Binding of [3H]nitrendipine to heart and brain membranes from normotensive and spontaneously hypertensive rats

Kaburagi, Takashi; Kurobe, Yoshiko; Ando, Joichi

doi:10.1016/0014-2999(83)90020-1

Cited by 41 publications

(10 citation statements)

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“…Such discrepancies might be explained by interactions between the anesthetics and central cardiovascular control mechanisms. 23 ' 24 Receptors for calcium channel blockers have been found in the rat brain, 16 -"•" and the calcium ion has been shown to be involved in the release in the central nervous system of various neurotransmitters, such as norepinephrine, acetylcholine, y-aminobutyric acid, 8 …”

Section: Discussionmentioning

confidence: 99%

“…Cardiovascular responses to centrally administered nifedipine and BAY k 8644 were more marked in SHR than in WKY. Ishii et al 16 have reported a 57% increase in the maximum number of binding sites for [ 3 H]nitrendipine (a dihydropyridine molecule similar to nifedipine) in brain membranes of SHR as compared with those in normotensive WKY. Whether this increase in the maximum number of binding sites reflects an increase in functional calcium channels and explains the increased responsiveness of SHR to the centrally administered calcium channel modulators nifedipine and BAY k 8644 remains to be determined.…”

mentioning

confidence: 99%

“…14 ' l5 Among calcium channel blockers, 1,4-dihydropyridines such as nifedipine are lipophilic substances and can easily cross the blood-brain barrier. Since specific receptors for dihydropyridines have been found in the rat brain, 16 ' 17 we examined in this study the effects on arterial pressure and HR of nifedipine administered into the lateral ventricle or the cisterna magna of pentobarbital-anesthetized rats. To facilitate conclusions about the involvement of the 1,4-dihydropyridine receptors, we compared these results with the effects of BAY k 8644, methyl-l,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyl-phenyl)-pyridine-5-carboxylate, administered in the same way.…”

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Opposite central cardiovascular effects of nifedipine and BAY k 8644 in anesthetized rats.

Laurent¹,

Girerd²,

Tsoukaris-Kupfer³

et al. 1987

Hypertension

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SUMMARY The central cardiovascular effects of the calcium channel blocker nifedipine and the calcium channel activator BAY k 8644 were studied in anesthetized and ventilated normotensive Wistar-Kyoto (WKY) or spontaneously hypertensive rats (SHR). Both drugs were administered in a 1.5-/U.1 volume into the lateral ventricle of the brain (i.c.v.) or into the cisterna magna (i.e.). The injection of vehicle alone (i.e. or i.c.v.) did not significantly change mean arterial pressure (MAP) or heart rate. Nifedipine (5 and 50 /ug/kg) and BAY k 8644 (5 and SO fig/kg) induced opposite effects on MAP when centrally injected. Nifedipine decreased MAP and induced a bradycardia (i.c.v.) or no change in heart rate (i.e.), and BAY k 8644 increased MAP without any significant change in heart rate (i.e. or i.c.v.). These effects were more marked with the highest dose of either drug. These effects seemed to be of central origin, since they were suppressed by gang!ionic blockade by hexamethonium (100 mg/kg i.v.), whereas after hexamethonium the hypotensive and the hypertensive responses to intravenously injected nifedipine and BAY k 8644, respectively, were preserved. Bilateral vagotomy suppressed the bradycardia induced by i.c.v. administered nifedipine. Previously i.c.v. administered nifedipine (5 /u.g/kg) antagonized the pressor response to BAY k 8644 (5 jug/kg i.c.v.). Changes in MAP and heart rate were significantly more marked in SHR than in WKY. These results indicate that a calcium channel inhibitor and a calcium channel activator can modulate in opposite fashion central mechanisms involved in blood pressure control. (Hypertension 9: 132-138. 1987) KEY WORDS • 1,4-dihydropyridine • calcium channel blocker • spontaneously hypertensive rats • central nervous system • BAY k 8644 C ALCIUM channel blockers produce an in vitro direct depression of myocardial contractility and sinus node automaticity as well as relaxation of isolated coronary and peripheral blood vessels 1 ' 2 by inhibiting calcium influx into the cells. 3 The direct effects of calcium channel blockers on cardiovascular function can be modifed by their effects on the autonomic nervous system. 4 Calcium channel blockers have been reported to act peripherally to decrease neurotransmitter release at the neuromuscular junction 5 -6 and to modulate carotid baroreceptor function.7 Some evidence suggests that calcium channel blockers influence the autonomic nervous system at the central level, thus altering cardiovascular function.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Opposite central cardiovascular effects of nifedipine and BAY k 8644 in anesthetized rats.

Laurent¹,

Girerd²,

Tsoukaris-Kupfer³

et al. 1987

Hypertension

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“…9 - 22 For example, such abnormalities are thought to include degrangements of the calcium pump (Ca.Mg-ATPase), 9 …”

Section: T He Intracellular Camentioning

confidence: 99%

Reduced calcium sensitivity of dihydropyridine binding to calcium channels in spontaneously hypertensive rats.

et al. 1991

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To explore the role of calcium channels in hypertension, dihydropyridine ([ 3 H]PN200-110) binding to heart, brain, and skeletal muscle microsomes of 4-, 8-and 15-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats was measured. At a constant Ca 2+ ion concentration (pCa 3.0), maximal binding (B^J of dihydropyridine binding to heart and brain microsomes was significantly enhanced in 8-and 15-week-old SHR compared with WKY rats (/?<0.01), whereas this phenomenon was not observed in 4-week-old SHR and WKY rats. B^, and dissociation constant (K d ) values for skeletal muscle microsomes from SHR showed no difference compared with WKY rats irrespective of age. Dihydropyridine binding to heart microsomes, brain microsomes, and solubilized skeletal muscle microsomes exhibited strong calcium dependence. The Ca 2+ -dependent dihydropyridine binding curves for heart showed a Hill slope, and pK 0.5 values for 15-week-old SHR and WKY rats were 0.70±0.12 and 4.66±0.12 versus 0.72±0.12 and 5.66±0.08 (n=4, mean±SD), respectively, indicating that 15-week-old SHR require 10-fold higher calcium concentration than WKY rats to promote dihydropyridine binding. The pK 0.5 values of calcium for brain and solubilized skeletal muscle calcium channels in 15-week-old SHR were also significantly lower than in WKY rats. This difference first became apparent in SHR and WKY rats as early as 4 and 8 weeks after birth. These results suggest that enhancement of calcium channel density might occur in the heart and brain of SHR in response to elevated blood pressure and that reduced calcium sensitivity of dihydropyridine binding to calcium channels might be a primary characteristic of this rat strain. (Hypertension 1991;17:234-241)

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“…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.…”

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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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Binding of [3H]nitrendipine to heart and brain membranes from normotensive and spontaneously hypertensive rats

Cited by 41 publications

References 4 publications

Opposite central cardiovascular effects of nifedipine and BAY k 8644 in anesthetized rats.

Opposite central cardiovascular effects of nifedipine and BAY k 8644 in anesthetized rats.

Reduced calcium sensitivity of dihydropyridine binding to calcium channels in spontaneously hypertensive rats.

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

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