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Biomedical subjects

M R MacLean

Publications and source records attributed to M R MacLean.

At least 55 records · Page 3Linked to original sources
PubMed1994

5-HT1-receptor-mediated vasoconstriction in bovine isolated pulmonary arteries: influences of vascular endothelium and tone.

Vasoconstrictor responses to 5-hydroxytryptamine (5-HT) and the 5-HT1D receptor agonist sumatriptan were studied in isolated bovine pulmonary artery rings. The effects of the antagonists, ketanserin (5-HT2A-receptors) and methiothepin (5-HT1- and 5-HT2A-receptors) on these responses were determined. The influences of vascular tone and the effect of removal of the vascular endothelium and pretreatment with the inhibitor of nitric oxide synthase, N omega-nitro-L-arginine methylester, were also studied. In the absence of tone, in the majority of vessels, sumatriptan did not induce significant contractions. 5-HT-induced responses were concentration-dependent and ketanserin and methiothepin antagonized these in a competitive fashion. Removal of the endothelium or inclusion of L-NAME potentiated responses to sumatriptan. The sensitivity to sumatriptan was increased by L-NAME only in the presence of the endothelium whilst maximum responses to sumatriptan were potentiated in both unrubbed and rubbed vessels. Removal of the endothelium and/or inclusion of L-NAME had no significant effect on responses to 5-HT. U46619-induced tone markedly increased sumatriptan-induced responses which were competitively antagonized by methiothepin but were relatively resistant to ketanserin, verifying activation of a 5-HT1D receptor. Responses to 5-HT were also potentiated and competitively antagonized by ketanserin, and further antagonized by methiothepin. With tone present, lower concentrations of 5-HT were ketanserin-resistant and methiothepin-sensitive, indicating activation of a 5-HT1-like receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1994

Endothelin ETA- and ETB-receptor-mediated vasoconstriction in rat pulmonary arteries and arterioles.

We investigated the endothelin (ET) receptors involved in the vasoconstrictor responses to ET-1 in rat pulmonary arteries and arterioles and the effect of endothelium removal, nitric oxide (NO) synthase inhibition, and hypoxia on ET-1-induced responses in the arteries. In isolated rat pulmonary artery rings (2-3 mm ID) prepared from the pulmonary artery branch before its entry into the lung, ET-1-induced vasoconstrictor responses. These responses were mediated by the ETA receptor as they were competitively antagonized by the ETA receptor antagonist FR 139317, and the ETB-receptor agonist sarafotoxin S6c (SXS6c) was a very weak vasoconstrictor in these vessels, inducing maximum contractions only 9% of those of ET-1. In contrast, in rat intrapulmonary resistance arteries (100-150 microns ID), SXS6c induced FR 139317-resistant contractions, and these vessels were more sensitive to SXS6c than to ET-1. SXS6c produced maximum contractions 92% those of ET-1, suggesting that ET-1-induced contractions were mediated by the ETB receptor in these resistance vessels. In the larger pulmonary arteries, the NO synthase inhibitor L-N omega nitroarginine methyl ester (L-NAME) (100 microM) potentiated responses to ET-1, an effect that was reversed by FR 139317. Endothelium removal also potentiated response to ET-1, and L-NAME had no effect on ET-1 responses in endothelium-denuded vessels, suggesting that in these vessels the ETA receptor-mediated responses to ET-1 are normally suppressed by endothelium-derived NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Endogenous nitric oxide modulates vasopressor responses, but not depressor responses, to spinal sympathetic nerve stimulation in pithed rats.

