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H F Oates

Publications and source records attributed to H F Oates.

At least 37 records · Page 2Linked to original sources
PubMed1977

Mechanism of the hypotensive action of prazosin.

The mechanism of action of prazosin was studied in anesthetized rats by comparison with the peripherally-acting anti-hypertensive agents, indoramin, hydralazine and diazoxide. Hydralazine and diazoxide retained full hypotensive potency after ganglionic blockade with pentolinium or alpha adrenoceptor blockade with phentolamine. Hydralzaine and diazoxide also attenuated angiotensin II pressor responses. In contrast, the hypotensive activity of prazosin was completely abolished, and that of indoramin was almost abolished by either pentolinium or phentolamine pre-treatment. Neither prazosin nor indoramin caused impairment of angiotensin II responsivity, but each was shown to possess alpha adrenoceptor blocking properties. Both agents antagonized the pressor action of norepinephrine and reversed responses to epinephrine. Thus, while hydralazine and diazoxide act directly upon the vasculature by mechanisms independent of sympathetic vasomotor tone, prazosin, like indoramin, acts as an alpha adrenoceptor blocking agent.

Angiotensin II↗
PubMed1976

Haemodynamic effects of prazosin.

Parzosin, 0.001 to 10 mg/kg, was administered intravenously to anesthetized normal rats. In the dose range 0.001 to 0.01 mg/kg, the drug induced highly significant, dose-related falls in blood pressure, pulse pressure and heart rate. With doses above 0.01 mg/kg, there was a plateau in hypotensive efficacy and a diminution in negative chronotropic activity. Both actions of prazosin (0.01 mg/kg) were unaffected by vagal blockade with atropine, while hypotensive potency was unimpaired after beta-adrenoreceptor blockade. The vasodilator, diazoxide, lowered blood pressure, widened pulse pressure and caused tachycardia in rats pre-treated with pentolinium. In contrast, all effects of prazosin were abolished by ganglion blockade. These findings, together with the absence of compensatory tachycardia or gross renin hypersecretion during prazosin-induced hypotension, are compatible with an antisympathotonic mode of action for the drug. However, consistent with its effects on cyclic nucleotide distribution, prazosin appears to enhance isoprenaline-induced beta-receptor stimulation.

Animals↗
PubMed1976

Suppression of renin release by timolol.

The beta-adrenergic blocking agent, timolol, administered to resting rabbits as an i.v. bolus (0.125 mg/kg) sustained by a 2-hr infusion at 0.0625 mg/kg/hr, caused significant depression of plasma renin activity (PRA) to 49% of the control level. Significant correlations emerged between the fall in mean blood pressure and changes in both heart rate and PRA. Timolol also antagonized isoprenaline-induced renin release. In anaesthetized normal rats, timolol (0.2 mg/kg i.p.) suppressed mean plasma renin concentration (PRC) to 16% of the pre-treatment value. Furthermore, the mean PRC of normal rats, bled immediately after decapitation, to avoid stimulating renin secretion, was reduced by 55% one hr after i.p. injection of timolol. The potency of timolol in this respect was 8 times that of dl-propranolol. Thus, in rabbits and rats, timolol effectively depresses both basal and stimulated plasma renin levels.

Adrenergic beta-Antagonists↗
PubMed1975

Angiotensin blockade in studies of the feedback control of renin release in rats and rabbits.

1. In rabbits actively immunized against angiotensin II (AII), the appearance of anti-AII antibodies was associated with a rise in plasma renin activity (PRA), which did not occur in mock-immunized controls. 2. In conscious rabbits, infusion of the angiotensin inhibitor, Sar1-Ala8-angiotensin II (P-113), at rates of 0.055, 0.22 or 1.1 nmol min-1 kg-1 into the renal artery, caused dose-related increases in arterial PRA and renal arteriovenous PRA difference. Renal blood flow fell with the high dose, but not with the low or medium doses. A fall in arterial pressure, asynchronous with peak renin secretion, accompanied the medium- and high-dose infusions. 3. Intravenous infusion of inhibitor P-113, 5.5 nmol min-1 kg-1, into anaesthetized rats produced highly significant increases in PRA and plasma renin concentration without reduction in arterial pressure. There were no changes in PRA or plasma renin concentration in saline-infused control rats. 4. These findings suggest that AII blockade interrupts a negative feedback loop controlling renin secretion.

