Selective imidazoline agonist moxonidine in obese hypertensive patients.

Obesity is the major risk factor for the development of hypertension. This association accentuates the risk of cardiovascular disease, as it is frequently accompanied by the components of the metabolic syndrome. This randomised open parallel study evaluated the chronic effects of moxonidine--a selective imidazoline receptor agonist--on blood pressure, plasma catecholamines, leptin, insulin and components of the metabolic syndrome in obese hypertensives. Amlodipine was used as the control drug. Our results showed that moxonidine and amlodipine significantly reduced blood pressure when measured using the oscillometric method and 24-hour blood pressure monitoring. Moxonidine therapy decreased systolic blood pressure from 160.4 +/- 2.4 to 142.1 +/- 3.3 mmHg (p < 0.005) and diastolic blood pressure from 102.4 +/- 1.3 to 89.7 +/- 1.6 mmHg (p < 0.005) after 24 weeks of treatment. Moxonidine administration reduced the supine arterial plasma levels of adrenaline from 63.2 +/- 6.6 to 49.0 +/- 6.7 pg/ml (p < 0.005), the supine arterial plasma levels of noradrenaline from 187.9 +/- 10.7 to 149.7 +/- 13.2 pg/ml (p < 0.01) and the orthostatic venous plasma levels of noradrenaline from 258.6 +/- 25.0 to 190.3 +/- 16.4 pg/ml (p = 0.03). Those variables were not changed by amlodipine. The plasma levels of leptin and insulin 120 min after a glucose load decreased after moxonidine administration from 27.2 +/- 3.5 to 22.6 +/- 2.9 pg/ml (p < 0.05) and from 139.7 +/- 31.2 to 76.0 +/- 15.2 U/ml (p < 0.05), respectively. Amlodipine, however, did not modify those variables. This study showed a comparable reduction in blood pressure with both antihypertensive drugs. Moxonidine decreased sympathetic nervous activity, improved insulin resistance and reduced the plasma levels of leptin.

Contribution of vanilloid receptors to the overt nociception induced by B2 kinin receptor activation in mice.

1. The vanilloid receptor (TRPV1) is viewed as a molecular integrator of several nociceptive stimuli. In the present study, we have investigated the role played by TRPV1 in the nociceptive response induced by the peripheral activation of kinin B(2) receptor in mice. 2. The intraplantar (i.pl.) administration of bradykinin (BK) and the selective B(2) agonist Tyr(8)-BK, or the vanilloid agonists resiniferatoxin and capsaicin, into the mouse paw induced a dose-related overt nociception of short duration. The B(2) receptor antagonist Hoe 140 inhibited BK-induced, but not capsaicin-induced, nociceptive response. On the other hand, the TRPV1 antagonist capsazepine inhibited both capsaicin- and BK-mediated nociception. 3. Repeated injections of BK or capsaicin produced desensitization to their nociceptive response. Capsaicin desensitization greatly reduced BK-induced nociception, but in contrast, the desensitization to BK increased the capsaicin response. 4. Administration of low doses of capsaicin or acidified saline did not produce nociception when administered alone, but caused a pronounced effect when administered in association with a subthreshold dose of BK. Moreover, the degeneration of the subset of primary afferent fibers, sensitive to capsaicin, abolished both capsaicin- and BK-induced nociception. 5. The inhibition of phospholipase C (PLC), protein kinase C or phospholipase A(2) markedly decreased the nociception caused by BK, but not that of capsaicin. BK administration increased leukotriene B(4) levels in the injected paw. Likewise, BK-induced overt nociception was decreased by lipoxygenase (LOX) inhibition. 6. These results demonstrate that BK produces overt nociception mediated by TRPV1 receptor stimulation, via PLC pathway activation and LOX product formation.

Evidence for the involvement of vanilloid receptor in the antinociception produced by the dialdeydes unsaturated sesquiterpenes polygodial and drimanial in rats.

This study investigated whether or not the neonatal treatment of rats with the sesquiterpenes polygodial or drimanial could cause persistent antinociception similar to that induced by capsaicin. Rats were injected subcutaneously 48 h after birth with capsaicin (50 mg/kg), polygodial (150 mg/kg), drimanial (150 mg/kg) or vehicle (1ml/kg). Six to eight weeks later, rats were tested in models of nociception. Treatment of rats with capsaicin, polygodial or drimanial produced significant inhibition of the first phase and, to a lesser extent, the second phase of formalin-induced nociception. A significant reduction in Complete Freund's Adjuvant and capsaicin-induced hyperalgesia was observed in the animals neonatally treated with capsaicin, polygodial or drimanial compared with vehicle-treated rats. Moreover, both sesquiterpenes caused inhibition of plasma extravasation induced by injection of capsaicin. The neonatal treatment with capsaicin, polygodial or drimanial significantly decreased [3H]-resiniferatoxin binding sites in the rat spinal cord, but only capsaicin neonatal treatment significantly reduced the expression of TRPV1 in dorsal root ganglia (DRG) when assessed by Western blot. These results extend our previous findings demonstrating that the neonatal treatment of rats with polygodial or drimanial, similar to that reported for capsaicin, produced persistent antinociception in adult animals associated with TRPV1 down-regulation in the spinal cord, but not TRPV1 expression in DRG.

Dual effect of agmatine in the bisected rat vas deferens.

The functional effects of the amine agmatine, the putative endogenous ligand for alpha(2)-adrenoceptors and imidazoline receptors, in rat vas deferens were investigated by using the epididymal and prostatic portions. Tissues were contracted by electrical stimulation or by exogenous drugs. In electrically stimulated portions, agmatine caused a dual effect on contractions. In the epididymal portion an inhibition on twitch contractions was observed, which was partially antagonised by idazoxan and yohimbine, indicating the involvement of at least a presynaptic alpha(2)-adrenoceptor-mediated mechanism, without the interference of imidazoline receptors. In the prostatic portion, agmatine enhanced the amplitude of twitches. In contractions induced by exogenous drugs, agmatine potentiated, only in the prostatic segment, the effects of noradrenaline (norepinephrine) or ATP; it also enhanced the effect of low concentrations of KCl and blocked the maximum effect of the higher concentrations. Effects induced by agmatine on the exogenous ATP in the prostatic portion were blocked by cromakalim, suggesting a blocking action on the postsynaptic K(+) channels, which explains, in part, the potentiation of the twitch amplitude. It was concluded that agmatine interferes with sympathetic neurotransmission, but the physiological relevance of this needs to be better understood because of the high doses employed to induce its effects.