The effects of N omega-nitro-L-arginine methylester (L-NAME), an inhibitor of nitric oxide (NO) synthase (1,5, and 10 mg/kg) on vasopressor and depressor responses to segmental sympathetic nerve stimulation were studied in the pithed rat preparation. Vasopressor responses were evoked by stimulation of the spinal sympathetic outflow at T6-T8 (30 V, 0.05 ms at 5 Hz with 10 pulses). This pressor response was biphasic: An initial transient response (to nerve stimulation) was followed by a later prolonged response (to adrenal catecholamine release). L-NAME 1, 5, and 10 mg/kg increased mean arterial blood pressure (MAP); this effect was maximal at 1 mg/kg L-NAME, but had no effect on heart rate (HR). L-NAME 1, 5, and 10 mg/kg potentiated both phases of the pressor response; the effect was maximal at 10 mg/kg. Vasodepressor responses were evoked by stimulation of the spinal sympathetic outflow at S2-L6 (30 V, 0.05 ms at 5 Hz with 10 pulses). L-NAME 1, 5, and 10 mg/kg did not inhibit these depressor responses. We conclude that inhibition of the synthesis of endogenous NO causes a hypertension in pithed rats that is associated with increased vasoconstriction in response to sympathetic nerve stimulation and adrenal catecholamine release. Systemic vascular depressor responses to segmental sympathetic nerve stimulation are not affected, however; therefore, NO cannot be the major mediator of these responses.

Animals↗
PubMed1993

Influences of the endothelium and hypoxia on neurogenic transmission in the isolated pulmonary artery of the rabbit.

1. The effects of nitric oxide (10(-6) M), N omega-nitro-L-arginine methylester (L-NAME, 10(-4) M, an inhibitor of nitric oxide synthase), endothelium removal, hypoxia and selective alpha-adrenoceptor antagonists on responses to nerve electrical field-stimulation (EFS) were studied in the rabbit isolated pulmonary artery. 2. EFS induced frequency-dependent contractions which were abolished by prazosin (alpha 1-adrenoceptor antagonist) and unaffected by rauwolscine (alpha 2-adrenoceptor antagonist). EFS-induced responses were potentiated by L-NAME and inhibited by nitric oxide. The effect of L-NAME was reversed by the presence of L-arginine (2 x 10(-4) M), which had no effect on its own. In the presence of L-NAME, the EFS-induced responses were reduced by rauwolscine and the residual responses were abolished by prazosin. 3. Removal of the vascular endothelium increased the maximum contractile response to EFS but did not inhibit the ability of L-NAME to potentiate contractile responses to EFS. 4. Hypoxia inhibited the contractile response to EFS. This effect of hypoxia was also seen in the presence of L-NAME and in endothelium rubbed preparations. 5. In conclusion, the endothelium modulates EFS-induced contractions in the rabbit pulmonary artery. The contraction induced by EFS was inhibited by nitric oxide, but potentiated by the nitric oxide-synthase inhibitor, L-NAME. The effect of L-NAME was not mediated solely through the endothelium and revealed involvement of alpha 2-adrenoceptors in EFS-induced contraction. Hypoxia inhibited neurogenic responses in rabbit isolated pulmonary arteries.

Adrenergic alpha-Antagonists↗
PubMed1993

Influences of the endothelium and hypoxia on alpha 1- and alpha 2-adrenoceptor-mediated responses in the rabbit isolated pulmonary artery.

