Dose-dependent Decrease In Heart Rate Research Articles

Cardiovascular effects of substance P receptor stimulation in the ventrolateral medullary pressor and depressor areas

The pressor (VLPA) and the depressor (VLDA) areas in the ventrolateral medulla were identified with the microinjection of l-glutamate (1.77 nmol/site) in artificially ventilated urethane-anesthetized male Wistar rats. Bilateral microinjection of a stable substance P (SP) agonist [pGlu 5, MePhe 8, Sar 9-SP(5–11), abbeviated as DiMe, into the VLPA (6–600 pmol/site) produced a dose-dependent increase in blood pressure (BP). The effects on heart rate (HR) were variable. Intravenous pretreatment with a ganglionic blocker chlorisondamine (3.0 mg/kg, i.v.), but not with a vasopressin antagonist, blocked these responses. Similar microinjection of DiMe (6–600 pmol/site) into the VLDA produced a dose-dependent decrease in HR but had no effect on BP levels. The DiMe-induced bradycardic response elicited from the VLDA was blocked by i.v. pretreatment with atropine methylbromide (0.5 mg/kg, i.v.). These findings indicate that there are SP receptors localized on sympathoexcitatory neurons in the VLPA and that SP may be an excitatory neurotransmitter in this area. In the VLDA, the SP receptors appear to be localized on a subpopulation of neurons that affect vagal, but not sympathetic, outflow to the heart.

Cardiovascular responses to κ opioid agonists in intact and adrenal demedullated rats

The effects of three κ opioid agonists namely, bremazocine, tifluadom and U-50,488H were studied on blood pressure and heart rate in urethane-anesthetized normal and bilateral adrenal demedullated rats. Bremazocine (0.2, 0.4 and 0.6 mg/kg i.v.) produced a dose-dependent decrease in heart rate, while only 0.4 mg/kg bremazocine produced marked hypotension. The effect appeared to be long lasting because even at 60 min following drug administration the decreases in both heart rate and blood pressure continued. Bilateral adrenal demedullation did not change bremazocine- increased fall in blood pressure but the bradycardia was partially blocked. Tifluadom (0.1–0.4 mg/kg i.v.) produced an initial arrest of heart beat followed by bradycardia which recovered in about 60 min. Except for a very transient fall soon after drug administration no significant effect was observed on blood pressure. In adrenal demedullated rats, tifluadom induced initial arrest of heart was not affected but the subsequent bradycardia was blocked. U-50,488H (0.2, 0.4 and 0.6 mg/kg i.v.) produced dose-dependent bradycardia and hypotension both of which were blocked following bilateral adrenal demedullation. Naltrexone methylbromide (MRZ 2663 BR), a quaternary opioid antagonist, injected 5 min prior to U-50,488H, blocked its cardiovascular effects. The results suggest that κ opioid agonists given i.v. depress cardiovascular system and these effects are mediated through the adrenal medulla and peripheral opioid receptors. The differential effects of κ opioid agonists on blood pressure and heart rate suggest that either the three κ agents interact differentially at the κ opioid receptors or the subtypes of receptors for the κ opioid exist.

Lack of presynaptic effects of ketanserin on cardiac noradrenergic nerve terminals in the SHR.

The potential cardiac presynaptic effects of ketanserin (K) (0.01-3.00 mg/kg IV) were investigated in pithed SHR in 4 experimental conditions: (a) basal heart rate (HR); (b) HR increased by selective cardiac sympathetic stimulation (SS); (c) HR increased by aminophylline infusion; and (d) HR increased by SS and brought back to basal value by clonidine. Control groups were treated with saline. In the 4 types of experiments, K, starting from 0.3 mg/kg, induced almost identical and dose-dependent decreases in HR (maximal reduction: 45 beats/(min at 3 mg/kg). Thus we conclude: (1) that K is devoid of any presynaptic facilitatory effect on norepinephrine release since it was unable to raise HR in experiment D; (2) that K is devoid of any presynaptic inhibitory effect on norepinephrine release since it lowered HR to the same extent in both experiments B (noradrenergic tachycardia) and (non-noradrenergic tachycardia); and C (3) that the bradycardia which was induced by high doses of K (much above those required to block 5-HT2 and alpha 1-adrenergic receptors) and which was of similar magnitude in the 4 experimental conditions is probably due to a direct, nonspecific depressant effect of K on the sinus node.

