Prostacyclin produced by the pregnant uterus in the dog may act as a circulating vasodepressor substance.

Uterine production of PGI2 (prostacyclin) was quantitated in late pregnant dogs to evaluate if PGI2 could act as circulating vasodepressor substance in pregnancy. In five anesthetized, laparotomized dogs, the uterine venous plasma concentration of 6-keto PGF1 alpha (the in vitro hydrolysis product of PGI2) was 6.7 +/- 1.9 ng/ml and the arterial plasma concentration was 2.6 +/0 0.8 ng/ml. In four nonpregnant female dogs the arterial plasma concentration of 6-keto PGF1 alpha was consistently below 0.2 ng/ml. In eight pregnant dogs we also evaluated the ability of the pregnant uterus to inactivate PGI2 by comparing the hypotensive response to increasing doses of PGI2 infused into the uterine artery to the hypotensive response to increasing doses of PGI2 infused into the inferior vena cava. In addition, the effect of PGI2 infused into the uterine artery on uterine blood flow and intraamniotic fluid pressure was evaluated. The dose-response curves of intrauterine and intravenous PGI2 in causing systemic hypotension were identical suggesting that the pregnant uterus does not inactivate infused PGI2. Intrauterine PGI2 had no consistent effect on uterine hemodynamics although it did increase intraamniotic fluid pressure significantly. These data demonstrate that the pregnant uterus has the capacity to produce large quantities of PGI2 which is not inactivated in the uterus and therefore can appear in the arterial blood to exert a systemic vasodepressor effect.

Indomethacin is a placental vasodilator in the dog. The effect of prostaglandin inhibition.

The effect of 8 mg/kg of indomethacin on uterine blood flow, prostaglandin production, and intraamniotic fluid pressure was examined in late pregnant dogs. Uterine blood flow was measured with 15 mum radiolabeled microspheres. Because we found that a significant percentage of the microspheres shunted through the placental circulation into the lungs, we calculated placental blood flow by adding the shunted microspheres through the placenta to the nonshunted microspheres in the placenta. Total uterine blood flow significantly increased from 271+/-69 ml/min during control period to 371+/-72 ml/min (P < 0.01) 30 min after indomethacin. This increase was attributable to the change in blood flow to the placental circulation (222+/-58 to 325+/-63 ml/min; P < 0.01). Associated with these hemodynamic changes we found an almost complete suppression of uterine prostaglandin E(2) production (1,654+/-305 to 51+/-25 pg/ml; P < 0.01) as measured by gas chromatography-mass spectrometry. In addition, we found that indomethacin treatment resulted in uterine relaxation as measured by intraamniotic fluid pressure changes (11.2+/-1.3 mm Hg to 8.5+/-1.2 mm Hg; P < 0.001). We conclude that indomethacin causes an increase in placental blood flow without any change in flow to the rest of the uterus, and that this dose of the drug inhibits greater than 95% of uterine prostaglandin production. In addition, indomethacin is responsible for uterine relaxation. The increase in placental blood flow after indomethacin is probably a result of uterine relaxation, which is secondary to prostaglandin synthesis inhibition.

Propranolol increases prostacyclin synthesis in patients with essential hypertension.

We tested the hypothesis that vascular prostacyclin synthesis is increased by propranolol and could account for some of the drug's antihypertensive effect. We studied 10 white patients with mild essential hypertension in a randomized, double-blind design to assess the effects of indomethacin with or without the addition of propranolol on blood pressure and vascular prostacyclin biosynthesis, as assessed by the urinary excretion of the major enzymatically produced metabolite of prostacyclin, 2,3-dinor-6-keto-prostaglandin F1 alpha (PGF1 alpha), F1 alpha (PGF1 alpha), measured by gas chromatography-mass spectrometry. Seven patients responded to propranolol with a lowering of mean arterial blood pressure in both supine and upright postures. The fall in mean arterial blood pressure (-14.1 +/- 2.1 mm Hg sitting; -17.4 +/- 1.7 mm Hg supine) with propranolol alone was significantly greater than that produced when propranolol was given to patients receiving indomethacin (-7.8 +/- 1.9 mm Hg sitting; -7.7 +/- 3.0 mm Hg supine). Our drug-responsive patients demonstrated a significantly lower excretion rate of 2,3-dinor-6-keto-PGF1 alpha than was found in an age and sex-matched group of normal volunteers. With propranolol treatment, drug-responsive patients showed a significant increase in the excretion of 2,3-dinor-6-keto-PGF1 alpha, such that the mean excretion was not significantly different from that in normal volunteers. Indomethacin caused a significant rise in mean arterial blood pressure and a significant fall in 2,3-dinor-6-keto-PGF1 alpha excretion, and it blocked the rise in urinary 2,3-dinor-6-keto-PGF1 alpha associated with propranolol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of platelet activating factor in the dog kidney in vivo.