Angiotensin II↗
PubMed1975

beta-Adrenergic receptors and renin release: studies with beta-adrenoreceptor-blocking agents in the conscious rabbit.

1. Plasma renin activity (PRA) and mean blood pressure were studied in conscious rabbits infused with beta-adrenoreceptor antagonists. 2. Oxprenolol and DL-propranolol each significantly reduced PRA and blood pressure, but prindolol, which had a strong blood pressure-lowering effect, increased PRA. 3. When prindolol was given to animals in which PRA and blood pressure had been reduced by DL-propranolol, PRA returned to control values but blood pressure remained low. Thus the increase in PRA caused by prindolol is not mediated by hypotension. These findings, together with the observation that compound H35/25 reduced PRA without altering blood pressure, suggest that the effects of the beta-adrenoreceptor-blocking drugs on blood pressure are unrelated to their effects on renin release. 4. Studies with D-propranolol and with blocking agents with either beta-1 or beta-2 specificity indicated that the effects of beta-adrenoreceptor blockade on renin are directly dependent upon their action on beta-adrenergic receptors, probably of the beta-2 type.

Adrenergic beta-Antagonists↗
PubMed1974

Role of extrapulmonary conversion in mediating the systemic pressor activity of angiotensin I.

The effect of antibodies against angiotensin II (AII) on systemic pressor responses to intravenously injected AII and angiotensin I (AI) was studied in a group of bioassay rats. AII antibody was only 29% as effective in neutralizing AI given intravenously as it was in neutralizing AII injected by the same route. Control plasma caused no change in the relative potencies of AI and AII. In a further series of experiments, AII antibody was significantly less effective in blocking intra-arterial AI than in blocking intravenous AI. The potency of intra-arterial AI, initially less than that of intravenous AI, became nearly twice that of intravenous AI after antibody administration, a result which could not occur if AI were inactive before lung transit. Thus, AI can elicit systemic pressor activity independently of pulmonary conversion to AII. However, since the intra-arterial AI responses were abolished by an inhibitor of angiotensin-converting enzyme, the activity would appear to be mediated by peripheral conversion to AII rather than by an intrinsic action of the decapeptide. Both series of experiments suggest that the efficacy of AII antibody in abolishing the systemic pressor activity of AI is highly dependent on the site of conversion of the AI to AII. The occurrence of localized intramural conversion of AI to AII near arteriolar receptors in vivo may so minimize exposure of the liberated AII to circulating antibody as to render AII immunization an inefficient means of blocking endogenous pressor activity of the renin-angiotensin system.

Angiotensin II↗
PubMed1974

Renal hypertension in rats immunized against angiotensin I and angiotensin II.

Rats, actively immunized against angiotensin I (AI) and angiotensin II (AII), were subjected to unilateral renal artery constriction to determine whether the resulting hypertension, which may still ensue in the animal immunized against AII, could be prevented by such combined immunity. Sustained immunity to both AI and AII neither changed preoperative blood pressures of the rats from those of control mock-immunized rats nor altered the incidence or severity of renal dip hypertension. Vascular hyperresponsiveness to small quantities of free angiotensin could not be invoked to explain the hypertension, for there was no significant difference between mock-immunized hypertensive animals, and those remaining normotensive, regarding pressor sensitivity to intravenous AI, AII, renin, and norepinephrine. (AI + AII)-immunized hypertensive rats required AI doses averaging 260 times greater than nonimmune hypertensives to elicit equipressor responses, and were refractory to renin, but not to norepinephrine. Thus, while previous studies have not excluded direct participation of endogenous AI in renal clip hypertension in rats, evidence from our experiments makes it extremely difficult to sustain any pressor function therein for circulating AI or AII. Our results also preclude involvement of AII produced from circulating AI by conversion within arteriolar walls, close to receptor sites, since AI immunity would block this mechanism of action.

Angiotensin II↗
PubMedDate not supplied

Plasma renin concentration in hypertension produced by unilateral renal artery constriction in the rat.