1. The effects of the inhibitor of nitric oxide synthase, N omega-nitro-L-arginine methylester (L-NAME, 10(-4) M), mechanical disruption of the endothelium and hypoxia on contraction to noradrenaline (alpha 1- and alpha 2-adrenoceptor agonist), phenylephrine (alpha 1-adrenoceptor agonist) and UK 14304 (alpha 2-adrenoceptor agonist) were compared in the rabbit isolated pulmonary artery. The effects of the selective antagonists rauwolscine (10(-6) M, alpha 2-adrenoceptors) and prazosin (10(-7) M, alpha 1-adrenoceptors) on the contractions to noradrenaline before and after exposure to L-NAME were also assessed. 2. Noradrenaline, phenylephrine and UK 14304 all produced concentration-dependent increases in vascular tone. The responses to noradrenaline were sensitive to both rauwolscine and prazosin (effect of prazosin >> rauwolscine). L-NAME increased the potency of both noradrenaline and UK 14304, and also the maximum tension achieved. It had no effect on the responses to phenylephrine. After L-NAME, contractions to noradrenaline, although still sensitive to both rauwolscine and prazosin, were now more sensitive to inhibition by rauwolscine. 3. Endothelium removal augmented the potency and maximum contractions to noradrenaline, phenylephrine and UK 14304. 4. Hypoxia decreased both the potency of phenylephrine and its maximum contractile response, but increased the maximum response to noradrenaline without effecting responses to UK 14304. 5. In conclusion, in the rabbit pulmonary artery, augmentation of contractile responses to noradrenaline by L-NAME involves a potentiation of alpha 2-adrenoceptor-mediated contraction probably through an effect on the synthesis of endothelium-derived nitric oxide. Experimental hypoxia had differential effects on all three agonists and did not mimic the effect of nitric oxide synthase inhibition.

Adrenergic alpha-Agonists↗
PubMed1992

The influence of endothelin-1 on human foeto-placental blood vessels: a comparison with 5-hydroxytryptamine.

1. The vasoconstrictor effect of endothelin-1 (3 x 10(-11) M-10(-7) M) was studied in successive generations of blood vessels of the foeto-placental vascular tree. These were the human umbilical arteries and veins, primary surface chorionic plate arteries, secondary chorionic plate arteries, tertiary surface chorionic plate arteries and veins and the secondary stem villus arterioles. The responses to endothelin-1 were compared with those to 5-hydroxytryptamine (10(-9) M-10(-5) M). Arterial preparations were gassed with 2.5% O2, 8% CO2 balance N2 and venous preparations were gassed with 5% O2, 6% CO2 balance N2 to simulate the conditions prevalent in utero. The influence of increasing the oxygen tension to 16% (that prevalent at birth) on the response to endothelin-1 on the umbilical arteries was also investigated. 2. All the arterial vessels tested were some ten times more sensitive to endothelin-1 than to 5-hydroxytryptamine and the venous preparations were ten times more sensitive to endothelin-1 than were their equivalent arteries. Increasing oxygen tension did not affect the responses to endothelin-1 in the umbilical artery. 3. Whilst the amplitude of the endothelin-1-induced response was uniform throughout the foetoplacental vascular tree, including the stem villus arterioles, the maximum response to 5-hydroxytryptamine decrease with successive generations and it had no significant effect on the stem villus arterioles.The ratios of the responses to 10- M endothelin-1: 10-7M 5-hydroxytryptamine in human umbilical arteries, primary surface chorionic plate arteries, secondary chorionic plate arteries,tertiary surface chorionic plate arteries and the secondary stem villus arterioles in the vessels (listed in order of decreasing vessel size) were 1:1.2, 1:0.36, 1:0.33, 1:0.35 and 1:0.04 respectively.4. In conclusion, endothelin-1 is a powerful vasoconstrictor at all levels of the foeto-placental vascular system including the stem villus resistance vessels. It may play an important role in maintaining foeto-plancental vascular resistance at the low oxygen tension which exists in this vascular system in utero.

Blood Vessels↗
PubMed1990

Effects of endothelin-1 on isolated vascular beds from normotensive and spontaneously hypertensive rats.

Endothelin-1 and noradrenaline induced dose-dependent pressor responses in isolated in situ blood perfused mesenteric arterial beds and isolated tail arterial beds of anaesthetised spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). In the tail the sensitivity and maximum to either agonist were the same in SHR and WKY whereas in the mesenteric bed the maximum pressor responses to both agonists were increased in SHR. This effect of endothelin-1 may contribute to the greater increase in blood pressure it induces in anaesthetised SHR compared with WKY.

Animals↗
PubMed1990

Alpha-1-adrenergic receptors in the nucleus tractus solitarii region of rats with experimental and genetic hypertension.

