Cardiovascular effects of methyleugenol, a natural constituent of many plant essential oils, in normotensive rats

Cardiovascular effects of intravenous (i.v.) treatment with methyleugenol (ME), a natural constituent of many plant essential oils, were investigated in normotensive rats. Additionally this study examined (I) whether the autonomic nervous system is involved in the mediation of ME-induced changes in mean aortic pressure (MAP) and heart rate (HR), and (II) whether the hypotensive effects of ME could result from its vasodilatory effects directly upon vascular smooth muscle. In both pentobarbital-anesthetized and conscious rats, i.v. bolus injections of ME (1 to 10 mg/kg) elicited similar and dose-dependent decreases in MAP. In anesthetized rats, ME decreased HR only at the highest dose (10 mg/kg), while changes of this parameter were not uniform in conscious rats. Pretreatment of anesthetized rats with bilateral vagotomy significantly reduced the bradycardia response to ME (10 mg/kg) without affecting the hypotension. In conscious rats, i.v. pretreatment with methylatropine (1 mg/kg) or hexamethonium (30 mg/kg) had no significant effect on ME-induced hypotension. In rat isolated thoracic aorta preparations, ME (0.006-1.68 mM) induced a concentration-dependent reduction of potassium (60 mM)-induced contraction. This is the first physiological evidence that i.v. treatment with ME in either anesthetized or conscious rats elicits hypotension; an effect that seems related to an active vascular relaxation rather than withdrawal of sympathetic tone.     

Hemodynamic responses to aortic depressor nerve stimulation in conscious L-NAME-induced hypertensive rats

The present study investigated whether baroreflex control of autonomic function is impaired when there is a deficiency in NO production and the role of adrenergic and cholinergic mechanisms in mediating reflex responses. Electrical stimulation of the aortic depressor nerve in conscious normotensive and nitro-l-arginine methyl ester (L-NAME)-induced hypertensive rats was applied before and after administration of methylatropine, atenolol, and prazosin alone or in combination. The hypotensive response to progressive electrical stimulation (5 to 90 Hz) was greater in hypertensive (-27 ± 2 to -64 ± 3 mmHg) than in normotensive rats (-17 ± 1 to -46 ± 2 mmHg), whereas the bradycardic response was similar in both groups (-34 ± 5 to -92 ± 9 and -21 ± 2 to -79 ± 7 beats/min, respectively). Methylatropine and atenolol showed no effect in the hypotensive response in either group. Methylatropine blunted the bradycardic response in both groups, whereas atenolol attenuated only in hypertensive rats. Prazosin blunted the hypotensive response in both normotensive (43%) and hypertensive rats (53%) but did not affect the bradycardic response in either group. Prazosin plus angiotensin II, used to restore basal arterial pressure, provided hemodynamic responses similar to those of prazosin alone. The triple pharmacological blockade abolished the bradycardic response in both groups but displayed similar residual hypotensive response in hypertensive (-13 ± 2 to -27 ± 2 mmHg) and normotensive rats (-10 ± 1 to -25 ± 3 mmHg). In conclusion, electrical stimulation produced a well-preserved baroreflex-mediated decrease in arterial pressure and heart rate in conscious l-NAME-induced hypertensive rats. Moreover, withdrawal of the sympathetic drive played a role in the reflex bradycardia only in hypertensive rats. The residual fall in pressure after the triple pharmacological blockade suggests the involvement of a vasodilatory mechanism unrelated to NO or deactivation of α(1)-adrenergic receptor.     

