for patients with unstable CAD. Neither is there evidence that they will reduce cardiovascular morbidity and mortality in patients with CAD when used for the chronic treatment of hypertension.

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Effects of long acting calcium channel blocker (CCB) and hydralazine on insulin sensitivity in spontaneously hypertensive rats (SHR).

Cited by 6 publications

References 0 publications

Sympathoinhibition by Central and Peripheral Infusion of Nifedipine in Spontaneously Hypertensive Rats

Sympathoinhibition by Central and Peripheral Infusion of Nifedipine in Spontaneously Hypertensive Rats

Sympathoinhibitory Effects of Central Nifedipine in Spontaneously Hypertensive Rats on High Versus Regular Sodium Intake

Relevance of 24 H blood pressure profile and sympathetic activity for outcome on short- versus long-acting 1,4-dihydropyridines

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