Data concerning cardiovascular effects of peripherally and centrally located histamine H3 receptor stimulation are contradictory, and despite excessive studies their role in the control of the cardiovascular function have not been cleared yet. Effect of histamine H3 receptors activation have been attributed to modulation of sympathetic system activity but exact role of peripherally and centrally located histamine H3 receptors stimulation in the modulation of vascular tone of the mesentery and intestinal metabolism remains unexplored. Aim of the present study was to evaluate the role of centrally and peripherally located histamine H3 receptors in the modulation of vascular tone of the mesentery and metabolic activity of intestinal tissue. In anesthetized rats total mesenteric blood flow (MBF), mucosal intestinal blood flow (LDBF), intestinal oxygen uptake (VO2) and arterial pressure (AP) were determined. Intestinal arterial conductance (C) was also calculated. Administration of the selective histamine H3 receptor agonist imetit (10 µmol/kg i.a) evoked marked changes in hemodynamic and metabolic parameters; MBF, LDBF, C and VO2 were significantly increased, whereas AP was significantly decreased. Pretreatment with histamine H3 receptor antagonist clobenpropit (4 µmol/kg i.a.) abolished imetit-induced circulatory and oxygen uptake responses. Clobenpropit (4 µmol/kg i.a.) alone failed to affect the MBF, LDBF, AP, C and VO2 values. Central administration of imetit (0.1 µmol i.c.v.) markedly increased AP and decreased MBF, LDBF, C and VO2. Pretreatment with histamine H3 receptor antagonist clobenpropit (0,4 µmol i.c.v.) diminished circulatory and metabolic responses to centrally injected imetit. Central histamine H3 receptors blockade by clobenpropit evoked no significant changes in the mesenteric arterial and mucosal microcirculatory blood flow, intestinal metabolism and mean arterial pressure. We conclude that, peripheral histamine H3 receptors when stimulated decreases vasoconstrictory tone of the mesenteric artery and precapillary structures and evokes increase of intestinal oxygen uptake. This might be in part due to inhibition of sympathetic postganglionic fibers vasopressor activity. Central histamine H3 receptor stimulation activates vasoconstrictory sympathetic adrenergic system with possible involvement of other, presumably non-histaminergic receptors system. At basal conditions neither central nor peripheral histamine H3 receptors are involved in the control of mesenteric macro - and microcirculation and intestinal oxygen consumption.
Orexin A influences the central cardiovascular regulation, since after intracerebroventricular (icv) administration it evokes short-lasting increases in mean arterial pressure (MAP) and heart rate (HR) in normotensive animals. The aim of the present study was to examine haemodynamic effects of orexin A in haemorrhage-shocked rats. Experiments were carried out in anaesthetized Wistar rats subjected for a critical irreversible haemorrhagic hypotension of 20-25 mmHg, which resulted in the death of all saline icv-treated control animals within 30 min. Orexin A (0.5-1.5 nmol; icv) administered at 5 min of critical hypotension evoked dose-dependent long-lasting increases in MAP, HR and renal, mesenteric and hindquarters blood flows, with a 100% survival of 2 h after treatment (1.5 nmol; icv). Changes in MAP and peripheral haemodynamics were inhibited by intravenous pretreatment with alpha1- and alpha2-adrenoceptor antagonists prazosin (0.5 mg/kg) and yohimbine (1.0 mg/kg), respectively. Moreover, both antagonists significantly decreased the survival rate to 16.6 and 33.3% (P<0.05 vs. orexin A [1.5 nmol]-treated group). In contrast, ß-adrenoceptor antagonist propranolol (1.0 mg/kg) completely blocked orexin A-induced HR changes, without influence on MAP, peripheral blood flows and the survival rate. Therefore, we conclude that centrally acting orexin A evokes the resuscitating effect in haemorrhage-shocked rats due to the activation of the sympathetic nervous system.
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The cardiovascular effects of the stimulation of arterial chemoreceptors are different in spontaneously breathing and artificially ventilated animals. Respiratory failure and long term sojourn at high altitude coincide frequently with the occurrence of gastric ulceration. In both these situations a profound stimulation of arterial chemoreceptors is present. The purpose of the paper was to investigate the reflex effect of stimulation carotid chemoreceptors on gastric mucosal blood flow in the rat. Arterial chemoreceptors were stimulated by two methods (I) substitution gas mixture of 10% oxygen in nitrogen for room air and (II) direct injection of acid saline ( 0.05 ml, pH=6.8) into the distal part of left common carotid artery. In artificially ventilated rats stimulation of arterial chemoreceptors caused significant increase in gastric mucosal vascular resistance, accompanied by marked decline in blood flow. This effect was mediated by adrenergic mechanism. On the contrary to artificially ventilated rats, decline of gastric mucosal vascular resistance with concomitant increase in blood flow was found in spontaneously breathing animals. This effect was not abolished either by phentolamine or atropine. As vasodilatatory effect of arterial chemoreceptors stimulation was abolished by bilateral vagotomy, we postulate that non adrenergic and non cholinergic vagal fibers mediate observed vascular changes in gastric mucosa in spontaneously breathing rats. We hypothesize that in artificially ventilated patients with respiratory failure stimulation of arterial chemoreceptors by hypoxemia and or acidosis may contribute to the development of gastric mucosal lesions.
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Hypertension is the main risk factor for left ventricular hypertrophy and development of diastolic heart failure. There is no yet treatment, which can effectively reduce mortality in patients suffering from heart failure with preserved systolic function. We tested whether the calcium sensitizer levosimendan and the AT1-receptor antagonist valsartan could protect from salt-induced hypertension, cardiovascular mortality and heart failure in Dahl/Rapp salt-sensitive rats fed for 7 weeks with a high salt diet (8% NaCl). Levosimendan (1 mg/kg/day via drinking water) and valsartan (30 mg/kg in the food) monotherapies and their combination prevented mortality in Dahl/Rapp rats. The drug combination evoked an additive effect on blood pressure, cardiac hypertrophy, cardiomyocyte cross-sectional area, target organ damage and myocardial ANP mRNA expression. There was a close correlation between systolic blood pressure and cardiac hypertrophy, cardiac and renal damage. As compared to Dahl/Rapp controls kept on low-salt diet (NaCl 0.3%). The high salt rats exhibited impaired diastolic relaxation as assessed by isovolumic relaxation time. Levosimendan alone and in combination with valsartan, improved diastolic relaxation without significantly improving systolic function. Our findings are evidence for an additive effect between levosimendan and valsartan on blood pressure and a blood pressure- dependent protection against the development of salt-induced target organ damage. The present study also demonstrates that levosimendan, alone or in combination with valsartan, can correct diastolic dysfunction induced by salt-dependent hypertension.