Showing papers in "Journal of Cardiovascular Pharmacology in 1987"

Cardiovascular response to 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in the rat: site of action and pharmacological analysis.

Abstract: Summary:The cardiovascular response to 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective putative 5-HT1A receptor agonist, has been investigated in the rat. Comparisons were made with clonidine, a centrally acting hypotensive agent with negligible affinity for 5-HT receptors. In consc

Evidence for an antagonism between caffeine and adenosine in the human cardiovascular system.

Abstract: A randomized, double-blind and placebo-controlled study was performed in 10 normotensive male subjects to analyze a possible antagonism between caffeine and adenosine with respect to their effects on the cardiovascular system in humans. Caffeine alone, 250 mg intravenously (i.v.), increased blood pressure by 9/12 mm Hg, and resulted in a fall of heart rate (HR) of 3 beats/min. Plasma epinephrine (E) rose by 114% after caffeine. Adenosine alone, in an increasing dose of 0.04-0.16 mg/kg/min, induced an increase in systolic blood pressure (SBP) (17 mm Hg), and HR (33 beats/min), a moderate fall in diastolic blood pressure (DBP) (-4 mm Hg), and no change of mean arterial pressure (MAP). At the highest adenosine infusion rate, forearm blood flow, skin temperature (ST), and transcutaneous oxygen tension were lowered, whereas plasma (nor)epinephrine was increased 227.2 and 215.9%, respectively. Adenosine infusion after caffeine induced comparable effects, but the fractional adenosine-induced changes of SBP, HR, plasma catecholamines, plasma renin activity (PRA), and aldosterone all were significantly reduced by previous administration of caffeine. Our results indicate an antagonism between caffeine and adenosine in humans, which may support the suggestion that some circulatory effects of caffeine are caused by an interaction with endogenous adenosine.

Repeated Administration of the Converting Enzyme Inhibitor Cilazapril to Normal Volunteers

Abstract: Summary: Cilazapril 1.25 and 5.0 mg p.o. q.d. was administered in double-blind fashion to two groups of six normal volunteers on 8 consecutive days. Blood pressure, heart rate, and plasma converting enzyme activity were measured each day prior to drug administration and up to 72 h after the last dose. Plasma renin activity, blood angiotensin I, plasma angiotensin II, and aldosterone as well as plasma cilazaprilat levels were determined on the first and the last day of active treatment at times 0, 4, and 24 h. The drug was very well tolerated by all volunteers. At 4 h postdrug, plasma converting enzyme activity was reduced in dose-dependent fashion on the first and the eighth day; plasma cilazaprilat levels were also clearly dose dependent. Nevertheless, 24 h postdrug cilazaprilat levels were similar on the first and last day of drug administration, and plasma converting enzyme activity was also stable throughout the 8 days. The various components of the renin-angiotensin system responded in the usual fashion. These results provide strong evidence that cilazapril is a very potent and highly effective converting enzyme inhibitor. Doses well below 5 mg/day will probably suffice for therapeutic efficacy. These data also confirm the hypothesis formulated in the preceding article, i.e., that there is no accumulation of the drug with repeated administration despite its long pharmacological half-life (t½).

Left ventricular hypertrophy and risk of cardiac failure: insights from the Framingham Study.

Abstract: The incidence of congestive heart failure (CHF), derived from more than 30 years of follow-up, is examined by electrocardiogram (ECG) and radiography in relation to cardiac hypertrophy. Cardiac failure occurred in 485 of 5,209 subjects participating in the Framingham Study. Hypertension was the dominant predisposing factor for both cardiac hypertrophy and cardiac failure. The ECG pattern of left ventricular hypertrophy (ECG-LVH) heralded serious cardiovascular disease of all varieties, but risk ratios were two- to fivefold greater for the development of CHF in men and women (ages 35-64 years) than for any other sequelae. Risk of CHF in those with ECG-LVH exceeded that for unrecognized ECG patterns at myocardial infarction (ECG-MI). The ECG pattern of left ventricular hypertrophy, characterized by increased voltage unaccompanied by a repolarization abnormality, carried a decreased risk, chiefly reflecting the severity of coexistent hypertension. The independent contribution of ECG-LVH with accompanying repolarization changes to the risk of CHF was equal in the two sexes and persisted with advancing age. The ECG pattern of left ventricular hypertrophy was more strongly associated with occurrence of CHF than was radiographic enlargement, and contributed to the risk of CHF (taking radiographic heart size into account). Echocardiographic evidence of LVH (ECHO-LVH) was more common in subjects with CHF than was ECG-LVH, occurring in 63% of women and 77% of men with CHF, and LVH was the most frequently observed echocardiographic finding. Cardiac hypertrophy was found to be an ominous harbinger of cardiac failure, particularly when it was manifested on an ECG with repolarization abnormality.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and disposition of carvedilol in humans.

