Interaction between Levodopa and Methyldopa

The interaction between methyldopa and levodopa was studied in 18 patients with Parkinsonism. Together they produced a fall in blood pressure in doses which when given alone had no effect or only a slight hypotensive effect. Severe hypotension never occurred. It is reasonable to give methyldopa to hypertensive patients on levodopa but the regimen should be initiated in hospital.     

Upregulation of vascular inducible nitric oxide synthase mediates the hypotensive effect of ethanol in conscious female rats.

Previous reports from our laboratory have shown that ethanol elicits hypotension in female but not in male rats and that this effect of ethanol is estrogen dependent (El-Mass MM and Abdel-Rahman AA. Alcohol Clin Exp Res 23: 624-632, 1999; El-Mass MM and Abdel-Rahman AA. Clin Exp Hypertens 21: 1429-1445, 1999). In the present study, we tested the hypothesis that ethanol lowers blood pressure in female rats via upregulation of the inducible nitric oxide synthase (iNOS) in vascular tissues. The effects of pretreatment with NG-nitro-L-arginine (NOARG; nonselective nitric oxide synthase inhibitor) or aminoguanidine (selective iNOS inhibitor) on hemodynamic responses elicited by intragastric (ig) ethanol were determined in conscious female rats. Changes in vascular (aortic) iNOS protein expression evoked by ethanol in the presence and absence of aminoguanidine were also measured by immunohistochemistry. Compared with control (water treated) female rats, ethanol (1 g/kg ig) elicited hypotension that was associated with a significant increase in the aortic iNOS activity. The hypotensive effect of ethanol was virtually abolished in rats infused with the nitric oxide synthase inhibitor NOARG, suggesting a role for nitric oxide in ethanol hypotension. The inability of ethanol to lower blood pressure in NOARG-treated rats cannot be attributed to the presence of elevated blood pressure in these rats because ethanol produced hypotension when blood pressure was raised to comparable levels with phenylephrine infusion. Selective inhibition of iNOS by aminoguanidine (45 mg/kg ip), which had no effect on baseline blood pressure, abolished both the hypotensive action of subsequently administered ethanol and the associated increases in aortic iNOS content. These findings implicate vascular iNOS, at least partly, in the acute hypotensive action of ethanol in female rats.     

Central and peripheral alpha adrenergic activity of imidazoline derivatives

Intravenous injection of a number of imidazoline derivatives into rats induced an increase in blood pressure due to peripheral alpha adrenergic receptor stimulation. Some of these compounds, however, caused a secondary, long lasting decrease which was caused by central nervous system alpha adrenergic receptor stimulation. This central hypotensive action was only observed in the case of 2-amino-imidazolines such as clonidine, tramazoline and St 600, a clonidine analogue. Imidazolines lacking the nitrogen between the imidazoline and the benzene or naphtalene group such as oxymetazoline, xylometazoline and naphazoline were found to exert no central hypotensive action.Within the series of 2-amino-imidazolines lipid solubility turned out to be a major factor in the potency of a drug's central hypotensive action.Oxymetazoline — peripherally a very potent alpha adrenergic receptor stimulating agent — did not even cause hypotension when injected into the anterior hypothalamus, a brain structure where alpha adrenergic receptors mediating depressor effects have been localized. These data show that the hypothalamic alpha adrenergic receptors differ from peripheral alpha receptors and that only imidazolines with 2-amino substitution show affinity for these central hypotensive alpha adrenergic receptors.     

Controlled Trial of Propranolol in Hypertension

A trial of oral propranolol as a hypotensive agent was designed to provide adequate treatment periods. Twenty-eight patients with essential hypertension, with a mean blood pressure of 190/111 mm. Hg, were controlled on 120-320 mg. of propranolol daily. Their mean treated blood pressure was 153/91. They then entered, on a randomized and double-blind basis, a cross-over trial of two 16-week periods, blood pressure being measured fortnightly. Propranolol caused a statistically significant fall in blood pressure when compared with placebo. When propranolol was withdrawn blood pressures rapidly rose to hypertensive levels, though not to untreated levels. No postural hypotension was found, but a small change in blood pressure levels on exercise was noted.     