BAY k 8644, a calcium channel agonist, reverses hypotension in endotoxin-shocked rats

The hypotension and depressed myocardial function frequently observed in endotoxin-induced shock are difficult to overcome pharmacologically. In this paper we demonstrate that the calcium channel agonist BAY k 8644 potently elevates blood pressure in endotoxin-shocked rats. A one time dose as low as 10 μg/kg of BAY k 8644 significantly elevated mean arterial pressure (MAP) in endotoxin-treated hypotensive rats while having minimal effects in normal rats. The maximum BAY k-induced percentage increase in MAP was greater in endotoxin-treated rats when compared with saline-treated control (153% vs. 120% increase respectively). BAY k 8644 also caused a dose-dependent decrease in heart rate of 37% in endotoxin-treated rats and 39% in control rats (NS vs. control). No differences in the regulatory properties of [ 3H]nitrendipine binding sites were discerned comparing control and endotoxin-treated rats. Thus, the enhanced activity of BAY k 8644 in hypotensive rats was not due to augmented affinity for the cardiac dihydropyridine binding site. These results demonstrate that the use of calcium channel agonists might represent a unique pharmacologic approach in pathologic states characterized by hypotension and diminished cardiac function.

Intrinsic Sympathomimetic Activity of Labetalol

In intact cats, cumulative doses (0.1-10 mg/kg i.v.) of labetalol produced dose-dependent decreases in heart rate and arterial blood pressure and dose-dependently reduced i.v. phenylephrine induced pressor responses. In spinal cats devoid of resting sympathetic tone, labetalol (1 mg/kg i.v.) produced a sustained elevation of heart rate and a transient fall in arterial blood pressure. In reserpine-pretreated, adrenalectomized cats, labetalol produced quantitatively the same effects as in spinal cats, indicating that the cardiovascular effects observed in cats with no resting sympathetic tone are due to a direct action of labetalol rather than via catecholamine release. The elevated heart rate due to labetalol in spinal cats was reduced by subsequent administration of the beta-adrenergic receptor antagonist, propranolol. Further, pretreatment with propranolol prevented the tachycardic and depressor effects of labetalol in spinal cats. In a separate group of spinal cats, labetalol administered in cumulative doses of up to 1 mg/kg i.v., produced graded increases in heart rate and also dose dependently reduced i.v. isoproterenol-induced tachycardic responses. Pindolol, a beta-adrenergic receptor antagonist with partial beta-agonist activity, produced similar effects in spinal cats at cumulative doses of 1-30 micrograms/kg. These results indicate that the alpha- and beta-adrenergic receptor antagonist, labetalol possesses partial beta-adrenergic receptor agonist activity. This intrinsic sympathomimetic action of labetalol appears to be more sustained on cardiac than on vascular beta-adrenergic receptors.

A novel 8-phenyl-substituted xanthine derivative is a selective antagonist at adenosine A1-receptors in vivo.

