Effects of Ranolazine and Ivabradine on Pulmonary Microhemodynamics in Experimental Model of Pulmonary Thromboembolism.

We studied changes of pulmonary microhemodynamics when modeling pulmonary artery thromboembolism on perfused isolated rabbit lungs after pretreatment with ranolazine and ivabradine. The increase in pulmonary artery pressure, pulmonary vascular resistance, and pre- and postcapillary resistance was less pronounced than in control animals, but was close to that in case of pulmonary thromboembolism after pretreatment with voltage-gated Na+ channel blockers lidocaine and ropivacaine. The increase of capillary filtration coefficient inversely correlated with values of capillary hydrostatic pressure. Thus, ranolazine and ivabradine exhibit the properties of voltage-gated Na+ channel blockers mainly in smooth muscles of pulmonary arterial vessels and promote the decrease in endothelial permeability.

Pulmonary Microcirculation in Experimental Model of Pulmonary Thromboembolism after Pretreatment with Chloroquine.

Changes of pulmonary microcirculation in response to pulmonary artery embolization after pretreatment with chloroquine were studied on the model of isolated perfused rabbit lungs. The increase in the pulmonary vascular resistance and pre- and postcapillary resistance was less pronounced than after pulmonary thromboembolism after pretreatment with mibefradil (T-type Ca2+ channels blocker) or nifedipine (L-type Ca2+ channels blocker). The shifts of capillary filtration coefficient correlated with changes in the precapillary resistance. When modeling pulmonary thromboembolism after pretreatment with chloroquine combined with glibenclamide (KATP channels blocker), the studied hemodynamics parameters increased to the same extent as after pretreatment with nifedipine. The results indicate that chloroquine exhibits the properties of an L- and T-type Ca2+ channels blocker and an activator of KATP channels.

Changes of Pulmonary Microhemodynamics in Experimental Pulmonary Thromboembolism after Pretreatment with K-Channel Activators.

Changes in pulmonary microhemodynamics in response to pulmonary embolism under conditions of activation of KATP channels with nicorandil, Kv channels with dapagliflozin, and BKCa channels with Evans blue were studied on isolated rabbit lungs. Under conditions of activation of KATP and BKCa channels, the constrictor reactions of the pulmonary arterial vessels during embolization of the pulmonary artery were less pronounced than in the control. Activation of BKCa channels reduced constrictor reactions of the pulmonary venous vessels, while activation of KATP and Kv channels eliminates them. The shifts of the capillary filtration coefficient are determined to a greater extent by the pre-/postcapillary resistance ratio, than by changes of the endothelial permeability. Pretreatment with dapagliflozin led to a decrease in the capillary filtration coefficient. It was established, that nimesulide exhibits properties of a BKCa-channel activator.

Pulmonary Microcirculation during Experimental Pulmonary Thromboembolism under Conditions of Activation and Blockade of Muscarinic Acetylcholine Receptors.

Changes in pulmonary microcirculation were studied in isolated perfused rabbit lungs during modelling pulmonary thromboembolism under conditions of acetylcholine infusion against the background of treatment with M1 acetylcholine receptor blocker pirenzepine or blockade of muscarinic acetylcholine receptors with atropine. In the first case, the increase in pulmonary artery pressure was less pronounced than in case of atropine treatment. In response to pulmonary embolism after acetylcholine infusion against the background of pirenzepine pretreatment, the capillary hydrostatic pressure and postcapillary resistance did not change, while after atropine treatment, these parameters increased. In case of pulmonary embolism after acetylcholine infusion combined with selective blockade of M1 muscarinic acetylcholine receptors, the capillary filtration coefficient increased to a greater extent, than in the control and after blockade of muscarinic acetylcholine receptors.

Role of ß3-Adrenoceptor Activation in Changes of Pulmonary Microhemodynamics after Experimental Pulmonary Thromboembolism.

Changes in pulmonary microhemodynamics during modelling of pulmonary thromboembolism against the background of nebivolol and mirabegron pretreatment were studied in isolated perfused rabbit lungs. In both cases, the pulmonary artery pressure and precapillary and pulmonary vascular resistance increased to a greater extent than in control animals, but the increase in capillary hydrostatic pressure was less pronounced. The postcapillary resistance did not change in pulmonary embolism against the background of nebivolol administration and increased in case of mirabegron pretreatment; capillary filtration coefficient after nebivolol pretreatment increased less markedly than after mirabegron administration. The increase in capillary filtration coefficient after activation of ß3-adrenoceptors with the specified drugs depended on the ratio of constriction of pulmonary veins, capillary hydrostatic pressure, and endothelial permeability.

[MECHANISMS OF GASTRODUODENAL DYSMOTILITY UNDER STRESS].

