Blood Pressure In Rabbits Research Articles

Effects of daily soman administration on rabbit blood pressure, temperature, body weight, and erythrocyte and plasma cholinesterases.

Soman (pinacolyl methylphosphonofluoridate), and other organophosphate acetylcholinesterase (ACHE) inhibitors, in toxic doses usually cause a marked reduction in blood pressure. With some AChE inhibitors (AChEI) this is due primarily to a bradycardia-induced reduction in cardiac output (Holmstedt, 1951; Daly and Wright 1956; Fukuyama and Stewart, 1961). However, these organophosphate AChEI also constrict peripheral blood vessels to increase vascular resistance, thus opposing the usually predominant decrease in blood pressure (Holmstedt, 1951; Daly and Wright, 1956; Fukuyama and Stewart, 1961). Hypotension, however, can also be observed in anesthetized rabbits in which bradycardia is blocked by atropine (Preston and Heath, 1972 a,b). This was attributed to decreased central vasomotor output. In several species including rats and dogs, and in human subjects, sub-lethal doses of AChEI increase blood pressure through a central mechanism (Buccafusco and Brezenoff, 1979; Phillippu, 1981; Brezenoff and Giuliano, 1982; Brezenoff et al., 1984). Effects of repeated sub-lethal soman injections on blood pressure and correlation with plasma and erythrocyte cholinesterases have not been done.

HP 663: A novel compound for the treatment of glaucoma

AbstractVarious studies suggest that the 7‐dihydroxypropionyl derivative of forskolin, HP 663, effectively lowers intraocular pressure (IOP) by a novel mechanism. Biochemically, HP 663 stimulates rat striatal adenylate cyclase and displays an affinity for forskolin binding sites similar to that of forskolin. Following topical administration this compound lowers IOP in both New Zealand White (NZW) and Dutch Belt (DB) rabbits. In NZW rabbits, concentrations from 0.05 to 2.0% in a buffered hydroxypropylmethylcellulose (HPMC) vehicle produce significant reductions in outflow pressures of 35–45% for 5–6 hr. Additionally, HP 663 is soluble in this vehicle up to a concentration of 0.25%. As mentioned, HP 663 also reduces IOP in DB rabbits; however, this response is not significant until a concentration of 1% is attained. The effect on aqueous humor inflow was indirectly determined by studying the rate of IOP recovery following rapid i.v. infusion of 20% NaCl. In NZW rabbits, HP 663 significantly reduced aqueous humor inflow as shown by a 40% decrease in the IOP recovery rate compared to control. Tolerance also does not appear to develop to the IOP lowering effects of HP 663 in NZW rabbits. This compound is still capable of significantly lowering IOP following twice daily treatment for 21 consecutive days. Following topical administration of concentrations which effectively lower IOP, HP 663 exhibits no significant effects on heart rate or blood pressure of NZW rabbits. Therefore, this compound does not appear to exhibit a potential for peripheral side effects after topical application. Based on the results of the present study, HP 663 appears to be a potent activator of adenylate cylase and may provide a novel and effective treatment for glaucoma.

Role of Brain Amine Transmitters and Some Neuromodulators in Blood Pressure, Heart Rate, and Baroreflex Control

We studied the acute effects of transmitter release induced by intracisternal (i.c.) 6-hydroxydopamine (6-OHDA) from mainly noradrenergic (NA) neurons and by 5,6-dihydroxytryptamine (5,6-DHT) from serotonergic (5HT) neurons. Each group of neurons affects blood pressure and heart rate in conscious rabbits through both suprapontine and bulbospinal pathways that alter both sympathetic and vagal function. Some of the pathways are complex with 5HT neurons and NA neurons in series with one another, while in others a given autonomic function is altered through parallel independent mechanisms. The central effects of α-methyldopa and clonidine on blood pressure and heart rate are mediated through both groups of neurons. We examined the role of the main bulbar NA neuron groups by producing bilateral electrolytic lesions of the Al, A2, Al + A2, A5, and A6 + A7 regions, allowing time for degeneration and noting which component of the 6-OHDA transmitter release response had become affected by the lesion. These studies suggest that each is an integrative site with distinctive NA projections to the different autonomic motoneuron pools. We also examined how physiological changes in plasma levels of angiotensin II (AII) modulate the properties of the baroreceptor-heart rate reflex. The vagal component of the reflex is depressed and this is mediated through the action of AII on peripheral vagal ganglia, so that less acetyl choline is released per nerve impulse. This provides one model of the mechanisms by which central peptide transmitters may alter the action of other transmitters.