Adenosine exerts various biological effects via an action on cell surface adenosine receptors (Daly 1983). Thes adenosine receptors are of two types: A1 and A2 (Fredholm 1982, Daly 1983). At both types of adenosine receptors, alkylxanthines (theophylline and caffeine being the prototypes) are competitive antagonists. These classical xanthines show affinities in the 10−5—10−4 m range and show little or no selectivity for either receptor type (Fredholm & Persson 1982). We have recently described a series of novel functionalized congeners of 1,3-dipropyl-8-phenylxanthine (Jacobson et al. 1985a), some of which show a high degree of selectivity towards A1-receptors. Adenosine produces a marked decrease in blood pressure dependent upon an A2-receptor mediated decrease in peripheral resistance (Jonzon et al. 1985) and a decrease in heart rate mediated via adenosine receptors of the A1-subtype (Jonzon et al. 1985). We have examined the ability of two recently synthesized xanthines to antagonize the hypotensive and negative chronotropic effects of a stable adenosine analogue N-5′-ethyl-carboxamidoadenosine(NECA) under in vivo conditions. One of these compounds, an amino congener, showed selectivity for A1-receptors in vitro, whereas the other, a carboxylic acid congener, did not (Jacobsen et al. 1985). The experiments were conducted on sodium pentobarbital anaesthetized male Sprague—Dawley rats (Alab Strain) weighing 250–300 g. The rats were tracheotomized and polyethylene catheters were inserted in the common carotid artery for continuous blood pressure and heart rate recording. Thirty minutes after the i.p. administration of the xanthine derivative increasing doses of NECA were given intravenously and the changes in blood pressure and heart rate were recorded. Full dose–response curves were constructed in at least three animals at each dose of the xanthine. Based on the shift in the NECA dose–response curves we calculated the dose of the xanthine derivatives that produced a doubling of the dose of NECA to achieve the same biological effect by a Shild plot. As seen in Figure 1, NECA caused a dose-dependent decrease in heart rate and in blood pressure in the anaesthetized rats. The amino congener of 1,3,-dipropyl-8-phenylxanthine produced a much larger shift of the dose–response curve for heart rate than for blood pressure at the same dose. By contrast, the carboxylic acid congener produced equivalent shifts to the right of the two dose–response curves. Fig. 1 The antagonism by two analogues of 1,3-dipropyl-8-phenylxanthine (structures of the 8-phenyl substituents are given in the upper right hand corner of the figure) of the negative chronotropic (upper panel) and hypotensive (lower panel) effect of NECA. ... The major finding of the present investigation is that an amino congener of 1,3-dipropyl-8-phenylxanthine is much more potent in antagonizing the effects of adenosine analogues on heart rate than on blood presssure (16-fold difference; 0.043 vs 0.68 mg kg−1. Since the adenosine effects on the heart are mediated via A1-receptors and those on blood pressure via A2-receptors, these results suggest that this novel xanthine derivative is more active as an antagonist at A1-receptors than at A2-receptors under in vivo conditions. By contrast, the carboxylic acid (congener) did not show such selectivity (0.165 vs 0.21 mg kg−1 were required to inhibit the negative chronotropic and hypotensive actions, respectively). The amino congener thus has potential as a very valuable research tool in such applications as elucidating the relative importance of A1- and A2-adenosine receptors in various peripheral tissues, including kidney and lung. There is also the intriguing possibility that a compound of this type could have clinical potential as an inotropic and diuretic agent.

The ventral surface of the medulla in the rat: Pharmacologic and autoradiographic localization of GABA-induced cardiovascular effects

Experiments were done to evaluate a rat model for studying the cardiovascular effects of pharmacological manipulations of the ventral surface of the medulla. GABAergic drugs were used because of their well-characterized actions at the ventral surface of the medulla in the cat. GABA and muscimol, applied to the exposed ventral surface with filter paper pledgets, produced dose-dependent decreases in heart rate (HR) and mean arterial pressure (MAP) which were reversed with bicuculline but not with strychnine. Bicuculline alone raised HR and MAP. The GABA- or bicuculline-induced cardiovascular effects were mediated primarily by inhibition of sympathetic outflow. The most sensitive site was localized to an intermediate area on the ventral surface of the medulla, between the trapezoid body and exits of the hypoglossal nerves and just lateral to the pyramids. Topical application of [ 3H]GABA to the intermediate area resulted in labeling that was concentrated at the site of application, and which penetrated the parenchyma 1 mm dorsally. The heaviest labeling was found primarily in the ventral halves of the lateral paragigantocellular nuclei. No tritium was detected in peripheral blood. These data provide evidence for a neuronal system at the ventral medullary surface of the rat which influences sympathetic outflow and is modulated by GABA.

Effects of bepridil on isolated rabbit perfused heart and guinea pig papillary muscles.