The binding of the alpha 1-adrenergic receptors antagonist, 125I-HEAT, to membranes of nucleus tractus solitarii (NTS) regions of the brains of neurogenic hypertensive, spontaneously hypertensive (SH), and deoxycorticosterone (DOCA)/salt hypertensive rats and their respective controls was studied to quantitate the expression of alpha 1-adrenergic receptors. Scatchard analysis of the binding studies revealed a 1.8-fold increase in the Bmax of alpha 1-adrenergic receptors in NTS region membranes of SH rats when compared to their Wistar-Kyoto (WKY) control without significant difference in the Kd for 125I-HEAT. A decrease in the Kd with no difference in Bmax of receptors for 125I-HEAT was observed in the NTS region membranes of neurogenic hypertensive rats when compared with their sham-operated controls. In contrast, comparison of the Bmax and Kd values for 125I-HEAT binding in NTS region membrane of the DOCA/salt hypertensive rats and its sham-operated control showed no significant differences. We suggest that alterations in baroreceptor afferent activity may be related to alterations in central alpha 1-adrenergic receptors binding in SH rats and rats with neurogenic hypertension.

Adrenergic alpha-Antagonists↗
PubMed1990

The influence of angiotensin II on catecholamine synthesis in neuronal cultures from rat brain.

Incubation of primary neuronal cultures prepared from the hypothalamus and brainstem of neonatal rats with angiotensin II (Ang-II) resulted in a concentration-dependent effect on the incorporation of [3H]-tyrosine ([3H]-Tyr) into [3H]-catecholamines ([3H]-CA). At concentrations of 1 nM-1 microM, Ang-II (60 min. incubation) caused significant decreases (31-52%) in neuronal [3H]-CA content compared with controls. Conversely, higher concentrations of Ang-II (10-100 microM; 60 min.) caused significant increases (20-60%) in neuronal [3H]-CA content compared with controls. Both of these effects were blocked by co-incubation with the Ang-II receptor antagonist Sar1Ile8-Ang-II. These observations demonstrate that neuronal cells in primary culture have the ability to synthesize [3H]-CA from [3H]-Tyr, and that Ang-II has a receptor-mediated biphasic influence on newly synthesized [3H]-CA (norepinephrine and dopamine).

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1990

Effects of pre-contraction with endothelin-1 on alpha 2-adrenoceptor- and (endothelium-dependent) neuropeptide Y-mediated contractions in the isolated vascular bed of the rat tail.