Effect of thyrotropin-releasing hormone injected into lateral ventricle on respiration and blood pressure in rabbits.

Experiments were carried out on 48 unanesthetized, vogotomized, gallamine triethiodide immobilized and artificially ventilated rabbits. Injection of thyrotropin releasing hormone (TRH) into lateral ventricle resulted in a marked increase in respiratory rate and phrenic nerve discharge frequency and a significant elevation of arterial blood pressure. However, no change in respiratory activity and blood pressure was observed when an equal dose of TRH was injected intravenously. On the contrary, morphine administered intravenously produced a decrease in respiratory activity and blood pressure, which could be reversed by TRH applied intralateral-ventricularly. These findings indicate that TRH can stimulate respiratory activity, elevate blood pressure centrally and antagonize morphine-induced depression in respiration and blood pressure.

Synthesis and pharmacological activity of N-alkyl-1,2-diphenylethanolamines.

A series of N-alkyl-1,2-diphenylethanolamines were synthesized and their pharmacological activities evaluated on various mammalian organs and systems. All compounds produced a generalized inhibitory effect on smooth and cardiac muscles and an increase in coronary flow as well as a brief reduction in rabbit blood pressure. The latter effect was not prevented by pretreatment of the animals with atropine, propranolol, or metoprolol. The compounds were devoid of local anesthetic activity and their inhibitions of the contraction of the isolated rabbit intestine and perfused heart were reversed by exogenous calcium ions. It is proposed that the compounds produce their effects through calcium-channel blockade. The inhibitory effects of some of these compounds were comparable to those of a known calcium-channel blocker.

Role of Brain Amine Transmitters and Some Neuromodulators in Blood Pressure, Heart Rate, and Baroreflex Control

Summary: We studied the acute effects of transmitter release induced by intracisternal (i.c.) 6-hydroxydopamine (6-OHDA) from mainly noradrenergic (NA) neurons and by 5,6-dihydroxytryptamine (5,6-DHT) from serotonergic (5HT) neurons. Each group of neurons affects blood pressure and heart rate in conscious rabbits through both suprapontine and bulbospinal pathways that alter both sympathetic and vagal function. Some of the pathways are complex with 5HT neurons and NA neurons in series with one another, while in others a given autonomic function is altered through parallel independent mechanisms. The central effects of α-methyldopa and clonidine on blood pressure and heart rate are mediated through both groups of neurons. We examined the role of the main bulbar NA neuron groups by producing bilateral electrolytic lesions of the A1, A2, A1 + A2, A5, and A6 + A7 regions, allowing time for degeneration and noting which component of the 6-OHDA transmitter release response had become affected by the lesion. These studies suggest that each is an integrative site with distinctive NA projections to the different autonomic motoneuron pools. We also examined how physiological changes in plasma levels of angiotensin II (AII) modulate the properties of the baroreceptor-heart rate reflex. The vagal component of the reflex is depressed and this is mediated through the action of AII on peripheral vagal ganglia, so that less acetyl choline is released per nerve impulse. This provides one model of the mechanisms by which central peptide transmitters may alter the action of other transmitters.

The effects of cadmium on blood pressure and renal sympathetic nerve discharges in rabbits.

The effects of intravenous administration of cadmium (Cd) on arterial blood pressure were investigated in anesthetized, artificially ventilated rabbits. In addition, cadmium's effects on renal sympathetic nerve discharges, ECG, and phrenic nerve efferent discharges were studied to elucidate the mechanisms of blood pressure change. Blood Cd levels were also determined in some animals.The follwed results were obtained:1) Intravenous injection of CdCl2 at doses of between 5 and 500μg/kg produced a biphasic fall in blood pressure. The first fall was sharp and transient, and recovered in about 5 minutes (min.). After this, the second fall slowly developed, and returned to the control value 30-60min. after injection. However, at doses of 200-500μg/kg, the first fall was not reversible and lasted for 30-60min.2) The heart rate was slightly decreased within 30 seconds. after injection. Then it increased during the next 1min., and the increase lasted about 30min.3) Renal nerve sympathetic discharges increased during the initial rapid fall of blood pressure at doses between 5 and 100μg/kg. These changes were reversible when the blood pressure recovered to normal. However, at higher doses of 200-500μg/kg, renal nerve discharges were reduced during the second blood pressure fall, and did not recover to the control levels.4) Cd had no discernible effect on the phrenic nerve discharges or end tidal CO2 concentration.5) The blood concentration of Cd was increased rapidly to the maximal value within about 1min. after injection. Then it decreased rapidly and became stable 30min. after the injection. The blood levels of Cd after doses of 10 and 50μg/kg were 1 and 2μM, respectively.