Psychogenic stress in rabbits caused dysmotility of the gastroduodenal zone: inhibition of contractile activity (CA) in antral and pyloric parts of the stomach simultaneously with the increase of CA in proximal and distal parts of duodenum. Stress induced inhibition of the gastric contractile activity is substantially "non-adrenergic non-cholinergic" and only in the initial phase of the reaction it appears to be "α-adrenergic". The strengthening of CA in the proximal duodenum resulted from the direct exciting action of endocrine stress factor on the smooth muscle of the gut. The strengthening of the CA in the distal duodenum is a result of the endocrine action of catecholamines on stimulating ß-adrenergic receptors of enteric cho linergic neurons. Stress induced dyscoordination of the gastroduodenal motility can cause duodenogastric reflux and as a consequence, erosive damage of the gastric mucosa.

Mechanisms of Discoordination of Contractile Activity in the Gastroduodenal Zone during Psychogenic Stress in Rabbits.

Inhibition of the contractile activity of the stomach induced by psychogenic stress persisted after blockade of muscarinic and nicotinic cholinergic receptors and α2 and ß1/ß2-adrenergic receptors. Stress-induced increase in contractile activity in the proximal part of the duodenum persisted during blockade of muscarinic and nicotinic cholinergic receptors, ß1/ß2-adrenergic receptors. At the same time, blockade of the above cholinergic and adrenergic receptors eliminated the stress-induced increase in contractive activity in the distal part of the duodenum.

Changes in contractile activity of the large intestine in rabbits during the poststress period before and after blockade of muscarinic and nicotinic receptors.

The rabbits were exposed twice to stress, fixation to a frame in the supine position, for 60 min. Contractile activity of all portions of the large intestine was shown to increase significantly during the poststress period. These changes were not observed under conditions of blockade of muscarinic and nicotinic receptors. This state can be considered as dyskinesia impairing large intestinal transit of chyme.

Changes in contractile activity of rabbit colon under stress conditions and during post-stress period before and after blockade of muscarinic and nicotinic cholinergic receptors.

Psychogenic stress in rabbits induced by fixation of the animal to a frame was accompanied by an increase in contractile activity of the initial portion of the distal colon, which was abolished by blockade of muscarinic and nicotinic cholinergic receptors. Increased contractile activity of the colon was due to centrogenic stimulation of preganglionic neurons of the parasympathetic nervous system followed by the involvement of the effector cholinergic neurons of the enteric nervous system into excitation.

[Changes of contractile activity of the colon under psychogenic stress before and after blockade of M- and N-cholinergic and beta-adrenoceptors].

In experiments on conscious rabbits, myoelectric activity (contractile activity index) was recorded in 2 sites of proximal and in 2 sites of distal part of the colon under psychogenic stress induced by firm fastening of the animal to a frame in supine position. Stressor impact caused decrease of the contractile activity in proximal and distal parts of the colon, due to "alpha-adrenergic" (in initial stage of stress reaction) and "nonadrenergic noncholinergic" inhibition. Stress-induced increase of the contractile activity of the colon was limited to the initial segment of its distal part, and was due to centrogenic stimulation of the preganglionic neurons of the parasympathetic nervous system and effector cholinergic neurons of the enteric nervous system.

Changes in contractile activity of the duodenum, jejunum, and ileum under conditions of psychogenic stress in rabbits.

Psychogenic stress in rabbits caused by fixation of the animal to a frame was accompanied by an increase in duodenal contractile activity. In the jejunum, initial inhibition of motor activity gave way to activation more pronounced in the proximal part. In both parts of the ileum, inhibition of contractile activity was noted. A proximodistal gradient of the excitatory and inhibitory effects on the motility of the small intestine was demonstrated.

Different mechanisms of intensification of contractile activity in the proximal and distal portions of the duodenum in psychogenic stress in rabbits.

Psychogenic stress in rabbits induced by fixation of the animals to a frame was accompanied by an increase in contractile activity of the duodenum. Against the background of blockade of muscarinic and nicotinic cholinergic receptors and ß(1)/ß(2)-adrenoceptors this increase was observed in postpyloric portion, but not in the distal third of the duodenum. The increase in contractile activity was determined by the direct effect of the hormonal stress factor on smooth muscles in the first case and by the influence of circulating catecholamines on excitatory ß-adrenoceptors of cholinergic neurons of the enteral nervous system in the second.

[Mechanism of inhibition of the contractile activity in the jejunum and ileum under psychogenic stress in rabbits].

