Evidence for a peripheral dopaminergic mechanism in the antihypertensive action of lergotrile

Lergotrile (0.5 mg/kg, i.p.) lowered blood pressure significantly in spontaneously hypertensive rats. This effect was antagonized by pretreatment with haloperidol, pimozide, or domperidone. In normotensive rats, administration of haloperidol or domperidone rapidly increased serum prolactin levels. Haloperidol also increased striatal levels of dihydroxyphenylacetic acid and homovanillic acid; however, domperidone did not, which confirms that this latter blocker probably acts primarily as a $\text{peripheral}$ dopamine antagonist. Taken together, these data suggest that lergotrile lowers blood pressure in hypertensive rats mainly by stimulating $\text{peripheral}$ dopamine receptors.     

Peripheral dopamine receptors, potential targets for a new class of antihypertensive agents. Part II: Sites and mechanisms of action of dopamine receptor agonists

Relatively selective dopamine receptor agonists, like bromocriptine, lergotrile, pergolide and N,N-di-n-propyl-dopamine, lower arterial pressure in conscious spontaneously hypertensive rats and in several anesthetized animal preparations. This effect has been attributed to stimulation of dopamine receptors since it can be specifically antagonized by several dopamine receptor blocking agents (domperidone, haloperidol, pimozide, sulpiride). The two main mechanisms which can theoretically intervene in the antihypertensive effects of dopamine agonists are direct smooth muscle relaxation mediated by stimulation of post junctional DA1-dopamine receptors and the reduction of the neural release of norepinephrine resulting from activation of of DA2-dopamine receptors on ganglionic bodies or sympathetic nerve terminals. Other accessory mechanisms of undoubted interest might be a natriuretic effect or a decrease of aldosterone release. On the basis of the presently available pharmacological results in experimental animals, it is not unreasonable to advance the hypothesis that agonists of DA1- and DA2-dopamine receptors produce cardiovascular changes most compatible with an antihypertensive activity being due to a fall in peripheral resistance. However, before any of these compounds can become of therapeutic interest further research in this field is necessary to explore whether it is possible to minimize or even entirely avoid certain unwanted effects (vomiting, nausea, endocrinological alterations) that appear to be intimately associated particularly with those agents stimulating the DA2-dopamine receptors subtype. A more thorough pharmacological characterization of human dopamine receptors would be useful to provide an insight into whether novel chemical approaches can solve some of these problems. Finally, the ideal profits of future dopamine receptor agonists aimed at the treatment of elevated arterial pressure is discussed.     

Prolactin and LH release in response to vasoactive intestinal peptide (VIP) administration in spontaneously hypertensive and normotensive rats.

Vasoactive intestinal peptide (VIP) was injected intravenously at a dose of 10 micrograms in spontaneously hypertensive and normotensive Wistar-Kyoto rats. In order to evaluate the hemodynamic and hormonal effects of this peptide, the mean arterial pressure, heart rate as well as a serum rLH and rPRL levels, the contents of LH-RH in hypothalamus and the content of LH in pituitary tissue were determined. The same procedure was applied in rats receiving placebo. Serum rPRL concentration was measured additionally after combined administration of VIP+dopamine. VIP injection produced a decrease in mean arterial pressure and an increase in heart rate in both spontaneously hypertensive and normotensive rats. Serum rPRL concentration was significantly increased at 10 minutes after injection. The combined therapy (VIP+dopamine) partially inhibited this response. Serum rLH concentration, the content of LH-RH in hypothalamic tissue as well as the content of pituitary LH after VIP injection in spontaneously hypertensive and normotensive rats did not differ from the values obtained for the control group. Conclusions: 1. VIP injection produced the dramatic hypotensive effects in hypertensive rats; 2. A marked increase in PRL concentration in response to VIP was partially inhibited by dopamine in hypertensive and normotensive rats; 3. VIP injection did not change LH-RH and LH release in both hypertensive and normotensive rats.     

Central neurotransmitter receptors in hypertensive rats

Muscarinic cholinergic ([³H]QNB), α₁ ? ([³H]WB-4101), and α₂ ? ([³H]clonidine) adrenergic ligand binding was measured in various regions of the brains of adult normotensive, spontaneously hypertensive, and DOCA-salt hypertensive rats. There was a 66% increase in the number of α₁-adrenergic receptors in hypothalamus of the spontaneously hypertensive rats as compared to normotensive controls, with no change in the K_d value. There were no other differences in the spontaneously hypertensive rats and none in the DOCA-salt model. α₁-Adrenergic binding was elevated in hypothalamus of spontaneously hypertensive rats 4–20 weeks of age even though blood pressure in the 4-week old animals was not at hypertensive levels (i.e., <150 mmHg). Treatment of adult spontaneously hypertensive rats with clonidine HCl significantly reduced blood pressure but failed to alter the binding of [³H]WB-4101 in hypothalamus. Thus, it appears that the enhanced number of α₁-adrenergic receptors in hypothalamus of spontaneously hypertensive rats is neither a consequence of the increased blood pressure, nor a phenomenon common to all models of hypertension.     