1. The pressor effects to bolus doses of the alpha 2-adrenoceptor agonist UK-14,304 were studied in the isolated vascular bed of the perfused rat tail before and after increasing the perfusion pressure with infusions of endothelin-1. Those of neuropeptide Y were studied before and after pre-constriction with endothelin-1 or 5-hydroxytryptamine. The pressor effects of neuropeptide Y were studied before and after functional disruption of the endothelium with the detergent CHAPS. 2. Endothelin-1 and the alpha 1-adrenoceptor agonist phenylephrine induced dose-dependent vasoconstriction, endothelin-1 being some 10(4) times more potent than phenylephrine [log dose (mol) of the ED50 for endothelin-1 and phenylephrine: -11.8 +/- 0.2 (n = 7), -8.2 +/- 0.2 (n = 5) respectively]. 3. Under control conditions, at basal perfusion pressures, UK-14,304 and neuropeptide Y were virtually inactive as vasoconstrictors. Following a sustained increase in perfusion pressure by infusions of endothelin-1 (2.5-10 nM at 0.8 ml min-1), however, both UK-14,304 and neuropeptide Y induced dose-dependent pressor responses and both were some 10(2) times more potent than phenylephrine [log dose (mol) of the ED50 for UK-14304 and neuropeptide Y: -10 +/- 0.5 (n = 6), -10.3 +/- 0.4 (n = 6) respectively]. Responses to neuropeptide Y also were uncovered when vascular tone was increased with 5-hydroxytryptamine (5-20 nM) [log dose (mol) of the ED50 for neuropeptide Y: -10.2 +/- 0.2 (n = 6)]. 4. Pre-constriction-induced pressor responses to UK-14,304 were inhibited by 1 microM rauwolscine whilst those to neuropeptide Y were inhibited by disruption of the endothelium. Removal of the endothelium had no significant effect on the pressor responses to 4pmol or 8pmol endothelin-1 and had no effect on the increase in perfusion pressure induced by the endothelin-1 infusions but did decrease the time-course of pressor responses to bolus injections of endothelin-1. Endothelial disruption had no significant effect on the vasoconstriction induced by all but one of the doses of phenylephrine administered [log dose (mol) of the ED5o for phenylephrine after CHAPS: -8.6 + 0.2 (n = 5)], indicating that the responsiveness of the vascular smooth muscle was not destroyed by CHAPS. This treatment did, however, slow the onset and prolong the time course of the phenylephrine-induced responses. 5. These results indicate that, in the isolated vascular bed of the rat tail, pressor responses to both alpha 2-adrenoceptor- and neuropeptide Y receptor-activation are uncovered by agonist-induced preconstriction including that to endothelin-1. Neuropeptide Y-induced vasoconstriction was endotheliumdependent.

Animals↗
PubMed1990

Effect of neuropeptide Y on cardiac output, its distribution, regional blood flow and organ vascular resistances in the pithed rat.

1. The effects of neuropeptide Y on cardiac output, its distribution and organ vascular resistances were determined with tracer microspheres in pithed rats. 2. Neuropeptide Y increased blood pressure by increasing both cardiac output and total peripheral resistance. The increase in cardiac output was due to an increase in stroke volume as heart rate was not changed. Increased vascular resistance in the splenic, renal, testicular, epididymal, skeletal muscle, large intestinal and mesenteric vascular beds contributed to the increase in total peripheral resistance. Vasoconstriction was most pronounced in the mesenteric bed. 3. This study indicates that neuropeptide Y increases blood pressure by increasing cardiac output and total peripheral resistance. The increased cardiac output is possibly due to an increase in venous return, whilst the increased total peripheral resistance was due to regional vasoconstriction, particularly in the mesenteric bed.

Animals↗
PubMed1989

Pressor effects of the alpha 2-adrenoceptor agonist B-HT 933 in anaesthetized and haemorrhagic rats: comparison with the haemodynamic effects of amidephrine.

1. Blood pressure responses to single and multiple bolus doses of the alpha 2-adrenoceptor agonist B-HT 933 were analysed in intact anaesthetized rats which were either normotensive or hypotensive as a result of haemorrhage. Single bolus doses of B-HT 933 in normotensive rats induced a fall in blood pressure, whilst further doses induced dose-dependent pressor responses which were inhibited by the alpha 2-adrenoceptor antagonist yohimbine and unaffected by the alpha 1-adrenoceptor agonist prazosin. In the haemorrhagic, hypotensive animals, single bolus doses of B-HT 933 induced immediate dose-dependent pressor responses; the maximum pressor responses to the bolus of B-HT 933 and its ED50 values were the same in both the normotensive and hypotensive, haemorrhagic animals. 2. Cardiac output, its distribution and tissue blood flows were determined with tracer microspheres in intact anaesthetized normotensive and haemorrhagic, hypotensive rats during depressor (normotensive) and pressor (normotensive and hypotensive) responses to B-HT 933. Haemodynamics were also determined during pressor responses to the alpha 1-adrenoceptor agonist amidephrine. 3. In control normotensive rats, a single dose of B-HT 933 (1 mg kg-1) reduced blood pressure by reducing cardiac output (through a decrease in heart rate). It increased the fractional distribution of cardiac output to the spleen and stomach, reduced it to the heart and liver and reduced cardiac and hepatic blood flow. A further dose of B-HT 933 (1 mg kg-1 bolus followed by 100 micrograms min-1 infusion) increased blood pressure by increasing total peripheral resistance, which was accompanied by decreased proportions of cardiac output passing to the heart, liver and testes. There was also increased fractional distribution of cardiac output to the lungs, spleen, kidneys and stomach but blood flows through the liver and testes were reduced. Amidephrine (6 micrograms kg-1 bolus followed by 0.5 micrograms min-1 infusion) increased blood pressure by increasing cardiac output through an increased stroke volume. It increased cardiac output distribution to the kidneys and brain, increasing blood flow through the heart, lungs, brain, testes, epididimides, skin and large intestine. 4. Haemorrhage caused a fall in blood pressure which resulted from decreased total peripheral resistance and cardiac output (the latter due to decreases in both heart rate and stroke volume). It reduced the proportion of cardiac output distributed to the lungs, spleen, kidneys, testes and pancreas/mesentery and decreased blood flow through these organs as well as through the heart, liver, brain, epididimides, skin and the gastrointestinal tract.4