Abstract: Pharmacokinetics of carvedilol (C) have been studied in healthy volunteers after a single i.v. and oral administration, and the metabolic disposition after oral administration of 14C-labeled drug. C demonstrates dose-linear behavior. The absolute bioavailability reaches 24% probably due to a first-pass effect. After a 50 mg oral dose, maximum concentrations of 66 micrograms/l are achieved within 1.2 h. C is extensively distributed to the tissues (Vz = 132 l) and eliminated primarily by hepatic metabolism (total clearance 590 ml/min, renal clearance 4 ml/min). Because of the longer half-life of 6.4 h after oral administration in contrast to 2.4 h after i.v. administration, C is assumed to be absorption dependent since no sustained-release formulation was used. The half-life of radioactivity in plasma is 39 h; 16% of C is excreted in urine in the form of metabolites and only 0.3% unchanged. The urinary metabolites consist of carvedilol glucuronide (5.2% of the dose), cleavage products of the beta-blocking side chain (2.1%), and ring-hydroxylated forms (2.9%). Sixty percent of the dose is recovered in the feces. A demethylated product of C exhibits only minor beta-blocking activity. This metabolite is detected in plasma in concentrations ten times lower than the parent compound.

Calcium channel blocking properties of amlodipine in vascular smooth muscle and cardiac muscle in vitro: evidence for voltage modulation of vascular dihydropyridine receptors.

Abstract: Summary:Amlodipine was twice as potent as nifedipine at inhibiting Ca2 + -induced contractions in depolarised rat aorta (IC50 1.9 nM vs. 4.1 nM) but, unlike nifedipine, displayed a very slow onset of action. Contractions induced by depolarising steps with 45 mM K+ were much less potently blocked by

Effect of in vivo nitroglycerin therapy on endothelium-dependent and independent vascular relaxation and cyclic GMP accumulation in rat aorta.

Abstract: Vascular relaxation by the organic (nitroglycerin) and inorganic (sodium nitroprusside) nitrovasodilators and the endothelium-dependent vasodilators (acetylcholine and histamine) has been associated with cyclic GMP accumulation. Tolerance to vasodilation by nitroglycerin commonly occurs following prolonged exposure to nitroglycerin. This study investigates the effects of in vivo nitroglycerin therapy on vascular relaxation and cyclic GMP accumulation induced by the nitrovasodilators and the endothelium-dependent vasodilators. Rats were injected with nitroglycerin or the propylene glycol diluent control for 4-7 days. Thoracic aortas from the nitroglycerin-treated rats were 750-fold less sensitive to the relaxant effects of nitroglycerin. In contrast, these aortas were only threefold less sensitive to the relaxant effects of sodium nitroprusside, while the maximum relaxation to acetylcholine and histamine was depressed by 50 and 41%, respectively. Desensitization to relaxation was associated with reduced cyclic GMP elevations to all the vasodilators. Relaxation to 8-bromo cyclic GMP, dibutyryl cyclic AMP, or diltiazem was unaffected by nitroglycerin therapy. Tolerance was also associated with an increased sensitivity to the contractile effects of low concentrations of norepinephrine. This increased sensitivity to norepinephrine was associated with a decrease in cyclic GMP levels. The present results suggest that: (1) desensitization to nitroglycerin, sodium nitroprusside, acetylcholine, and histamine by nitroglycerin therapy may be at the level of cyclic GMP accumulation; (2) cyclic GMP is the common mediator of relaxation induced by the nitro- and endothelium-dependent vasodilators; (3) the mechanisms involved in the activation of guanylate cyclase and relaxation by sodium nitroprusside, acetylcholine, and histamine are probably different than those of nitroglycerin; and (4) cyclic GMP may be acting as a physiological negative feedback signal in agonist-induced contraction.

Physiologic versus pathologic hypertrophy and the pressure-overloaded myocardium

Abstract: The myocardium consists of myocytes and capillaries embedded in a connective tissue matrix. Myocardial mass, which is predominantly a function of myocyte size, is determined by systolic tension; when systolic pressure is gradually elevated above the normal range, mass will increase. The hypertrophic process is a continuum consisting of subtle transitions that take place within the muscular, collagenous, and vascular compartments; these transitions, however, need not be temporarily concordant. We would identify three phases to the hypertrophic process. First, there is an evolutionary phase, whereby the structural and biochemical remodeling of the various compartments of the myocardium is in transition, with each compartment having its own rate of adjustment. During this evolutionary phase, myocardial contractility, as reflected by stress-length and stress-velocity relations, may or may not be normal, but ventricular pump function and O2 delivery are preserved. Second, there is a physiologic phase during which the structural and biochemical remodeling of the compartments reaches a coordinated balance. The myocardial stress-length relation and ventricular function are each normal, but rate-dependent indices of contractility may be abnormal. During the physiologic phase of hypertrophy, the remodeled myocardium will revert to normal when the abnormal loading condition is removed. Finally, there is a pathologic phase. In this phase, compartment remodeling is no longer balanced (e.g., the ratio of structural versus maintenance proteins), and length and rate-dependent indices of myocardial contractility are depressed. Ventricular pump function is also abnormal in the pathologic phase; consequently. O2 delivery to the tissues is impaired. This imbalance in O2 demand and supply may be apparent at rest in more advanced expressions of disease or may appear during the physiologic stress of exercise in less severe disease. In the latter case, the patient's aerobic capacity is reduced to the extent that it can be used to grade the severity of heart failure and to predict the cardiac reserve. During the pathologic phase of hypertrophy, the structural and biochemical remodeling of the myocardium may be irreversible, although this may not be the case for each compartment. Finally, it is important to distinguish cardiac (or myocardial) failure from the clinical syndrome of congestive heart failure. The latter arises from congested organs and hypoperfused tissues; its clinical manifestations are dependent on the activation of the adrenergic nervous and renin-angiotensin-aldosterone systems and the presence of a salt-avid kidney. Congestive heart failure is a late clinical feature of chronic pressure overload and pathologic hypertrophy.