Effect of increased intracranial pressure on blood pressure, heart rate, respiration and catecholamine levels in neonatal and adult rabbits.

The effect of increased intracranial pressure (ICP) on heart rate, respiratory rate and blood pressure was measured in 2-day-old and adult rabbits. Neonates and adults exhibited the Cushing reflex with hypertension, bradycardia and decreased respirations when exposed to elevated ICP. Adult animals had a lower threshold of response to elevated ICP, implying a more sensitive adrenergic response compared to neonates. Although control levels of epinephrine and norepinephrine were higher in neonates compared to adults, the ratio of maximum concentration during increased ICP to control concentration was higher in adults (27.0 for epinephrine and 25.2 for norepinephrine in adults: 3.5 for epinephrine and 2.93 for norepinephrine in neonates). Injection of epinephrine was used to induce a maximal sympathetic response in both groups of rabbits studied. In adults, the cardiovascular response was the same after injection of epinephrine or after increasing ICP. In neonates, the blood pressure rise after injection of epinephrine was significantly higher (p less than 0.05) than the blood pressure rise after increasing ICP. The results demonstrate an immature adrenomedullary axis in neonates who have higher resting levels of catecholamines with a relatively smaller increase in catecholamines in response to stress when compared to adults.

Role of Brain Amine Transmitters and Some Neuromodulators in Blood Pressure, Heart Rate, and Baroreflex Control

We studied the acute effects of transmitter release induced by intracisternal (i.c.) 6-hydroxydopamine (6-OHDA) from mainly noradrenergic (NA) neurons and by 5,6-dihydroxytryptamine (5,6-DHT) from serotonergic (5HT) neurons. Each group of neurons affects blood pressure and heart rate in conscious rabbits through both suprapontine and bulbospinal pathways that alter both sympathetic and vagal function. Some of the pathways are complex with 5HT neurons and NA neurons in series with one another, while in others a given autonomic function is altered through parallel independent mechanisms. The central effects of alpha-methyldopa and clonidine on blood pressure and heart rate are mediated through both groups of neurons. We examined the role of the main bulbar NA neuron groups by producing bilateral electrolytic lesions of the A1, A2, A1 + A2, A5, and A6 + A7 regions, allowing time for degeneration and noting which component of the 6-OHDA transmitter release response had become affected by the lesion. These studies suggest that each is an integrative site with distinctive NA projections to the different autonomic motoneuron pools. We also examined how physiological changes in plasma levels of angiotensin II (AII) modulate the properties of the baroreceptor-heart rate reflex. The vagal component of the reflex is depressed and this is mediated through the action of AII on peripheral vagal ganglia, so that less acetyl choline is released per nerve impulse. This provides one model of the mechanisms by which central peptide transmitters may alter the action of other transmitters.

Effects of highly purified eicosapentaenoic acid on vascular reactivity to angiotensin II and norepinephrine in the rabbit

There is disagreement about whether supplementation of the diet with fish oil, which is rich in eicosapentaenoic acid (EPA), lowers blood pressure. We gave highly purified EPA in a soft capsule (90% ethyl ester form of EPA; EPA-E), to female rabbits (100 mg/kg/day) for 4 weeks. Vascular response to vasoconstrictor agents was assessed serially by measuring the systolic blood pressure using a Grand-Rothschild capsule in the ear. There was no change in systolic blood pressure of rabbits treated with EPA-E, but rabbits given EPA-E for one week or longer were significantly less respomsive to the pressor effects of angiotensin II than the controls. Responses to noripinephrine did not change. Rabbits given EPA-E for four weeks had significantly more EPA in the serum, but there were no differences in serum levels of triglycerides, total cholesterol, or high-density lipoprotein cholesterol. These results suggest that vascular responses to exogenous angiotensin II can be selectively depressed by short-term treatment with EPA-E in rabbits without changing systolic blood pressure.