Adrenergic alpha-Agonists↗
PubMed1989

Effects of moderate hypoxia, hypercapnia and acidosis on haemodynamic changes induced by endothelin-1 in the pithed rat.

1. Pithed rats were respired at a fixed rate of 54 cycles min-1 and with a ventilation volume of either 20 (control) or 10 ml kg-1. In these two preparations, the dose-response relationships for the systemic blood pressure responses to endothelin-1, administered i.v., were examined. Also, cardiac output, its distribution, tissue blood flows and vascular resistances were determined at both respiratory volumes in pithed rats given saline or during pressor responses to endothelin-1 (750 ng, i.v.). Finally, a comparison was made of the pressor responses to endothelin-1 in the blood perfused superior mesenteric arterial bed of pithed rats respired at 10 or 20 ml kg-1. 2. In control rats the systemic blood pressure responses to i.v. endothelin-1 were biphasic with an initial, transient (30 s) decrease in blood pressure followed by a well sustained pressor response. These responses were dose-dependent (the ED50 for the pressor response being 0.27 +/- 0.04 micrograms). The pressor effect of endothelin-1 was due to an increase in total peripheral resistance with no change in heart rate or cardiac output. This increased total peripheral resistance was due to vasoconstriction of the spleen, stomach, large intestine, small intestine and the pancreas/mesentery (in which it was most severe). Endothelin-1 also increased blood flow through the heart, lungs, liver, epididimides, fat and skin through redistribution of cardiac output to these vascular beds. 3. At the lower ventilation volume there was moderate acidosis, hypoxia and hypercapnia relative to those rats respired at 20 ml kg-1. With respiration at 10 ml kg-1, the pressor response to endothelin-1 was not sustained and, after oscillations in both blood pressure and heart rate, death occurred 15-20 min after administration. The pressor effect resulted from increases in cardiac output (due to increased stroke volume) and total peripheral resistance: the latter was caused by vasoconstriction in the stomach, small intestine, large intestine and pancreas/mesentery. Endothelin-1 increased blood flow through the heart, lungs, liver, kidneys, testes, fat and skin due to either an increase in cardiac output, redistribution of cardiac output or both. 4. Endothelin-1 induced dose-dependent pressor responses in the mesenteric bed in situ. At the lower ventilation volume the potency of endothelin-1 in this vascular bed was increased approximately two fold with the ED50 being 68 +/- 7 pmol compared to 113 +/- 15 pmol in the rats respired at 20 ml kg-1. 5. This study indicates that, in normoxic control pithed rats, the pressor response to endothelin-1 was due largely to vasoconstriction of the splanchnic vascular bed. In rats with moderate hypoxia, hypercapnia and acidosis, the pressor response was due to vasoconstriction of the gastrointestinal tract as well as an increase in cardiac output. Endothelin-1 induced profound vasoconstriction in the mesenteric bed of the pithed rat both in vivo and in situ. The potency of endothelin-1 on this bed in situ was doubled by lowering the ventilation volume. An increase in cardiac contractility and severe gastrointestinal vasoconstriction may be the initial events leading to the eventual toxic effect of endothelin-1 in the hypoxic pithed rat.

