Baroreceptor reflexes and vascular reactivity during inhibition of nitric oxide synthesis in conscious rabbits.

The effect of the nitric oxide (NO) synthase inhibitor N-nitro-L-arginine (NOLA) on vascular reactivity and the baroreceptor heart rate reflex was examined in chronically instrumented conscious rabbits. NOLA (15 mg/kg i.v.) significantly increased mean arterial pressure and hindlimb vascular resistance and decreased heart rate. Increases and decreases in arterial pressure were produced by the intravenous injection of phenylephrine and sodium nitroprusside respectively and the values obtained relating mean arterial blood pressure to heart rate were fitted to a sigmoid curve. NOLA significantly reduced the lower plateau of the arterial pressure--heart rate curve but did not significantly affect baroreceptor sensitivity. Depressor and hindlimb vasodilator responses to acetylcholine were significantly impaired by NOLA whereas responses to sodium nitroprusside were significantly enhanced. The pressor and hindlimb vasoconstrictor responses to phenylephrine were significantly enhanced in the presence of NOLA. We conclude that the bradycardia produced by NOLA does not result from a change in baroreceptor sensitivity. The continuous generation of NO appears to be important in regulating basal vascular resistance and in modulating vascular reactivity to both vasodilator and vasoconstrictor agents.     

Do antidepressants cause postural hypotension by blocking cardiovascular reflexes?

Summary Postural changes in blood pressure, respiratory sinus arrhythmia, the heart rate response to Valsalva's manoeuvre and to standing, and the blood pressure and heart rate responses to isometric exercise have been measured in seven young women taking antidepressant medication and compared with seven controls. Among the patients there was a significant rank order correlation between the degree of postural hypotension and the daily dose of antidepressant medication. There was a significant impairment among the patients of all cardiovascular reflex responses measured, suggesting both cholinergic and adrenergic blockade. These results suggest that postural hypotension associated with antidepressant medication is caused in large part by a failure of reflex peripheral vasoconstriction.     

Myocardial nutritional circulation in rabbits after doxorubicin injection

The effect of doxorubicin on myocardial nutritional circulation in rabbits was determined by means of the isotopic [133Xe] method. The drug was injected iv in doses of 1, 3, and 6 mg/kg and the influence of doxorubicin on myocardial circulation was examined 1, 15, 30, 45, and 60 min after its administration. The results indicate that a single injection of doxorubicin produces an increase in myocardial nutritional circulation.     

Adrenergic control of tendon jerk reflexes in man

1. Tendon jerk responses and H reflexes were recorded from conscious human volunteers before and after intravenous injection of methylamphetamine, thymoxamine and propranolol, and during intravenous infusion of noradrenaline.2. Methylamphetamine produced a significant increase in the amplitude of the tendon jerk, whereas noradrenaline had no effect in doses which caused a greater pressor response than methylamphetamine.3. Thymoxamine produced a dose-related reduction in the tendon jerk.4. Propranolol had no significant effect on the jerk.5. None of these drugs significantly affected the H reflex.6. It is suggested that central adrenoceptors, possibly alpha in type, exist in man, and that stimulation of these receptors facilitates tendon jerk reflexes by an action on the fusimotor system.     

Effect of adenosine on pulmonary circulation of rabbits

The effect and mechanism of action of adenosine on the pulmonary circulation of rabbits were studied. Adenosine (10(-5)-10(-3) M) produced a concentration-dependent decrease in pulmonary arterial tension of precontracted pulmonary arterial rings. Removal of endothelium (denuded) augmented the adenosine-induced vasodilation in the pulmonary arterial rings. Theophylline (5 x 10(-5) M), an adenosine receptor antagonist, reduces the vasodilation induced by adenosine in intact and denuded rings. Pretreatment of the pulmonary rings with the cyclooxygenase inhibitor indomethacin (5 x 10(-6) M) significantly attenuated the adenosine-induced relaxation in denuded but not in the intact pulmonary arterial rings. Methylene blue (5 x 10(-5) M), a guanylate cyclase inhibitor, significantly reduced the relaxation induced by adenosine in both the intact and the denuded arterial rings. Adenosine significantly attenuated the pressor responses of serotonin and acetylcholine in the intact and denuded rabbit's pulmonary arterial rings. The results of this study indicate that adenosine induces pulmonary vasodilation and that functional endothelium is not required to evoke this dilation. In addition, guanylate cyclase activity and the generation of cGMP is essential for adenosine to induce vasodilation in the rabbit lung. Furthermore, the results of this study may suggest that adenosine could be used to reduce the severity of pulmonary hypertension and possibly pulmonary edema.     