The effect of platelet activating factor (PAF) on renal hemodynamics and function was examined in anesthetized dogs. The infusion of PAF into the renal artery at 5, 10, and 20 ng X min-1 X kg-1 body weight resulted in dose-dependent reductions in renal blood flow, glomerular filtration rate, urine volume, and urinary sodium excretion, whereas the infusion of vehicle alone in the contralateral kidney did not result in significant changes in these parameters. The maximum decrease expressed as the percent change from baseline was 22.2 +/- 1.7% for renal blood flow, 50.8 +/- 11% for glomerular filtration rate, 67.3 +/- 4.2% for urine volume, and 69.0 +/- 8.5% for urinary sodium excretion, respectively. These renal effects were not accompanied by significant alterations in systemic arterial blood pressure and heart rate. Pretreatment with indomethacin to block prostaglandin synthesis enhanced the effect of PAF on kidney function. Our data demonstrate that, unlike the rat kidney, intrarenal PAF infusion into the intact dog results in vasoconstriction and serve reduction in glomerular filtration rate.

Lack of an effect of age on the response to clonidine.

The plasma concentration and appearance rate of norepinephrine are increased in the elderly. A hypothesis to explain this observation is that the elderly have a diminished response of the alpha 2-adrenoreceptor in the brainstem that modulates peripheral sympathetic tone. To evaluate the effect of age on alpha 2-adrenoreceptor function, we studied 12 healthy elderly subjects and 12 healthy young volunteers and compared the decrease in plasma norepinephrine and blood pressure in response to increasing doses of orally administered clonidine. We found that, for the same plasma clonidine concentration, the blood pressure and plasma norepinephrine concentration fell equivalently in both groups. These data imply that the increased plasma norepinephrine and the elevated blood pressure in the healthy elderly population do not appear to be secondary to a decrease in alpha 2-adrenergic response to an agonist in the central nervous system.

The effect of age on the sensitivity of the alpha 1-adrenoceptor to phenylephrine and prazosin.

Certain beta-adrenoceptor-mediated functions seem to diminish with age; however, information on alpha-adrenoceptor-mediated function is sparse and often conflicting but overall suggests little age-related change. To assess an age-related alteration in the responsiveness to an alpha 1-adrenergic agonist and to estimate changes in the apparent affinity of the alpha 1-adrenoceptor for the antagonist prazosin, we infused phenylephrine into 12 healthy elderly subjects and 12 healthy young subjects before and after an oral dose of prazosin, and we compared the shift in the dose-response curves for the two groups. With this protocol we were unable to detect any age-related decline in sensitivity of the alpha-adrenoceptor to either agonist or antagonist. However, oral prazosin resulted in higher plasma concentrations and a consistently greater hypotensive effect in the elderly subjects than in the young subjects. We concluded that there was no difference in alpha 1-adrenoceptor sensitivity in the elderly persons, but that the kinetics of prazosin may be altered and that the response of the blood pressure to prazosin was increased because of the kinetic changes and possibly the physiologic changes associated with aging.

The antihypertensive efficacy of hydrochlorothiazide is not prostacyclin dependent.