Acidosis↗
PubMed1988

Inhibitory regulation by co-released peptides of catecholamine secretion by the canine adrenal medulla.

1. We have stimulated the peripheral end of the cut left splanchnic nerve in anaesthetized dogs while collecting the venous effluent of the left adrenal gland for catecholamine estimation. 2. With low frequency stimulation the resting output of catecholamines was inhibited but at high frequencies it was augmented. 3. The inhibition of catecholamine output by low frequency stimulation was reversed by opiate antagonists (naloxone and nalmefene) but enhanced by angiotensin converting enzyme inhibitors (captopril and enalapril).

Adrenal Medulla↗
PubMed1988

Effect of artificial respiratory volume on the cardiovascular responses to an alpha 1- and an alpha 2-adrenoceptor agonist in the air-ventilated pithed rat.

1. The effect of varying artificial respiratory volume (at a fixed rate of 54 min-1) on cardiac output, its distribution and tissue blood flows were determined with tracer microspheres in control pithed rats or during pressor responses to either the alpha 1-adrenoceptor agonist phenylephrine or the alpha 2-agonist xylazine. Phenylephrine was investigated in the presence of propranolol (3 mg kg-1). The rats were pithed under halothane anaesthesia. 2. A respiratory volume of 15 ml kg-1 produced modest hypercapnia (PaCO2 = 47 mmHg), hypoxia (PaO2 = 60 mmHg) and acidosis (pH = 7.35) relative to control animals respired at 20 ml kg-1 (PaCO2 = 32 mmHg; PaO2 = 77 mmHg; pH = 7.47). In rats respired at 15 ml kg-1, total peripheral resistance was lower, and cardiac output greater (due to increased stroke volume), than in the controls. Lowering respiratory volume reduced distribution of cardiac output to the kidneys, increased it to the large intestine and also increased blood flow through the gastrointestinal tract, skin and spleen. A respiratory volume of 30 ml kg-1 gave mild hypocapnia (PaCO2 = 19 mmHg), hyperoxia (PaO2 = 101 mmHg) and alkalosis (pH = 7.59) compared to 20 ml kg-1 but had no effect on cardiac output distribution or organ blood flow although heart rate was 29% greater at 30 ml kg-1. 3. Xylazine (500 micrograms bolus followed by 100 micrograms min-1 infusion) at all three respiratory volumes gave well-sustained mean pressor responses of 62-64 mmHg by increasing both total peripheral resistance and cardiac output (resulting from increased stroke volume). It increased the proportion of cardiac output passing to the liver, reduced that going to the spleen and gastrointestinal tract and increased cardiac, renal and hepatosplanchnic blood flows. 4. The secondary, relatively sustained, pressor effect of phenylephrine (5 micrograms bolus followed by 0.4 micrograms min-1 infusion, i.v.) varied at the 3 respiratory volumes with mean values from 32 to 53 mmHg. This response was due to both increased total peripheral resistance and cardiac output (resulting from greater stroke volumes and/or heart rates). Phenylephrine increased the proportion of cardiac output passing to the gastrointestinal tract, heart, kidneys and hepatosplanchnic bed and increased cardiac, hepatosplanchnic, renal and gastrointestinal blood flows. 5. Respiratory volume had no effect on the cardiovascular effects of xylazine. However, respiratory volume modified the effects of phenylephrine on heart rate and changed the relative contributions of stroke volume and heart rate to the increased cardiac output. It also influenced the effects of phenylephrine on cardiac output distribution to the liver, epididimides and hepatosplanchnic bed and on blood flow through skeletal muscle and the large intestine. 6. Changes in respiratory volume of air ventilated pithed rats thus influence cardiac output, its distribution and regional blood flows. Such changes can also differently influence the responses of various vascular beds to phenylephrine whilst having no effect on their responses to xylazine.