Circadian rhythm in hypotensive effect of sodium nitroprusside in rats and its relevance to sympathetic nervous activity

Circadian rhythmicity in the hypotensive effects of sodium nitroprusside (SNP) was determined to characterize the rhythmicity in hypotension mediated by nitric oxide (NO) donor in rats. When SNP was infused for 90 seconds every hour for 48 hours and the mean blood pressure was determined automatically by telemetry under light-dark conditions (LD), the degree of SNP-induced hypotension was shown to be minimal at the onset of the dark phase and to have marked circadian rhythmicity. The possible relationship between the circadian rhythm of the sympathetic nervous system (SNS) activity and SNP-induced hypotension was examined under LD conditions. The SNS activity assessed by blood pressure beat-to-beat variability analysis using the maximum entropy method (MEM) was higher at the preinfusion time at the onset of the dark phase than during the middle of the light phase. In addition, pretreatment with an alpha-blocker, phentolamine, followed by SNP infusion at the onset of the dark phase restored the SNP-induced hypotension and consequently dampened the daily variation in the degree of SNP-induced hypotension. The circadian rhythmicity determined by MEM was weakened, but persisted, in constant dark conditions (DD), suggesting partial involvement of endogenously driven circadian rhythms. In conclusion, the hypotensive effect of hourly infused SNP in rats was decreased in the dark phase in LD, especially at the onset of the dark phase, and clearly showed circadian rhythmicity in both LD and DD. The SNP-induced hypotension may be affected by rapid activation of the SNS at the onset of the dark phase in LD, and regulation of the circadian rhythm in SNP-induced hypotension in rats may be affected by both exogenous light stimuli and the endogenous biological clock.     

Central cardiovascular and thermal effects of prostacyclin in rats

Prostacyclin (PGI₂) induced a dose-dependent decrease in blood pressure with slight increases in heart rate and body temperature, when administered at the doses of 0.1–100 μg into the lateral cerebral ventricle (i.c.v.) of the urethane-anaesthetised rat. When the same doses were administered intravenously, both the blood pressure and heart rate decreased. Central pretreatment with sodium meclofenamate (1 mg/rat i.c.v.) antagonised the central hypotensive effect of PGI₂ but i.c.v. pretreatment of the rats with indomethacin (1 mg/rat) failed to affect the PGO₂-induced hypotension. Central pretreatment with two histamine H₂-receptor antagonists, cimetidine (500 μg/rat i.c.v.) or metiamide (488 μg/rat i.c.v.), antagonised the blood pressure lowering effect of 0.1 μg dose of PGI₂ but failed to affect the hypotension induced by higher PGI₂ doses. Therefore the main central hypotensive effect of PGI₂ seems not to be associated with the stimulation of histamine H₂ -receptors in the brain.The hypotensive effect of i.c.v. administered PGI₂ appears to be due to an action upon the central nervous system rather than to a leakage into the peripheral circulation. This assumption is supported by the fact that sodium meclofenamate i.c.v. antagonished the effect of PGI₂. In addition, the chronotropic response to i.c.v. PGI₂ was opposite to that induced by intravenous administration. The results also suggest that there may be differences in the mode of action between sodium meclofenamate and indomethacin.     

Effect on rat arterial blood pressure of chemically generated peroxyl radicals and protection by antioxidants

Convincing evidence suggests that blood redox changes play a role in the development of various cardiovascular disorders including hypertension. Nutritional antioxidants have been suggested to play a role in cardiovascular disease prevention. In this study, we investigated in vivo changes in rat arterial blood pressure induced by acute exposition to an increased load of peroxyl radicals and by the administration of selected antioxidants after chemically induced oxidative stress. Hydrosoluble and liposoluble peroxyl radicals, generated by 2,2'-azobis-(2-amidinopropane) dihydrochloride and 2,2'-azobis 2,4-di-methylvaleronitrile, induced a dose-dependent decrease in rat blood pressure. All antioxidants tested (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, vitamin C, glutathione and dithiothreitol) returned peroxyl radical-induced hypotension to normal. Of the various antioxidants tested, glutathione was the most effective in restoring blood pressure after peroxyl radical generation. Treatment of rats with a thiol-chelating agent (N-ethylmaleimide) and an oxidizing agent (5,5'-dithiobis-2-nitrobenzoic) inhibited peroxyl radical-mediated hypotension. Our results suggest that acute exposition to peroxyl radicals have a hypotensive effect on blood pressure and that thiols play an active role in the redox regulation of blood pressure. Other experiments are needed to clarify the role played by oxidative potentials on blood pressure and the mechanism of action of nutritional antioxidants.     

