Significant food interactions observed with a nifedipine modified-release formulation marketed in the European Union.

The objective of this study was to compare the rate and extent of nifedipine bioavailability after single dose administration of Adalat OROS 30 (Reference) and Nifedipine Sandoz retard 30 tablets (Test). Both modified release formulations are marketed in Member States of the European Union. Prior to the clinical study the in vitro dissolution characteristics were investigated. There was a significant pH dependency observed with the Test product but drug release with the Reference product was almost independent of the experimental conditions used. In the subsequent open, randomized, controlled, 4-way crossover study both pharmaceutical products were administered to 28 healthy male volunteers, either after fasting overnight or immediately after a high-fat American breakfast. Blood sampling was performed over 48 hours post-dose for the determination of pharmacokinetic profiles of nifedipine. Considerable differences were observed between the two formulations when administered to fasted subjects where maximum nifedipine plasma concentration (C(max)) were higher in the case of the Test formulation. Differences were even more pronounced after a high-fat American breakfast. Under these conditions a significant food interaction was detected in the case of Nifedipine Sandoz retard 30 with a three-fold increase in the mean C(max) when compared to values obtained in fasting subjects. In contrast, food intake had no clinically relevant effect on bioavailability of nifedipine (rate and extent) in the case of Adalat OROS 30. The pharmacokinetic findings in this study were reflected in the adverse event pattern which indicated a potential tolerability problem in the case of Nifedipine Sandoz retard 30. The results confirm the relationship between the in vitro dissolution profile results and the effects of the drug in vivo. Dose dumping after intake of a high-fat meal could be shown. Nifedipine Sandoz retard 30 is not bioequivalent to Adalat OROS 30 and produced highly variable and poorly predictable nifedipine plasma concentrations. The differences observed between the two products investigated may have direct therapeutic relevance when switching from one formulation to the other and, in particular, when administration conditions change i.e. administration in the fasting state and administration with a meal, since the pharmacological and therapeutic actions of nifedipine are closely associated with the concentration.

Vasopressin receptor antagonists: pharmacological tools and potential therapeutic agents.

The present survey deals with the development and applications of non-peptidergic vasopressin receptor antagonists. The existence of at least three vasopressin receptors (V(1), V(2) and V(3) respectively) is firmly established. V(1)-receptors play a relevant role in the regulation of vascular tone, whereas V(2)-receptors are known to mediate the antidiuretic activity of vasopressin at the level of the renal collecting ducts. The V(3)-receptor appears to be involved in the release of the adreno-corticotropic hormone. Vasopressin receptor antagonists which are peptides have been known for several decades, more recently, both V(1)- and V(2)-receptor blockers which are non-peptidergic have been introduced, as well as agents with affinity for both V(1)- and V(2)-receptor subtypes. A survey of these non-peptidergic antagonists is presented here. Such compounds are useful as pharmacological tools, and they can also be thought of as therapeutic agents as therapeutic agents in cardiovascular and renal diseases. Selective V(1)- and V(2)-receptor antagonists were used to study the interaction between vasopressin receptors and sympathetic neurones. Depending on the experimental model used this interaction can occur at either the pre- or postsynaptic sites. In both cases predominantly V(1)-receptors are involved. A brief survey is given of the potential use of V-receptor antagonists in the drug therapy of syndrome of inappropriate antidiuretic hormone secretion and other water retaining disorders, congestive heart failure and certain forms of hypertension (in particular in the Negroid hypertensive patients).

Angiotensin II receptor antagonists (AT1-blockers, ARBs, sartans): similarities and differences.

A survey is presented of the registered non-peptidergic angiotensin II receptor antagonists (AT1 blockers, ARBs, sartans) and their general properties and similarities. Accordingly, their receptor profile, pharmacokinetic and therapeutic applications are discussed. In addition, attention is paid to the individual characteristics of the AT1 blockers now available. A few components of this category offer additional potentially beneficial properties, owing to their pharmacological or metabolic characteristics. Such additional properties are critically discussed for eprosartan, losartan, telmisartan and valsartan.

The metabolic syndrome - background and treatment.

