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PubMed2000

Alpha2-adrenoceptor agonists in anaesthesia: a new paradigm.

Since the first report of alpha2-adrenoceptor agonists, the list of clinical indications for this class of drugs continues to expand. Alpha2-adrenoceptor agonists have several beneficial actions during the perioperative period. They exert a central sympatholytic action, thus improving haemodynamic stability in response to endotracheal intubation and surgical stress, reducing anaesthetic and opioid requirements, and causing sedation, anxiolysis and analgesia. Furthermore, alpha2-adrenoceptor agonists may offer benefits in the prophylaxis and treatment of perioperative myocardial ischaemia and their role in pain management and regional anaesthesia is increasing. The development of new, highly selective compounds which not only reduce anaesthetic requirements but induce anaesthesia by themselves may provide a new concept for the administration of anaesthesia.

Journal Article↗

PubMedDate not supplied

Cardiovascular responses to the intravertebral artery injection of hypertonic contrast media in the dog.

Central nervous system-mediated cardiovascular responses to contrast medium (CM) are believed the result of a vagal or of a sympatholytic response; these effects may be enhanced in the setting of dehydration. The purpose of this investigation was to evaluate neurally mediated effects of intravertebral artery CM injections on blood pressure (BP), heart rate (HR) and regional vascular resistances in euvolemic and dehydrated dogs. Animal preparation consisted of food and water ad libitum (n = 7) vs. 2.0 ml/kg i.m. furosemide and 48 hours thirsting (n = 7). During pentobarbital anesthesia BP, HR and renal and femoral blood flows were continuously monitored and meglumine iothalamate 60% (1 ml/kg) injected via a left vertebral artery catheter at 3 ml/sec; matched volume injections of normal saline served as control. Decreases in BP, HR and femoral and renal vascular resistances post CM injection were observed in the first 10 seconds before the CM had reached the systemic circulation. Significant decreases in both BP (-10.6 +/- 1.7%) and HR (-11.5 +/- 1.6%) post CM injection were noted with dehydration (n = 7). In the euvolemic dogs (n = 7) the decrease in HR (-7.3 +/- 2.0%) was significant but the decrease in BP (-3.9 +/- 2.4%) was not. The decrease in femoral vascular resistance was -22.7 +/- 9.0% in euvolemic dogs and -21.9 +/- 8.8% in dehydrated dogs. No significant changes were noted with the intravertebral artery injections of normal saline in control euvolemic and dehydrated animals. The early cardiovascular responses to CM suggest a direct action on the vasomotor center of the medulla. The effects on BP and HR are more severe in the dehydrated than in the euvolemic state.

Animals↗

PubMed1996

Renal protection in diabetes: an emerging role for calcium antagonists.

BACKGROUND: The combination of diabetes and hypertension increases the chances of progressive renal disorder and, ultimately, renal failure. Roughly 40% of all diabetics, whether insulin-dependent or not, develop diabetic nephropathy. Diabetic nephropathy is the single most important cause of end-stage renal disease in the Western world and accounts for more than a quarter of all end-stage renal diseases. Diabetic nephropathy is a major cause of increased morbidity and mortality in diabetic patients. Increased arterial blood pressure is an early and common phenomenon in incipient and overt diabetic nephropathy. The relationship between arterial blood pressure and diabetic nephropathy is a complex one, with diabetic nephropathy increasing blood pressure and blood pressure accelerating the course of nephropathy. OVERVIEW: Calcium antagonists antagonize preglomerular vasoconstriction. Additional putative mechanisms include the ability to retard renal growth and possibly to attenuate mesangial entrapment of macromolecules, and to attenuate the mitogenic effect of diverse growth factors. Calcium antagonists (except the original short-acting dihydropyridine drugs) reduce microalbuminuria and preserve kidney function in diabetic patients with incipient diabetic nephropathy. There are still no long-term trials using the new long-acting dihydropyridine calcium antagonists to treat patients with incipient nephropathy. A recent, 1-year, randomized, double-blind study in hypertensive insulin-dependent diabetic patients with diabetic nephropathy showed a better attenuation of the rate of decline in glomerular filtration in patients treated with nisoldipine (long-acting dihydropyridine) than with an angiotension converting enzyme (ACE) inhibitor. The mean 24-h arterial blood pressure during this study was almost identical in both treatment groups, at 103 (SD 9) and 101 (SD 11) mmHg, respectively. Furthermore, a recent 5-year randomized open study in hypertensive non-insulin-dependent patients with diabetic nephropathy has revealed the same beneficial effect of a calcium antagonist and of ACE inhibition on the progression of nephropathy. In a third group treated with sympatholytic drugs, creatinine levels doubled in more than 50% of the subjects compared to less than 10% in the two other groups mentioned above. However, long-term studies are needed to consolidate these findings and expand them to insulin-dependent diabetic patients with diabetic kidney disease.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Left ventricular mass is linked to cardiac noradrenaline in normotensive and hypertensive patients.