Acute effects of L- and T-type calcium channel antagonists on cardiovascular reflexes in conscious rabbits

1. The effects of the relatively selective T-type voltage- operated calcium channel (VOCC) antagonist mibefradil were compared with verapamil, an L-type VOCC antagonist, on a range of autonomic reflexes in conscious rabbits. 2. Mean arterial pressure (MAP), heart rate (HR), the baroreceptor-HR reflex, postural adaptation reflex (90 degrees head-up tilt), Bezold-Jarisch-like reflex and the vasoconstrictor component of the nasopharyngeal reflex were assessed before and during i.v. infusion of vehicle (saline), mibefradil or verapamil. Doses of mibefradil that gave low (M1; 0.45 +/- 0.02 microg/mL) and high (M2; 0.93 +/- 0.05 microg/mL) plasma concentrations, or verapamil (0.059 +/- 0.004 microg/mL; n = 6 each) were chosen to mimic clinically observed therapeutic levels. 3. At steady state infusion over 30-90 min, MAP was significantly lower in M2 (- 7 mmHg) and verapamil (- 6 mm Hg) treatments, but only verapamil caused a significant tachycardia (+ 31 b.p.m.) compared with vehicle. Mibefradil (M2) and verapamil decreased the HR range of the baroreflex by 27 and 29%, respectively, but neither treatment affected the vagal or sympathetic constrictor components of the Bezold-Jarisch-like and nasopharyngeal reflexes, respectively. 4. In response to 90 degrees tilt, vehicle- and verapamil-treated rabbits responded with small rises in MAP of 4 +/- 2 and 8 +/- 2 mm Hg, respectively, 5 s into the upright posture, while M1 and M2 caused falls in MAP of 6 +/- 4 and 9 +/- 3 mm Hg, respectively, at 5 s. 5. Thus, both L- and T-type VOCC antagonists, at plasma concentrations in the clinical range, lowered MAP in the conscious rabbit, but only mibefradil caused postural hypotension. We conclude that T-type VOCC may play an important role in the venoconstrictor reflex in response to tilt in the rabbit.     

Effect of suloctidil on cerebral circulation patterns of conscious rabbits

Suloctidil (SUL) produces calcium antagonistic and antispasmodic effects on peripheral and pial arteries. The present studies were performed with the aim of evaluating the action of SUL on cerebral blood flow (CBF), which was taken as an index for evaluating the cerebral circulation. The drug was administered by rapid intravenous injection to groups of unanaesthetized rabbits at doses of 100-200 micrograms/kg and by intravenous infusion at doses of 10-20 micrograms/kg/min. In other experiments, SUL was chronically administered p.o. to normal rabbits and to rabbits receiving Kritchevsky's atherogenic diet; the daily dose of the drug was about 16 mg/kg. Cerebral blood flow and its compartmental distribution were determined in unanaesthetized animals by the intracarotid 133Xe clearance method. The data demonstrate that the atherogenic diet brings about a significant impairment of CBF; SUL is inactive in normal rabbits, while in the atherosclerotic rabbits it induces a pronounced increase in cerebral blood flow in the grey matter and an enhancement of the corresponding circulatory compartment. These changes are less evident in the white matter.     

Pharmacokinetics of intravenous luxabendazole in rabbits: influence of the enterohepatic circulation