Similarity and dissimilarity in the mode and mechanism of action between nicorandil and classical nitrates: an overview.

Abstract: Nicorandil, which is structurally a nitrate and also a nicotinamide, differs from classical nitrates such as nitroglycerin and isosorbide dinitrate in the following respects. It dilates preferentially resistive vessels (arterioles); and it produces the increase in potassium conductance in the membranes of cardiac and some vascular smooth muscle cells that is responsible for its negative inotropic and chronotropic and vasodilator effects. Nicorandil has the following characteristics of a nitrate. (a) It is capable of dilating large conductive coronary arteries, although the effect is weaker than that of classical nitrates. (b) It is capable of reducing venous return, although this effect is less pronounced than that of classical nitrates. (c) It produces an increase in intracellular cyclic guanosine-3',5'-monophosphate (cyclic GMP) in vascular smooth muscle. The activity of nicorandil to increase the membrane potassium conductance resides in the nicotinamide moiety. However, this activity is greatly enhanced by the presence of the nitrate group at an appropriate distance from the nicotinamide group. The nitrate moiety per se has also its own action. The presence of these two pharmacologically active groups in the molecule appears to cause nicorandil to have rather complex cardiovascular actions.

Pharmacological Profile of Carvedilol as a β-Blocking Agent with Vasodilating and Hypotensive Properties

Abstract: Carvedilol is a new beta-receptor blocking and vasodilating drug that is presently undergoing clinical trials in hypertension and coronary heart disease. In this article, the pharmacodynamic properties of carvedilol are compared with those of standard drugs. The beta-blocking activity was characterized in isolated organs and in conscious rats, rabbits, and dogs. For the beta 1-blockade in guinea pig atria, the pA10 values were 7.44 +/- 0.16 for carvedilol and 6.77 +/- 0.08 for propranolol. Carvedilol is a noncardioselective beta-blocker. The i.v. doses that inhibited the tachycardia by 50% induced by 1 microgram/kg isoprenaline were 62 micrograms/kg in dogs, 138 micrograms/kg in rabbits and 841 micrograms/kg in rats. In rabbits carvedilol was slightly more active and in rats less active than propranolol. In all models, carvedilol was much more active than labetalol or prizidilol. In contrast to propranolol, carvedilol relaxed rat aortic strips. A dose-dependent decrease in arterial blood pressure was seen in different in vivo models. The total peripheral and coronary resistance were decreased in conscious dogs. The doses required for both beta-blockade and decrease in blood pressure were in the same range. The drug was also active after oral administration. There is no hint for development of tolerance.

Pharmacokinetics of the converting enzyme inhibitor cilazapril in normal volunteers and the relationship to enzyme inhibition: development of a mathematical model.

Abstract: The pharmacokinetics of the new converting enzyme inhibitor cilazapril were investigated in 12 healthy male volunteers. Single oral doses of 1.25, 2.5, 5, and 10 mg of cilazapril were tested in groups of six subjects, each of whom received two different doses. A 2-week interval was allowed between treatments. Plasma levels of cilazaprilat, the active form of cilazapril, were measured for up to 3 days after drug administration. Peak plasma levels and 24-h areas under the curve (AUCs) were almost directly proportional to dose, and the elimination half-life (t1/2) during the first 8 h after dosing was 1.5 h. From 24 h on, there was a prolonged terminal phase with a t1/2 of approximately 50 h, and there was only slight dose-dependency during this phase. These data suggest that the pharmacokinetics of cilazapril are nonlinear. A physiologically realistic model based on saturable binding to converting enzyme was developed to account both for the drug kinetics and for the relationship of the kinetics to the dynamics of plasma converting enzyme inhibition. A number of conclusions relevant to the therapeutic application of cilazapril in hypertension are drawn from the data and from the pharmacokinetic-pharmacodynamic model.

Possible role of endothelial thromboxane A2 in the resting tone and contractile responses to acetylcholine and arachidonic acid in canine cerebral arteries.

Abstract: The amount of immunoreactive thromboxane B2 (iTXB2) released from isolated canine arteries was determined by radioimmunoassay. The amount of iTXB2 released from the cerebral, coronary, mesenteric, and saphenous arteries was 47.0 +/- 7.2, 4.0 +/- 0.6, 4.9 +/- 0.5, and 2.7 +/- 0.4 pg/mg wet weight tissue/30 min, respectively. The release of iTXB2 from the cerebral artery was decreased to less than 50% by the administration of indomethacin (10(-5) M) or OKY-046 (10(-4) M), and by intimal rubbing. The release of iTXB2 was enhanced nearly twofold by the addition of arachidonic acid (AA) (10(-5) M) to the medium, but not by the addition of acetylcholine (ACh) (10(-6) M). The cerebral arterial strips maintained the resting tone, which was reduced maximally by papaverine (10(-4) M). The resting tone was also reduced dose dependently by a cyclooxygenase inhibitor (indomethacin), a thromboxane A2 (TXA2) synthetase inhibitor (OKY-046), and a TXA2 antagonist (ONO-3708). The resting tone of rubbed strips was about half that of intact strips. ACh and AA induced similar transient contractions in the cerebral artery. Contractions produced by these agents were attenuated by indomethacin (10(-7) M), aspirin (5 X 10(-5) M), OKY-046 (10(-6) M), and ONO-3708 (10(-8) M), and abolished by intimal rubbing. From these results, it is concluded that TXA2 is produced in the endothelial cells and may be involved in maintaining the resting tone and contractile response to AA in the canine cerebral artery.

