Rafael F. Schäfers

TAMSULOSIN TREATMENT OF 19,365 PATIENTS WITH LOWER URINARY TRACT SYMPTOMS: DOES CO-MORBIDITY ALTER TOLERABILITY?

PURPOSE We compare the tolerability and blood pressure effects of 0.4 mg. tamsulosin once daily in patients with lower urinary symptoms suggestive of benign prostatic obstruction with or without concomitant disease and/or antihypertensive medication. MATERIALS AND METHODS Data from 2 open label, observational studies (study 1, 9,507 patients treated for 4 weeks and study 2, 9,858 patients treated for 12 weeks) were analyzed for global tolerability and effects on blood pressure stratifying for co-morbidity (none, diabetes, hypertension, other cardiovascular disease) and co-medication (diuretics, beta-blockers, calcium channel blockers, angiotensin converting enzyme inhibitors). RESULTS Overall 90 and 95% of patients in studies 1 and 2, respectively, reported good or very good tolerability. While global tolerability was slightly reduced in patients with concomitant disease or some forms of medication (p < 0.05), it was rated as good or very good by more than 90 and 95% of patients even in those groups. In control patients, that is those with neither co-morbidity nor co-medication, the tamsulosin induced blood pressure reductions were similar to those previously reported for placebo treatment but were statistically significant (p < 0.05). Mean additional blood pressure reductions in patients with concomitant disease or medication were not more than 2 mm. Hg. CONCLUSIONS Tamsulosin is well tolerated and has marginal effects on blood pressure in the majority of patients. It largely maintains its good global tolerability and minimal blood pressure effects in patients with cardiovascular co-morbidity or diabetes, or those on co-medication with antihypertensive agents.

Influence of adrenoceptor and muscarinic receptor blockade on the cardiovascular effects of exogenous noradrenaline and of endogenous noradrenaline released by infused tyramine

Abstract This study aimed firstly to compare the in vivo cardiovascular effects of exogenously administered and of endogenously released noradrenaline; secondly to characterize the adrenoceptors mediating these responses; thirdly to assess the influence of parasympathetic tone on the cardiovascular effects of noradrenaline. In two randomised placebo-controlled studies, healthy, young, male volunteers received intravenous (i.v.) infusions of noradrenaline at six incremental doses of 10–160 ng/kg/min and – in order to release endogenous noradrenaline – tyramine at four incremental doses of 5–20 μg/kg/min. Noradrenaline and tyramine were administered in the absence and presence of α1-adrenoceptor blockade with doxazosin (2 mg p.o.), α2-adrenoceptor blockade with yohimbine (15 mg p.o.), selective β1-adrenoceptor blockade with bisoprolol (15 mg p.o.) and muscarinic receptor blockade with atropine (15 μg/kg i.v. loading dose followed by 0.15 μg/kg/min by i.v. infusion). Vasoconstrictor effects were assessed by measurement of diastolic blood pressure (Pdiast) and myocardial effects by measurement of systolic time intervals, namely the duration of electromechanical systole corrected for heart rate (QS2c). I.v. noradrenaline increased Pdiast (Δmax 17 mmHg) and this was nearly completely suppressed by doxazosin but only slightly blunted by yohimbine. Noradrenaline also slightly shortened QS2c (Δmax –22 ms), and this was potentiated by both doxazosin and yohimbine and completely blocked by bisoprolol. I.v. tyramine reduced Pdiast (Δmax –7 mmHg), which was not affected by α1-adrenoceptor blockade, and profoundly shortened QS2c (Δmax -104 ms) which was significantly correlated with a marked increase in systolic blood pressure (Psyst) (Δmax 57 mmHg). The shortening of QS2c and the rise in Psyst were not influenced by α-adrenoceptor blockade but were antagonized by bisoprolol. Atropine potentiated the blood pressure rise and the shortening of QS2c induced by i.v. noradrenaline and converted the fall in Pdiast induced by i.v. tyramine into an increase. Thus the cardiovascular effects of exogenous noradrenaline are mainly characterized by α1-adrenoceptor-mediated vasoconstriction and the actions of endogenous noradrenaline (released by i.v. tyramine) by β1-adrenoceptor-mediated positive inotropic effects. The rise in Psyst with i.v. tyramine most likely reflects positive inotropism and not a vascular ‘pressor’ response.