BACKGROUND: Left ventricular hypertrophy constitutes a powerful independent risk factor for heart failure, sudden death and ventricular dysrhythmia. Experimental data suggest that, apart from increased cardiac work load, noradrenaline may be one of the factors triggering myocardial hypertrophy. OBJECTIVE: To test the hypothesis that the extent of left ventricular hypertrophy is coupled to cardiac noradrenaline independently from the magnitude of arterial blood pressure. PATIENTS AND METHODS: Following exclusion of coronary artery disease by cardiac catheterization, cardiac noradrenaline release was measured in relation to left ventricular mass in 25 patients with arterial hypertension (HT), of whom five had left ventricular hypertrophy (HT + LVH) and 20 had normal left ventricular mass (HT - LVH), seven normotensive patients with hypertrophic cardiomyopathy (HCM) and a normotensive control group (n = 7). Noradrenaline was measured in arterial and coronary venous plasma using high-performance liquid chromatography. Coronary blood flow was quantified using the gas chromatographic argon method. Indices of left ventricular mass were calculated from the end-diastolic thicknesses of the interventricular septum and the posterior wall determined by echocardiography. RESULTS: The coronary venous plasma concentration of noradrenaline was significantly higher in HT - LVH, HT + LVH and HCM than it was in normotensives. Whereas in normotensives there was a net uptake of noradrenaline (17 +/- 10 pmol/min) across the coronary circulation, a net release of noradrenaline was observed in HT - LVH (69 +/- 26 pmol/min), in HT + LVH (121 +/- 55 pmol/min) and in HCM (341 +/- 96 pmol/min). In a multivariate linear regression analysis model, left ventricular mass correlated significantly with the net noradrenaline release rate (r = 0.64, P < 0.001), whereas arterial blood pressure as an additional independent variable did not correlate with left ventricular mass. CONCLUSION: The present data demonstrate that an increased left ventricular mass in normotensive and in hypertensive patients is closely coupled to an increased cardiac sympathetic activity, supporting the need for additional studies to determine whether adjunctive sympatholytic therapy is beneficial in patients with left ventricular hypertrophy and increased cardiac noradrenaline release.

Cardiac Catheterization↗

PubMed1997

Cardiovascular care with the new T-type calcium channel antagonist: possible role of attendant sympathetic nervous system inhibition.

DIFFERENCES AMONG TYPES OF CALCIUM ANTAGONISTS: Calcium antagonists lower blood pressure, relieve angina pectoris and improve chronic heart failure, primarily through peripheral and coronary vasodilation. The debate as to whether short-acting, long-lasting (L)-channel calcium influx antagonists of the 1,4-dihydropyridine type might be involved in excess cardiac mortality has raised new controversies with respect to the cardiac morbidity and mortality outcome for all calcium antagonists. Different pharmacodynamic effects (short-acting vasodilation inducing pulsatile sympathetic reflex stimulation) may explain differences in outcome with calcium antagonist therapies. Calcium antagonists also differ in their direct effects on the sympathetic nervous system, and on its long endocrine arm, the renin-angiotensin-aldosterone system. These differential effects relate to the cardiac conduction system and ventricular ectopic activity, to cardiac and vascular remodelling and hypertrophy, and perhaps also to the development of hypertension. L-CHANNEL CALCIUM ANTAGONISTS: Depending on their pharmacodynamic characteristics, L-channel calcium antagonists of the dihydropyridine, verapamil or diltiazem type reflexly activate the sympathetic nervous system and blunt beta-adrenoceptor-mediated calcium influx, thus eliciting negative inotropy and activation of the renin-angiotensin system. Both verapamil and diltiazem slow down pacemaker activity and atrioventricular conduction. MIBEFRADIL: The new-class T-channel blocker mibefradil exhibits vascular selectivity and induces peripheral and coronary vasodilation. There is no reflex sympathetic activation and no negative inotropic effect. It increases coronary blood flow without increasing oxygen consumption and causes a slight slowing of the heart rate, thereby inducing diastolic relaxation. The latter improves subendocardial and small artery perfusion. There is a sympatholytic effect, owing to T-channel expression in neurones, sinoatrial and atrioventricular nodes and Purkinje fibres. In experimental models, ventricular ectopic activity is reduced with mibefradil. The renin-angiotensin-aldosterone system and endothelin effects are blunted by T-channel inhibition. These and other factors reduce smooth muscle cell proliferation, hypertrophy and matrix deposition. T-type calcium channel inhibition, over and above its antihypertensive and anti-ischaemic effects, and afterload-reducing effects in chronic heart failure, offers the potential for a cardiovascular protective benefit, which may be critically related to interference with the sympathetic nervous system.