Naloxone inhibits the centrally-mediated hypotensive actions of BHT-933 (azepexole)

Central administration of BHT 933, a highly selective alpha 2 agonist, to pentobarbital-anesthetized, normotensive dogs resulted in a rapid, significant decrease in blood pressure. The maximal response occurred at 30 min and remained significantly decreased for 60 min. Concomitant with the hypotensive response was a decrease in heart rate. Pretreatment with naloxone 15 min prior to the administration of BHT 933 completely abolished the hypotensive response and significantly inhibited the bradycardia. These results suggest a role for central opioidergic systems in the control of blood pressure which may serve as important sites of antihypertensive drug action. The central regulation of sympathetic tone by catecholaminergic systems plays an important role in the control of cardiovascular function in both normal and pathological states. A high density of catecholaminergic nerve terminals is found in regions of the brainstem involved in cardiovascular control. Stimulation of the alpha receptors in these areas decreases peripheral sympathetic tone and subsequently lowers blood pressure. Recent histochemical evidence has demonstrated the presence of opioid peptides in the nucleus tractus solitarii, nucleus ambiguous and hypothalamus as well as other discrete brain areas associated with cardiovascular control. Activation of the opiate receptors in these brain areas decreases sympathetic tone and blood pressure. Additionally, both catecholaminergic and opioidergic systems have been implicated in the reaction to certain stimuli (i.e., pain, stress) which entail important hemodynamic adaptations. The similarity between the central opiate and catecholaminergic systems suggests a relationship between the two systems in blood pressure control and a potential site of antihypertensive drug action. The purpose of the present study was to determine if an opioidergic component is involved in the hypotensive action of BHT 933 (azepexole). BHT 933 is a relatively new hypotensive agent which is a much more specific alpha 2 agonist than clonidine.     

Head Turning-Induced Hypotension in Elderly People

Carotid sinus hypersensitivity has a high prevalence in the elderly and is a possible cause of falls. In carotid sinus hypersensitivity, external triggers cause sudden reductions in blood pressure, leading to dizziness or syncope, resulting in falls. Turning of the head is considered an important example of such an external trigger in everyday life, wherein rotation of the neck is thought to manipulate the hypersensitive carotid sinus. However, direct evidence for this is lacking. The aim of this study was to investigate the effects of head turning in elderly with carotid sinus hypersensitivity. We performed a prospective, observational study in 105 elderly patients who visited a geriatric falls clinic in a university teaching hospital and in 25 community dwelling healthy elderly subjects. Continuous measurements of blood pressure and heart rate (Finapres) were performed before, during, and after head turning. Head turning-induced hypotension was defined as a drop in systolic blood pressure of at least 20 mmHg during head turning. Carotid sinus hypersensitivity was examined with carotid sinus massage. We also tested for two other common geriatric hypotensive syndromes, orthostatic hypotension and post prandial hypotension, using active standing and a meal test. All three hypotensive syndromes were defined using consensus definitions. Head turning resulted in hypotension in 39% of patients (mean systolic blood pressure drop 36 mm Hg) and in 44% of the healthy elderly, irrespective of the direction of the head movement. Carotid sinus hypersensitivity was associated with head-turning induced hypotension (OR= 3.5, 95% CI= 1.48 to 8.35). We conclude that head turning is indeed an important cause of sudden drops in blood pressure in elderly with carotid sinus hypersensitivity.     

Beta-blockers: once or three times a day?

In a double-blind, crossover trial 16 hypertensive patients were treated, in random order, with placebo, metoprolol 300 mg in a single daily dose, or metoprolol 300 mg/day in three doses. Both therapeutic regimens produced detectable plasma metoprolol concentrations and appreciable beta-blockade, estimated from exercise tachycardia, throughout the day. Fluctuations throughout the day in plasma drug concentrations and degree of beta-blockade were insignificant on the thrice-daily regimen, but they varied considerably on the single-dose regimen. Both therapeutic regimens also significantly lowered blood pressure throughout the day. Although the thrice-daily regimen again tended to produce a stronger and less fluctuating hypotensive action, the differences in hypotensive effect between the two regimens were not statistically significant. A single-dose of 300 mg of metoprolol can therefore be recommended if the only aim is to reduce blood pressure but not if a steady degree of beta-blockade is needed.     

Hypotensive effectiveness and metabolic effects of indapamide in patients with primary arterial hypertension

Indapamide--a non-thiazide diuretic agent--was given to 28 patients with mild and moderate hypertension in a daily dose of 2.5 mg for 12 weeks. Statistically significant decrease in both systolic and diastolic blood pressure and complete normalization of the arterial blood pressure were achieved in 82% of the treated patients. Adverse reactions were mild and transient. However, low but statistically significant decrease in blood serum potassium and changes in the carbohydrate metabolism were seen. No significant effect of the-drug on lipid metabolism was found except the low but statistically significant increase in total cholesterol. Indapamide is an efficient and well tolerated hypotensive agent. However, biochemical indices should be checked up during the treatment due to the potential adverse reactions.     