BRL 34915, a novel antihypertensive agent: comparison of effects on blood pressure and other haemodynamic parameters with those of nifedipine in animal models.

Abstract: The effects of BRL 34915, (+/-) 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl)-2H-b enzo [b]-pyran-3-ol, on blood pressure and other haemodynamic parameters in animals have been investigated in comparison with those of nifedipine. In conscious spontaneously hypertensive rats and renal hypertensive cats and dogs the oral doses of BRL 34915 lowering blood pressure are 10 to 30 times lower than those of nifedipine. Tachycardia evoked by BRL 34915 tends to be less than that produced by nifedipine in the cat and of similar magnitude in the dog. The antihypertensive response to BRL 34915 in these models is reproducible on repeat once daily dosing without rebound hypertension on cessation of dosing. In studies using electromagnetic flow probes to measure regional blood flow in anaesthetised cats the intravenous administration of BRL 34915, unlike that of nifedipine, markedly increases renal blood flow yet BRL 34915 lacks the marked effect of nifedipine on femoral blood flow. BRL 34915, a compound structurally unrelated to existing cardiovascular drugs, is a potent new antihypertensive agent having an interesting profile of activity that renders this compound of clinical interest.

Prejunctional and postjunctional effects of neuropeptide Y at the noradrenergic neuroeffector junction of the perfused mesenteric arterial bed of the rat.

Abstract: The effect of neuropeptide Y (NPY) on periarterial nerve stimulation-induced release of norepinephrine (NE) and increase in perfusion pressure in the perfused mesenteric arterial bed of the rat was examined. Perfusate effluents were continuously collected and assayed for endogenous NE by high-pressure liquid chromatography (HPLC) coupled to electrochemical detection. Perfusion pressure was continuously monitored by means of a pressure transducer. Periarterial nerve stimulation (8 or 16 Hz, 60 V, 2-ms duration for 30 s) resulted in a readily detectable increase in NE release and perfusion pressure that was attenuated by the prior administration of tetrodotoxin (TTX) (10(-5) M) or guanethidine (5 X 10(-5) M). NPY exerted both prejunctional and postjunctional effects on noradrenergic neurotransmission in this preparation. The peptide produced a concentration-dependent reduction in the release of NE over a concentration range of 10(-10) - 10(-7) M. A similar inhibition effect occurred at 8, 10, and 16 Hz. In contrast, low concentrations (10(-10) and 10(-9) M) decreased the effect of nerve stimulation on perfusion pressure, whereas higher concentrations (10(-7) M) produced a marked potentiation. The alpha 2-adrenoceptor antagonist, yohimbine, did not alter the inhibitory effect of NPY on evoked NE release or the effect on perfusion pressure. Prazosin similarly did not alter the inhibitory effect of NPY on NE release but prevented the increase in perfusion pressure. We conclude that NPY modulates noradrenergic neurotransmission in the mesenteric arterial bed by decreasing the evoked release of NE and producing a concentration-dependent biphasic response on vascular smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Converting enzyme inhibitors in the treatment of hypertension.

Abstract: The renin-angiotensin system has a wide range of physiological actions, and thus interference with the system has attractive therapeutic potential. The orally active angiotensin converting enzyme (ACE) inhibitors have so far been the most successful drugs in this area. They lower arterial pressure both in renovascular and essential hypertension, and their effects are enhanced by concomitant diuretic therapy or dietary salt restriction. Since, in renovascular hypertension, the affected kidney depends on enhanced local generation of angiotensin II to help preserve its function, the circulation and excretory capacity of this kidney may be compromised with ACE inhibition. ACE inhibitors can improve exercise tolerance and diminish cardiac ventricular arrhythmias in patients with heart failure. Because these drugs lower plasma aldosterone, they tend to correct potassium deficiency and hypokalemia, which may have been induced by diuretic treatment. Hypotension can occur with the first dose of ACE inhibitor, especially in sodium-depleted subjects; in patients on prior antihypertensive therapy, particularly if this includes a diuretic; and in the elderly. Not all of the actions of ACE inhibitors are necessarily due to lowering of plasma angiotensin II: accumulation of kinins may be responsible for some of the effects and side effects. Common to all ACE inhibitors are occasional rashes, cough, and, more rarely, angioedema. Apparently peculiar to captopril, and less often seen with the lower doses now employed, are taste disturbance, proteinuria, and marrow depression. ACE inhibitors, should not be used in pregnant women.

Placebo-Controlled Study of Lisinopril in Congestive Heart Failure: A Multicentre Study

Abstract: A double-blind randomised, parallel, placebo-controlled study was performed in patients with congestive heart failure, at 13 centres in 10 countries, to assess the efficacy and safety of lisinopril, a new antiotensin-converting enzyme inhibitor. After a 2-week run-in period, 130 patients receiving digoxin and/or diuretics were randomised to 12 weeks of treatment with lisinopril 5 mg daily (87 patients) or with placebo (43 patients), with an option to increase lisinopril dosage to 10 or 20 mg. Patients treated with lisinopril improved significantly more than placebo-treated patients (p

The influence of heart rate on coronary artery atherosclerosis.