Pergolide: a potent dopaminergic antihypertensive.

Pergolide, a potent centrally acting dopamine agonist, lowered both blood pressure and heart rate of spontaneously hypertensive rats and normotensive rats. Its blood pressure-lowering activity in both types of rats was more potent than that of lergotrile, a weaker dopamine agonist. The parallelism between the antihypertensive activity and the dopaminergic potency of the two compounds and the complete antagonism of the antihypertensive activity of pergolide by haloperidol, a dopaminergic blocker, indicate the involvement of dopaminergic mechanisms in maintaining the homeostasis of blood pressure and perhaps in the pathology of hypertension such as that in spontaneously hypertensive rats.     

Pharmacological characterization of apomorphine-induced hypothermia in the spontaneously hypertensive rat

The dopamine agonist apomorphine was more potent in eliciting hypothermia in spontaneously hypertensive rats (SHRs) than in normotensive Wistar rats (NWRs), while normotensive Wistar-Kyoto rats (WKYs) were intermediate in response. Various drug interventions were attempted in an effort to explain the greater sensitivity of SHRs to apomorphine. Haloperidol produced abolition of apomorphine-induced hypothermia in SHRs but at greater doses than required for antagonism of the drug effect in WKYs and NWRs. Chronic hydralazine treatment that reduced the high blood pressure of SHRs failed to appreciably influence the magnitude of apomorphine-induced hypothermia, compared to the response in control SHRs that received no hydralazine. These findings suggested to us that the enhanced hypothermic effect of apomorphine in SHRs was entirely dopamine receptor-mediated and that it was also independent of the high blood pressure. We also found that chronic lithium treatment that had no influence upon apomorphine-induced hypothermia in WKYs and NWRs significantly reduced the drug effect in SHRs. Based on this finding, we suggest that the greater hypothermic effect induced by apomorphine in SHRs might be due to a supersensitivity of hypothermia-mediating dopamine receptors in the hypertensive strain.     

Inhibitory effects of pergolide on peripheral adrenergic neurotransmission in spontaneously hypertensive rats

Intraperitoneal injection of pergolide (12.5–500 μg/kg) produced dose-related and sustained arterial hypotension in anesthetized spontaneously hypertensive rats (SHR) which was accompanied by bradycardia at higher tested doses. During the time frame of hypotension produced by pergolide (50 μg/kg, i.p.), diastolic blood pressure and cardiac rate responses to electrical stimulation of the sympathetic outflow in pithed SHR were attenuated, whereas comparable responses induced by exogenous norepinephrine were unaffected. Pretreatment of SHR with sulpiride abolished pergolide-induced hypotension and prevented its inhibitory effect on neurogenic vasoconstrictor responses. Sulpiride alone had no effect on responses to electrical stimulation or injected norepinephrine. Yohimbine or vagotomy plus atropine did not attenuate the hypotensive effect of pergolide while hexamethonium or pithing reversed it; increments in pressure produced by pergolide after each of the latter interventions were probably mediated by postsynaptic alpha receptors, since vasoconstrictor responses to pergolide (10?100 μg/kg, i.v.) in pithed preparations were attenuated by phentolamine.The data suggest that pergolide lowers arterial blood pressure and cardiac rate by inhibiting peripheral sympathetic nerve function through a dopaminergic mechanism. The probable site of action of pergolide is at presynaptic (neuronal) dopamine receptors which are known to mediate inhibition of neurogenic release of norepinephrine.     

Indirect systolic and mean blood pressure determination by a new tail cuff method in spontaneously hypertensive rats

A new tail cuff method for determining systolic and mean blood pressure in rats was developed based on photoelectric detection of tail arterial blood flow and pulsatile volume oscillation. Indirect systolic and mean blood pressure measured by this method correlated well with direct systolic and mean blood pressures recorded by a transducer and polygraph after carotid artery cannulation in stroke-resistant spontaneously hypertensive rats (SHR), stroke-prone SHR and normotensive Wistar Kyoto rats. Blood pressures were sharply, and transiently raised for about 1 min when rats were picked up by an investigator to be placed in a hot box or immobilized in a restrainer for measuring blood pressure. Therefore, blood pressures should be measured at least 1 min after the rats are put in a restrainer. This new tail cuff method for measuring blood pressure provides reliable mean blood pressure readings in conscious rats.     