The metabolic syndrome (MBS) is characterised by a clustering of cardiovascular and metabolic risk factors. This syndrome is now widely recognised as a distinct pathological entity, and it is receiving a great deal of attention in the medical literature but also in the lay press. Globally speaking, persons with MBS have a clustering of the following risk factors: [List: see text] MBS is associated with important cardio/cerebrovascular and metabolic risks. Prevention and treatment are therefore of great importance. Preventive measures involving lifestyle are mandatory. In addition, MBS patients require pharmacological treatment, usually for the rest of their lives. Complex patterns of drug treatment will be required, since all the different, heterogenous pathophysiological problems will require appropriate treatment. After an introduction to MBS, this article provides an extensive and critical review of the drug treatment of this complex pathological entity.

The influence of antihypertensive drug treatment on the prevention and regression of left ventricular hypertrophy.

Left ventricular hypertrophy (LVH) has been recognized as an important cardiovascular risk factor. Hypertensive disease is the most frequent background of LVH and it is generally felt that anti-hypertensive treatment should not only lower blood pressure but also cause regression of LVH. In the present survey the patho-physiology of LVH, its measurements and animal models used to study LVH are briefly discussed. Subsequently, the effects of various drugs in animal models and in human hypertensives are reviewed. It has been shown repeatedly that various types of antihypertensive drugs show differential activities on the prevention or regression of LVH. It is not only the lowering of blood pressure which determines the anti-LVH activity, but also the interaction of drugs with neuro-endocrine mechanisms such as the renin-angiotensin-aldosterone system and the sympathetic nervous system.

Effects of losartan on vasoconstrictor responses to angiotensin II in the forearm vascular bed of healthy volunteers.

OBJECTIVES: The angiotensin type 1 (AT1) receptor antagonist, losartan (orally administered), decreases vasoconstrictor effects of angiotensin II (Ang II). Oral losartan is converted into the active metabolite, Exp3174, which causes most of the antagonistic effects. Effects of losartan as such have not been studied after its intra-arterial administration in humans. Therefore, we investigated the effects of both intra-arterially and orally administered losartan on AT1-receptor-mediated vasoconstriction. METHODS: Forearm vascular resistance (FVR) was determined by venous occlusion plethysmography in 24 healthy subjects. Ang II (0.01, 0.1, 1.0, and 10.0 ng/kg/min) was infused into the brachial artery, before and after losartan, administered intra-arterially (dose range 100-3000 ng/kg/min) or orally (50 mg once daily for 5 days). RESULTS: Ang II concentration-dependently increased FVR (P < 0.05); tachyphylaxis did not occur. Losartan alone did not change FVR. Intra-arterially infused losartan dose-dependently inhibited Ang-II-induced vasoconstriction. At a concentration of 10(-8) M Ang II, losartan reduced FVR, as a percentage of baseline values, from 287 +/- 30 to 33 +/- 8% (mean +/- s.e.m.; P < 0.05). Orally given losartan reduced FVR from 297 +/- 40 to 73 +/- 19% (P < 0.05). CONCLUSIONS: Losartan, intra-arterially administered, causes no effect on baseline vascular resistance, but markedly inhibits Ang-II-induced vasoconstriction in the human forearm vascular bed. Relatively high doses of intra-arterial losartan were required when compared to the antagonism by the orally administered drug. These data indicate that Ang-II-induced vasoconstriction is mediated by AT1-receptors, which are blocked by losartan. The more effective antagonism exerted by oral losartan is presumably explained by the formation of Exp3174. Endogenous Ang II does not contribute to baseline vascular tone in healthy, sodium-replete, subjects.

Calculation of plasma concentrations of intra-arterially infused compounds in forearm plethysmography.