Abstract: Elevated "casual" heart rate (HR) has been found to be an independent predictor of coronary heart disease (CHD) in human beings. The current study provides data on the association between coronary artery atherosclerosis (CAA) and naturally occurring individual differences in the casual HRs of cynomolgus macaques (Macaca fascicularis). The data demonstrate that naturally occurring differences in casual HR are related to CAA (plaque area in mm) with high HR monkeys having lesions more than twice as extensive as those of low HR monkeys (high HR; n = 7, 159 beats/min: 0.76 mm2 +/- 0.21 SD; low HR; n = 8, 133 beats/min: 0.31 mm2 +/- 0.30; t = 3.01, p less than 0.01). The data show further that the distribution of individual differences in casual HR is consistent and stable over periods of at least 12 months. Importantly, the relationship between elevated casual HR and CAA was independent of the association between an index of HR "responsivity" to stress and CAA, found in the same monkeys. Similar to a recent finding in human beings, high casual HR also was associated with significantly lowered serum concentrations of high-density lipoprotein cholesterol; differences in CAA were, however, independent of the lipid difference. The CAA differences may depend instead on HR-induced differences in coronary blood flow between high and low HR monkeys. Subsequent work with beta-adrenergic blockade suggested that elevated casual HRs in monkeys are associated with sympathetic arousal.

Microvascular mechanisms involved in calcium antagonist edema formation.

Abstract: The effects of calcium antagonists on microcirculation in cat skeletal muscle were studied using a plethysmographic technique. Nifedipine given locally intraarterially decreased vascular resistance in a dose-dependent way by means of vasodilatation that was relatively more pronounced in precapillary vessels than in postcapillary vessels. This led to an increase in capillary hydrostatic pressure, which was the main force for the concomitant transcapillary fluid filtration from blood to tissue. Capillary filtration coefficient, which reflects precapillary sphincter tone (and thus the capillary surface area available for fluid exchange) and specific capillary permeability, was not changed much by nifedipine, even when vasodilatation was pronounced. A comparison of five different calcium antagonists (diltiazem, felodipine, nifedipine, nimodipine, and verapamil) showed that at the same degree of vasodilatation these agents caused the same increase in capillary hydrostatic pressure and the same net transcapillary fluid transfer, but caused no change in capillary filtration coefficient. Nifedipine also interfered with local vascular control in the tissue, leading to an impairment of "autoregulation of capillary hydrostatic pressure" at variations in arterial blood pressure and an impairment of protection against increased hydrostatic load in dependent vascular beds. It is concluded that peripheral edema (usually ankle edema) during treatment with calcium antagonists may result from vasodilatation alone and an inhibition of local vascular (myogenic) control.

Tissue Renin-Angiotensin System: Sites of Angiotensin Formation

Abstract: The classical concept of the renin-angiotensin system as an endocrine system, whereby angiotensin is generated in the circulation and conveyed by blood to peripheral tissues, is being increasingly challenged by evidence that suggests that peripheral tissues are the major site of generation of angiotensin I and II. The concentrations of angiotensins I and II in arterial and venous blood, taken together with their efficient metabolic clearance by peripheral tissues and their slow rate of generation in blood, indicate that peripheral tissues are the major site of generation of these peptides. Most angiotensin I and II in blood is generated within tissues by the action of plasma-derived renin on plasma-derived angiotensinogen, and the action of tissue converting enzyme. In addition, there is increasing evidence for the synthesis of renin by tissues other than the kidney, and of angiotensinogen by tissues other than the liver. The relative contribution of plasma renin and angiotensinogen, and of locally synthesized renin (or renin-like enzyme) and angiotensinogen, to angiotensin generation in each tissue is unknown, and probably differs between tissues. These two mechanisms for local generation of angiotensin within tissues have the potential to produce changes in tissue concentrations of angiotensin that are independent of the circulating level of renin and angiotensin.

Effects of glyceryl trinitrate on endothelium-dependent and -independent relaxation and cyclic GMP levels in rat aorta and human coronary artery

Abstract: The effects of glyceryl trinitrate-induced desensitization on relaxations and/or elevated cyclic GMP levels due to the nitrogen oxide-containing vasodilators (glyceryl trinitrate and sodium nitroprusside), the endothelium-dependent vasodilators (acetylcholine and the Ca2+ ionophore A23187), and the atrial peptides (atriopeptin II) were investigated in the rat thoracic aorta and human coronary artery. Prior exposure of rat thoracic aorta to glyceryl trinitrate decreased relaxations to glyceryl trinitrate, sodium nitroprusside, and acetylcholine, whereas relaxations to atriopeptin II and 8-bromo cyclic GMP remained unaltered. In human coronary artery, glyceryl trinitrate pretreatment inhibited relaxations to glyceryl trinitrate, sodium nitroprusside, and the Ca2+ ionophore A23187. Relaxation to glyceryl trinitrate was inhibited more than that to sodium nitroprusside in both tissues. Acetylcholine-induced relaxation in rat thoracic aorta was slightly inhibited, whereas relaxation to the Ca2+ ionophore A23187 in human coronary artery was markedly depressed. Pretreatment with glyceryl trinitrate decreased the elevated cyclic GMP levels due to glyceryl trinitrate and acetylcholine in rat thoracic aorta and to glyceryl trinitrate and the Ca2+ ionophore A23187 in human coronary artery. Removal of the endothelium abolished the increased cyclic GMP levels and relaxation due to the Ca2+ ionophore A23187 and decreased basal cyclic GMP levels in the human coronary artery. In contrast, atriopeptin II-induced increased cyclic GMP levels were unaltered by glyceryl trinitrate pretreatment in rat thoracic aorta. The present results suggest that: glyceryl trinitrate-induced desensitization inhibits relaxation to the nitrogen oxide-containing vasodilators and endothelium-dependent vasodilators in both the rat thoracic aorta and human coronary artery: the inhibition of relaxation is associated with decreased formation of cyclic GMP;(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma neuropeptide Y concentration is increased after hemorrhage in conscious rats: relative contributions of sympathetic nerves and the adrenal medulla

