Direct and reflex cardiostimulating effects of hydralazine

Khatri, Ibrahim M.; Uemura, Nobuhiro; Notargiacomo, Aldo; Freis, Edward D.

doi:10.1016/0002-9149(77)90097-2

Cited by 88 publications

(20 citation statements)

References 9 publications

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“…Deglin/Jain/Harris occur with hydralazine in dogs (12) and, by one investigative group (13) but not another (14), in isolated papillary muscles. In dogs Khatri et al (12) concluded that hydralazine increases myocardial contractility not only reflexly in response to arterial hypotension but also, perhaps by activating 0-adrenergic receptors either directly or through the release of norepinephrine, nonreflexly.…”

Section: Discussionmentioning

confidence: 92%

“…In dogs Khatri et al (12) concluded that hydralazine increases myocardial contractility not only reflexly in response to arterial hypotension but also, perhaps by activating 0-adrenergic receptors either directly or through the release of norepinephrine, nonreflexly. Although consistent with an increase of positive inotropy induced by hydralazine in heart failure patients, the present results do not indicate whether this increase is a direct action of hydralazine or its metabolites or an indirect one mediated reflexly or otherwise.…”

Section: Discussionmentioning

confidence: 99%

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Noninvasive Assessment of Left Ventricular Effects of Hydralazine in Heart Failure

Deglin¹,

Jain²,

Harris³

1980

Cardiology

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In order to develop a noninvasive means for following left ventricular responses to hydralazine, we measured the systolic time intervals serially in 6 patients with heart failure. Without affecting heart rate or arterial pressure, hydralazine lengthened the left ventricular ejection time relative to the heart rate (LVET_c) 19 ± 7 msec (p < 0.05) and shortened the preejection period 23 ± 3 msec (p < 0.001), restoring it to normal in 4 patients. The data suggest that preejection period shortening and LVET_c lengthening provide the basis for a noninvasive method of assessing the effects of hydralazine on left ventricular performance in heart failure.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Noninvasive Assessment of Left Ventricular Effects of Hydralazine in Heart Failure

Deglin¹,

Jain²,

Harris³

1980

Cardiology

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“…Ganglionic blockade blunted, but did not abolish, the ability of hydralazine to lower cardiac NE levels. 18 Khatri et al 20 reported that the direct injection of hydralazine into a coronary artery of anesthetized dogs caused a localized increase in myocardial contractile force which was blocked by the intravenous administration of propranolol. Spokas and Wang 7 found no localized change in myocardial contractility when equivalent doses of hydralazine were injected into a coronary artery of anesthetized dogs.…”

Section: Figure 3 Relationships Between the Changes In Heart Rate (Amentioning

confidence: 99%

“…In conclusion, hydralazine appears to possess only weak tyramine-like properties. " 20 Chevillard et al 21 studied the effects of hydralazine on the release of 3 H-NE from the isolated rat tail artery during field stimulation. Concentrations hydralazine equivalent to those observed in plasma of hypertensive patients after intravenous 22 or oral 23 administration inhibited the overflow of tritium caused by electrical stimulation at 10 Hz.…”

Section: Figure 3 Relationships Between the Changes In Heart Rate (Amentioning

confidence: 99%

Increased plasma norepinephrine accompanies persistent tachycardia after hydralazine.

Lin

McNay

Shepherd³

et al. 1983

Hypertension

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SUMMARY To determine the role of the peripheral sympathetic nervous system in the persistent tachycardia caused by the antihypertensive drug hydralazine, we examined the temporal relationships between the changes in heart rate and plasma norepinephrine concentration and the reduction in blood pressure produced by a range of doses of hydralazine administered intravenously to five hypertensive patients. Significant linear correlations were found between the increases in heart rate and plasma norepinephrine concentration and the reduction in blood pressure at IS and 30 minutes after injection. However, at 240 minutes after Injection, changes in heart rate and plasma norepinephrine were not correlated with changes in blood pressure and were disproportionately elevated relative to the reduction in blood pressure. A significant linear correlation between changes in heart rate and plasma norepinephrine concentration was noted at 15, 30, and 240 minutes after injection. The temporal discordance of the changes of both heart rate and plasma norepinephrine relative to the reduction in blood pressure and the significant linear correlation between the increases in heart rate and plasma norepinephrine concentration suggest that continued activation of the peripheral sympathetic nervous system contributes to the persistent tachycardia seen after the administration of hydralazine. (Hypertension 5: 257-263, 1983) KEY WORDS • sympathetic nervous system • heart rate • vasodilation T HE decrease in blood pressure (BP) caused by the peripheral vasodilator hydralazine is associated with an increase in heart rate (HR).' 2 The tachycardia is of clinical importance since it favors an increase in cardiac output, which would tend to offset the antihypertensive effect of hyralazine. Accordingly, suppression of hydralazine-induced tachycardia by the coadministration of beta-adrenoceptor antagonists is believed to contribute to the increased efficacy of this combined drug therapy in the treatment of hypertension. 3 ' 4 In addition, the increase in myocardial oxygen consumption associated with the tachycardia may precipitate myocardial ischemia in the presence of atherosclerotic heart disease. Received for publication April 20, 1982; revision accepted September 10, 1982. baroreflexes in response to a reduction in BP, researchers have recognized that the increase in HR persists disproportionately longer than the vasodepressor effect. 6 In addition, several investigators 7 8 have demonstrated that restoration of the systemic BP to normal by the infusion of vasodepressor agents does not completely reverse the tachycardia seen after administration of hydralazine to animals. Thus, arterial baroreflex activation of the peripheral sympathetic nervous system cannot completely account for the persistent tachycardia caused by hydralazine.Although plasma norepinephrine (NE) concentration is known to be increased following administration of hydralazine to animals, 9 the quantitative relationship between the increase in plasma catecholamine levels a...

