The beta-blocker nebivolol is a racemic mixture of D- and L- enantiomers that displays negative inotropic as well as direct vasorelaxant activity. In addition, it has been proposed that nebivolol ...exerts endothelium-protective effects caused by its antioxidant properties. In the present study we investigated the effect of D-, L-, and d/l-nebivolol on reactive oxygen species (ROS)-induced endothelial damage and compared it with carvedilol and metoprolol. Isolated rat aortic rings were exposed to ROS by electrolysis of the organ bath medium. Before and after electrolysis, endothelial function was measured by preconstricting the vessels with phenylephrine followed by the addition of methacholine. Carvedilol and nebivolol protected against ROS-induced endothelial damage, whereas metoprolol did not. The protective effect of nebivolol proved not to be stereoselective. Furthermore, we attempted to determine whether nebivolol acts a scavenger itself or whether another mechanism is involved. By means of HPLC measurements it was shown that nebivolol concentrations were decreased after exposure to electrolysis-induced ROS, thus indicating that nebivolol is degraded by its reaction with ROS. Functional experiments, in the rat aorta, demonstrated that exposure of nebivolol to ROS also affects its vasodilator activity. In conclusion, the present study demonstrates that nebivolol alleviates ROS-induced impairment of endothelium-dependent vasorelaxation. This protective effect is very likely the result of a direct ROS-scavenging action by the nebivolol molecule itself.
In the pithed rat model, endogenously generated angiotensin (Ang) II can enhance sympathetic neurotransmission by acting on Ang II type 1 (AT1) receptors that are located on sympathetic nerve ...terminals.
To compare the inhibitory potency of candesartan, valsartan, eprosartan and embusartan in blocking presynaptically and postsynaptically located AT1 receptors.
To investigate blockade of presynaptic AT1 receptors, we studied the effect of AT1 receptor blockade on the sequelae of electrical stimulation of the thoracolumbar sympathetic outflow (0.25-8 Hz). To investigate the interaction between postsynaptic AT1 blockers and alpha-adrenoceptors, the effects of these compounds on pressor responses to exogenous noradrenaline were determined. To investigate blockade of postsynaptic AT1 receptors, we studied the effect of the AT1 antagonists on dose-response curves elicited by exogenous Ang II.
The stimulation-induced increase in diastolic blood pressure (DBP) and the Ang II-elicited DBP response were dose-dependently reduced by all AT1 receptor blockers. Interestingly, the greatest doses of the AT1 antagonists caused less than maximal reduction in the stimulation-induced increase in DBP, resulting in a U-shaped dose-response relationship. To compare sympathoinhibitory potencies, the doses that, at 2 Hz, reduced the change in DBP by 20 mmHg (ED20 values, expressed as -log mol/kg) were calculated; they were 5.50 +/- 0.12, 5.77 +/- 0.10, 6.32 +/- 0.12 and 5.62 +/- 0.13 for valsartan, candesartan, eprosartan and embusartan, respectively. The order of potency, therefore, was eprosartan> valsartan = candesartan = embusartan (where > signifies P < 0.05). To compare the order of potency for inhibition of the Ang II-induced increase in DBP, we calculated pA2 values (the X intercept in Schild regression). They were 7.20 +/- 0.17, 8.01 +/- 0.01, 7.20 +/- 0.03 and 7.25 +/- 0.16, for valsartan, candesartan, eprosartan and embusartan, respectively. Accordingly, the order of potency for inhibition of the direct pressor effects of Ang II was candesartan> valsartan = eprosartan = embusartan (where > signifies P < 0.05).
In the pithed rat, the effects on DBP of stimulation of the thoracolumbar spinal cord are partly dependent on endogenously formed Ang II. These effects can be counteracted by blockade of presynaptically located AT1 receptors. No interaction was found between postsynaptically located AT1 receptors and alpha-adrenoceptors. The order of potency of the agents tested for sympathoinhibition clearly differed from that for inhibition of the direct pressor effects of Ang II. These findings suggest considerable differences in affinity of the various AT1 blockers for pre- and postsynaptic AT1 receptors.