OBJECTIVE: Forearm blood flow plethysmography is a widely accepted in vivo technique for pharmacologic and functional studies in peripheral resistance vessels and veins. Pharmacological effects on forearm blood flow (FBF) are usually expressed by means of dose-response relationships. This approach does not consider the influence of variations in FBF on the actual plasma concentrations of compounds infused, and is less suitable for quantitative comparison of the pharmacologic characteristics of different compounds. The aim of this study was to validate an equation to estimate the plasma concentrations of intra-arterially infused compounds. This was done at different levels of FBF, using an indicator dilution technique with constant rate infusions of indocyanine green (ICG) and inulin. METHODS: ICG (0.5 mg/min) and insulin (5 mg/min) were infused into the brachial artery in the presence of sodium nitroprusside (10 ng/kg/min; to obtain high FBF), vehicle (0.9% saline; for intermediate FBF), and methoxamine (1 microgram/kg/min; for low FBF), FBF was measured using venous occlusion plethysmography in six healthy male volunteers. Plasma concentrations of the indicators, measured in venous blood samples, were compared with the calculated values. RESULTS: Excellent correspondence was observed between calculated and measured plasma concentrations for both ICG and inulin. Venous plasma concentrations of ICG (> or = 95% protein binding) reached steady-state within four min independent of FBF. Alternatively, the time required for venous plasma concentrations of inulin (not bound to protein) to reach steady-state appeared dependent on FBF. CONCLUSION: Total plasma concentrations of intra-arterially infused drugs can be appropriately estimated at the level of the arterioles by the proposed equation.

Cardiac sympathetic neuronal function in left ventricular volume and pressure overload.

OBJECTIVES: In heart failure cardiac sympathetic neuronal function and activity appear to be altered. Although these changes are widely accepted, controversy exists concerning the neurohormonal changes occurring in pressure and volume overloaded hearts. The present study in rabbits was performed to assess the effects of mechanical overload on cardiac sympathetic neuronal function and beta-adrenoceptor density, in relation to left ventricular function. METHODS: In nine rabbits the aortic valve was perforated to induce left ventricular volume overload. Pressure overload was induced by suprarenal banding of the aorta abdominalis (group 1). Five animals were sham operated (group 2). Subanalysis of group 1 was performed for non-failing (n = 5) and failing (n = 4) hearts. Heart failure was defined as any reduction in left ventricular fractional shortening 2 weeks after the second operation compared to baseline. RESULTS: In animals with cardiac overload, left ventricular weight was higher compared with the control animals, 7.99 +/- 1.13 vs. 6.16 +/- 0.86 g (P < 0.02). Left ventricular end diastolic diameter increased from 1.35 +/- 0.16 to 1.57 +/- 0.15 cm (P < 0.005) after surgically induced overload. Left ventricular end systolic diameter and fractional shortening did not change significantly. Myocardial noradrenaline (NA) concentration and beta-adrenoceptor density were significantly lower in group 1 than in group 2, 1005 +/- 393 vs. 1643 +/- 109 ng/g (P < 0.02) and 167 +/- 36 vs. 224 +/- 36 fmol/mg protein (P < 0.03), respectively. Myocardial [123I]-MIBG uptake did not significantly differ between group 1 and 2, 2.1 +/- 0.58 vs. 1.8 +/- 0.44 (%ID/g x kg). A significant positive correlation between myocardial NA concentration and beta-adrenoceptor density was found (r = 0.66, P < 0.02). Myocardial NA concentration was inversely related to left ventricular weight (r =-0.75, P < 0.003). CONCLUSION: The present data indicate that in a condition of cardiac volume and pressure overload, sympathetic activity is enhanced as shown by myocardial noradrenaline depletion and beta-adrenoceptor downregulation. In contrast, no cardiac neuronal dysfunction is observed, even in the stage of early heart failure.

The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine.

