HIV-associated cardiovascular diseases have been widely described, but clinical studies aimed at establishing cause-effect relationships between HIV-associated cardiovascular disease and either the HIV infection or antiretroviral therapy have been problematic. Endothelial dysfunction is a sensitive marker and early event in atherosclerosis, and many have suggested that protease inhibitors promote endothelial dysfunction indirectly by inducing elevations in circulating lipids. To determine whether nucleoside reverse transcriptase inhibitors and/or protease inhibitors induce endothelial dysfunction, and to test whether this effect is dependent upon drug-mediated alteration in plasma lipid concentrations, we treated male Sprague-Dawley rats with pharmacological doses of azidothymidine (AZT), indinavir, or AZT plus indinavir through their drinking water for 1 month and assessed endothelial function in aortic rings using an isometric force measurement. Circulating levels of plasma lipids and endothelin-1, a marker for endothelial injury and/or dysfunction, were also determined. We found that AZT and AZT plus indinavir treatments dramatically reduced endothelium-dependent vessel relaxation. However, AZT treatment did not significantly alter plasma levels of cholesterol or triglyceride. In addition, plasma endothelin-1 levels were elevated in rats treated with AZT plus indinavir. Indinavir treatment alone increased plasma cholesterol levels but had no effect on endothelial function. These findings suggest that in addition to modulating plasma lipid levels, antiretrovirals, particularly AZT and perhaps other nucleoside reverse transcriptase inhibitors, may have direct effects on the vascular endothelium. Together with other increased risk factors for atherosclerosis in HIV patients, AZT-induced endothelial dysfunction may contribute to the cardiovascular diseases associated with HIV antiretroviral therapy.

Basal contractility and responses to beta-adrenoceptor activation are compromised in hearts from rats with chronic portal vein stenosis. Here we report the effect of partial ligation of the portal vein on myocardial G protein expression, beta-adrenoceptor-G protein coupling, and excitation-contraction coupling (ECC). Contractility (dT/dt) was reduced 30-50% in right and left ventricles, but the rate of relaxation (-dT/dt) was unaffected. Isoproterenol-induced positive inotropism was diminished, but there was no difference in ED(50). The concentration-dependent increase in -dT/dt was unaffected. G(s)alpha and G(i)alpha expression, cholera toxin- and pertussis toxin-induced ADP-ribosylation, and formation of the agonist-receptor-G(s) complex were unaffected by portal vein stenosis. Of the components of ECC examined, the caffeine-sensitive sarcoplasmic reticulum Ca(2+) pool was reduced 35%, although the Ca(2+) uptake and release processes were unchanged; the apparent density of L-type Ca(2+) channels decreased 60% with no change in affinity; the dihydropyridine Ca(2+) channel agonist BAY K 8644 produced relative changes in dT/dt that were similar in both groups, suggesting normal function in the remaining Ca(2+) channels; and Na(+)/Ca(2+) exchange was reduced 50% in the portal vein stenosis group. These data suggest that the effect of portal vein stenosis on the myocardium is the result of alterations to ECC.