In chronic experiments on rabbits, myoelectric activity (contractile activity index) in proximal and distal part of the jejunum and proximal part of the ileum was studied under psychogenic stress caused by rigid fastening of the rabbit to table in supine position. Inhibition of contractile activity in the proximal and distal parts of thejejunum in the 1st phase of the stressor response manifested on the background of blockade of presynaptic alpha 2-adrenoceptor with yohimbin, nonselective blockade of alpha-adrenoceptor with dihydroergotoxin, or blockade of beta 1/beta 2-adrenoceptor with propranolol. Conclusion is made that the stressor inhibition of contractile activity in the proximal and distal parts of the jejunum was not "adrenergic cholinergic" or "adrenergic" in origin. The contractile activity inhibition of the jejunum was actualized with the contribution of "nonadrenergic noncholinergic" inhibitory mechanism and mediated via nonadrenergic inhibitory neurons of the enteric nervous system. Depression of the contractile activity in the proximal part of ileum being preserved after blockade of presynaptic "alpha 2-adrenoceptor" or blockade of beta 1/beta 2-adrenoceptor, was not "adrenergic cholinergic" or "beta-adrenergic". Nonselective blockade of alpha-adrenoceptor resulted in diminished stressor inhibition of the contractile activity in the proximal part of ileum. The data obtained suggest that the stressor inhibition of the contractile activity in the proximal part of ileum was caused by "nonadrenergic noncholinergic" inhibitory mechanism with participation of the "alpha-adrenergic" inhibition. The "nonadrenergic noncholinergic" inhibition of the contractile activity in the jejunum and ileum might result from activation of enteric inhibitory neurons with a stressor factor of hormonal nature.

Mechanism for the inhibition of contractile activity of the gastric antrum and pylorus in rabbits during psychogenic stress.

Psychogenic stress in rabbits (fixation to a frame) was accompanied by the inhibition of contractile activity of the gastric antrum and pylorus. These changes persisted during blockade of muscarinic receptors, nicotinic receptors, alpha(2)-adrenoceptors, and beta(1)/beta(2) adrenoceptors. A stress-induced decrease in gastric motor activity was mediated by the nonadrenergic noncholinergic mechanism. It resulted from the influence of a hormonal stress factor on the stomach, which was probably realized through nonadrenergic inhibitory neurons of the enteric nervous system.

[Mechanism of strengthening of the contractile activity in the duodenum and in the jejunum in psychogenic stress in rabbits].

In experiments on unanaesthetized rabbits myoelectric activity (contractile activity index) of proximal (postpyloric) and distal sites of duodenum, and proximal part of jejunum was studied under stress induced by fastening a rabbit to a table in supine position. In both sites of duodenum, the stress impact induced a short-time decrease of contractile activity which was followed by its increase that exceeded the initial level. In the proximal part ofjejunum, the increase of contractile activity took place only during the second part of stress response. The strengthening of the contractile activity of the proximal part of duodenum was preserved after muscarinic or nicotinic cholinoceptor blockage, and after beta-receptor blockage. It was concluded that the contractile response of the proximal part of duodenum did not result from the contribution of central or local neurogenic mechanism, including excitatory cholinergic one, but was humoral in origin. The strengthening of the contractile activity of the distal part of duodenum and proximal part ofjejunum was abolished by muscarinic cholinoceptor and beta-receptor blockage, and resulted from the action of circulating catecholamines on the excitatory beta-adrenoceptor, localized on the cholinergic neurones of the enteric nervous system.

[On the mechanism of gastroduodenal motility inhibition under psychogenic stress in rabbits].

In experiments on unanaesthetized rabbits, myoelectric activity (contractile activity index) in antral and pyloric parts of the stomach and in two sites of proximal duodenum was studied under stress induced by fastening rabbit to a table in supine position. The stressor impact induced inhibition of contractile activity in antrum and pylorus. The duodenal contractile activity after initial complete suppression overshot its initial level. Blockade of beta1/beta2-adrenoceptor with propranolol and blockade of alpha2-adrenoceptor with yohimbine did not influence qualitatively the pattern of the stressor responses of antrum and pylorus, and of the postpyloric part of duodenum. In conditions of unselective blockade of alpha-adrenoceptor with dihydroergotoxin there was no initial complete inhibition of duodenal contractile activity, and its strengthening was more expressed than in the control experiments. The received data indicate that the stressor inhibition of antral and pyloric contractile activity possibly results from activation of non-adrenergic inhibitory neurons of the enteric nervous system. The initial short-term suppression of duodenal motility resulted from its "adrenergic" inhibition which can also be a factor limiting the manifestation of stimulating effect of the humoral agent on the duodenal motility. In the period after release of the animal, index of antral and pyloric contractile activity did not significantly differ from its initial level; after beta1/beta2-adrenoceptor blockade in antral and after alpha2-adrenoceptor blockade or nonselective alpha-blockade in antral and pyloric parts of the stomach, there was decrease of contractile activity compared with its initial level; after alpha2- or beta1/beta2-adrenoceptor blockade there was no poststressor exceeding of the initial level of the duodenal contractile activity, observed in the control experiments.