Hypertension in childhood; treatment of acute nephritis with a derivative of veratrum viride

Alkavervir (Veriloid(R)), a new derivative of veratrum viride was used in the treatment of hypertension in ten children with acute nephritis. The patients had a variety of complications associated with hypertension-heart failure, convulsions, vomiting and headache. In all of them the blood pressure decreased soon after the drug was given.     

Contribution of atenolol,bendrofluazide, and hydrallazine to management of severe hypertension.

The efficacy of various combinations of atenolol, bendrofluazide, and hydraliazine given twice daily was assessed in a double-blind trial on 39 patients with moderate to severe essential hypertension. Concurrent treatment with all three drugs proved most effective and produced a mean reduction in blood pressure of 43/31 mm Hg. In the dosage used, hydrallazine affected only the diastolic blood pressure, and when added to either bendrofluazide or bendrofluazide plus atenolol it produced a further mean reduction in pressure of 6 mm Hg. Once-daily treatment with atenolol and bendrofluazide was as effective in reducing blood pressure as the same combination given twice daily, and the hypotensive effect was still present at least 24 hours after the last dose of tablets. A combined tablet of atenolol and bendrofluazide taken once daily would be a simple regimen to follow and would provide almost as much hypotensive effect as a twice-daily regimen incorporating a modest dose of hydrallazine. The hypotensive effect of atenolol was equal to that of bendrofluazide on systolic pressure but significantly better than that of bendrofluazide on diastolic pressure. Atenolol reduced plasma renin and urate concentrations but increased plasma potassium levels. The biochemical effects of atenolol, therefore, may be an advantage over those of bendrofluazide when deciding on first-line treatment for essential hypertension.     

The effects of ouabain in the medullary site of the hypotensive action of clonidine

Blood pressure was studied in pentobarbital anesthetized rats and cats after central administration of ouabain. Intracerebroventricular (i.c.v.) injections caused a classical biphasic effect, a short lasting hypotension followed by a hypertensive phase. When injected directly into the nucleus reticularis lateralis region (NRL), ouabain (0.01–2 μg/kg) caused a dose-dependent pressor effect. In the same region, kryptofix 221, a sodium complexing agent, produced a fall in blood pressure. Moreover, central administration of ouabain prevented the hypotensive effect of i.v. clonidence whereas the central hypotensive effect of muscimol was not affected. It is concluded that sodium movements play an important role in the blood pressure regulation within the NRL region. We also report here that ouabain antagonizes the hypotensive effect of clonidine suggesting that sodium movement might be the essential link of this action.     

Effect of human atrial natriuretic peptide on blood pressure after sodium depletion in essential hypertension.

Human atrial natriuretic peptide was infused over four hours in three patients with essential hypertension. When the patients had a sodium intake of 200 mmol (mEq) daily an infusion of 0.5 micrograms atrial natriuretic peptide/min caused no significant change in blood pressure, whereas an infusion of 1.0 micrograms/min caused a gradual decrease in blood pressure and an increase in heart rate. After two to three hours of infusion with the higher dose two patients showed a sudden decrease in heart rate, with symptomatic hypotension. When the same patients had an intake of 50 mmol sodium daily their blood pressure was more sensitive to infusion of atrial natriuretic peptide; one patient again developed symptomatic hypotension, this time during an infusion of 0.5 micrograms/min. During all infusions distinct natriuresis occurred irrespective of whether blood pressure was affected. Prolonged, relatively low dose infusions of atrial natriuretic peptide can cause unwanted symptomatic hypotension. The effect on blood pressure is enhanced after sodium depletion, and blood pressure should be monitored carefully during longer infusions of atrial natriuretic peptide in patients with essential hypertension.     