Abstract: Summary Most peripheral noradrenergic nerves have been shown to contain the coexisting peptide, neuropeptide Y (NPY). The aim of this study was to determine whether NPY is released together with catecholamines during activation of the sympathoadrenal system by hemorrhagic stress in conscious rats. Plasma NPY rose from a baseline value of 7.7 ± 1.2 to 14.4 ± 2.7 and 14.9 ± 2.3 ng/ml (mean ± SEM, n = 8) 10 and 30 min after hemorrhage, respectively. Plasma norepinephrine (NE) and epinephrine concentrations rose immediately after hemorrhage and at 30 min were increased twofold and ninefold, respectively. To determine the source of the increase in circulating NPY after hemorrhage, rats were subjected to adrenalectomy or to chemical sympathectomy with intravenous (i.v.) 6-hydroxydopamine (6-OHDA). 6-OHDA-treated rats had no significant increase in plasma NPY after hemorrhage, whereas adrenalectomized rats had an enhanced NPY response to hemorrhage. These results suggest that the sympathetic nerves make the major contribution to the increase in plasma NPY concentrations after activation of the sympathoadrenal system by hemorrhagic stress.

Controlled multicenter study of the antihypertensive effects of lisinopril, hydrochlorothiazide, and lisinopril plus hydrochlorothiazide in the treatment of 394 patients with mild to moderate essential hypertension.

Abstract: Lisinopril (LIS) is a lysine analog of enalaprilat, the active metabolite of enalapril, an angiotensin-converting enzyme inhibitor (ACEI). Unlike enalapril, the precursor of enalaprilat, LIS is not a prodrug but has equal ACEI efficacy and potency and a slightly longer duration of action after oral administration. Short-term (12 weeks) and long-term (24 weeks) blood pressure control has been studied with LIS, hydrochlorothiazide (HCTZ), and LIS + HCTZ when given once a day. Drug treatment had three phases: (i) 2-4 weeks of single-blind placebo washout; (ii) 12 weeks of double-blind comparison therapy with LIS 20, 40, and 80 mg vs. HCTZ 12.5, 25, and 50 mg, vs. LIS + HCTZ 20 + 12.5, 40 + 25, and 80 + 50 mg; (iii) 13-24 weeks single-blind LIS vs. LIS + HCTZ. Starting double-blind therapy at the lowest dose, all three groups doubled the dose at weeks 4 and 8 if BP was not controlled with sitting diastolic BP (SDBP) less than 90 mm Hg. At the end of 12 weeks of double-blind therapy, uncontrolled HCTZ-only and LIS-only treatment groups were advanced to combination LIS + HCTZ therapy but uncontrolled LIS + HCTZ patients were dropped. Mean BP reductions (systolic/diastolic, mm Hg) for all three groups after 12 weeks of double-blind comparison therapy were: (i) LIS (n = 162), -16.6/-12.5; (ii) HCTZ (n = 155), -10.4/-6.8; (iii) LIS + HCTZ (n = 74), -23.9/-18.2 with p less than 0.01 for all groups compared to baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Reperfusion-induced arrhythmias and free radicals: studies in the rat heart with DMPO.

Abstract: SummaryWe have shown that the free radical spin trap DMPO (5,5-dimethyl-l-pyrroline-N-oxide) reduces reperfusion-induced arrhythmias in a dose-dependent manner in the isolated perfused rat heart subjected to 10 min regional ischemia and 3 min reperfusion. At its optimal concentration (1,000 μmol/L)

Neuropeptide Y potentiates contraction and inhibits relaxation of rabbit coronary arteries.

Abstract: The effects of neuropeptide Y (NPY) on contraction and relaxation of isolated rabbit coronary arteries were studied NPY alone caused a weak contraction of coronary arteries with a mean EC50 value of 29 +/- 20 nM Following exposure of coronary arteries to 30 nM NPY, the potencies of norepinephrine (in the presence of 3 microM timolol) and histamine in causing contraction were increased twofold, with no change in maximal contraction After half-maximal contraction of coronary arteries with histamine and addition of 30 nM NPY, relaxation produced by norepinephrine (in the presence of 3 microM phentolamine), adenosine, and acetylcholine was inhibited Concentration-response curves for all vasodilators were shifted to the right 10-22-fold by 30 nM NPY Maximal relaxation caused by adenosine and norepinephrine was not changed by NPY, whereas the maximal response to acetylcholine was 37% less in the presence of NPY Correlation of the tension produced by NPY with the shift in agonist contraction or relaxation concentration-response curves indicated that NPY-induced increases in baseline tone had no effect on the degree of shift in agonist concentration-response curves These results show that NPY causes a modest potentiation of agonist-induced contraction and a dramatic blockade of vasodilator-induced relaxation of rabbit coronary arteries

Biochemical mechanisms for the inotropic effect of the cardiotonic drug milrinone.