1. Plasma renin concentration (PRC) and blood pressure were studied sequentially, 24 h to 42 days post-operatively, in rats subjected to unilateral renal artery constriction without contralateral nephrectomy. 2. The PRC of rats failing to develop hypertension remained normal, whereas the mean PRC of twenty-two rats that became hypertensive was five times normal on day 14 of the study when the hypertension was becoming established. 3. In eleven of the twenty-two rats that became hypertensive, PRC did not exceed the upper limit of normal. In the remaining hypertensive rats, the increase in PRC was not always temporally related to the increase in blood pressure. A significant correlation between PRC and blood pressure did not emerge until day 35 of the study. 4. Despite these anomalies, linear regression analysis of 169 pairs of PRC and blood pressure measurements during the 42 day period of development of hypertension in twenty-two rats revealed a highly significant correlation between log PRC and blood pressure (P smaller than 0.001). 5. It is concluded that factors other than the plasma concentration of renin are involved in the early stages of development of hypertension induced by renal artery constriction. Nevertheless, PRC and blood pressure are intricately related.

Animals↗
PubMedDate not supplied

Role of the renin-angiotensin system in hypertension produced by unilateral renal artery constriction in the rat.

1. Conscious rats which had undergone unilateral renal artery constriction were infused for 1 h with a specific antagonist of angiotensin II, 1-Sar-8-Ala-angiotensin II (P-113). 2. There was a highly significant correlation between the change in blood pressure induced by P-113 and the pre-infusion plasma renin concentration (PRC), regardless of initial blood pressure or the duration of stenosis. However, the blood pressure fall was not significantly greater in nineteen hypertensive rats than in eleven which remained normotensive. P-113 did not abolish the hypertension. 3. The extent to which angiotensin II supports blood pressure in rats with renal artery constriction is directly related to the PRC.

Angiotensin II↗
PubMedDate not supplied

Interactions between prazosin, clonidine and direct vasodilators in the anaesthetized rat.

1. Prazosin, clonidine, hydrallazine and diazoxide were administered intravenously, alone or in various combinations, to anaesthetized rats. 2. Prazosin and clonidine were equipotent. Their combined hypotensive effects in no instance exceeded the maximum effect attainable with either agent alone. The hypotensive effects of hydrallazine or diazoxide were, in contrast, additive to those of either prazosin or clonidine. 3. Pressor responses to clonidine were antagonized by prazosin. Prazosin may prove useful in hypertensive crises provoked by clonidine.

Animals↗
PubMedDate not supplied

Studies in the rat on the haemodynamic overshoot response to withdrawal of guanfacine or clonidine treatment.

1. Normal rats were injected intramuscularly twice daily for either 3 days or 3 weeks with guanfacine (0.1 or 1.0 mg/kg), clonidine (0.01 or 0.1 mg/kg) or 0.9% saline. All were anaesthetized at various times before or after the last injection, and their arterial pressures and heart rates were monitored via a carotid artery catheter. 2. Overshoots in systolic and diastolic pressure and heart rate, reaching peak values as soon as 16 h after the last injection, occurred in all rats withdrawn from guanfacine or clonidine treatment, but in no control rats. 3. Post-withdrawal blood pressures and heart rates of rats which had received the low dose of guanfacine or clonidine were as great as those of rats which had received the ten-fold greater dosage. Moreover, withdrawal responses were as great in rats which had been treated for only 3 days as in those treated for 3 weeks. 4. The dosages and duration of treatments used in these experiments thus did not influence the magnitude of the haemodynamic overshoots provoked by withdrawal of guanfacine or clonidine. However, all groups of rats from which guanfacine was withheld exhibited significantly greater peak overshoots in systolic and diastolic pressure than did those withdrawn from clonidine treatment.

Animals↗
PubMedDate not supplied

Profile of a new prazosin congener, BL-5111A. Studies in the rat.

1. The effects on blood pressure and heart rate of prazosin and a structurally-related congener, BL-5111A, were compared in conscious and anaesthetized rats. 2. Both agents induced dose-related falls in systolic and diastolic blood pressure, with relatively little effect on heart rate. The hypotensive potency of prazosin was twenty-fold greater than that of BL-5111A. 3. The hypotensive activity of prazosin was abolished by pretreatment with the ganglionic blocking agent, pentolinium, or the alpha-adenoceptor blocking agent, phentolamine, whereas BL-5111A retained significant hypotensive activity (up to 28%) after either pretreatment. 4. Both prazosin and BL-5111A attenuated pressor responses to noradrenaline, and reversed the responses to adrenaline, prazosin being, in this respect, 6 times more potent than BL-5111A. There was a highly significant relationship between the alpha-adrenoceptor blocking activity of either agents and its hypotensive effect. 5. BL-5111A differed from prazosin in possessing, in addition to its predominant alpha-adrenoceptor blocking action, a minor component of action attributable to direct vasodilatation.

Anesthesia↗