Clonidine (Catapres, Catapresan), guanfacine (Estulic), and methyldopa (Aldomet) are the prototypes of centrally acting antihypertensive drugs. Clonidine and guanfacine are lipophilic drugs that readily penetrate into the brain, where they stimulate alpha-adrenergic receptors in the pontomedullary region. The stimulation of these central alpha-adrenergic receptors has been shown to activate an inhibiting neuron, which causes a reduction of peripheral sympathetic tone and a subsequent fall in arterial blood pressure and heart rate. Both a centrally initiated reduction of vagus reflex activity and the activation of presynaptic alpha 2-adrenergic blocking agents in the heart may contribute to the bradycardia. Studies indicate that methyldopa also penetrates into the brain, where it is converted into alpha-methylnorepinephrine. This amine may stimulate the same central alpha-adrenergic receptors as those activated by clonidine, which will result in a hypotensive effect. Possibly, alpha-methyldopamine might also play a role. Accordingly, the modes of action of clonidine and alpha-methyldopa probably are very similar at a basic level. The central adrenergic receptors probably are located postsynaptically. Their receptor demand corresponds more closely to that of the alpha 2-subtype. Central alpha 1-adrenergic receptors might possibly play a part in the modulation of vagally induced baroreflex bradycardia. A discussion on the pharmacological basis of the side effects of the centrally acting antihypertensives has been limited to those adverse reactions that are somehow related to alpha-adrenergic receptors. Sedation, a common side effect, appears to be mediated by central alpha 2-adrenergic receptors, at least in animal models.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacology of calcium entry blockers: interaction with vascular alpha-adrenoceptors.

The pharmacology of calcium entry blockers (CEB), as used in various types of cardiovascular disease, is reviewed. Their vasodilator potency is analyzed, which is the most common therapeutic characteristic of all CEB, apart from the antiarrhythmic activity of verapamil. All CEB relax vascular smooth muscle, particularly in arteriolar beds, thus reducing peripheral vascular resistance. Arteriolar relaxation appears to be associated with inhibition of transmembrane calcium influx. Recent studies have demonstrated that vasoconstriction induced by stimulation of vascular postsynaptic alpha 2-adrenoceptors, using selective agonists, is reduced by CEB through a noncompetitive mechanism. However, vasoconstriction evoked by selective excitation of vascular alpha 1-adrenoceptors remains virtually uninfluenced by CEB. The selective interference of CEB with alpha 2-adrenoceptor stimulation suggests that calcium movement is associated with alpha 2-adrenoceptor stimulation. This mechanism may further contribute to the vasodilator effect of CEB by inhibiting that part of vascular tone evoked by the stimulation of alpha 2-adrenoceptors by endogenous catecholamines.

Regional vascular effects of serotonin and ketanserin in young, healthy subjects.

The local hemodynamic effects of serotonin (5-hydroxytryptamine; 5-HT) and the selective 5-HT2 antagonist ketanserin were investigated in the forearm of 20 healthy volunteers. Single doses of 5-HT (0.1-80 ng/kg/min) and ketanserin (5-125 ng/kg/min) were administered intra-arterially. The relative alpha 1-adrenergic receptor and 5-HT2 blocking potencies of ketanserin were investigated using intra-arterial infusions of cumulative doses of methoxamine (0.1, 0.3, and 0.5 microgram/kg/min), tyramine (0.25, 0.50, and 1.25 microgram/kg/min), and 5-HT (10, 30, and 80 ng/kg/min) together with a low dose (5 ng/kg/min) and a high dose (50 ng/kg/min) of ketanserin. Forearm blood flow was measured by venous occlusion plethysmography. Heart rate and intra-arterial blood pressure were recorded semicontinuously. Intra-arterial infusion of 5-HT induced an initial transient vasodilatation, followed by a steady vasodilatation for the low doses of 5-HT (0.1-10 ng/kg/min; p less than 0.05). A steady vasoconstriction was only obtained at the highest dose of 5-HT. Ketanserin induced a dose-dependent increase in forearm blood flow from 15 ng/kg/min (p less than 0.05) onward. The vasodilatation induced by 5-HT (1 ng/kg/min) was significantly enhanced by ketanserin (125 ng/kg/min; p less than 0.05), whereas the vasoconstriction elicited by 5-HT (80 ng/kg/min) was reversed by ketanserin (50 ng/kg/min; p less than 0.05), thus confirming that 5-HT2 receptors were stimulated by 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo characterization of muscarinic receptor subtypes that mediate vasodilatation in patients with essential hypertension.