Abstract: Milrinone is a new inotropic agent for the treatment of refractory congestive heart failure. Our understanding of the mechanisms(s) of action of this synthetic cardiotonic drug is incomplete. We examined the effects of milrinone and the parent compound amrinone on sarcoplasmic reticulum function (45Ca-uptake and Ca-ATPase); radioligand binding to adenosine, beta-adrenergic, and cholinergic muscarinic receptors; cyclic AMP accumulation; and inhibition of various forms of cyclic AMP phosphodiesterases. Comparisons were made to observe how these effects correlate with the inotropic response of heart. Milrinone was shown to be a potent phosphodiesterase inhibitor that was 40 times more potent than amrinone and 10 times more potent at inhibiting the high-affinity (Km = 0.23 microM) form (Ki = 22 microM) than the low-affinity (Km = 140 microM) form (Ki = 225 microM) of cyclic AMP phosphodiesterase in heart. The potency of milrinone as a phosphodiesterase inhibitor was the same in the presence and absence of calcium. Concentrations of milrinone that increased cyclic AMP accumulation also produced positive inotropy. A comparison of milrinone with amrinone and methylxanthines revealed the order of potency to be isobutylmethylxanthine greater than milrinone greater than theophylline greater than caffeine greater than amrinone. Milrinone and amrinone had no effect on 45Ca-uptake or Ca-ATPase activity in myocyte sarcoplasmic reticulum. However, milrinone did bind weakly to adenosine receptors (KD = 466 microM) but not to cholinergic muscarinic or beta-adrenergic receptors. Also, in combination with isoproterenol high concentrations of milrinone blocked the negative inotropic response to the adenosine agonist phenylisopropyladenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical pharmacology of lisinopril.

Abstract: Lisinopril is an orally active, nonsulfhydryl angiotensin-converting-enzyme (ACE) inhibitor that is not metabolized or bound to protein. Peak serum concentrations occur 6-8 h after oral dosing. Lisinopril bioavailability (approximately 25%) is not significantly affected by food, age, or coadministration of hydrochlorothiazide (HCTZ), propranolol, digoxin, and glibenclamide. Lisinopril is excreted unchanged in the urine. Steady state is achieved in 2-3 days with little accumulation. Significant accumulation occurs in patients with severe renal impairment (creatinine clearance less than or equal to 30 ml/min). Lisinopril inhibits ACE activity, thereby reducing plasma angiotensin II and aldosterone and increasing plasma renin activity. Lisinopril produces a smooth, gradual blood pressure (BP) reduction in hypertensive patients without affecting heart rate or cardiovascular reflexes. The antihypertensive effect begins within 2 h, peaks around 6 h, and lasts for at least 24 h. Lisinopril produces greater systolic and diastolic BP reductions than HCTZ. Lisinopril is similar to atenolol and metoprolol in reducing diastolic BP, but superior in systolic BP reduction. Lisinopril and nifedipine produce comparable reductions in systolic and diastolic BP. When lisinopril is given once daily as monotherapy, the range of BP reductions is 11-15% in systolic and 13-17% in diastolic. HCTZ addition enhances its antihypertensive effect. Lisinopril does not produce hypokalemia, hyperglycemia, hyperuricemia, or hypercholesterolemia. Lisinopril has natriuretic properties; renal blood flow remains stable or increases. Lisinopril increases cardiac output, and decreases pulmonary capillary wedge pressure and mean arterial pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics. Human experience to date (2,800 patients/subjects) indicates that lisinopril is well tolerated and has a good safety profile.

Effects of antihypertensive drugs on sympathetic vascular control in relation to neuropeptide Y.

Abstract: The present paper summarizes some recent studies supporting that neuropeptide Y (NPY) is involved as a cotransmitter or modulator with catecholamines (CA) in peripheral, sympathetic, and cardiovascular control, and that many drugs used for the studies or treatment of hypertensive disorders influence NPY mechanisms both at the pre- and postjunctional levels. Neuropeptide Y is stored in large dense-cored vesicles and coreleased with noradrenaline (NA) from postganglionic, sympathetic nerves, and with adrenaline (ADR) from the adrenal medulla. Neuropeptide Y release occurs mainly upon high stimulation frequencies or during strong sympathetic reflex activation in animals and humans. Neuropeptide Y inhibits nerve stimulation-evoked NA release via a prejunctional action, causes vasoconstriction in most vascular beds in vivo, exerts variable contractile effects, and enhances NA responses on isolated blood vessels in vitro. The NPY effect can occur independently of adrenergic mechanisms and seems to be mediated via specific, high-affinity receptors, where the C-terminal amidation is essential for binding and biological effects. Most evidence favors a local role for NPY in neurotransmission, while systemic plasma levels of NPY are only sufficiently high to induce vasoconstriction under severe stress. Guanethidine inhibits the NPY release from sympathetic nerve terminals. alpha 2-Adrenoceptor agonists like clonidine inhibit the nerve stimulation-evoked NPY release and treatment with clonidine elevates the tissue content of NPY. The alpha 1-adrenoceptor antagonist prazosin does not influence the NPY release to any major extent, while alpha 2-antagonists enhance NPY release. The beta-adrenoceptor antagonist propranolol facilitates nerve-evoked vasoconstriction in the presence of alpha-adrenoceptor antagonists, unmasking "nonadrenergic" responses. Reserpine treatment depletes the tissue content of NPY via increased local release in excess of resupply. The nerve-evoked NPY release that is enhanced after reserpine treatment is related to remaining vasoconstrictor effects. The NA uptake inhibitor desipramine reduces NPY release. Calcium antagonists such as nifedipine inhibit the vasoconstrictor actions of NPY on arteries, but not on veins. The prejunctional inhibitory effects of NPY on NA release from perivascular nerves are not influenced by nifedipine.