Luxabendazole (LBZ) is a new benzimidazole carbamate chemotherapeutic agent, which has proved to be very effective against adult and immature stages of the major gastrointestinal nematodes, trematodes and cestodes. While information on the efficacy of LBZ in several animal species is available, there seems to be no published information describing the disposition kinetics in any of them. As a part of the clinical development of luxabendazole, the pharmacokinetics of a single intravenous dose was investigated in parasite-free rabbits. Serial blood samples were collected at timed intervals for 12 h following administration of the dose, and concentrations in plasma were determined by a sensitive and specific HPLC method. Published data on LBZ point to the possible existence of an enterohepatic cycle (EHC), and so, it seemed appropriate to carry out two different forms of test. In the first, the possibility of intestinal reabsorption of LBZ excreted via the bile was allowed for (Treatment 1), while in the second it was interrupted by the oral administration of activated charcoal (Treatment 2). In both cases the animals were given a single dose of 10 mg kg⁻¹ of LBZ intravenously (i.v). Comparison of the areas under the curve (AUCs) of LBZ concentrations in plasma samples taken from the animals receiving each treatment showed significant difference (p <0.05). The given dose (10 mg kg⁻¹) was converted in Treatment 1 to an effective dose of 13.9 mg kg⁻¹ through recycling of LBZ. With Treatment 2 a bicompartmental distribution model for this drug was confirmed, together with high apparent distribution volumes: V_c=1.87 L kg⁻¹, and V_β=7.09 L kg⁻¹. © 1998 John Wiley & Sons, Ltd.     

Effect of beraprost sodium on peripheral circulation insufficiency in rats and rabbits

Beraprost sodium (sodium (+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2- hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H- cyclopenta[b]benzofuran-5-butyrate, TRK-100) is a chemically and biologically stable epoprostenol analogue which possesses both potent antiplatelet and peripheral vasodilating actions. Its effect on obstruction of the peripheral artery was studied in three different models: 1. acute thrombosis induced by electrical-stimulation of the femoral artery in rabbits, 2. occlusion induced by intra-arterial injection of sodium laurate in rats and 3. tail gangrene induced by subcutaneous injections of both ergotamine and epinephrine in rats. Oral administration of beraprost sodium resulted in suppression of thrombus formation in the acute thrombosis model, marked improvement of macroscopic and histological observations in the laurate-occlusion model and inhibition of tail gangrene extension. In contrast, ticlopidine improved thrombus formation in the acute thrombosis model and slightly improved histological observation in the laurate-occlusion model, but not in the tail gangrene model. Cilostazol suppressed lesions in the acute thrombosis model, but not in the tail gangrene model. These findings suggest that beraprost sodium may be very useful clinically for the therapy of peripheral circulation insufficiency diseases such as Buerger's disease and Raynaud's disease.     

Neuronal control of mesenteric circulation]

The mesenteric circulation plays an important role in maintenance of systemic blood pressure and regulation of tissue blood flow. The tone of the mesenteric artery and resistance blood vessels are mainly regulated by sympathetic adrenergic nerves through the release of neurotransmitter noradrenaline and also controlled by nonadrenergic noncholinergic (NANC) nerves and possibly by parasympathetic cholinergic nerves. Noradrenaline and adrenergic cotransmitters including neuropeptide Y and adenosine triphosphate act as a vasoconstrictor neurotransmitter for sympathetic nerves. While, dopamine, calcitonin gene-related peptide and acetylcholine act as a vasodilator neurotransmitter for adrenergic, NANC and cholinergic nerves, respectively. In the mesenteric circulation, these nerves containing various neurotransmitters and cotransmitters interact and modulate each other via feedback autoregulatory mechanisms and neuromodulation of various vasoactive substance to regulate vascular resistance.     

Neurochemical control of cerebral blood circulation

A neurochemical approach to a study of the mechanisms by which cerebral circulation is controlled made it possible to discover the capability of GABA, GHBA, gamma-butyrolactone and pyrrolidone-2 to enhance cerebral circulation, to relax and enlarge an isolated flap of the cerebral arteries. GABA and specific GABA-receptors were found in the tissues of the walls of the cerebral arteries. Glutamate decarboxylase and GABA-transaminase were discovered in the cerebral vessels, with the endothelial and muscle layers of the arterial walls showing the highest GABA-transaminase activity. It is evident that as regards certain biochemical characteristics there is a definite similarity between GABA-ergic neurons and tissues of cerebral artery walls, which may ensure similar and undirectional neurochemical reactions in the brain and in the walls of its arteries. The latter circumstance is responsible for the mechanisms that control the functioning of the cerebral vessels.     