Numerous studies have shown that angiotensin II enhances sympathetic nervous transmission. The objective of the present study was to quantify the inhibitory effect of the angiotensin II type 1 (AT1) ...receptor blockers losartan, irbesartan and telmisartan and the angiotensin converting enzyme (ACE) inhibitor captopril on sympathetic neurotransmission and to compare the potency of these agents both at the presynaptic and the postsynaptic levels.
In the male, normotensive pithed rat model, we studied the effect of losartan (1, 3, 10 and 30 mg/kg), irbesartan (3, 10, 30 and 60 mg/kg), telmisartan (0.3, 1, 3 and 10 mg/kg) and captopril (1.5, 5, 15 and 45 mg/kg) on electrical stimulation of the thoraco-lumbar spinal cord. To investigate the interaction between postsynaptic AT1-receptors and alpha-adrenoceptors, the effects of these compounds on pressor responses to exogenous noradrenaline were studied.
Stimulation of the thoracolumbar spinal cord caused a stimulation-frequency dependent rise in diastolic blood pressure (DBP) that could be dose-dependently reduced by both AT1 receptor blockade and ACE inhibition. Interestingly, the highest doses of the AT1 antagonists caused less than maximal reduction in the rise in DBP. This phenomenon was not observed after ACE inhibition by captopril. In experiments with exogenous noradrenaline, no effect of AT1 blockade or ACE inhibition on alpha-adrenoceptor-mediated blood pressure responses was seen.
We conclude that, in the pithed rat model, the effects of stimulation of the thoraco-lumbar spinal cord on DBP are counteracted by blockade of presynaptically located AT1 receptors. The order of potency concerning sympatico-inhibition is telmisartan > losartan > irbesartan. Regarding the inhibition of angiotensin II-induced facilitation of sympathetic neurotransmission, marked differences were observed between selective AT1 blockade and ACE inhibition. The finding that all three AT1 blockers cause less than maximal inhibition in their highest doses, as opposed to captopril, suggests that this is a class effect of the AT1 antagonists.
The effect of the AT1-receptor antagonists losartan, irbesartan, and telmisartan on angiotensin II (Ang II)-induced facilitation of noradrenergic neurotransmission was investigated in the isolated ...rat mesenteric artery under isometric conditions. Electrical field stimulation (2, 4, and 8 Hz) caused a frequency-dependent increase of contractile force. At stimulation frequencies of 2, 4, and 8 Hz, Ang 11 (10 nM) increased the stimulation-induced vasoconstrictor responses by a factor 4.8 +/- 0.9, 2.9 +/- 0.7, and 1.3 +/- 0.1, respectively (p < 0.05 compared with control for all frequencies). The enhancement could be concentration-dependently antagonized by losartan (1 nM-1 microM), irbesartan (0.1 nM-0.1 microM), and telmisartan (0.01 nM-0.01 microM). At a stimulation frequency of 2 Hz, the relation between stimulation-induced vasoconstrictor responses (in presence of Ang II 10 nM) and the concentration of the AT1-antagonists used could be described by linear regression. The order of potency concerning sympathoinhibition was telmisartan > irbesartan > losartan (p < 0.05 between linear regression lines). Contractile responses to exogenous noradrenaline were unaltered in the presence of Ang II 10 nM. We conclude that the facilitating effect of Ang II on noradrenergic neurotransmission is mediated by presynaptically located AT1-receptors. Conversely, this facilitating effect can be dose-dependently counteracted by blockade of these receptors. Sympathoinhibitory properties are likely to contribute to the therapeutic effect of AT1-blockers, in particular in conditions in which the sympathetic nervous system is activated, such as congestive heart failure and hypertension.
Metabolic syndrome is characterized by a clustering of cardiovascular and metabolic risk factors. This syndrome is now widely recognized as a distinct pathologic entity. It is receiving a great deal ...of attention in the medical literature and also in the lay press. People with metabolic syndrome have a clustering of the following risk factors, including detrimental changes in glucose tolerance and insulin resistance, abdominal (visceral) obesity, atherogenic dyslipidemia, and hypertension. Metabolic syndrome is associated with important cardiovascular and cerebrovascular and metabolic risks. Prevention and treatment are therefore of great importance. Preventive measures involving lifestyle are mandatory. In addition, metabolic syndrome patients will require pharmacologic treatment, usually for the rest of their lives. Complex patterns of drug treatment are required. This review provides an extensive and critical review of the drug treatment of this complex pathologic entity.
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