Effect of the C825T Polymorphism of the G Protein β3 Subunit on the Systolic Blood Pressure–Lowering Effect of Clonidine in Young, Healthy Male Subjects

The T allele of the C825T polymorphism in the gene encoding the G‐protein β3 subunit (GNB3) is associated with hypertension. An enhanced signal transduction in response to α2‐adrenergic receptor stimulation has been shown in carriers of the T allele in vitro. We hypothesized that T allele carriers would show an enhanced antihypertensive response to stimulation of central α2‐adrenergic receptors by clonidine. We compared the response to intravenous clonidine in 30 young, healthy male subjects with and without the T allele (15 CC, 10 CT, and 5 TT). Clonidine lowered blood pressure and total peripheral resistance, lengthened the duration of electromechanical systole (QS2c), and slowed down pulse wave velocity. Carriers of the T allele showed significantly greater reductions in systolic blood pressure (P = .009; mean change ± SEM: CC, −8.9 ± 0.5; CT and TT, −10.6 ± 0.4) and total peripheral resistance (P < .0001; mean change ± SEM: CC, 40 ± 17; CT and TT, −48 ± 14) and more marked lengthening of QS2c (P = .002; mean change ± SEM: CC, 2.2 ± 0.5; CT and TT, 4.7 ± 0.6) and slowing of pulse wave velocity (P = .012; mean change ± SEM: CC, −0.25 ± 0.02; CT and TT, −0.33 ± 0.03). The results of this study suggest that the 825T allele may be a relevant pharmacogenetic marker in the use of centrally acting sympatholytic drugs.

EFFECTS OF NORADRENALINE AND NEUROPEPTIDE Y ON RAT MESENTERIC MICROVESSEL CONTRACTION

We have studied the contractile effects of the sympathetic transmitter noradrenaline and its cotransmitter neuropeptide Y (NPY) given alone and in combination on isolated rat mesenteric resistance vessels (200–300 μm diameter). Noradrenaline and NPY each concentration-dependently contracted rat mesenteric microvessels (EC50 ≈ 800 nM and 10 nM, respectively), but noradrenaline caused considerably greater maximal effects than NPY (14.3 mN vs. 3.5mN). A low antagonistic potency of yohimbine indicated that the response to noradrenaline did not involve α2-adrenoceptors, and the subtype-selective antagonists 5-methylurapidil, tamsulosin and chloroethylclonidine indicated mediation via an α1A-adrenoceptor. Shallow Schild regressions for prazosin and 5-methylurapidil indicated that an α1-adrenoceptor subtype with relatively low prazosin affinity might additionally be involved. Studies with the NPY analogues PYY, [Leu31, Pro34]NPY and NPY18–36 demonstrated that NPY acted via a Y1 NPY receptor. In addition to its direct vasoconstricting effects NPY also lowered the noradrenaline EC50 but did not appreciably affect maximal noradrenaline responses indicating possible potentiation. The potentiating NPY response occured with similar agonist potency as the direct contractile NPY effects and also via a Y1 NPY receptor. The Ca2+ entry blocker nitrendipine (300 nM) reduced direct contractile responses to noradrenaline and NPY but did not affect the potentiation response to NPY.

Genetics of arterial hypertension and hypotension

Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na+ have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the renin–angiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

The nitric oxide synthase inhibitor L-nmma potentiates noradrenaline-induced vasoconstriction: effects of the alpha2-receptor antagonist yohimbine

Objective Alpha2-adrenoceptors can be found both on vascular smooth muscle cells and on the endothelium, where they exert opposing effects on vascular tone. In vitro, the stimulation of α2-adrenoceptors on endothelial cells leads to the release of vasodilating substances like nitric oxide (NO) and prostanoids. Little is known of this mechanism in vivo. Design and methods We investigated the effects of the NO-synthase inhibitor L-NMMA (10−6 mol) and the α2-adrenoceptor antagonist yohimbine (YO, 10−10−10−6 mol) on noradrenaline (NA, 10−12−10−8 mol)-induced vasoconstriction in the forearm skin microcirculation of 16 healthy volunteers using double injection technique and laser Doppler flowmetry. Results are expressed in perfusion units (PU) as differences from baseline and control in mean ± SEM; the area under the time–response-curve was calculated (AUC). Results NA (10−8–10−12 mol) caused a marked, dose-dependent reduction in blood flow (mean effect − 745 ± 84 AUC PU;P < 0.001 versus saline). NA-induced vasoconstriction was enhanced by L-NMMA (mean effect − 916 ± 72 AUC PU;P< 0.001 versus NA). YO (10−6–10−10 mol) induced a significant, dose-dependent vasodilation (mean effect + 446 ± 110 AUC PU;P < 0.05 versus control); high doses of YO (10−6 mol) inhibited NA constriction (P < 0.001 versus NA), whereas lower doses of YO (10−8/10−10 mol) had no effect or even increased NA-induced constriction. In the presence of L-NMMA, YO (10−8 and 10−10 mol) further potentiated NA-induced vasoconstriction (mean effect − 1165 ± 108 AUC PU; NS versus NA). Conclusion These data demonstrate, that in humans in vivo, endogenous NO attenuates noradrenergic constriction. The effects of YO suggest that endothelial α2-adrenoceptors are involved in the release of NO and other vasodilating substances. Furthermore, there is an additive NO-independent vasodilation, which can be unmasked by L-NMMA.