Bremazocine Causes Sympatho-Inhibition and Hypotension in Rabbits by Activating Peripheral K-Receptors

We have studied the effects of bremazocine on the peripheral sympathetic nervous system and the arterial blood pressure of pithed rabbits with electrically (2 Hz) stimulated sympathetic outflow, and compared them with the effects of Leu-enkephalin and fentanyl. The 3H-noradrenaline plasma clearance and the plasma concentration of noradrenaline were used to calculate the rate of spillover of endogenous noradrenaline into the plasma; the spillover rate reflects the overall release of noradrenaline from postganglionic sympathetic neurones. Bremazocine (10 and 100 micrograms kg-1, followed by an infusion of 2 and 20 micrograms kg-1 h-1, respectively, i.v.) persistently decreased the noradrenaline spillover rate as well as blood pressure. Both effects were antagonized by naloxone. Leu-enkephalin (70 and 350 micrograms kg-1 min-1 i.v.) caused only transient hypotension. Fentanyl decreased blood pressure only at a very high dose (250 micrograms kg-1, followed by an infusion of 500 micrograms kg-1 h-1 i.v.). The effects of Leu-enkephalin and fentanyl were also antagonized by naloxone. When the blood pressure of pithed rabbits was raised by an intravenous infusion of noradrenaline, rather than by electrical stimulation, bremazocine, Leu-enkephalin, and fentanyl failed to produce hypotension. The results indicate that bremazocine inhibits the release of noradrenaline and, in consequence, lowers arterial pressure by activation of peripheral, probably prejunctional, opioid receptors. The receptors appear to be of the kappa-type.

Animal pharmacology of guanfacine

The pharmacologic data obtained from animal experiments with guanfacine, a novel, centrally acting antihypertensive agent, are reviewed. When given orally, guanfacine lowers systemic blood pressure in conscious DOCA-NaCl-hypertensive rats, Grollman rats and spontaneously hypertensive rats in a dose-dependent manner. It is also effective in renal hypertensive cats. Guanfacine reduces blood pressure in cats, rabbits and rats after injection into the lateral cerebral ventricle and in dogs after infusion into the vertebral artery at intravenously ineffective doses. Vagally mediated reflex bradycardia in dogs is enhanced. The preganglionic splanchnic (sympathetic) nerve activity is reduced in cats. In rats, guanfacine reduces the noradrenaline turnover in the brain stem. All these findings indicate a central site of action. Peripheral α-adrenoceptor stimulant properties of guanfacine have been demonstrated in various studies. In addition to postsynaptic stimulant effects, presynaptic guanfacine-induced inhibition of sympathetic heart nerve stimulation is antagonized by rauwolscine but not by prazosin, indicating a highly preferential α 2-agonistic presynpatic action of the drug. In receptor binding studies using rat cortex membranes and human platelets, guanfacine exhibited a high selectivity for α 2 adrenoceptors. Guanfacine has the advantage over other centrally acting antihypertensives of being less sedative and causing no rebound hypertension after discontinuation of treatment. The latter is mainly due to its pharmacokinetic properties.

Ocular effects of a relatively selective alpha 2 agonist (UK-14, 304-18) in cats, rabbits and monkeys.

