Prostacyclin Can Either Increase or Decrease Heart Rate Depending on the Basal State

Chiavarelli, Mario; Moncada, Salvador; Mullane, Kevin

doi:10.1111/j.1476-5381.1982.tb08779.x

Cited by 13 publications

(4 citation statements)

References 19 publications

(24 reference statements)

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“…the presence of atropine, we have found no evidence for this mechanism either, with the same increase in heart rate found as in the absence of atropine. It has been proposed that in dogs the heart rate response to epoprostenol depends on the basal heart rate, and tachycardia is seen only if the basal rate is low (Chiavarelli et al, 1982). We have found no correlation of the heart rate response to epoprostenol with basal heart rate in over 40 experiments with basal rates ranging from 45 to 115 (following atropine, /3-adrenoceptor blocker or no pretreatment, and including unpublished experiments).…”

Section: Discussionmentioning

confidence: 51%

The cardiovascular and platelet effects of epoprostenol (prostacyclin, PGI2) are unaffected by beta‐adrenoceptor blockade in man.

Hassan¹,

Pickles²,

Fish³

et al. 1982

Brit J Clinical Pharma

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1 Atenolol 0.2 mg/kg i.v., propranolol 0.2 mg/kg i.v. or placebo were given in a double‐blind crossover study to six healthy male subjects, and the effects of a subsequent infusion of epoprostenol (prostacyclin, PGI2) 0‐6 ng kg‐1 min‐1 monitored. 2 PGI2 caused a tachycardia, a fall in diastolic blood pressure, a rise in pulse pressure, reduction in pre‐ ejection period (PEP) and rise in left ventricular ejection time index (LVETI), headache and facial flushing at doses of PGI2 greater than 2 ng kg‐1 min‐1, (P less than 0.05). 3 Beta‐adrenoceptor blockade did not prevent the tachycardia in response to PGI2, and did not interact with any of the other dynamic effects of PGI2. 4 In vitro, PGI2 at 1 and 2 ng/ml inhibited platelet aggregation to ADP (P less than 0.01), although no significant effect on platelet aggregation was seen in the in vivo study. Atenolol and propranolol at a final concentration of 1 microgram/ml did not affect this in vitro study. Atenolol and propranolol at a final concentration of 1 microgram/ml did not affect in vitro effect of PGI2 on platelet aggregation. 5 Pretreatment with atropine 0.04 mg/kg i.v. in three subjects did not attenuate the tachycardia caused by PGI2 infusion, even though the baseline heart rate was increased. 6 Adverse effects to PGI2 infusion included sudden bradycardia, pallor and sweating, suggesting that the Bezold‐Jarisch reflex seen in animals in response to PGI2 may also occur in humans. 7 Neither increased sympathetic drive nor vagal withdrawal are likely causes of the tachycardia following PGI2 infusion.

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Section: Discussionmentioning

confidence: 51%

The cardiovascular and platelet effects of epoprostenol (prostacyclin, PGI2) are unaffected by beta‐adrenoceptor blockade in man.

Hassan¹,

Pickles²,

Fish³

et al. 1982

Brit J Clinical Pharma

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“…This may be due to Figure 4a, is a well known sympathetic reflex response to the hypotension induced by this drug (Gross, 1977). Prostacyclin, depending on the doses used and the basal heart rate, has been shown to induce both tachycardia, as a result of stimulation of baroreceptor reflexes, and bradycardia, due to stimulation of a vagal reflex (Chiavarelli et al, 1982). In the present experiments, 160 ng kg-' min' prostacyclin was found to induce tachycardia (Figure 4b) output of dogs during infusion of prostacyclin (Armstrong et al, 1977).…”

Section: Tumoursmentioning

confidence: 99%

Modification of the 31P magnetic resonance spectra of a rat tumour using vasodilators and its relationship to hypotension

Tozer

Maxwell²,

Griffiths³

et al. 1990

Br J Cancer

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Summary The effects of different doses of hydralazine and prostacyclin on the 31P magnetic resonance spectra of the LBDS, fibrosarcoma were investigated and related to their effects on mean arterial blood pressure (MABP) and heart rate. The effect of reducing MABP by bleeding the animals, via the tail artery, was also investigated. Tumour spectral changes following high dose drug treatment (an (Hahn, 1974;Overgaard & Bichel, 1977;Overgaard & Nielsen, 1980). Hydralazine has also been shown to potentiate the cytotoxicity in solid rodent tumours in vivo of the bioreductive drugs RSU-1069(Chaplin & Acker, 1987 and SR4233 (Brown, 1987). These drugs are cytotoxic to hypoxic cells and their potentiation by hydralazine is presumably brought about by induced hypoxia secondary to a decrease in tumour blood flow.Selective reduction of tumour blood flow also has potential in more conventional chemotherapy. Stratford et al. (1987) showed that a carefully timed administration of hydralazine could increase the cytotoxic action of melphalan in transplanted rodent tumours whilst normal tissue toxicity remained unaffected. This could be explained by a hydralazine-induced selective reduction in tumour blood flow leading to entrapment of melphalan in the tumour tissue.Hydralazine is used clinically to control hypertension. Its plasma half-life in man is less than 60 min (Shepherd et al., 1980), but its half-life in vascular smooth muscle may be as high as 30 h (Gross, 1977) which is a possible disadvantage for application in tumour therapy. Horsman et al. (1989) have shown that, in mice, the mean arterial blood pressure, which falls on administration of hydralazine, has not returned to normal 8 h after injection. Tumour blood flow was not measured directly but there was also some indication that it too had not returned to pre-drug levels by 8 h. Any longterm reduction in the tumour blood supply would be a disadvantage for radiotherapy. Therefore, in the present study, the effect of hydralazine on cardiovascular parameters and tumour energy metabolism was compared with that of prostacyclin, an endogenous vasodilator formed from arachidonic acid (Moncada et al., 1976). This compound is rapidly hydrolysed in whole blood and plasma with a half-life of around 6 min (Orchard & Robinson, 1981). In man, the onset and offset of the cardiovascular actions of prostacyclin are rapid, less than 5 min, which means that its effects can be easily reversed (O'Grady et al., 1980;Lewis & Dollery, 1983