We tested the hypothesis that vascular prostacyclin synthesis is stimulated by hydrochlorothiazide and could account for some of the drug's antihypertensive effect. We studied 13 patients with mild essential hypertension in a randomized, double-blind design to assess the effects of indomethacin on hydrochlorothiazide's ability to lower blood pressure, alter body weight, stimulate plasma renin activity, and modulate vascular prostacyclin biosynthesis as assessed by the urinary excretion of the major enzymatically produced metabolite of prostacyclin, 2,3-dinor-6-keto-prostaglandin F1 alpha (PGF1 alpha), measured by GC/MS. Administration of hydrochlorothiazide, 50 mg daily for 2 weeks, was associated with a significant decrease in both systolic and diastolic blood pressure in both supine (systolic, 148 +/- 3 to 136 +/- 3 mm Hg; diastolic, 97 +/- 2 to 94 +/- 3 mm Hg) and upright (systolic, 151 +/- 4 to 131 +/- 2 mm Hg; diastolic, 103 +/- 2 to 97 +/- 3 mm Hg) positions. Hydrochlorothiazide administration resulted in a 1 kg weight loss and stimulation of plasma renin activity from 1.7 +/- 0.4 to 5.3 +/- 1.1 ng angiotensin I/ml/hr. However, the urinary excretion of 2,3-dinor-6-keto-PGF1 alpha was unchanged after administration of hydrochlorothiazide (86 +/- 13/ng/gm creatinine during placebo, 74 +/- 13 ng/gm during week 1 of hydrochlorothiazide, and 70 +/- 9 ng/gm during week 2 of the drug). Administration of indomethacin, 50 mg twice a day, resulted in greater than 60% inhibition of 2,3-dinor-6-keto-PGF1 alpha excretion but did not affect the antihypertensive response to hydrochlorothiazide. Indomethacin did not oppose the diuretic effect of hydrochlorothiazide as assessed by weight loss but did attenuate the rise in plasma renin activity. Our data demonstrate that the blood pressure-lowering effect of a thiazide diuretic does not require enhanced prostacyclin synthesis and the cyclooxygenase inhibitor indomethacin does not antagonize the antihypertensive efficacy of hydrochlorothiazide.

Age does not alter human vascular and nonvascular beta 2-adrenergic responses to isoproterenol.

beta-Adrenoceptor-mediated functions appear to diminish with aging, but the exact scope of these changes is unknown, because most studies have been limited to beta 1-adrenergic cardiac phenomena. To evaluate both a vascular and a nonvascular beta 2-adrenergic response in the aged, we have studied 12 healthy elderly and 12 healthy young subjects infused with increasing doses of isoproterenol and compared the change in peripheral vascular resistance, measured by venous occlusion plethysmography, and insulin release. In both groups vascular resistance fell and insulin concentrations increased. These changes were equivalent in both groups, and we therefore infer no significant decline in either of these beta 2-adrenergic functions in the elderly.

Beta-adrenergic receptors in the elderly are not less sensitive to timolol.

The elderly have been reported to be less sensitive to the beta-adrenergic blocking effect of propranolol. However, propranolol is a racemate, and age-related changes in stereoselective metabolism or protein binding could confound interpretation of the data. To avoid these problems, we studied timolol in 12 young and 12 elderly healthy subjects. The dose of isoproterenol required for a heart rate increase of 25 bpm (I25) was determined before and 2 hours after an oral 10 mg dose of timolol. A dose ratio (DR) was calculated for each subject as the I25 after timolol/I25 before timolol. The binding constant for timolol binding to the receptor was calculated as the plasma timolol concentration divided by (DR-1). The I25 for the elderly group was significantly greater than the I25 for the young group, but the timolol binding constant was the same for both groups. We conclude that, although the elderly are less sensitive to isoproterenol, they are not less sensitive to timolol, and thus our data do not implicate a change in the interaction of beta-adrenoceptors with antagonists.

The balance between vascular alpha- and beta-adrenoceptors is not changed in the elderly.

It has been suggested that beta-adrenoceptor-mediated functions are diminished with aging and that these responses are reduced to a greater extent than are alpha-adrenoceptor-mediated responses. The resulting imbalance in the elderly may produce an increased vascular resistance from the unopposed alpha-adrenoceptor stimulation in the peripheral vasculature. To evaluate this hypothesis, we studied 12 healthy elderly and 12 healthy young subjects during a graded infusion of epinephrine and compared blood pressure response, vascular resistance, and calf blood flow as determined by venous occlusion plethysmography. In both groups, heart rate increased, blood flow to the leg increased, and vascular resistance fell in response to epinephrine infusion, but in the elderly the systolic blood pressure failed to rise as it did in the young subjects. From these data we conclude that the overall vascular response to epinephrine does not change with age and that the balance between beta-adrenoceptor-mediated vasodilation and alpha-adrenoceptor-mediated vasoconstriction is therefore unchanged in the elderly.