Human immunodeficiency virus-1 antiretroviral treatment is associated with an increased incidence of atherosclerosis. We hypothesized that antiretrovirals directly impair endothelial function after short-term exposure and that with chronic exposure, this dysfunction promotes a proliferative response, inducing neointimal hyperplasia, thus contributing to vascular lesion formation. To test this hypothesis, we treated mice with the nucleoside reverse transcriptase inhibitor azidothymidine (AZT), the protease inhibitor indinavir, or AZT + indinavir. Treatment with AZT or AZT + indinavir for 5 days impaired endothelium-dependent vessel relaxation. Though indinavir treatment alone did not alter vessel relaxation, it potentiated the impairment of endothelium-dependent relaxation induced by AZT. Coadministration of the antioxidant Mn (III) tetrakis (1-methyl-4-pyridyl) porphyrin attenuated antiretroviral-induced endothelial dysfunction, suggesting that oxidant production may have a causal role in the observed endothelial dysfunction. To test whether the antiretrovirals promote a proliferative response following endothelial dysfunction, we treated mice with antiretrovirals for 14 days and then induced a carotid endothelial injury. Two weeks later, we observed a dramatic increase in neointimal formation in all antiretroviral-treated animals, and the newly formed neointima was comprised mainly of proliferated smooth muscle cells. Although a functional endothelium surrounding the lesioned area and re-endothelialization across the area of injury is important in reducing proliferation in this model, we tested whether the neointimal hyperplasia was associated with endothelial dysfunction. Plasma levels of asymmetric dimethylarginine, a biomarker of endothelial dysfunction, increased after treatment with indinavir or AZT + indinavir. On the other hand, treatment with AZT or AZT + indinavir increased endothelial vascular cell adhesion molecule staining. We conclude that short-term treatment with antiretrovirals elicited a direct impairment in endothelial function, in part via an oxidant-dependent pathway. These antiretrovirals also exacerbated injury-induced vascular smooth muscle cell proliferation and neointimal hyperplasia, likely because of their inhibition of endothelial function.

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Inadequate blood flow and increased vasoconstriction of the placenta contribute to pregnancy associated disorders such as preeclampsia (PE). Because placental vessels lack autonomic innervation, humoral effects of the placenta must play critical roles in regulation of fetal-placental vascular contractility. In this study, we examined the nature of humoral factors produced by PE trophoblasts on placental vessel contractility using an organ bath perfusion model. Vasomotor responses were studied in vitro using placental chorionic plate arteries. Vessel rings from third branch chorionic plate arteries were dissected from human placentas following normal or PE delivery. The arterial rings were equilibrated in Krebs Henseleit buffer and exposed to placental conditioned medium, which was prepared by culture of villous tissue from PE placentas. Receptor antagonists for angiotensin II (ANG II), thromboxane (TX), and endothelin (ET) were used to determine which humoral factor produced by placental tissue (trophoblasts) was more effective in promoting vasoconstriction. The role of angiotensin converting enzyme (ACE) and non-ACE ANG II generating enzymes in regulation of placental vasomotor tone were also investigated. A total of 80 arterial rings from 48 placentas were studied. Our results showed: 1) enhanced vasomotor tone in arteries from PE placentas compared to those from normal placentas; 2) PE-CM induced vaso-constrictive activity could be partially attenuated by receptor antagonists for TX, ANG II and ET, respectively; and 3) chymostatin (a chymase inhibitor) produced a stronger inhibitory effect than captopril (ACE inhibitor) on PE conditioned medium induced vasoconstriction. Our data demonstrate increased vasocontractility in PE placentas and suggest that the non-ACE pathway is probably a major source of ANG II produced in the human placenta.

SUMMARY The purpose of this investigation was to differentiate primary cardiac participation in systemic anaphylaxis from a cardiac reaction secondary to respiratory distress. Hemocyaninsensitized guinea pigs were anesthetized with sodium pentobarbital and artifically ventilated. The chest was opened and the left ventricle cannulated. The electrocardiogram, bronchial resistance, arterial blood pressure, and left ventricular pressure and its first derivative were recorded. Following intravenous administration of antigen, the sinus rate increased by about 50-60 beats/ min, left ventricular dP/dt increased by a factor of 3, and mean arterial pressure doubled. Conduction disturbances occurred in all of the experiments and ventricular fibrillation in four of six. These changes were concomitant with a 4-fold rise in bronchial resistance. To separate the cardiac and respiratory components, antigen was administered directly into the left ventricle to expose the heart to antigen before the lungs. The intracardiac challenge resulted in increases in sinus rate and left ventricular and arterial pressures quantitatively similar to changes recorded from guinea pigs after the intravenous challenge. However, all these changes preceded the rise in bronchial resistance by 60 seconds. Arrhythmias occurred as frequently as with the intravenous challenge. Our findings show that by use of an appropriate route for administration of antigen, cardiovascular and respiratory components of systemic anaphylaxis can be separated. Our data also indicate that anaphylactic cardiovascular changes can be dissociated temporally into two sets of events: an initial primary cardiac reaction caused by intracardiac release of histamine and a subsequent cardiovasular reaction secondary to systemic release of mediator.SEVERE disturbances of cardiovascular function occur during systemic anaphylaxis in the guinea pig. 5 include sinus tachycardia, atrioventricular conduction block, increased ventricular automaticity, and histamine release. The similarities between the effects on the heart of anaphylaxis in vivo and in vitro led us to the conclusion that the guinea pig heart reacts as a primary target organ in systemic hypersensitivity reactions.3 However, because cardiac and respiratory events occur at the same time during systemic anaphylaxis, the possibility could not be excluded that certain cardiovascular changes were secondary to the effects of bronchospasm.The present investigation describes an experimental model in which injection of antigen directly into the left ventricle of sensitized guinea pigs permits identification of the primary cardiac effects of anaphylaxis in vivo. MethodsThirty-two Hartley guinea pigs of either sex were sensitized by two consecutive weekly intraperitoneal injections of 1 mg of alum-precipitated keyhole limpet hemocyanin (K.LH); 15-30 days after sensitization blood samples were taken by puncture of the retro-orbital plexus, and the serum level of anti-KLH anaphylactic antibody was determined by passive cutaneous anaphylaxi...