UK-14, 304-18 (UK), a relatively selective alpha 2-agonist, was examined for its effects on intraocular pressure (IOP) and pupil diameter (PD) in rabbits, cats and monkeys and on noradrenergic function in the cat nictitating membrane (CNM) preparation. Topical, unilateral administration of UK (0.0005-0.5 mg) produced dose-dependent decreases in IOP and pupil size in normal, unanesthetized rabbits, cats and monkeys. The ocular hypotensive effect of UK in the ipsilateral eye was delayed relative to the contralateral eye in all three species; UK produced an initial transient ocular hypertension in rabbits which was abolished by surgical transection of three major extraocular muscles. Mean arterial blood pressure in rabbits was not affected by 0.005 mg UK topically. The ocular hypotensive and miotic effects of UK were attenuated in superior cervical ganglionectomized (SX) cats and rabbits. Intra-arterially administered UK (0.33, 1.0, 3.3 and 10 micrograms) produced dose-related systemic hypotension and inhibition of contractions of the CNM elicited by electrically stimulating the pre- and postganglionic sympathetic trunks in the urethane/chloralose anesthetized cat. This inhibition was reversed and prevented by 300 micrograms rauwolscine but not by 300 micrograms domperidone. UK also enhanced the contractile response of the CNM to injected norepinephrine (10 micrograms). UK suppressed ocular hypertension induced by water loading and IOP recovery rate following hypertonic saline infusion in rabbits suggesting that aqueous flow was inhibited. These results indicate that UK lowers IOP, in part, by suppressing sympathetic neuronal function which causes a reduction in aqueous flow.

Cardiovascular pharmacology of Panax notoginseng (Burk) F.H. Chen and Salvia miltiorrhiza.

The cardiovascular pharmacology of two Chinese herbs, Salvia miltiorrhiza (SM) and Panax notoginseng (Burk) F. H. Chen (PNG) were studied both in vivo and in vitro. Extracts of both herbs suppressed systemic blood pressure in albino rats and rabbits, an effect which was blocked or reversed by atropine, propranolol, and chlorpheniramine plus cimetidine. This reversed hypertension was blocked by phenoxybenzamine. These results indicate that these herbs have multiple effector sites in the cardiovascular system. This could be due to an increased utilization of extracellular calcium ions since the activity of SM on isolated blood vessels of rabbits was enhanced by 2 mM Ca++. The effects of aqueous extract of SM and purified active principles of SM (tanshinones) on rat and rabbit blood vessels in vitro were very similar both qualitatively and quantitatively. Both caused vasodilation of coronary arteries at all concentrations tested but induced vasodilation of renal, mesenteric and femoral arteries only at low concentrations. At higher concentrations, vasoconstriction was induced in these vessels. These results indicate that an economical decoction of SM is as efficacious as the more expensive isolated tanshinones. Both SM and PNG would be useful as antianginal agents since they dilate coronary vessels. Their use in hypertension is questionable since they induce both vasodilation and vasoconstriction depending on dose and target vessel.

Effect of age on blood pressure and small vessel reactivity in male rabbits.

Direct blood pressure measurements were made on male rabbits from 3 to 55 months old to determine if blood pressure increases with age in this animal model as it does in humans. To assess the effects of age on vascular reactivity, strips of small ear artery and skeletal muscle artery were taken from these animals and tested with norepinephrine, potassium, histamine, and isoproterenol in vitro. Heart rate did not differ between age groups, but blood pressure was significantly higher in older age groups compared to 3-month-old-rabbits. Vessels from older animals were thicker and less sensitive to norepinephrine. Responses to potassium, histamine, and isoproterenol were not different between age groups. The results suggest that male rabbits offer a good model of age-related increases in blood pressure, and that changes in vascular adrenergic reactivity may occur with age in male rabbits.

Effects of intravenous infusion of doxorubicin on blood chemistry, blood pressure and heart rate in rabbits.

The effects of a 1 h continuous infusion of doxorubicin (12.5 mg kg-1, 200 mg M-2) on blood chemistry was examined in rabbits over a 6-h period. Plasma glucose levels remained unchanged while insulin levels were significantly decreased to 39, 45 and 61% of the zero time value (12.8 +/- 2.9 ng ml-1) at 30, 60 and 120 min, respectively, after starting the drug infusion. Plasma cortisol levels were increased to 141, 140 and 131% of the initial zero time value (12.3 +/- 2.2 ng ml-1) at 120, 240 and 360 min, respectively. Doxorubicin had no effect on plasma electrolytes, osmolality and urea nitrogen but significantly increased plasma creatinine over the corresponding control value (2.2 +/- 0.8 micrograms ml-1 to 4.9 +/- 0.7 micrograms ml-1) at 120 min and the level remained elevated for the remaining period of the study. Systolic and diastolic pressure, and heart rate were also depressed at 240 and 360 min. The data collected in the present study indicate that the doxorubicin infusion might have a direct effect on beta cells in the pancreas as well as muscle tissue. Changes in cortisol, blood pressure and heart rate appear to be secondary to other effects produced by doxorubicin.