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“…Interpretation of the observations is elusive, but consider a provocative postulate centered on the properties of PGI 2 . A potent vasodilator synthesized by arterial blood vessels, PGI 2 can promote bradycardic, 27 and plasma levels correlate tightly with depressor aspects of the ANG II response. 13 Thus, for relatively high rates of PGI 2 synthesis, we might predict an increased pressor response to indomethacin and an initial cardiovascular response to vasopressor that is characterized by a relatively reduced pressor action and enhanced bradycardia.…”

Section: Discussionmentioning

confidence: 99%

The influence of indomethacin on blood pressure during the infusion of vasopressors.

Rowe¹

1986

Hypertension

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SUMMARY The effect of indomethacin and its vehicle on blood pressure was studied in conscious rabbits during the infusion of three vasopressors. The cyclooxygenase inhibitor raised mean arterial pressure 12 (vehicle: 3) mm Hg during norepinephrine infusion, 5 (vehicle: 0) mm Hg during angiotensin II infusion, and 5 (vehicle: -8 ) mm Hg during arginine vasopressin infusion. When saline was given in place of vasopressors, indomethacin failed to alter blood pressure. Since indomethacin elevated pressure in the presence, but not the absence, of all three vasopressors, the possibility that elevation of blood pressure per se stimulates synthesis of vasodilator prostaglandins was considered. A pressor action of indomethacin was observed in ganglion-blocked animals, in which absolute blood pressure remained below normotensive levels during angiotensin II infusion. Thus, indomethacin raised arterial pressure during the infusion of norepinephrine, angiotensin II, and vasopressin, and this action was not influenced by manipulation of blood pressure. These results suggest that each vasopressor promotes prostaglandin synthesis independently to a degree sufficient to restrain its pressor action. (NE) and arginine vasopressin (AVP) play a A. A . central role in the regulation of arterial blood pressure, and all three affect the production of vasodilator prostaglandins (PGs). For example, they stimulate the formation of arachidonic acid metabolites in the kidney, and inhibition of PG synthesis potentiates their renal vasoconstrictor actions.1 ' 2 Similar relationships have been demonstrated in other tissues; inhibition of PG synthesis enhances vasoconstrictor responses to NE in splenic, cutaneous, and mesenteric vasculatures and to ANG II in the heart and uterus.2 Available evidence, then, argues favorably for a compensatory role of PGs in the control of local blood flow when levels of vasoconstrictor hormones are increased; however, the impact of these local relationships on the regulation of arterial blood pressure is unclear. Currently, the relationship of vasopressors, PGs, and the regulation of arterial blood pressure is not well defined. Several reports suggest that PGs attenuate increases in blood pressure induced by NE or ANG II in humans or animals with elevated plasma renin activity. 2 Evidence for a similar relationship in normal physiological states is fragmented. Some reports indicate that cyclooxygenase inhibitors enhance the pressor response to ANG II 3 " 5 and NE 6 -7 in normal animals and humans, while others do not. The negative data are concealed in the control groups of studies focusing on animals with a compromised renin-angiotensin system. For example, cyclooxygenase inhibitors amplify the ANG II pressor response in pregnant rabbits 8 and sodium-restricted rats 9 and the response to NE in pregnant rabbits, 10 but all studies report no effect in the physiologically intact control groups. The concept that PGs modify vasopressor responses is not new, nor is it surprising in hyperreninemic conditions, in which...

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Prostacyclin Can Either Increase or Decrease Heart Rate Depending on the Basal State

Cited by 13 publications

References 19 publications

The cardiovascular and platelet effects of epoprostenol (prostacyclin, PGI2) are unaffected by beta‐adrenoceptor blockade in man.

The cardiovascular and platelet effects of epoprostenol (prostacyclin, PGI2) are unaffected by beta‐adrenoceptor blockade in man.

Modification of the 31P magnetic resonance spectra of a rat tumour using vasodilators and its relationship to hypotension

The influence of indomethacin on blood pressure during the infusion of vasopressors.

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