Attenuated cholinergic vasodilatation has been suggested as an endothelium-related mechanism involved in essential hypertension. We investigated the role of muscarinic (M) receptor subtypes in the forearm resistance vasculature. In eight white men with essential hypertension and eight matched normotensive control subjects (age of both groups, 47 +/- 4 years; mean +/- SEM), we infused the nonselective agonist methacholine in the presence of saline and the antagonists atropine (nonselective), pirenzepine (M1-selective), and AF-DX 116 (M2-selective) into the brachial artery and measured forearm blood flow and forearm vascular resistance using venous occlusion plethysmography. Affinity constants (pKb values) were determined from calculated plasma concentrations of the infused compounds and EC50 values. Sodium nitroprusside was given as an endothelium-independent control, and minimal forearm vascular resistance after 10 minutes of ischemia was used as a marker of structural vascular changes. Hypertensive patients showed higher minimal forearm vascular resistance, indicating structural vascular changes. However, sodium nitro-prusside- and methacholine-induced vasodilatation was similar in both groups, with apparent EC50 values (log moles per liter; mean +/- SEM) of -7.32 +/- 0.13 and -7.51 +/- 0.21 in hypertensive patients and -7.37 +/- 0.13 and -7.45 +/- 0.02 in control subjects, respectively. Atropine, pirenzepine, and AF-DX 116 caused a shift to the right of the concentration-response curve of methacholine, with apparent pKb values of 8.63 +/- 0.08, 6.81 +/- 0.13, and 5.51 +/- 0.29 in hypertensive individuals and 8.62 +/- 0.10, 6.98 +/- 0.08, and 5.49 +/- 0.09 in control subjects, respectively. Again, there were no statistically significant differences in these pharmacological parameters between hypertensive patients and normotensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

The acute and chronic antihypertensive effects of ketanserin cannot be explained by blockade of vascular serotonin, type 2, receptors or alpha 1-adrenergic receptors.

The mechanism underlying the antihypertensive effect of acute and chronic administration of ketanserin was investigated in eight hypertensive patients. Intrabrachial artery infusions of serotonin and the selective alpha 1-adrenergic receptor agonist methoxamine were given before and 1 hour after a single oral dose of 20 mg ketanserin and after 4 weeks of treatment with 20 to 40 mg twice daily. Blood pressure was reduced by ketanserin both after the initial dose (p less than 0.01) and after 4 weeks of treatment (p less than 0.01). During placebo, serotonin, 1 ng/kg/min, increased forearm blood flow by 51% +/- 9% (p less than 0.01), whereas the highest dose induced a decrease in flow (-33% +/- 6%; p less than 0.01). Methoxamine elicited a vasoconstriction (p less than 0.001). These effects of serotonin and methoxamine were not influenced by either the initial dose of ketanserin or after 4 weeks of treatment. It is concluded that serotonin cannot be considered a general endogenous pressor agent in these patients. The antihypertensive effects of ketanserin cannot be attributed to either vascular alpha 1-receptor or serotonin, type 2, receptor blockade.

Role of alpha adrenoceptors in hypertension and in antihypertensive drug treatment.

Recent plethysmographic experiments suggest that both postsynaptic alpha 1 and alpha 2 adrenoceptors in human resistance vessels play an important role in the maintenance and regulation of vascular tone. Central alpha 2 adrenoceptors are assumed to be involved in the central regulation of blood pressure. Radioligand binding studies on the density and characteristics of alpha adrenoceptors have not revealed consistent differences between normotensive and hypertensive subjects, with the exception of pheochromocytoma, in which a consistent down regulation of alpha 2 adrenoceptors in thrombocytes has been demonstrated. The radioligand binding studies are limited, since they cannot be performed on vascular tissues. Alpha adrenoceptors are vitally important as targets of several antihypertensive drugs; the activities of these agents and the principles and clinical relevance of mechanisms involving alpha adrenoceptors are reviewed.

Specific binding of threo 1-(1-[2-(1,4-benzodioxane-2-yl)-2-hydroxyethyl]4-piperidyl)-2-benzimidazolinone (R 29814), to rat brain membranes.