Platelet alpha 2-adrenergic receptor responsiveness is increased in elderly men but not in elderly women.

We ascertained platelet alpha 2-adrenergic receptor responsiveness in healthy young and elderly men and women by determining the minimum concentration of methylnorepinephrine, a selective alpha 2-adrenergic receptor agonist, required to initiate the primary and secondary aggregation response in platelet-rich plasma. We observed that platelets from elderly men required a smaller concentration of methylnorepinephrine to stimulate primary aggregation than did platelets obtained from young men. However, the concentration of alpha 2-adrenergic receptor agonist to trigger the secondary aggregation response did not vary with age. There was no difference in the responsiveness of platelets from young and elderly women for either the primary or secondary aggregation response. We conclude that platelet alpha 2-adrenergic receptor responsiveness is increased with age rather than decreased, as predicted from some studies of the density of platelet alpha 2-adrenergic receptors and their coupling to adenylyl cyclase. Furthermore, the increase in alpha 2-adrenergic receptor responsiveness is gender specific.

Timolol-induced up-regulation of polymorphonuclear leukocyte beta 2-adrenergic receptors in the elderly.

Drug-induced up-regulation of beta-adrenergic receptors is impaired in the brains of aged rats but not in myocardia. To investigate age-related changes in receptor regulation in human beings, young (24 to 35 years of age) and elderly (62 to 78 years of age) healthy volunteers were treated with the beta-adrenergic receptor blocking agent timolol maleate (10 mg b.i.d.) for 8 days. Baseline densities of beta 2-adrenergic receptors on polymorphonuclear leukocyte (PMNL) membranes and heart rates were the same in the two age groups. However, systolic blood pressures were higher in the elderly subjects. Administration of timolol produced similar plasma levels in the two groups. In response to timolol, the density of PMNL beta-adrenergic receptors increased at a similar rate and to the same extent (threefold) in both age groups. Likewise, hemodynamic changes were not related to age. These results suggest that up-regulation of peripheral beta 2-adrenergic receptors in human beings is not impaired with aging.

Sulindac is not renal sparing in man.

We investigated the claimed renal-sparing effect of the cyclooxygenase inhibitor sulindac. Fifteen normal women following a diet of 50 mEq salt a day were randomly assigned to 5 days of either placebo, sulindac, 200 mg b.i.d., or indomethacin, 25 mg q.i.d., after first serving as their own controls. Renal effects were assessed by the excretion rate of prostaglandin (PG) E2 (an index of renal PG synthesis), sodium balance, plasma renin activity (PRA), and the response to furosemide. Systemic effects were assessed by collagen-induced platelet aggregation and thromboxane B2 formation and by the urinary excretion of a systemically formed metabolite of PGF2 alpha (PGF-M). Both sulindac and indomethacin resulted in a positive sodium balance and a reduction in 24-hour urinary PGE2 excretion (range -49% to -86%). Basal PRA was decreased by indomethacin only, but the increases in PRA and in urinary PGE2 excretion in response to furosemide were inhibited by both sulindac and indomethacin. Sulindac reduced the natriuresis induced by furosemide, and indomethacin reduced the rise in inulin clearance after furosemide. Thus the two nonsteroidal anti-inflammatory drugs had similar effects on the kidney. Indomethacin had a greater effect than sulindac on the inhibition of collagen-induced platelet aggregation and thromboxane synthesis and the two drugs had equivalent effects on the reduction of PGF-M excretion. Peak plasma drug concentration of indomethacin (1.9 +/- 0.4 microgram/ml) and sulindac sulfide (7.7 +/- 1.9 microgram/ml) were those associated with clinical efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

The hypotensive action of captopril and enalapril is not prostacyclin dependent.