Effects of neuropeptides on the sumatriptan-disturbed circulation in the optic nerve head of rabbits

The purpose of this work was to study 'in vivo' the vascular responses of retinal vessels of New Zealand white rabbits to substance P (SP), neurokinin A (NKA), neurokinin B (NKB), senktide, capsaicin (CAPS), and calcitonin gene related peptide (CGRP) before and after selective antagonist administration. We examined the effects of these neuropeptides on the normal circulation in the optic nerve head of the rabbit. Drugs were injected via pars plana through a micropipette system. Ten minutes before perivascular injection of 10 nmol/l sumatriptan (to contract the vessel), a selective antagonist or its solvent was administered. Then, cumulative injection of the agonist was performed. The other eye was used as control. Direct measurement of retinal arteriole diameters was performed using digital angiography. The quantification of the relaxing effect is expressed as percentage related to the precontracted vascular diameter. Microinjection of SP (NK1 receptor agonist) up to 10 nmol/l induced a dose-dependent arteriolar dilating effect [E(max) (mean +/- SEM) 21.3 +/- 2.3%]. After the perivascular preinjection of 1 nmol/l L-668,169 or 1 nmol/l L-733,060 (NK1 receptor antagonists), the SP dose-response curve was shifted to the right. The same results were obtained with NKA (NK2 receptor agonist) which induced the most potent effect of all neuropeptides (E(max) 53.3+/-2.5%). The NK2 receptor antagonists L-659,877 and GR 159897 (1 nmol/l) strongly inhibited this arteriolar vasodilation. As for CGRP, doses up to 10 nmol/l induced a marked vasodilation (E(max) 41.1+/-0.4%) which decreased after microinjection of the selective antagonist CGRP8-37. The NK3 receptor agonists (senktide and NKB) showed a minor vasodilating effect (E(max) 5.1+/-1.2 and 8.0+/-0.9%, respectively). On the contrary, CAPS showed a marked dose-dependent vasodilating effect (E(max) 43.2+/-2.9%), antagonized by the tachykinin receptor antagonists and CGRP8-37. These results suggest, for the first time, the presence of NK1, NK2, and CGRP receptors on the retinal arteriolar wall of the rabbit.     

Vasomotor control of the pulmonary circulation]

It was demonstrated that pulmonary vessels, in contrast to systemic vessels, 1) have a low basal vascular tone, 2) constrict in response to hypoxia and 3) do not display significantly prominent vasomotion during autonomic nerve stimulation. However, details about these characteristics have not been clarified sufficiently by conventional methods; namely, measuring pressure-flow relationships and vascular tension of isolated larger conduit pulmonary vessels. Recent technological advances in studying pulmonary circulation now permit us to reveal that vasomotor responses to respiratory gases and neurohumoral factors differ not only quantitatively but also qualitatively between the central conduit and peripheral resistance vessels (approximately 100- to 500-micron diam.). They also reveal that an increase in pulmonary sympathetic nerve activity can cause pulmonary vasodilation as well as vasoconstriction. The former has been partly explained by the most recent findings regarding the distribution differences of NO synthases and K+ channels between the resistance and conduit vessels. Concerning the latter, initial vascular tone appears to play an important role. The increased pulmonary sympathetic nerve activity has a beta-receptor-mediated pulmonary vasodilator effect under low pulmonary vascular tone conditions but an alpha-receptor-mediated constrictor effect under enhanced vascular tone conditions. This may serve to maintain homeostasis of the pulmonary circulation and a good balance between the right and left ventricle outputs. Here, I have reviewed new developments related to the mechanisms for controlling pulmonary vascular tone under different states: normal, acute and chronic hypoxia, and hemorrhagic hypotension. I have also described the effects of inhaled NO and PGI2 as selective pulmonary vasodilators used for pulmonary hypertension.     

A method for evaluating postural hypotension in conscious rabbits as a model to predict effects of drugs in man

Because of the importance of postural hypotension as a side effect of antihypertensive drugs in man, an experimental model has been developed that permits the investigation of blood pressure response to tilting. Conscious rabbits were placed on a tilting table and tilted rapidly from horizontal to vertical position. Blood pressure was recorded continuously throughout the whole period. The individual orthostatic reaction was expressed as an orthostatic index. The experimental data obtained with guancydine, clonidine, guanethidine, prazosin and dihydralazine were compared with clinical observations with regard to the impairment of orthostatic reaction; dihydralazine did not agree, but there was a good agreement for guancydine, clonidine, guanethidine, and prazosin.Although complete agreement between the experimental data and clinical observations does not exist, the model seems to be sufficient to differentiate between drugs with low or high potential for postural hypotension.