The binding of 3[H]R 29814, the pharmacologically less active threoisomer of the potent hypotensive agent erythro-R 28935, was assayed in rat brain membranes and compared with published data on 3[H]R 28935 binding. The 3[H]R 29814 bound to homogenates of rat brain with one saturable component with high affinity (KD = 1.1 nM). The specific binding was rapid and reversible. It was not affected by sodium or magnesium ions, or by guanosine triphosphate. The maximum number of binding sites amounted to approximately 135 fmol/mg protein. The drug specificity of the 3[H]R 29814 binding site was not associated with that of any known drug recognition site, but corresponded to that of erythro 3[H]R 28935. A linear relationship was derived between the affinities of drugs for inhibiting 3[H]R 29814 and 3[H]R 28935 binding. The results suggest that identical sites were labeled by 3[H]R 29814 and 3[H]R 28935 in rat brain membranes with comparable affinity. Since the hypotensive activities of R 29814 and R 28935 greatly differ, it is concluded that the high affinity binding sites of 3[H]R 29814 as well as those of 3[H]R 28935 are not compatible with the sites responsible for the hypotensive effect.

Central imidazoline (I1) receptors as targets of centrally acting antihypertensives: moxonidine and rilmenidine.

Clonidine, guanfacine, guanabenz and alpha-methyl-dioxyphenylalanine (DOPA), the prototypes of centrally acting antihypertensives, are assumed to induce peripheral sympathoinhibition and a reduction in blood pressure via the stimulation of alpha2-adrenoceptors in the brain stem. More recently, central imidazoline (I1)-receptors have been recognized to be another target of centrally acting antihypertensive drugs. Clonidine is considered to be a mixed agonist that stimulates both alpha2- and I1-receptors. Moxonidine and rilmenidine are considered to be moderately selective I1-receptor stimulants, although it still remains unknown whether these agents act directly on the receptor as genuine agonists. A survey is given on the location, characteristics and functional aspects of imidazoline I1-receptors as targets of centrally acting antihypertensives. Furthermore, the pharmacology and clinical potential of selective I1-receptor agonists such as moxonidine and rilmenidine are discussed. Although far from perfect, these compounds have shown that it may potentially be possible to develop agents with which the well-known side effects caused by alpha2-receptor agonists can be separated from the central antihypertensive mechanism.

Beneficial interactions between pharmacological, pathophysiological and hypertension research.

The treatment of essential hypertension continues to be carried out by drugs, combined with the adaptation of life style. The development of various types of antihypertensive drugs has not only greatly improved the management of hypertension, but also offered significant methodological sophistication of the pharmacological and pathophysiological sciences. Antihypertensive drugs and related experimental agents have been widely used in pharmaco-logical and pathophysiological research. The beneficial effects of such agents will be illustrated by means of several examples, emphasizing the sympathetic nervous system, the renin-angiotensin-aldosterone system, and calcium homeostasis as major targets. As pharmacological tools, which are also antihypertensives, we discuss various types of centrally acting antihypertensives, ganglionic and peripheral neuronal blocking agents, alpha- and beta-adrenoceptor antagonists, angiotensin converting enzyme (ACE)-inhibitors, renin-inhibitors, angiotensin II-receptor antagonists (AT1-blockers) and calcium antagonists. Finally, a few remarks will be made concerning the beneficial therapeutic effects of classic and newer antihypertensive drugs, such as beta-blockers, diuretics, calcium antagonists, ACE-inhibitors and AT1-blockers.

Characterization of the muscarinic receptors in the mesenteric vascular bed of spontaneously hypertensive rats.