Electrophysiological effects of a new antianginal agent, bepridil (BEP), were studied in 15 rabbits and 29 guinea pigs. In Langendorff-perfused heart, BEP at concentrations above 1μM-2μM caused a dose-dependent decrease in heart rate (HR) and developed tension, atrioventricular (AV) conduction delay or block, and a prolongation of effective refractory period (ERP) of left ventricule. The conduction delay was observed not only in AV node but also in ventricular conduction system. We also measured transmembrance action potential in isolated guinea pig papillary muscle driven at a rate of lHz.BEP at concentrations above 5μM caused significant decreases in maximum upstroke velocity at phase 0 (Vmax) and 30 % repolarization time (APD30).

Species differences in renal vascular effects of dipyridamole and in the potentiation of adenosine action by dipyridamole.

The effects of dipyridamole and adenosine on the renal vasculature and on the enhancement by dipyridamole of the action of adenosine were studied in pigs, dogs, rabbits, and rats. Intravenous adenosine in doses of 10-300 micrograms/kg produced dose-dependent decreases in heart rate and blood pressure of rabbits and rats. Potentiation of adenosine action by intravenous infusion of dipyridamole occurred only in rabbits. When administered into the renal artery of pigs, dogs, rabbits, and rats, adenosine caused dose-dependent vasoconstriction in all species, whereas dipyridamole produced vasoconstriction in rabbits and vasodilation in pigs and rats. In dogs, the renal vascular response to dipyridamole depended on the perfusion method used. In kidneys perfused at a fixed flow rate with a pump, intrarenal dipyridamole elicited vasoconstriction, but in kidneys perfused by their own systemic blood pressure without the use of a pump, it caused vasodilation. The adenosine-induced renal vasoconstriction was enhanced by dipyridamole in pigs, dogs, and rabbits, but not in rats. Species differences and the perfusion method used are important for the renal vascular effects of dipyridamole. Dipyridamole appears to possess not only an indirect action on blood vessels which is related to adenosine, but also a direct vasodilator effect.

COMPARISON OF THE CHRONOTROPIC RESPONSES TO LOCAL ANESTHETICS (PROCAINE, LIDOCAINE, PRILOCAINE, MEPIVACAINE AND BUPIVACAINE) OF THE CANINE SINUS NODE IN SITU

AbstractEffects of local anesthetics (procaine, lidocaine, prilocaine, mepivacaine and bupivacaine) on the sinus node of the nerve-intact dog heart were studied in situ by means of selective perfusion of the sinus node through the sinus node artery. The agents caused a dose-dependent decrease in heart rate and the order of their potency in decreasing the heart rate was as follows, bupivacaine>lidocaine=mepivacaine=prilocaine>procaine. The decrease in heart rate produced by these local anesthetics was not affected by prior administration of atropine. With procaine and prilocaine, the decrease in heart rate was followed by an increase which was inhibited by propranolol given into the sinus node artery or was suppressed in reserpine-pretreated dogs. Tetrodotoxin also prevented the positive chronotropic effect of procaine. From these results the following conclusion can be drawn: the negative chronotropic effects of these agents are induced mainly by a direct inhibitory action on the sinus node, and partly by blockade of sympathetic tone, and the interaction with the postganglionic adrenergic nerves plays an important role in the induction of the positive chronotropic responses to procaine and prilocaine.

Mechanisms of Chronotropic Effects of Volatile Inhalation Anesthetics

The chronotropic effects of all currently available volatile anesthetics were investigated in isolated rat atrial preparations. Anesthetic ethers, diethyl ether, methoxyflurane, and enflurane elicited a dose-dependent positive chronotropic effect. Fluroxene produced a slight depression at low concentrations. The halogenated hydrocarbon anesthetics, halothane, chloroform, and trichloroethylene, did not show a uniform pattern. Halothane's effect was small and biphasic. Chloroform caused a dose-dependent decrease in heart rate, and trichloroethylene caused a marked positive chronotropic effect. The dose-response curves in all anesthetics remained unaltered in the presence of either 3 x 10(-7) M dl-propranolol or 1 x 10(-6) M atropine. It is concluded that volatile anesthetics elicit significant direct chronotropic actions on rat atrial preparations. The mechanism of their actions does not involve stimulation of beta-adrenergic or cholinergic receptors.