Antihypertensive properties of Allium sativum (garlic) on normotensive and two kidney one clip hypertensive rats

Allium sativum (garlic) is reported to act as an antihypertensive amidst an inconsistency of evidence. In this study, we investigated the cardiovascular effects of aqueous garlic extracts (AGE) on normotensive and hypertensive rats using the two-kidney one-clip (2K1C) model. Mean arterial blood pressure (MAP) and heart rate (HR) were measured in normotensive and 2K1C rat models anesthetized with thiopentone sodium (50 mg/kg body weight i.p.) through the left common carotid artery connected to a recording apparatus. The jugular vein was cannulated for administration of drugs. Intravenous injection of AGE (5-20 mg/kg) caused a significant decrease in both MAP and HR in a dose-dependent manner in both the normotensive and 2K1C models, with more effects on normotensive than 2K1C rat model. The dose of 20mg/kg of AGE significantly reduced systolic (16.7 ± 2.0%), diastolic (26.7 ± 5.2%), MAP (23.1 ± 3.6%) and HR (38.4 ± 4.3%) in normotensive rats. In 2K1C group, it significantly reduced systolic (22.2 ± 2.1 %), diastolic (30.6 ± 3.2%), MAP (28.2 ± 3.1%) and HR (45.2 ± 3.5%) from basal levels. Pulse pressure was significantly elevated (33.3 ±5.1%) in the 2K1C group. Pretreatment of the animals with muscarinic receptor antagonist, atropine (2 mg/kg, i.v.), did not affect the hypotensive and the negative chronotropic activities of the extract. AGE caused a decrease in blood pressure and bradycardia by direct mechanism not involving the cholinergic pathway in both normotensive and 2K1C rats, suggesting a likely involvement of peripheral mechanism for hypotension.     

Renin and hemodynamic changes via central adrenergic, cholinergic, and sodium receptor mechanisms in conscious rats.

The effects of centrally administered autonomic drugs and hypertonic saline on renin release were studied in the conscious rat. A 0.3 mug intraventricular dose of isoproterenol, which is one-thirtieth of the intraperitoneal dose required to stimulate renin release, induced the release of renin into the systemic circulation. Norepinephrine had no effect on renin release in the same dose range. Hypertonic saline and carbachol suppressed renin release. Alterations in renin release were preceded by a reciprocal change in blood pressure. These results suggest a central nervous system site for sodium, beta-adrenergic, and cholinergic receptors in altering renin release and blood pressure.     

Potential usefulness of renal vasodilators in hypertension and renal disease: SK&F 82526

SK&F 82526 and its enantiomers have been shown to increase renal blood flow and decrease renal vascular resistance in the anesthetized dog. The effect of the racemate on lowering systemic blood pressure in the anesthetized dog and the spontaneously hypertensive rat has been shown to be caused by the R-enantiomer with the S-enantiomer being devoid of significant activity on blood pressure. The mechanism by which the R-enantiomer decreases blood pressure is not systemic vasodilatation or prejunctional inhibition of norepinephrine release but appears to result from a unique stimulation of the postjunctional dopamine receptor. Racemic SK&F 82526 also has been shown to increase renal blood flow in an ischemic model of acute renal failure.     

Oxytocin-induced renin secretion in conscious rats

Arterial hypotension and hypovolemia are known to stimulate neurohypophysial secretion of oxytocin (OT) in rats, although the physiological function of OT under these circumstances is uncertain. We now report that OT infused intravenously into conscious rats at 125 ng x kg(-1) x h(-1), a dose selected to mimic plasma OT levels during hypotension or hypovolemia, increased plasma renin concentration and plasma renin activity by twofold. This effect was prevented by systemic pretreatment with an OT receptor antagonist [[1-(3-mercaptopropionic acid)-2-O-ethyl-D-Tyr-Thr(4)-Orn(8)]-OT]. The OT antagonist did not block renin secretion induced by systemic injection of the beta-adrenergic receptor agonist isoproterenol, indicating that the OT antagonist does not interfere nonselectively with renin release. Pretreatment of rats with the beta-adrenergic receptor antagonist nadolol also prevented OT-induced renin secretion. Similarly, nadolol injected during infusion of OT markedly reduced the elevated plasma renin levels. These observations raise the possibility that pituitary OT secretion during hypotension or hypovolemia in rats may serve to support blood pressure by enhancing activation of the renin-angiotensin system via a beta-adrenergic receptor-dependent mechanism.     