Haemodynamic characterization of young normotensive men carrying the 825T-allele of the G-protein beta3 subunit.

A C825T polymorphism was recently identified in the gene for the G-protein beta3 subunit, the T-allele being associated with hypertension. To better understand the underlying pathophysiological mechanisms, we compared the haemodynamics of young healthy males with and without the T-allele. In three studies, subjects were investigated with regard to cardiac and vascular function at rest and following intravenous administration of the beta-adrenoceptor antagonist, propranolol, and the alpha2-adrenoceptor agonist, alpha-methylnoradrenaline, and with regard to local venous vasoconstriction in the dorsal hand vein in situ following infusion of the alpha2-adrenoceptor agonist, azepexol. alpha2-Adrenoceptor agonists were chosen as vasoconstrictor drugs since alpha2-adrenoceptors couple to pertussis toxin (PTX)-sensitive G-proteins and since in-vitro studies have demonstrated enhanced signal transduction of PTX-dependent pathways in the presence of the T-allele. Total peripheral resistance was determined as a parameter of vasoconstrictor tone and heart rate, stroke volume and systolic time intervals for cardiac function. T-allele carriers had a significantly elevated stroke volume and lower total peripheral resistance at baseline. After propranolol, their fall in stroke volume was significantly greater. During alpha-methylnoradrenaline infusion, elevation of total peripheral resistance was not increased relative to controls. Similarly, the constriction response of the dorsal hand vein to azepexol was not different. Our study does not support the idea of increased vasoconstrictor tone in T-allele carriers either at rest or during stimulation of alpha2-adrenoceptors. However, this allele may be associated with elevated cardiac stroke volume.

Venous response to nitroglycerin is enhanced in young, healthy carriers of the 825T allele of the G protein β3 subunit gene (GNB3)

The ultimate mode of action by which nitroglycerin elicits vasodilation remains elusive. Animal studies point to an involvement of pertussis toxin–sensitive G proteins. The 825T allele of the GNB3 C825T polymorphism in the gene encoding the G protein β3 subunit is associated with enhanced signal transduction via pertussis toxin–sensitive pathways in vitro. We hypothesized that G proteins have a role in nitroglycerin‐mediated vasodilation and that carriers of the 825T allele would exhibit a stronger response to nitroglycerin.

Effects of systemic endothelin A receptor antagonism in various vascular beds in men: in vivo interactions of the major blood pressure-regulating systems and associations with the GNB3 C825T polymorphism.

We used the orally available endothelin A (ETA) receptor antagonist darusentan to characterize interactions between the major blood pressure‐regulating systems in healthy men. Mediators of the endothelin system, the sympathetic nervous system, and the renin‐angiotensin system act via G protein‐coupled receptors with a possible involvement of the G‐protein β3 subunit (GNB3) C825T polymorphism. We studied the influence of this polymorphism on the responses to ETA antagonism in the presence of endothelin 1 (ET‐1), norepinephrine (NA), and angiotensin II (ANGII).

Modulation of noradrenaline-induced microvascular constriction by protein kinase inhibitors.

Abstract. We have tested the role of various protein kinases in noradrenaline-induced, α1A-adrenoceptor-mediated constriction of mesenteric and intrarenal rat microvessels. The protein kinase C inhibitors, H7 and staurosporine, inhibited constriction in both vessel types in concentrations which also inhibit myosin light chain kinase. The more selective protein kinase C inhibitors, bisindolylmaleimide I and Gö 6976, did not inhibit microvessel constriction in concentrations selective for protein kinase C. Moreover, the protein kinase C-activating phorbol ester, phorbol-12-myristate-13-acetate, did not cause constriction. The tyrosine kinase inhibitors, genistein and tyrphostin 23, inhibited constriction in concentrations compatible with tyrosine kinase inhibition. An inhibitor of the extracellular signal-regulated kinase cascade, PD 98059, also caused concentration-dependent inhibition. While chelation of extracellular Ca2+ abolished noradrenaline-induced constrictions, the Ca2+-ATPase inhibitor, thapsigargin, had no effects. We conclude that tyrosine kinases and extracellular signal-regulated kinase (but not protein kinase C) may be involved in noradrenaline-induced rat mesenteric and intrarenal microvessel constriction but this appears to occur independently of an effect on sarcoplasmic Ca2+ storage.