SUMMARY To evaluate the ability of histamine to induce ventricular arrhythmias, we studied the effects of histamine on ventricular rhythmicity in the isolated guinea pig heart with complete atrioventricular conduction block. As a function of dose (0.1-30 pg), histamine enhanced the idioventricular rate by increasing the rate of firing of the original pacemaker and also by causing the sudden appearance of faster idioventricular rhythms that coincided with changes in pacemaker site. Anaphylaxis in the isolated guinea pig heart with complete atrioventricular conduction block caused histamine release and acceleration of idioventricular rate. The effects of histamine on idioventricular rhythmicity were not attenuated by the histamine Hi receptor antagonist chlorpheniramine, but were antagonized by the Hi receptor antagonist cimetidine. Moreover, the selective Hi agonist 4-methylhistamine (4MeH) accelerated the idioventricular rate, whereas 2-(2-thiazolyl) ethylamine (ThEA), at doses selective for Hi receptor activation, did not. The effects of histamine on idioventricular rhythmicity were not modified by the /J-adrenergic blocker pindolol. The mechanism by which histamine increases idioventricular rate probably involves two components: (1) an enhancement in automaticity of the original pacemaker, and (2) IN THE course of our studies on the cardiac effects of histamine we had become intrigued by the fact that histamine, whether exogenously administered or endogenously released, could induce ventricular dysrhythmias ranging from isolated multifocal ectopic beats to ventricular tachycardia and fibrillation. The severity of the arrhythmia was related to the amounts of histamine injected or released (Levi, 1972;Capurro and Levi, 1975;Levi and Capurro, 1975;Zavecz and Levi, 1977). The purpose of the present study was to investigate the mechanism of histamine-induced ventricular tachyarrhythmias by studying the influence of histamine on ventricular rhythmicity. We chose as an experimental model the isolated mammalian heart with complete atrioventricular conduction block. In this preparation idioventricular rate is not influenced by atrial pacemakers. MethodsMale Hartley guinea pigs weighing 300-400 g were stunned by a blow to the base of the skull. The heart was quickly excised and mounted in a Langendorff apparatus (Levi, 1972) and was perfused at constant pressure (40 cm H 2 O) with oxygenated Ringer's solution at 37°C. The ionic composition of the Ringer's solution was (in mM): Na + , 160; Cl~, 164; K + , 5.6; Ca ++ , 2.2; HC0J, 5.9; glucose, 5.5 The apex of the heart was connected by a nylon thread to a force-displacement transducer (model FT03B, Grass Instruments). Isometric ventricular contractions were displayed on a pen recorder (model R511, Beckman Instruments, Inc.). A bipolar surface electrogram, recorded from the right atrium and the left ventricle, was displayed on another channel of the pen recorder.Following an equilibration period of 30-45 minutes, the right atrium was cut open and a ligature (5-0 surgical...

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