Influence of local converting enzyme inhibition on angiotensin and bradykinin effects in ischemic rat hearts.

Abstract: To investigate the influence of local cardiac converting enzyme (CE) inhibition on the effects of angiotensin I (ANG I), ANG II, and bradykinin (BK), experiments were performed in ischemic isolated perfused working rat hearts. Acute regional myocardial ischemia was induced by 15 min occlusion of the left coronary artery followed by reperfusion. In ischemic isolated rat hearts, perfusion with ramiprilat (100 ng/ml, 2.58 x 10(-7) mol/l), the active moiety of the CE inhibitor ramipril, after coronary occlusion protected against ventricular fibrillation that invariably occurred in untreated control hearts in the reperfusion period. Addition of ANG I and ANG II to the perfusate enhanced, whereas BK reduced postischemic reperfusion arrhythmias, which were almost abolished in the hearts from ramipril (1 mg/kg p.o.) pretreated rats. Perfusion with ANG I and ANG II reduced cardiac function and coronary flow, increased the activities of lactate dehydrogenase and creatine kinase in the perfusate, and decreased high-energy-rich phosphates and glycogen in the myocardium. In contrast, BK reduced the enzymatic activities in the perfusate and improved the metabolic parameters in the myocardium. In hearts from ramipril pretreated animals, the ANG I effects were abolished, whereas the ANG II actions remained unchanged. The results of these experiments are consistent with the hypothesis that the beneficial effects of CE inhibitors on ventricular arrhythmias, cardiac function, and metabolism are due to local interference with CE in the coronary vascular wall or heart tissue and subsequent reduction of local ANG II generation and BK degradation.

Concentration-dependent protection by captopril against myocardial damage during ischemia and reperfusion in a closed chest pig model.

Abstract: We previously reported concentration-dependent protection of captopril against ischemia-reperfusion injury in the isolated rat heart. In order to study these effects in vivo, we developed a closed-chest pig model. Reversible occlusion of the left coronary artery was achieved with a PTCA catheter during one hour. Captopril (C) i.v. was given in two different concentrations (0.6 mg/kg/10 min + 0.3 mg/kg/2 hr and 6 mg/kg/10 min + 3.0 mg/kg/2 hr) during the experiments to 11 and 10 pigs, respectively, versus 12 controls, who received only saline. Due to malignant ventricular arrhythmias, nine pigs died during ischemia. At the end of the reperfusion period of two hours, eight pigs were alive in each group. In the C-treated pigs, maximum creatine kinase after two hours of reperfusion was significantly lowered to 6,337 +/- 709 U/L in the high dose group versus 8,285 +/- 851 U/L in the low dose group and 9,635 +/- 1,115 U/L in the saline group. A reduction of local inosine overflow in the coronary sinus was seen. Maximum noradrenaline overflow after 5 min reperfusion diminished dose-dependently to 695 +/- 284 and 3,129 +/- 1,728 pg/ml in the C treated groups versus 4,693 +/- 2,277 pg/ml in the saline group. Mean arterial blood pressure and cardiac output decreased significantly during ischemia and reperfusion, but no significant differences occurred between the treated and untreated groups. Reperfusion arrhythmias, mainly accelerated idioventricular rhythm disturbances, were comparable among the three groups. We conclude that in vivo administration of C reduces myocardial damage upon reperfusion after one hour of ischemia in a dose-dependent way.(ABSTRACT TRUNCATED AT 250 WORDS)

The safety and tolerability of lisinopril in clinical trials.

Abstract: The safety and tolerability of lisinopril were assessed in 1,476 patients [1,165 hypertensives and 311 patients with congestive heart failure (CHF)] and 211 normal volunteers. The duration of lisinopril therapy ranged from 1 day to 16 months, with a mean duration of 105 days. In the hypertensive population, the most frequent clinical adverse experiences on lisinopril alone were headache, dizziness, cough, and diarrhea. Not all of these adverse experiences were thought to be drug related. Five percent of patients were discontinued because of adverse clinical experiences; cough and dizziness were the most common reasons for discontinuation. Two of 1,165 (0.17%) hypertensive patients treated with lisinopril died, compared to 0.41% of hypertensive patients on other therapies. Neither case was considered to be drug related. In patients with CHF, the most frequent clinical adverse experiences were dizziness, diarrhea, hypotension, fatigue, headache, and rash. Not all of these adverse experiences were thought to be drug related. The percent of CHF patients discontinuing because of an adverse clinical experience was 7.4%; the most frequent causes for discontinuation were hypotension, dizziness, or renal impairment. Twelve deaths occurred in 311 CHF patients treated with lisinopril (3.9%) compared to 4/104 (3.8%) of CHF patients treated with placebo and 2/65 (3.1%) treated with captopril. Hypotension, orthostatic effects, or dizziness following the initial lisinopril dose occurred infrequently in patients treated with lisinopril. In hypertensive patients with normal renal function, including those treated previously or concomitantly with diuretic therapy, a first-dose hypotensive episode was reported in six of 955, or 0.6%. The incidence was higher (6.7%) in hypertensive patients with impaired renal function.(ABSTRACT TRUNCATED AT 250 WORDS)