Angina Pectoris↗

PubMed2000

Postural hypotension following N-type Ca2+ channel blockade is amplified in experimental hypertension.

OBJECTIVE: To determine the relative importance of the cardiac and vascular sympathetic components of the orthostatic response to 90 degrees head-up tilt after N-type calcium-channel blockade in normotensive (sham renal cellophane wrap) and hypertensive (renal wrap) conscious rabbits. METHODS: The effects of N-type calcium-channel blockade with omega-conotoxin GVIA (omega-CTX, 10 microg/kg i.v. bolus) were assessed in the absence or presence of cardiac block by propranolol and methscopolamine. These were contrasted with the effects of alpha1-adrenoceptor antagonism (prazosin 0.5 mg/kg i.v. bolus, in the presence of cardiac block) or ganglion blockade (mecamylamine 4 mg/kg i.v. bolus). RESULTS: In vehicle (0.9% saline) treatment groups, the response to tilt consisted of a small pressor effect (4 +/- 2 and 7 +/- 1 mmHg) and tachycardia (29 +/- 6 and 17 +/- 6 beats/min) in sham (n = 6) and wrap (n = 5) rabbits, respectively. After prazosin administration (with cardiac block), there were significant falls in MAP of 3 +/- 1 and 7 +/- 2 mmHg in sham (n = 7) and wrap (n = 6) rabbits, respectively, in response to tilt omega-CTX caused postural hypotensive responses of 8 +/- 2 and 13 +/- 2 mmHg in sham (n = 6) and wrap (n = 7) rabbits, respectively, and 7 +/- 1 and 14 +/- 2 mmHg in sham (n = 7) and wrap (n = 7) rabbits with prior cardiac block. Similarly, mecamylamine caused falls in MAP of 8 +/- 1 and 10 +/- 2 mmHg in response to tilt in sham (n = 6) and wrap (n = 9) animals, respectively. CONCLUSION: Sympathetic vasoconstrictor effectors are primarily responsible for maintaining blood pressure during tilt in conscious rabbits. The postural hypotension caused by sympatholytic agents is about double in hypertensive rabbits, and N-type calcium-channel blockade is as effective as ganglion blockade at inducing this syndrome.

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Effects of chronic beta-adrenoceptor antagonism on plasma catecholamines and blood pressure in hypertension.

Plasma catecholamines were measured before and after treatment with beta-adrenoceptor antagonists in 17 hypertensive patients. Chronic treatment with beta-adrenoceptor antagonists caused substantial reductions in heart rate and intra-arterial blood pressure recorded continuously during ambulation. Before treatment, a quantitative relationship was observed between plasma norepinephrine and blood pressure and heart rate during a variety of activities; a similar relationship was also observed after chronic treatment five of six patients, suggesting that plasma norepinephrine remains an index of sympathetic activity despite the influence of beta-adrenoceptor antagonism. After treatment, plasma norepinephrine tended to be higher at any level of blood pressure, although not significantly so. Chronic treatment caused no significant change in mean resting plasma levels of norepinephrine and epinephrine. During exercise, plasma norepinephrine and epinephrine levels were significantly elevated above control after acute but not after chronic treatment. These observations do not support the hypothesis that beta-adrenoceptor antagonist drugs lower blood pressure in hypertensive man through a sympatholytic mechanism in he central nervous system or at peripheral presynaptic receptors.