Differences in effects of sultopride and sulpiride on dopamine turnover in rat brain

Sultopride and sulpiride are both chemically similar benzamide derivatives and selective antagonists of dopamine D2 receptors. However, these drugs differ in clinical properties. We compared the effects of sultopride and sulpiride on dopamine turnover in rats following the administration of these drugs alone or in combination with apomorphine. The administration of sultopride or sulpiride markedly accelerated dopamine turnover in the rat brain. The increase in the level of dopamine metabolites in the striatum was more marked in the sultopride-treated rats. Sulpiride affected the limbic dopamine receptors preferentially, whereas sultopride affected the striatal and the limoic dopamine receptors equally. A low dose of apomorphine induced a reduction in the concentration of dopamine metabolites in the striatum and the nucleus accumbens by approximately 55%, but not in the medial prefrontal cortex. Sultopride was more effective in preventing an apomorphine-induced reduction in dopamine metabolite levels. These results from rat experiments would model the pharmacological differences observed between sultopride and sulpiride in clinical use.     

Fasudil attenuates sympathetic nervous activity in the adrenal medulla of spontaneously hypertensive rats

We investigated the effects of fasudil, a Rho kinase inhibitor, on hypertension in spontaneously hypertensive rats and on the catecholamine synthetic pathway. Ten-week-old male SHR and Wistar-Kyoto rats were administered fasudil (10 mg/kg/day s.c.) for 4 days. Systolic blood pressure was measured using the tail-cuff method. Catecholamine levels were measured with high-performance liquid chromatography-ECD methods. Tyrosine hydroxylase protein levels were measured in Western blot analysis. The tyrosine hydroxylase mRNA level was measured using real-time PCR methods. Fasudil significantly decreased systolic blood pressure in spontaneously hypertensive rats, but not in Wistar-Kyoto rats. Fasudil also significantly decreased catecholamine, tyrosine hydroxylase protein, and tyrosine hydroxylase mRNA levels in the adrenal medulla of spontaneously hypertensive rats. These results suggest that the depressor effects of fasudil on hypertension in spontaneously hypertensive rats may be related to inhibition of the catecholamine synthetic pathway.     

Antihypertensive effects of fluoxetine and L-5-hydroxytryptophan in rats.

The combination of fluoxetine (10 mg/kg) and L-5-hydroxytryptophan (5-HTP) (10 mg/kg) significantly lowered blood pressure in spontaneously hypertensive rats and in rats made hypertensive by treatment with deoxycorticosterone (DOCA) and saline. Fluoxetine alone also had a significant effect on blood pressure in DOCA hypertensive rats, but not as great an effect as the combination. Since fluoxetine is an inhibitor of serotonin reuptake and 5-HTP is the serotonin precursor, the antihypertensive effect of this drug combination strengthens previous evidence that serotonin neurons have a role in the central regulation of blood pressure.     

AT2 receptors contribute to acute blood pressure-lowering and vasodilator effects of AT1 receptor antagonism in conscious normotensive but not hypertensive rats

The aims of this study were to determine the contribution of the AT2 receptor to the antihypertensive and regional vasodilatory effects of AT1 receptor blockade in adult spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive (2K1C) rats, and sham-operated normotensive rats. Several studies have provided evidence to support the notion that the AT2 receptor may have opposing effects to those mediated by the AT1 receptor. We therefore tested the hypothesis that the depressor and vasodilator effects of acute AT1 receptor blockade are dependent on AT2 receptor activation. Heart rate, mean arterial pressure, and regional hemodynamics were measured over a 4-day protocol in rats that received the following treatments in randomized order: saline vehicle, the AT1 receptor antagonist candesartan (0.1 mg/kg iv bolus), the AT2 receptor antagonist PD-123319 (50 microg.kg(-1).min(-1)), or both antagonists. Intravenous candesartan reduced mean arterial pressure in all groups of rats, and this was accompanied by renal and mesenteric vasodilation. Neither saline nor PD-123319 significantly affected these variables. Concomitant PD-123319 administration partially reversed the depressor and mesenteric vasodilator effects of candesartan in sham-operated normotensive rats but not in SHR or 2K1C rats. These data indicate that the AT2 receptor contributes to the blood pressure-lowering and mesenteric vasodilator effects of AT1 receptor blockade in the acute setting in conscious normotensive but not hypertensive rats.     