Angiotensin converting enzyme inhibitors have been proposed to have a prostaglandin-dependent component to their hypotensive action. The aim of this study was to assess whether the structurally dissimilar angiotensin converting enzyme inhibitors captopril and enalapril stimulate the synthesis of prostacyclin, whether their hypotensive action is blunted by indomethacin, and whether these biochemical or physiologic parameters differ for the two drugs, in white subjects with essential hypertension. Twelve patients were enrolled and 11 finished the study. The study consisted of a double blind, randomized, double-crossover design. All patients received either placebo or 50 mg indomethacin twice a day for 3 weeks; after 1 week of placebo or indomethacin either 50 mg captopril or 10 mg enalapril twice a day was added and continued for 2 weeks. Each patient received every possible combination. Neither captopril nor enalapril stimulated prostacyclin production as determined by measurement of the urinary excretion rate of its main enzymatic metabolite, 2,3-dinor-6-keto-prostaglandin-F1 alpha. Although indomethacin reduced the urinary excretion of the enzymatic metabolite of prostacyclin by more than 50%, it did not influence the hypotensive effect of captopril or enalapril. We conclude that neither captopril nor enalapril have a significant prostacyclin-dependent component to their hypotensive action.

Terbutaline-induced desensitization of polymorphonuclear leukocyte beta 2-adrenergic receptors in young and elderly subjects.

Potential age-related differences in cardiovascular responsiveness and receptor regulation induced by short-term administration of a selective beta 2-adrenergic receptor agonist were investigated. Young (age range, 23 to 31 years) and elderly (age range, 64 to 73 years) healthy subjects were treated with terbutaline (5 mg, three times daily) for 5 days. Similar plasma terbutaline concentrations were achieved in the two age groups. The elderly group had higher baseline plasma norepinephrine concentrations and mean arterial pressures, neither of which were altered by terbutaline administration. During terbutaline treatment, heart rate increased in both age groups while subjects were supine but consistently increased only in the young group while subjects were standing. In both age groups, the density of beta 2-adrenergic receptors on polymorphonuclear leukocyte membranes was reduced by 50% during terbutaline administration and returned to baseline values at similar rates after drug administration was stopped. Isoproterenol-stimulated cyclic adenosine monophosphate accumulation in polymorphonuclear leukocytes from elderly subjects was regulated similarly. These findings suggest that the ability of terbutaline to increase standing heart rate is selectively impaired in the elderly, whereas the ability of polymorphonuclear leukocyte beta 2-adrenergic receptors to down-regulate and to return to baseline values is not.

Lack of interaction between tricyclic antidepressants and clonidine at the alpha 2-adrenoceptor on human platelets.

The pharmacologic interaction between tricyclic antidepressants and clonidine at the alpha 2-adrenoceptor was examined in human platelets by quantifying the ability of tricyclic antidepressant drugs to inhibit clonidine-stimulated platelet aggregation in vitro. Platelet aggregation induced by increasing concentrations of clonidine (0.3 to 3 microM) was not altered by pretreatment of the platelets with 10 microM imipramine. Imipramine at concentrations above 100 microM attenuated clonidine-induced platelet aggregation, but this was a nonspecific drug effect because the high concentrations of imipramine inhibited adenosine diphosphate-induced platelet aggregation as well. Desmethyldoxepin and nortriptyline also inhibited platelet aggregation nonspecifically at higher concentrations (greater than 10 microM). We were also not able to establish a specific interaction between alpha-methlnorepinephrine (the active metabolite of methyldopa) and the tricyclic antidepressants at the platelet alpha 2-adrenoceptor. Our data suggest that if there is an adverse dynamic interaction between tricyclic antidepressants and clonidine, the interaction occurs at a site other than the alpha 2-adrenoceptor.

Delavirdine: clinical pharmacokinetics and drug interactions.