Adolescent↗

PubMed1985

Regression of cardiac hypertrophy after therapy in animal hypertension.

Studies on spontaneously hypertensive rats (SHR), which represent a model of genetically determined arterial hypertension, revealed that cardiac hypertrophy can be controlled by blood pressure normalization by use of various antihypertensive drugs such as hydralazine, captopril, metoprolol, guanethidine, and alpha-methyldopa. Adrenergic influences seem to play a part except for left ventricular (LV) systolic unloading on cardiac hypertrophy, because LV hypertrophy was quantitatively less expressed after a combined therapy with both metoprolol and hydralazine than after a single hydralazine treatment, although blood pressure was not different between the groups. To study whether nifedipine can cause an already existing cardiac hypertrophy to regress, 20-week-old SHR were treated with nifedipine for a period of 20 weeks. After nifedipine treatment, LV muscle mass/body weight ratio was significantly less than before therapy (2.13 +/- 0.18 vs. 2.37 +/- 0.30 mg/g; p less than 0.05). Mass to volume ratio, i.e., quotient of LV muscle mass and LV end-diastolic volume, dropped from 3.40 +/- 0.66 to 3.07 +/- 0.30 mg/microliters (p less than 0.05) after therapy. Accordingly, an antihypertensive treatment with the calcium channel blocker nifedipine can cause an already existing LV hypertrophy in SHR to regress. Because blood pressure reduction resulting from therapy with beta-receptor-blockers, vasodilators, sympatholytic drugs, angiotensin converting enzyme inhibitors, and calcium channel blockers has qualitatively similar effects with respect to causing regression of hypertrophy, reversal of cardiac hypertrophy seems to be mainly related to the reduced LV systolic load. Specific pharmacodynamic effects may only modulate the extent of LV mass reduction along with blood pressure normalization.

Animals↗

PubMed1986

Echocardiographic evaluation of left ventricular hypertrophy.

Echocardiography represents an innovative diagnostic method in patients with mild hypertension because it allows evaluation of target organ involvement and, thus, potentially may be of value in determining which patients might most benefit from treatment. In large-scale observations of mild to moderate hypertension, the electrocardiogram and the chest x-ray film each identified approximately 5% of patients as having left ventricular hypertrophy (LVH), whereas echocardiography demonstrated this finding in almost 50%. This high sensitivity also was found in a study of young hypertensive patients (average age 28 years) among whom over 30% had left ventricular muscle wall thicknesses greater than the highest value found in age-matched normotensive controls; additionally, evidence for LVH was documented in a subgroup of young patients with labile hypertension whose blood pressure actually were normal at the time of the echocardiographic procedure. Blood pressure is not the only cause of LVH. Other factors, including heightened activity of the sympathetic nervous system and the renin axis, may be important. Thus, treatment of hypertension with agents such as diuretics or vasodilators that fail to decrease sympathetic activity, or which might even increase it, often fails to produce regression of LVH. In contrast, agents with sympatholytic properties may exhibit beneficial effects on left ventricular muscle mass that are independent of their actions on blood pressure.

Aging↗

PubMedDate not supplied

Studies on bethanidine and meobentine: direct and indirect effects of antifibrillatory drugs.

The electrophysiological effects of bethanidine and meobentine were studied on isolated canine cardiac tissues and the in situ dog heart using standard techniques. The "direct" electrophysiological effects of bethanidine (in the beta-adrenergic-blocked Purkinje fiber) resemble the effects of meobentine in the normal canine Purkinje fiber; both drugs produce use-dependent decreases of the maximum rate of depolarization of phase 0 and action potential amplitude. In addition, meobentine prolongs action potential duration (100%) of Purkinje fibers. In ventricular muscle cells, the only significant effect of meobentine is a decrease in the maximum rate of depolarization. In studies of ouabain-induced tachycardias and 24-h infarct-induced ventricular arrhythmias, bethanidine tends to increase heart rate and/or exacerbate the ectopic activity (due to its sympathomimetic effects), whereas meobentine tends to reduce heart rate and restore normal sinus rhythm. Both bethanidine and meobentine increase ventricular fibrillation threshold. This increase is evident following bethanidine injection after the subsidence of the sympathomimetic effects. Finally, moderate increases of ventricular fibrillation threshold following treatment with meobentine are accompanied by partial cardiac sympathetic blockade, as indicated by reduced chronotropic responses to stellate ganglion stimulation. The antiarrhythmic and antifibrillatory effects of bethanidine and meobentine may be explained by the use-dependent effects of these drugs on phase 0 of the action potential and by their sympatholytic actions on the autonomic nervous system. Meobentine may, in addition, exert antiarrhythmic effects by decreasing automaticity in partially depolarized cells.