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“…En-couraging results have been reported in clinical trials using hydralazine and isosorbide dinitrate to prolong survival in patients with mild-to-moderate heart failure (V-Heft I and V-Heft II; Cohn et al, 1986;. While the major benefit of hydralazine is generally believed to be mediated through its vasodilator action, the drug may also elicit positive inotropic and chronotropic responses in both animal models and man (Gershwin et al, 1967;Khatri et al, 1977;Leier et al, 1980). Moreover, a positive inotropic response to hydralazine can be demonstrated under conditions in which the rate of myocardial contraction is held constant (Rabinowitz, 1986;Azuma et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Cellular mechanism of the positive inotropic effect of hydralazine in mammalian myocardium

Hurrell

Perreault

Lin

et al. 1993

British J Pharmacology

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1 The purpose of this study was to elucidate the cellular mechanism of the positive inotropic effect of hydralazine, a vasodilator widely used for afterload reduction in patients with heart failure that has also been reported to have positive inotropic effects on the heart. After isolation, right ventricular papillary muscles from the ferret were maintained in bicarbonate-buffered salt solution (30°C). A concentrationresponse relationship was obtained for hydralazine (10-6 to 10-3 M). In order to mimic different levels of catecholamine release found in heart failure, we utilized two methods of stimulation: (a) threshold punctate pulses and (b) suprathreshold punctate stimulation with voltage approximately 10% above threshold. 2 In a first group of muscles (n = 16), a maximally effective concentration of hydralazine (10-3 M) increased peak isometric tension by 39 ± 9% (P< 0.05). Doses lower than 10-5 M had no significant effect. The bioluminescent Ca2" indicator, aequorin, was loaded into a subset of these muscles (n = 7). A significant increase in peak light (i.e., intracellular Ca2") developed, concurrently with an increase in peak tension (38 ± 5% to 66 ± 8%). This inotropic response was associated with a decrease in time to peak tension (ms), 221 ± 7 to 186 ± 5 (P < 0.05), and time to peak light, 65 ± 4 to 52 ± 2 (P < 0.05). These effects were markedly attenuated by pretreatment with autonomic blocking agents. 3 In a second group of muscles (n = 12), histamine was used to stimulate cyclic AMP production in the presence of propranolol. Hydralazine (3 x 10-4 M) led to a shift in the pD2 (i.e. the negative log of the concentration of histamine producing 50% of the maximal response) from 6.1 ± 0.1 to 5.9 ± 0.1 (P <0.05), thus increasing the sensitivity of the muscles to histamine. Hydralazine also increased maximum tension from 160 ± 77% to 195 ± 57% (P <0.05) above baseline. Thus, hydralazine altered the potency and efficacy of histamine despite the presence of 13-adrenoceptor blockade. 4 A third group of muscles were chemically skinned to examine the effects of hydralazine on myofilament Ca2+ responsiveness. Pretreatment of ferret papillary muscles with hydralazine (10-3 M) before skinning did not shift the force-pCa curve after skinning (n = 16). However, hydralazine added to previously skinned fibres desensitized the myofilaments, as indicated by a rightward shift of the force-pCa curve (n = 12). Maximum tension development was not changed. 5 The pharmacological effects of hydralazine are characteristic of inotropic drugs that act mainly via cyclic AMP; however, the increase in peak tension demonstrated with histamine in the presence of hydralazine also suggests an effect on cyclic AMP-independent second messenger pathways. These data are consistent with reports that large doses of hydralazine may increase cellular levels of cyclic AMP, as well as other second messengers, by direct cardiac and indirect neuronal mechanisms.

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Direct and reflex cardiostimulating effects of hydralazine

Cited by 88 publications

References 9 publications

Noninvasive Assessment of Left Ventricular Effects of Hydralazine in Heart Failure

Noninvasive Assessment of Left Ventricular Effects of Hydralazine in Heart Failure

Increased plasma norepinephrine accompanies persistent tachycardia after hydralazine.

Cellular mechanism of the positive inotropic effect of hydralazine in mammalian myocardium

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