Effects of endomorphin-2 on arterial blood pressure and pain threshold in spontaneously hypertensive rats and modification of these effects by beta-funaltrexamine and nor-binaltorphimine

The effects of intracerebroventricular (icv) administration of endomorphin-2 (E2) on arterial blood pressure and pain threshold in spontaneously hypertensive rats (SHR) and modification of these effects by K [OP2] and mu [OP3] opioid receptors antagonists were investigated. Endomorphin-2 administrated icv in doses of 8, 16 and 32 mcg produced dose-dependent analgesic and hypotensive effect. In SHR decrease in blood pressure amounted 2.667, 4.0 and 6.534 kPa, respectively. Pain threshold increased by 1.7, 3.6 and 8.9 (g x 10). In Wistar Kyoto (WKY) strain, being the normotensive controls, E2 in doses of 8 and 16 mcg decrease in blood pressure was less pronounced and amounted 1.200 and 1.467 kPa, respectively, whereas the pain threshold increased by 7.2 and 10.4 (g x 10), respectively. Both E2 effects were antagonized by equimolar icv doses of beta-funaltrexamine (beta-FNA). Equimolar doses of nor-binaltorphimine (nor-BNI) attenuated analgesic action of E2, but were without hypotensive action produced by E2. A strong correlation between drop in blood pressure and increase in pain threshold observed in the SHR and WKY strains after icv administration of E2, indicate close interaction between systems responsible for pain perception and blood pressure control.     

Development of the sympathetic nervous system response to endotoxicosis in the rat: importance of non-baroreflex mechanisms in pre-weanlings and adults.

The sympathetic nervous system response to endotoxicosis was studied in the rat at ages before (11-12 days) and after (19-20 days) maturation of the baroreflex and in adults by recording preganglionic impulses during i.v. infusions of endotoxin (S. enteriditis). At all ages, the discharge rate increased before there was any decrease in arterial blood pressure. The magnitude of the increase (65%) was the same in 11-12 days-old and adult rats while 19-20 days-old rats were hyperactive (278% increase). Subsequently, in the hypotensive phase of the endotoxicosis (diastolic pressure decrease 50-60%) there was an additional increase in discharge in the 19-20 days- old rats (43% and in adults (70%) but not in 11-12 days-old rats. The hypotensive discharge rate of the 11-12 days-old rat reached only 20% of the maximum; it reached 80% in the hyperactive 19-20 days-old rat and 65% in adults. At all ages, the elevated hypotensive discharge rate persisted after steady state blood pressure was raised by infusing dextran. The discharge rate was diminished transiently during pressor responses to accelerated infusion or bolus injections of dextran. The conclusions are: (i) endotoxic stimulation of sympathetic outflow is initiated by a non-baroreflex mechanism in adult as well as in pre-weaning rats; (ii) there is added stimulation during hypotension after the baroreflex is mature, but (iii) the non-baroreflex stimulation continues to excite the preganglionic neurons and obtunds baroreflex feedback inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)     

HYPERTENSION IN CHILDHOOD—Treatment of Acute Nephritis with a Derivative of Veratrum Viride

Alkavervir (Veriloid®), a new derivative of veratrum viride was used in the treatment of hypertension in ten children with acute nephritis. The patients had a variety of complications associated with hypertension—heart failure, convulsions, vomiting and headache. In all of them the blood pressure decreased soon after the drug was given.     

Effect of dinitrosyl iron complex with glutathione as a nitric oxide donor on blood circulation in healthy animals

It has been shown that the hypotensive action of the nitric oxide donor, the dinitrosyl complex of iron with glutathione, on the organism of healthy rats, which is caused by a decrease in the general peripherical immunity, does not impair the microcirculation and is accompanied by an enhancement of the contractile activity of the myocardium. In hypotension caused by the dinitrosyl iron complex, neither the tension of oxygen and nitrogen in the blood nor its basic-acidic status changes. Thus, the possible inhibitory action of this complex on some enzymes and proteins in the animal organism does not affect the functioning of the heart, vessels, and blood. The dinitrosyl iron complex with glutathione only causes a decrease in arterial pressure. It is assumed that these complexes as well as dinitrosyl complexes of iron with other thiol ligands may be considered as the basis for designing a novel type of drugs for the treatment of cardiovascular diseases.     

Vasopressin: An essential pressor factor for blood pressure recovery following hemorrhage

Two experimental approaches were used to evaluate the importance of the pressor effects of vasopressin in blood pressure recovery following hypotensive hemorrhage. Experiments using homozygous Brattleboro rats demonstrated that the hemodynamic recovery of these animals was subnormal, even though the activation and efficacy of the sympathetic nervous and renin-angiotensin systems were intact. Experiments using an antipressor vasopressin analogue in normal rats during hypotensive hemorrhage demonstrated significantly blunted blood pressure recovery in the presence of the analogue. Thus, both experiments indicate that the pressor effects of circulating vasopressin play an essential role in blood pressure recovery following hypovolemic hypotension induced by hemorrhage.