[Contractile activity of duodenum, jejunum, and ileum at psychogenic stress in rabbits before and after muscarinic or nicotinic cholinoceptor blockade].

In chronic experiments on rabbits, myoelectric activity (contractile activity index) in distal part of the duodenum, proximal and distal parts of the jejunum and proximal part of the ileum was studied under psychogenic stress caused by rigid fastening rabbit to a table in supine position. In duodenum, the stressor impact rendered stimulating, and in an ileum--inhibitory influence on their motility. In a jejunum the inhibition with the subsequent stimulation was observed, the latter being more expressed in a proximal part of the intestine. The proximo-distal gradient of exitatory and inhibitory influences of the psychogenic stress on contractile activity of the small bowel was revealed: in distal direction, inhibitory influences strengthen and stimulatory ones weaken. The muscarinic receptor blockade abolished increase of the duodenal and jejunal contractile activity obsereved in the control. The nicotinic cholinoceptor blockade abolished increase of the duodenal contractile activity in the 1-st phase of the stressor response and did not exclude an increase of the duodenal contractile activity in the 2-nd phase of the response. Muscarinic or nicotinic blockade did not influence the manifestation of the inhibitory reaction of proximal part of the ileum. In the period after release of the animal, the duodenal and jejunal contractile activity exeeded its initial level. This exeeding did not preserve after muscarinic cholinoceptor blockade but did preserve after nicotinic one in duodenum and proximal jejunum. The received data allow to conclude, that produced by the stress increase of the contractile activity of the distal part of duodenum, proximal and distal parts of jejunum produced by the stress, as well as exceeding the initial contractile activity level in the period after release of an animal, are mediated by cholinergic effector neurones of the enteric nervous system.

[The mechanism of the duodenal motility strengthening under psychogenic stress in rabbits].

In experiments on unanaesthetized rabbits, myoelectric activity (contractile activity index) of two sites of duodenum and of antral and pyloric parts of the stomach was studied under stress induced by fastening a rabbit to a table in supine position. In both sites of duodenum, the stress impact induced a short-time inhibition of contractile activity which was followed by its strengthening that exceeded the initial level. Meanwhile in antrum and pylorus, the whole period of stress impact was characterized by suppression of contractile activity, the latter being more pronounced in the antrum. The strengthening of the duodenal contractile activity was preserved after muscarinic ornicotinic cholinoceptor blockade. It was concluded that the contractile response of duodenum seemed to be of humoral origin.

[Mechanisms of inhibition of the contractile activity in the ileo-caecal zone in rabbits under psychogenic stress].

In experiments on unanaesthetized rabbits, myoelectric activity (contractile activity index) of distal ileum, caecum, and proximal colon in two sites was studied under stress induced by fastening a rabbit to the table in supine position. The stress caused sharp decrease (up to complete disappearance) of the contractile activity in all studied compartments of the ileocaecal intestine with partial or complete restoration after release of the animal. Nonselective blockade of pre- and postsynaptic alpha-adrenoceptor with dihydroergotoxin abolished the initial component of the specified inhibitory response. The latter was caused by "adrenergic inhibition" as a result of action of catecholamines circulating in blood on inhibitory smooth muscle alpha-adrenoceptor. Against the background of muscarinic cholinoceptor blockade, the stressor inhibition of ileocaecal contractile activity observed in control experiments was completely preserved. The periods of supression of ileoceacal contractile activity under stress resistant to blockade of alpha-, beta-adrenoceptor and muscarinic cholinoceptor, are caused by the mechanism of "nonadrenergic noncholinergic inhibition", which is realized at the expence of activation of the enteric inhibitory neurones.

[Mechanisms of serotonin effect on motility of ileocaecal zone in alert rabbits].

I.V. administration of serotonin (2 mg kg(-1)) to alert rabbits changed the ileal, caecal, and colon motility including excitatory and inhibitory components. Initial rise of contractile activity was quickly replaced by its diminishing followed by a longer enhancement of the motility, and then by the final, inhibitory, phase. Under blockade of beta1- and beta2-adrenoreceptors with propranolol inhibition of ileal and caecal contractile activity with serotonin was preserved, the effect of circulating catecholamines on beta-adrenoreceptors of smooth muscle cells seems to be excluded as a cause of the serotonin inhibitory effect. In conditions of blockade of pre- and postsynaptic alpha-adrenoreceptors with phentolamine, there was no significant diminishing of the contractile activity in the ileo-caecal zone below the initial level induced by serotonin in control experiments. Intensification of the ileo-caecal zone contractile activity under the effect of serotonin persisted in conditions of blockade of muscarinic cholinoreceptors and was proceeding with participation of non-cholinergic excitatory mechanism.