The vasoactive proteins in human urine

We have purified vasoactive polypetides from the urine of normotensive humans by gel filtration on Sephadex G150 superfine ionic exchange chromatography on DEAE-cellulose and isoelectric focusing in poly- acrylamide gels using a pharmalyte pH range of 2.5–5.0. The purified polypetide fraction yielded four bands by isoelectric focusing with isoelectric points at pH 4.15, 4.05, 3.9 and 3.8. On dodecyl sulphate/polyacryl- amide gel electrophoresis (page) two bands appeared, one small band with a M r of 29 000 and one broad band ranging from M r 49 000 to M r 42 500. The polypetides lower the blood pressure of rabbits in a bioassay and cleave D-valyl-L-leucyl-L-arginine-4-nitroanilide with a specific activity comparable to that of kallikrein.

A new mechanism in one-kidney, one clip hypertension.

The renin-angiotensin system does not appear to be involved in the maintenance of elevated blood pressure in experimental one-kidney, one clip hypertension. Paradoxically, direct immunization with purified hog kidney renin lowers the blood pressure of rabbits with this form of hypertension. Antirenin antibodies were removed and the IgG fraction prepared from the plasma of such immunized rabbits. The antibodies thus obtained lowered the blood pressure of other hypertensive rabbits. The same antibodies, detected with a fluorescein-labeled second antibody, stained the cytoplasm of smooth muscle and certain other cells in sections of kidney, aorta, carotid artery, heart, liver, pancreas, adrenal gland, and small intestine from normal and hypertensive rabbits. We suggest that renin is converted into a form that is present most conspicuously in arterial and arteriolar smooth muscle. Its function in this location is unknown but must involve vasoconstriction as its neutralization by specific antibody lowers the blood pressure of one-kidney, one clip hypertensive rabbits.

Increased Pressor Response to Angiotensin II after Stricture of the Abdominal Aorta in Pregnant Rabbits

The abdominal aorta of 7 pregnant rabbits was treated below the renal arteries on the 21st day of pregnancy, producing a stricture which reduced the lumen to 2.0 mm in diameter. The pressor response to angiotensin II was assessed by measuring the systolic blood pressure of the ear using a Grant-Rothschild capsule. After stricture of the abdominal aorta, the systolic blood pressure in pregnant rabbits was not statistically different from that of sham operated rabbits. However, a significant increase in vascular reactivity to infused angiotensin II was demonstrated during the remaining gestational period.These findings suggest that interference with the blood supply of the pregnant uterus is an important factor in determining the vascular reactivity to angiotensin II in pregnant rabbits

Contribution of Central and Peripheral Mechanisms to the Antihypertensive Effects of α-Methyldopa in the Rabbit

We compared the effects of one intracisternal (0.6 mg/kg i.c.) and two intravenous (25 and 50 mg/kg i.v.) doses of alpha-methyldopa (alpha-MD) on blood pressure, heart rate, and plasma catecholamines in rabbits before and 2-3 weeks after intracisternal administration of 6-hydroxydopamine (6-OHDA). Intracisternally administered alpha-MD lowered heart rate, blood pressure, and plasma noradrenaline levels. Peak effects on heart rate and blood pressure were observed 2-3 h after administration. Three hours after intracisternally administered alpha-MD, plasma noradrenaline levels were reduced by 58%. Two to three weeks after 6-OHDA administration, the central mechanism responsible for the falls in heart rate, blood pressure, and plasma noradrenaline levels was abolished. The effects of intravenously administered alpha-MD (50 mg/kg) on heart rate, blood pressure, and plasma noradrenaline levels were attenuated but not completely abolished by destruction of central catecholaminergic neurons with 6-OHDA. These residual effects of alpha-MD most probably represent the peripheral effects of alpha-methylnoradrenaline at sympathetic terminals. The relative magnitudes of central to peripheral effects of alpha-MD on heart rate and blood pressure are dose dependent. After the lower intravenous dose (25 mg/kg), which achieves plasma alpha-MD concentrations similar to those found in humans, central mechanisms predominant. At higher doses, central and peripheral mechanisms contribute equally to these effects.