Action Potentials↗

PubMed1989

The sympathetic nervous system and converting enzyme inhibition.

Angiotensin II appears to have important actions in modulating sympathetic nerve activity; conversely, sympathetic stimulation alters renin release. Drugs that inhibit angiotensin II formation would be expected then not only to offset the direct vasoconstricting and aldosterone releasing actions of this peptide but also to reduce sympathetic nerve activity. Hypertension and cardiac failure are two major conditions in which converting enzyme inhibitors have found important therapeutic roles; both are considered to be associated with increased activity of the renin-angiotensin-aldosterone and sympathetic nervous systems. However, in spite of considerable experimental evidence for a sympatholytic action of converting enzyme inhibitors, direct proof has been difficult to obtain in humans. In part, this results from the lack of any satisfactory way of assessing sympathetic activity in the clinical situation. Nevertheless, our failure to understand the pathophysiology of disease and the precise mechanism of action of drugs has not precluded exploiting the salutatory effects of inhibition of converting enzyme.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1990

Calcium antagonists in the treatment of hypertension: state of the art.

Treatment of hypertension constitutes an important part of all medical care provided in industrialized countries today. During the last three to four decades, several groups of effective and well-tolerated antihypertensive compounds have become clinically available, e.g., the thiazide diuretics, the centrally acting sympatholytic drugs, the vasodilators, and the beta-blockers. The calcium antagonists can be viewed as the latest important addition to the antihypertensive armamentarium. In this article we review briefly some of the aspects of calcium antagonist therapy that are of relevance for the treatment of arterial hypertension.

Animals↗

PubMed1993

Effects of clonidine on plasma catecholamines and neuropeptide Y in hypertensive patients at rest and during stress.

Neuropeptide Y (NPY), a potent vasoconstrictor agent reported to be released, in addition to norepinephrine (NE), by sympathetic nerve endings during stress, may contribute to the pressor response to various stimuli. The objectives of this study were to determine (a) whether plasma NPY concentrations are altered during different types of stress (cold pressor test, mental stress, and active orthostatism) and (b) whether clonidine, via its central sympatholytic effect, affects the stress-induced blood pressure, NPY, and/or catecholamine changes. Eighteen untreated patients with mild essential or borderline hypertension participated in an acute randomized, double-blind, parallel study. The blood pressure and heart rate were recorded during three control periods, each followed by either a cold pressor test (CPT), a mental stress test (MS: mental arithmetic), or active orthostatism (AO), performed in a random order. Venous blood samples for catecholamines and NPY determination were taken at the end of each control and test period. This entire procedure was repeated after oral clonidine (150 micrograms) or placebo. Before treatment, a CPT, MS, or AO increased the blood pressure to the same extent. The stress-induced increase in plasma NE was greater during AO (+99 +/- 23%) than during CPT (+35 +/- 8%) and MS (+55 +/- 12%). The stress-induced increase in plasma epinephrine was only significant during MS (+142 +/- 69%). A small but significant increase in NPY (p < 0.05) was observed during AO only (+10 +/- 7%). Compared to placebo, clonidine significantly decreased the basal blood pressure and the pressor response to CPT, but did not change the pressor response to MS and AO.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Hemodynamic and autonomic reflex effects of chronic N-type Ca2+ channel blockade with omega-conotoxin GVIA in conscious normotensive and hypertensive rabbits.