OBJECTIVE: The nature of the muscarinic (M) receptor subtype mediating endothelium-dependent vasodilation was investigated in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). DESIGN: Characterization of the muscarinic receptor mediating vasodilation and the possible hypertension-induced effects on the nature of this receptor, which have both received little attention in resistance vessels of the SHR. METHODS: After a methoxamine-induced vasoconstriction, the vessels were dilated with acetyl-beta-metacholine (MCh). The MCh-induced vasodilation was analysed by means of the M1-selective antagonist pirenzepine, the M2-selective antagonists AF-DX116 and AQ-RA 741 and the M3-selective antagonists 4-DAMP and p-FHHSiD. The potency of these compounds was quantified by means of pA2 values. Atropine, a non-selective muscarinic antagonist, was used for comparison. RESULTS: The rank order of potency for the muscarinic receptor antagonists in preparations taken from SHR and WKY rats appears to be atropine > 4-DAMP > p-FHHSiD > pirenzepine > AQ-RA 741 > AF-DX 116. This rank order corresponds to that found in isolated conduit arteries. CONCLUSIONS: The pA2 values for the various compounds were not significantly different in SHR and WKY rat preparations, indicating that the nature of this receptor is not influenced by hypertension. The high potency of the M3-selective drugs and the weak activity of pirenzepine and the M2-selective antagonists suggest a major role of M3-receptors in the cholinergic vasodilation in the perfused mesenteric vascular bed both in SHR and WKY rat preparations.

The differential time courses of the vasodilator effects of various 1,4-dihydropyridines in isolated human small arteries are correlated to their lipophilicity.

OBJECTIVES: To investigate a possible relationship between the time courses of action of various calcium antagonists and their lipophilicity, characterized as log P-values. METHODS: The functional experiments were performed in vitro in human small subcutaneous arteries (internal diameter 591 +/- 51 microm, n = 7 for each concentration), obtained from cosmetic surgery (mamma reduction and abdominoplasty). The vessels were investigated in an isometric wire myograph. The vasodilator effect of the calcium antagonists was quantified by means of log IC50-values, and the onset of the vasodilator effect for each concentration studied was expressed as time to Eeq90-values (time to reach 90% of the maximal effect). RESULTS: Log IC50-values were -8.46 +/- 0.09, -8.33 +/- 0.25 and -8.72 +/- 0.16 for nifedipine, felodipine and (S)-lercanidipine, respectively (not significant). On average, nifedipine reached time to Eeq90 in 11 +/- 1 min. For felodipine and (S)-lercanidipine the corresponding values were 60 +/- 11 min and 99 +/- 9 min, respectively. The differences between these values were statistically significant (P< 0.01). In spite of these differences in the in-vitro human vascular model, the three calcium antagonists are equipotent with regard to their vasodilator effects. Linear regression analysis of the correlation between the logarithm of the membrane partition coefficient (log P-values) of the calcium antagonists tested [2.50, 4.46 and 6.88 for nifedipine, felodipine and (S)-lercanidipine, respectively] and their respective values found for time to Eeq90 was highly significant. CONCLUSIONS: It appears that a higher log P-value is correlated with a slower onset of action.

Impaired inotropic response to alpha 1- but not to beta-adrenoceptor stimulation in isolated hearts from spontaneously hypertensive rats.

OBJECTIVES: Hypertension in humans and experimental animals is known to be associated with an increase in left ventricular myocardial mass. The development of cardiac hypertrophy is not caused by increased blood pressure alone; the autonomic nervous system may also play an important role. DESIGN: The functional responses to the beta-adrenoceptor agonists isoprenaline, dobutamine, salbutamol and terbutaline, and the alpha 1-adrenoceptor agonists methoxamine, cirazoline and phenylephrine were studied in isolated (Langendorff) hearts from spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) controls. The results were compared with data from radioligand binding experiments. RESULTS: There was no significant difference in the increase of left ventricular pressure induced by all beta-adrenoceptor agonists studied in SHR and WKY rat hearts. Although there was no significant difference in the response to phenylephrine, the inotropic responses to cirazoline and methoxamine proved to be significantly weaker in hearts from SHR than in those from WKY rats. Binding experiments with 3H-prazosin revealed no differences in density or affinity for cardiac tissues from SHR and WKY rats. CONCLUSIONS: Long-standing hypertension leads to an impaired response of the isolated heart to alpha 1-adrenoceptor stimulation, without changes in alpha 1-receptor density or affinity. It seems likely that changes in postreceptor events are responsible for the impaired inotropic response to alpha 1-adrenoceptor agonists in hearts from SHR.