Effect of cyclo(Leu-Gly) on the supersensitivity of dopamine receptors in spontaneously hypertensive rats

Spontaneously hypertensive rats exhibited dopamine receptor supersensitivity as evidenced by a greater hypothermic response to apomorphine in comparision with normotensive Wistar-Kyoto rats. A single injection of cyclo(Leu-Gly) given prior to apomorphine administration did no alter apomorphine induced hypothermia in either the normotensive or the hypertensive rats. Chronic administration of cyclo(Leu-Gly) for 7 days did not affect apomorphine response in normotensive rats, but blocked the exaggerated response to apomorphine in the hypertensive rats. These studies suggest that cyclo(Leu-Gly) interacts with the dopamine receptors and that the central dopamine receptors may play a role in the pathophysiology of hypertension.     

Dopamine D1 and D2 receptors in spontaneously hypertensive rat brain striatum

Since it has been reported that dopamine D2 receptors are elevated in the brain striatum of spontaneously hypertensive (SH) rats, and since both D1 and D2 receptors may interact with one another, we measured the densities of both these receptors in SH rat striatum, as well as those in the normotensive Wistar-Kyoto rat striatum. The D1 receptor density in both strains was virtually the same, 72.9 +/- 2.2 and 71.3 +/- 3.2 pmol/g, respectively (mean +/- SD). The D2 receptor densities were also almost identical, 16.3 +/- 0.6 and 16.8 +/- 1.0 pmol/g, respectively (mean +/- SD). Thus, these data do not support the concept of a dopamine receptor related role in spontaneous hypertension.     

Reductions in blood pressure after acute exercise by hypertensive rats

Postexercise reductions in blood pressure at rest have been reported for hypertensive subjects. To determine whether post-exercise hypotension would occur in spontaneously hypertensive rats and to test the hypothesis that any reductions would result because of decreases in regional vascular resistances, hypertensive rats (n = 19) were instrumented with indwelling arterial catheters and Doppler probes to measure regional blood flows from the iliac, superior mesenteric, and renal arteries. Data were collected from animals who performed a 20- and a 40-min treadmill test at between 60 and 70% of their maximum O2 uptake. When the animals ran for 20 min, there was a pre- to postexercise drop in mean arterial pressure (MAP) from 158 +/- 3.6 to 150 +/- 3.6 mmHg (P less than 0.05), which was recorded 30 min after the exercise had ceased. The pre- to postexercise reduction in MAP after 40 min of treadmill running was from 154 +/- 3.1 to 138 +/- 3.0 mmHg (P less than 0.05) as recorded 30 min postexercise. Postexercise heart rate was significantly lower after the 40-min exercise bout, from a preexercise mean of 351 +/- 3 beats/min to 324 +/- 5 beats/min 30 min after the treadmill had stopped. Surprisingly, marked pre- to postexercise reductions in regional vascular resistance were not observed in either the iliac, superior mesenteric, or renal vascular beds. These data demonstrated the existence of postexercise hypotension in genetic hypertensive rats and suggested that reductions in cardiac output were the primary hemodynamic mechanism for this finding.     

Reduced number of beta-adrenergic receptors in the myocardium of spontaneously hypertensive rats.

Inotropic response to β-adrenergic stimulation of the myocardium is decreased in hypertension. A biochemical basis for this decrease was provided by the observation that the number of β-adrenergic receptors — as reflected in specific [³H]dihydroalprenolol binding — was diminished in the myocardium of spontaneously hypertensive rats without a change in the affinity of dihydroalprenolol for the binding sites or in the capacity of isoproterenol to displace dihydroalprenolol. The decline in β-adrenergic receptor numbers is not secondary to blood pressure elevation and may be related to increased sympathetic drive in spontaneously hypertensive rats.     

The effects of dopaminergic antagonism by sulpiride on TRH and VIP-induced prolactin release in nonsuckled lactating rats

Prolactin (PRL) release was studied in female rats during midlactation using pharmacologic manipulations designed to mimic the hypothalamic effects of suckling. In the first experiment pituitary dopamine (DA) receptors were blocked by sulpiride (10 micrograms/rat i.v.). One hour later, thyrotropin-releasing hormone (TRH, 1.0 micrograms/rat i.v.) was given to induce PRL release. TRH released significantly more PRL following DA antagonism than when no DA antagonism was produced, suggesting that DA receptor blockade increased the sensitivity of the AP to TRH. In a second experiment, VIP (25 micrograms/rat) increased plasma prolactin 3-4 fold but this effect was not enhanced significantly by prior dopamine antagonism with sulpiride. We conclude that dopamine antagonism enhances the PRL releasing effect of TRH but not VIP in lactating rats.     