The effects of chronic administration of omega-conotoxin GVIA (omega-CTX), an N-type Ca2+ channel blocker, on hemodynamics and autonomic reflexes were studied in conscious normotensive (sham) and hypertensive (wrap) New Zealand white rabbits. During surgery, a pulsed Doppler-flow probe was implanted around the lower abdominal aorta, and both kidneys were wrapped in cellophane (wrap) or left undisturbed (sham). Rabbits were studied 4 weeks later on 5 consecutive days. On days 1-4, hemodynamics, the baroreceptor-heart-rate (HR) reflex induced by drugs and the Bezold-Jarisch-like reflex evoked by serotonin, were measured before and 2 h after administration of omega-CTX (10 micrograms/kg i.v. bolus). On day 5, hemodynamics and reflexes were again assessed, but no further omega-CTX was given. On day 1, omega-CTX caused falls in mean arterial pressure (MAP) of 17 +/- 3 and 27 +/- 5 mm Hg in sham (n = 6) and wrap (n = 11) rabbits, respectively, with tachycardia. Hindquarter vascular conductance (HVC) increased > 35% in both groups. On days 2-4, omega-CTX still caused falls in MAP; however it was progressively less than on day 1. HR and HVC did not change. After omega-CTX on day 1, there was marked attenuation of the sympathetic components and decrease in the vagal components of the baroreceptor-HR reflex curves, with HR range decreasing by > 61% in sham and wrap rabbits. These curves remained similar over the next 4 days, and were unaffected by further omega-CTX. However, omega-CTX had no effect on the vagally mediated Bezold-Jarisch-like reflex. In auxiliary experiments in vitro, omega-CTX (1 nM) inhibited sympathetic, but not vagal, responses to electrical nerve stimulation of rabbit-isolated right atria. Thus, omega-CTX is a potent hypotensive agent in normotensive and hypertensive rabbits, predominantly via a peripheral sympatholytic action with no effect on vagal-cardiac efferent activity. However, it may affect the vagal component of the baroreceptor-HR reflex by an unknown central mechanism.

Animals↗

PubMed1995

Cardiac hypertrophy in rats after intravenous administration of CI-959, a novel antiinflammatory compound: morphologic features and pharmacokinetic and pharmacodynamic mechanisms.

CI-959 is an antiallergic/antiinflammatory agent currently in development. In rats, daily bolus intravenous administration of CI-959 at doses > or = 10 mg/kg was associated with development of cardiac hypertrophy. There was no morphologic or biochemical evidence of myocyte injury, and cardiac hypertrophy rapidly reversed after treatment was discontinued. Cardiac hypertrophy was not evident when CI-959 was given orally or by continuous intravenous infusion with ALZA osmotic pumps. Maximum plasma drug concentrations (Cmax) were significantly higher when CI-959 was given by bolus intravenous injection, suggesting that cardiac effects were dependent on high Cmax concentrations. When neonatal rat cardiomyocytes were exposed to CI-959 in vitro, there was no evidence of myocyte enlargement or increased protein content. Cardiac hypertrophy was prevented by pretreatment with nonselective beta- and beta 1-selective adrenoceptor blockers as well as with central sympatholytics. beta 2- and alpha-adrenoceptor blockers were ineffective in preventing cardiac hypertrophy. Bolus intravenous CI-959 administration resulted in prolonged hypotension and associated increase in plasma catecholamine levels, with apparent inhibition of reflex tachycardia. We conclude that CI-959-associated cardiac hypertrophy in rats was not a direct drug effect but instead was probably mediated by endogenous catecholaminergic stimulation of cardiac beta 1-adrenoceptors.

Administration, Oral↗

PubMed1996

Neurons and receptors in the rostroventrolateral medulla mediating the antihypertensive actions of drugs acting at imidazoline receptors.

A group of clinically useful antihypertensive agents, including clonidine, moxonidine, and rilmenidine, are all ligands at alpha(2)-adrenergic and imidazoline (I-) receptors, the latter principally of the I1-subclass. These agents all lower blood pressure by reducing the activity of tonically active sympathoexcitatory reticulospinal neurons of the C1 area of the rostroventrolateral medulla (RVL). They tonically excite preganglionic sympathetic neurons in the spinal cord by release of L-glutamate and mediate most reflexes influencing blood pressure. The RVL contains alpha(2)-adrenergic and I1-receptors, and there is evidence to suggest that both receptors may participate in the hypotensive actions of the drugs. However, because only activation of the alpha(2)-adrenergic receptors appears responsible for somnolence, the imidazoline-receptor agonists moxonidine and rilmenidine, both relatively selective for I-receptors, may have superior clinical utility in antihypertensive therapy, since they are sympatholytic and also suppress the generation of angiotensin II.