Delavirdine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is a potent and specific inhibitor of HIV-1 reverse transcriptase. The approved therapeutic regimen for delavirdine is 400mg 3 times daily in combination with appropriate antiretroviral agents; however, a dose of 600mg twice daily appears to provide similar systemic exposure. The steady-state pharmacokinetics of delavirdine are not appreciably affected by food. Delavirdine undergoes extensive metabolism by cytochrome P450 (CYP) with little urinary excretion of unchanged drug. Metabolic drug interactions between delavirdine and nucleoside reverse transcriptase inhibitors are unlikely as their metabolic pathways differ; delavirdine has no effect on the pharmacokinetics of zidovudine. Concomitant use of CYP inducers, such as rifampicin (rifampin), rifabutin, phenytoin, phenobarbital or carbamazepine, should be avoided since delavirdine plasma concentrations are significantly lowered. Reduction in gastric acidity (pH > 3) decreases the extent of delavirdine absorption, so administration of antacids and the buffered formulations of didanosine should be separated from that of delavirdine by at least 1 hour. Delavirdine, unlike other currently available NNRTI agents, is an inhibitor rather than an inducer of CYP isozymes. Consequently, the drug interaction profile and rationale for combining delavirdine with other antiretroviral agents is unique among the current NNRTI agents. Delavirdine inhibits the CYP3A4-mediated metabolism of HIV protease inhibitors and thereby increases systemic exposure to protease inhibitors. The ability of delavirdine to enhance the pharmacokinetic profiles of protease inhibitors may permit the use of simplified administration regimens. Combining delavirdine and indinavir removes the food restrictions during indinavir administration. Furthermore, the superior virological response observed in antiretroviral regimens containing delavirdine and protease inhibitors has been attributed to the favourable pharmacokinetic interactions and the introduction of a new drug class in NNRTI-naïve therapy-experienced patients. Pharmacokinetic drug interactions are an important consideration in selecting an HIV treatment regimen, due to the multiplicity of drugs that are coadministered and the varying direction and magnitude of interaction that can occur. Considerations for utilising delavirdine in a treatment regimen are different than for other NNRTI agents due to the unique drug interaction profile of delavirdine.

The failure of indomethacin to alter ACTH-induced adrenal hyperaemia or steroidogenesis in the anaesthetized dog.

1 The response of adrenal blood flow to adrenocorticotropic hormone (ACTH) was measured with radioactive microspheres in anaesthetized, dexamethasone-treated, mongrel dog. 2 Adrenocorticotropic hormone (2 u/h i.v.) increased adrenal blood flow within 15 min and this persisted for the duration of the infusion. 3 Cortisol concentrations also rose with ACTH infusion. 4 Indomethacin (6 mg/kg i.v. followed by 1 mg/min) did not effect the adrenal response to ACTH although plasma concentrations of indomethacin (21.9 +/- 2.5 micrograms/ml) adequate to suppress prostaglandin synthesis were achieved. 5 We conclude that prostaglandins are not required for steroidogenesis or the adrenal haemodynamic response to ACTH.

The role of histamine receptors in the release of renin.

1 The effect of intrarenal histamine, dimaprit (H2-agonist) and 2-(2-pyridyl) ethylamine (H1-agonist) on renin release was examined in anaesthetized dogs. 2 In dogs with intact kidneys, histamine and dimaprit administration resulted in renal vasodilatation, a two fold increase in urinary sodium excretion, and no change in renal renin release. 2(2-Pyridyl) ethylamine administration resulted in renal vasodilatation, a 25% decrease in urinary sodium excretion and a significant increase in renin release. 3 In dogs with non-filtering kidneys, dimaprit administration resulted in renal vasodilatation and a significant increase in renin release, while 2(2-pyridyl) ethylamine administration resulted in renal vasodilatation but no change in renin release. 4 Our data suggest that histamine is a potential participant in the release of renin through stimulation of H2-receptors, but it is a weak agonist. 5 In addition, the direct effect of histamine analogues on renin release is modulated by their effects on electrolyte excretion probably by influencing the renal chemoreceptor release of renin mediated by the macula densa.

Prazosin does not alter canine renin release in response to systemic hypotension or intrarenal isoprenaline and prostaglandin I2 infusion.

1. The effect of a hypotensive dose of intravenous prazosin (0.2 mg/kg) on heart rate and plasma renin activity was evaluated in anaesthetized mongrel dogs pretreated with indomethacin. 2. The effect of prazosin on the renin release elicited by the beta-adrenoceptor agonist isoprenaline and by prostaglandin I2 was also evaluated. 3. Prazosin administration was associated with a significant increase in heart rate and increase in plasma renin activity. 4. Prazosin did not interfere with the increase in plasma renin activity in response to either isoprenaline or prostaglandin I2. 5. We conclude that prazosin is not a unique peripheral vasodilator since hypotensive doses are associated with an increase in heart rate and plasma renin activity. In addition, prazosin does not inhibit the release of renin induced by either isoprenaline or prostaglandin I2.