Adrenergic alpha-Agonists↗
PubMed1988

Effects of enalapril on changes in cardiac output and organ vascular resistances induced by alpha 1- and alpha 2-adrenoceptor agonists in pithed normotensive rats.

1. Cardiac output, its distribution and regional vascular resistances were determined with tracer microspheres in pithed rats in the presence of the angiotensin converting enzyme inhibitor enalapril. The effects of enalapril on the cardiovascular responses elicited by either the alpha 1-adrenoceptor agonist phenylephrine or the alpha 2-adrenoceptor agonist xylazine were determined. 2. Enalapril decreased diastolic and mean blood pressure by decreasing cardiac index and total peripheral resistance. It induced vasodilatation in the kidney, epididimides, epididimidal fat and pancreas/mesentery. Vasoconstriction in the lungs, testes and liver was evident following enalapril administration as well as a decrease in the proportion of cardiac output passing to them, whilst the pancreas and mesentery received a greater proportion of the cardiac output. All the above effects of enalapril were reversed by infusion of angiotensin II at a rate of 75 ng kg-1 min-1. 3. Xylazine increased blood pressure by increasing both cardiac output and total peripheral resistance. Enalapril did not affect the increase in cardiac output caused by xylazine but decreased the effect of the alpha 2-agonist on blood pressure by preventing the increase in total peripheral resistance. Inhibition by enalapril of xylazine-induced vasoconstriction in the kidneys, testes, fat and gastrointestinal tract contributed to the decrease in total peripheral resistance. Enalapril also inhibited xylazine-induced changes in cardiac output distribution to the liver, lungs and heart. All the above effects of enalapril were reversed by infusion of angiotensin II. 4. Enalapril decreased the sustained phase of the pressor response to an infusion of phenylephrine whilst having no effect on the initial peak pressor response to a bolus injection of phenylephrine. Phenylephrine increased both cardiac output and total peripheral resistance and enalapril abolished its effect on total peripheral resistance whilst having no effect on the increase in cardiac output. Enalapril inhibited phenylephrine-induced vasoconstriction in the testes, fat, muscle, spleen and gastrointestinal tract. Enalapril also inhibited phenylephrine-induced changes in cardiac output distribution to the lungs and liver. The infusion of angiotensin II did not fully reverse the inhibitory effect of enalapril either on the phenylephrine-induced increases in diastolic blood pressure or on the vasoconstriction in the fat, spleen and gastrointestinal tract, but did reverse all other effects of enalapril.

Adrenergic alpha-Agonists↗
PubMed1986

Effects of the renin-angiotensin system on the reflex response of the adrenal medulla to hypotension in the dog.

We have studied the influence of the renin-angiotensin system on the control of catecholamine release from innervated and denervated adrenal glands of anaesthetized dogs. Captopril reduced the resting release of catecholamines and inhibited release evoked either by lowering carotid sinus pressure or by stimulating the peripheral end of the cut splanchnic nerve. Both responses were restored by exogenous angiotensin II, and the reflex response could also be restored by corticotrophin. Cycloheximide, in the presence of captopril, further reduced the resting release of catecholamines and prevented the restoration of the reflex response by angiotension II. Plasma renin activity did not rise during baroreceptor tests lasting 10 min, but catecholamine release was evoked from the first minute. We conclude that the response of the adrenal medulla to sympathetic activity requires a minimum circulating concentration of angiotensin II. It is severely impaired by inhibition of the renin-angiotensin system but function can be restored either by exogenous angiotensin II or by corticotrophin.

Adrenal Medulla↗