Animals↗

PubMed1997

Prolonged cardiovascular effects of the N-type Ca2+ channel antagonist omega-conotoxin GVIA in conscious rabbits.

omega-Conotoxin GVIA (omega-CTX) is an N-type Ca2+ channel antagonist that is considered to be only partially reversible in vitro. In vivo, its effects after 24 h are unknown. To assess the duration of action of this peptide in vivo, the effects of a single intravenous injection of omega-CTX on mean arterial pressure (MAP), heart rate (HR), postural adaptation, and the baroreflex were investigated in conscious rabbits. MAP, HR, the baroreflex induced by i.v. glyceryl trinitrate (0.4-20 micrograms/kg) and phenylephrine (0.1-15 micrograms/kg) and orthostatic responses to 1 min 90 degrees head-up tilt were assessed before (0 h) and 2-168 h after administration of omega-CTX (10 micrograms/kg i.v. bolus: n = 6-9) or vehicle (0.9% saline; n = 6). Acute phase I: By 2 h after omega-CTX administration, MAP had decreased from 75 +/- 3 mm Hg to 60 +/- 2 mm Hg; HR increased from 220 +/- 7 beats/min to 249 +/- 5 beats/min (n = 9). There was marked attenuation of the baroreflex curve (HR range decreasing by 61%). By 24 h. MAP and HR had returned to control values, but the HR range was still 18% less than that of control. Phase II: MAP and HR then decreased steadily over the next 96 h to significantly lower values by 120 h after omega-CTX administration (delta-8 +/- 2 mm Hg and -29 +/- 2 beats/min, respectively; n = 6). Thereafter, MAP and HR values increased and by 168 h these parameters, and the baroreflex, were similar to control values. In response to 90 degrees tilt, there was no change in MAP at 0 h; however, 1 h after omega-CTX, significant postural hypotension was observed with decreases of 14 +/- 1 mm Hg(n = 9). Smaller orthostatic responses were still observed 48 h after omega-CTX administration: however, by 72 h, head-up tilt no longer induced a significant change in MAP. In the vehicle-treatment group, there were no changes in cardiovascular parameters during 0-168 h. Thus omega-CTX (10 micrograms/kg i.v.) causes acute hypotension, as well as postural hypotension, and has sympatholytic and vagolytic effects that are mostly reversed after 48 h in the conscious rabbit. However, a second hypotensive and bradycardic phase lasting a further 96 h ensues, suggesting that other prolonged effects from central neural or hormonal mechanisms or fluid shifts may occur.

Animals↗

PubMed2000

Antihypertensive drugs and the sympathetic nervous system.

The sympathetic nervous system (SNS) plays an important role in the regulation of blood pressure homeostasis and cardiac function. Furthermore, the increased SNS activity is a predictor of mortality in patients with hypertension, coronary artery disease and congestive heart failure. Experimental data and a few clinical trials suggest that there are important interactions between the main pressor systems, i.e. the SNS, the renin-angiotensin system and the vascular endothelium with the strongest vasoconstrictor, endothelin. The main methods for the assessment of SNS activity are described. Cardiovascular drugs of different classes interfere differently with the SNS and the other pressor systems. Pure vasodilators including nitrates, alpha-blockers and dihydropyridine (DHP)-calcium channel blockers increase SNS activity. Finally, central sympatholytics and possibly phenylalkylamine-type calcium channel blockers reduce SNS activity. The effects of angiotensin-II receptor antagonists on SNS activity in humans is not clear; experimental data are discussed in this review. There are important interactions between the pressor systems under experimental conditions. Recent studies in humans suggest that an activation of the SNS with pure vasodilators in parallel increases plasma endothelin. It can be assumed that, in cardiovascular diseases with already enhanced SNS activity, drugs which do not increase SNS activity or even lower it are preferable. Whether this reflects in lower mortality needs to be investigated in intervention trials.

Animals↗