Effect of chronic dietary treatment with L-tryptophan on the maintenance of hypertension in spontaneously hypertensive rats

Chronic dietary administration of L-tryptophan at 2.5 and 5.0% by weight reduced the elevated systolic blood pressure of spontaneously hypertensive (SH) rats. Blood pressure was reduced significantly by 3 weeks after initiation of treatment and continued to fall during the course of the 15 weeks of treatment. Body weights of the treated rats were not affected significantly by treatment, nor were daily food and fluid intakes and urine outputs. SH rats, treated with the higher dose of tryptophan, also significantly reduced their urinary outputs of epinephrine and norepinephrine compared with SH controls, while both doses of tryptophan increased urinary outputs of dopamine significantly above that of SH controls. Treatment with tryptophan increased significantly the specific binding of [125I]angiotensin II (Ang II) to membranes from the diencephalon in a dose-dependent manner. Measurement of catecholamine concentration of the supernatant from homogenates used for the Ang II binding assay revealed a significant correlation between the specific binding of Ang II to brain membranes of the two tryptophan-treated groups and the concentration of norepinephrine in the supernatant. There was also a significant correlation between the specific binding of Ang II and the concentration of dopamine in the supernatant of the control group and the group treated with the higher dose of tryptophan. These results show that chronic dietary administration of tryptophan can reduce the elevated blood pressure of SH rats and support the possibility that this neutral amino acid may act via its effect on the concentration of the neurohormones, norepinephrine and dopamine, in the diencephalon to regulate the binding of Ang II to its receptors.     

原发性高血压患者红细胞抗高血压因子对高血压...

The effects of antihypertensive factor (AHF) from erythrocytes of essential hypertensive human subjects on the systolic blood pressure (SBP) and diastolic blood pressure (DBP) in spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR), Wistar-Kyoto rats (WKY) and Wistar rats were examined. Single intraperitoneal injection of AHF (1.6 mg/kg body weight) resulted in a significant decrease in SBP of SHR and RHR. At 10 min postinjection, AHF lowered the SBP in SHR by 34.0 mmHg. SBP recovered to the original level at 3 h. The maximal decrease of SBP in RHR by 92.5 mmHg was at 24h postadministration and the SBP did not recover until the 9th day. When AHF was administered via femoral vein (0.8 mg/kg body weight), the maximal decrease values of the SBP and the DBP were 42.8 and 48.2 mmHg in SHR at 12 min and 38.3 and 42.5 mmHg in RHR at 25 min postinjection respectively. The DBP in Wistar rats decreased considerably (from 96.7 +/- 12.9 to 83.3 +/- 11.7 mmHg) at 5 min postadministration of AHF, but no effect on DBP in WKY rats was observed. The depressor effect of AHF on SBP in RHR was dose-dependent. AHF could also antagonize the pressor effect of norepinephrine in Wistar rats.     

Sexual dimorphism of blood pressure in spontaneously hypertensive rats is androgen dependent

Intact male and female spontaneously hypertensive rats showed a progressive increase in blood pressure with growth; male attained systolic blood pressure levels of 244 +/- 6 mmHg, and females 205 +/- 3 mmHg at age 22 weeks. Orchidectomy at age 4 weeks significantly attenuated the systolic blood pressure elevation in the male (195 +/- 4 mmHg at age 22 weeks), but ovariectomy at age 4 weeks had no effect on the development of hypertension in the female. The pattern of development of hypertension in orchidectomized males was the same as that in intact and ovariectomized females. Administration of testosterone propionate to gonadectomized rats of both sexes conferred a male pattern of blood pressure development. These results indicate that the sexually dimorphic pattern of hypertension in the spontaneously hypertensive rat is androgen dependent, rather than estrogen dependent. Plasma norepinephrine levels did not differ between the sexes, nor were they altered by gonadectomy or testosterone replacement, suggesting that the higher blood pressures in the intact male and androgen treated male and female SHR are not dependent on increased sympathetic outflow in the established phase of hypertension. Stores of norepinephrine in the posterior hypothalamic region were significantly greater in intact male rats and testosterone treated rats of both sexes than in intact or ovariectomized females, and were higher in the pons of intact female rats than in all other groups. These alterations in central catecholamine stores were not correlated with blood pressure. Further study is needed to assess the functional significance of these androgen mediated alterations in posterior hypothalamic neurons as a determinant of the androgen mediated sexual dimorphism of blood pressure in the spontaneously hypertensive rat.