Possible involvement of GABA mechanisms in central cardiovascular and respiratory control. Studies on the interaction between diazepam, picrotoxin and clonidine

Various doses (0.1-1 mg/kg) of diazepam were given to chloralose anesthetized rats, with both systemic (i.p.) and central injections being tested. Arterial pressure, heart rate, respiration depth and frequency were recorded. Diazepam caused a dose-dependent decrease in the arterial pressure after systemic administration and also decreased it after central administration. However, only intraventricular but not intracisternal injections of diazepam were effective. The hypotensive effect of systemic diazepam was competitively counteracted by pretreatment with picrotoxin, a putative gamma-aminobutyric acid receptor blocking agent. The hypotensive effect of the centrally acting alpha-adrenoreceptor agonist clonidine was not influenced by picrotoxin pretreatment. The effect of diazepam on heart rate was inconsistent. Diazepam caused a reduction of respiratory frequency, which was not counteracted by picrotoxin pretreatment. It is concluded that central gabergic mechanisms are to some extent involved in the hypotensive effect of diazepam, probably at a supramedullary level. The hypotensive effect of a threshold dose of diazepam was blocked by a small dose of clonidine. Likewise, diazepam pretreatment could counteract the hypotension, bradycardia and respiratory frequency reduction caused by a threshold dose of clonidine. These results suggest that gabergic and/or other benzodiazepine-sensitive receptors may interact with alpha-adrenoreceptors in the control of central cardiovascular and respiratory mechanisms.     

Designing potent derivatives of ovokinin(2-7), an anti-hypertensive peptide derived from ovalbumin

We obtained a potent anti-hypertensive peptide, RPFHPF, by replacing the amino acid residues of ovokinin(2-7) (RADHPF), an orally active anti-hypertensive peptide derived from ovalbumin. After intravenous administration in anesthetized Wistar rats, the designed peptide [Pro2, Phe3]-ovokinin(2-7) had a long-lasting hypotensive activity at a dose of 10 mg/kg, while that of ovokinin(2-7) was only transient even at a dose of 100 mg/kg. After oral administration in conscious spontaneously hypertensive rats (SHRs), [Pro2, Phe3]-ovokinin(2-7) significantly lowered the systolic blood pressure in a dose-dependent manner. It is noteworthy that the minimum effective dose of [Pro2, Phe3]-ovokinin(2-7) was 0.3 mg/kg, about one-thirtieth of that of ovokinin(2-7). On the other hand, orally administered [Pro2, Phe3]-ovokinin(2-7) did not show any significant hypotensive effect in normotensive Wistar-Kyoto rats (WKYs) even at a dose of 3 mg/kg. Taken together, [Pro2, Phe3]-ovokinin(2-7) proved to be an ideal, potent anti-hypertensive peptide with little effect on normal blood pressure when given orally.     

Cardiovascular effects of 1,8-cineole,a terpenoid oxide present in many plant essential oils,in normotensive rats

The cardiovascular effects of i.v. treatment with 1,8-cineole, a monoterpenic oxide present in many plant essential oils, were investigated in normotensive rats. This study examined (i) whether the autonomic nervous system is involved in the mediation of 1,8-cineole-induced changes in mean aortic pressure (MAP) and heart rate (HR) and (ii) whether the hypotensive effects of 1,8-cineole could result from its vasodilatory effects directly upon vascular smooth muscle. In both pentobarbital-anesthetized and conscious, freely moving rats, bolus injections of 1,8-cineole (0.3-10 mg/kg, i.v.) elicited similar and dose-dependent decreases in MAP. Concomitantly, 1,8-cineole significantly decreased HR only at the highest dose (10 mg/kg). Pretreatment of anesthetized rats with bilateral vagotomy significantly reduced the bradycardic responses to 1,8-cineole (10 mg/kg) without affecting hypotension. In conscious rats, i.v. pretreatment with methylatropine (1 mg/kg), atenolol (1.5 mg/kg), or hexamethonium (30 mg/kg) had no significant effects on the 1,8-cineole-induced hypotension, while bradycardic responses to 1,8-cineole (10 mg/kg) were significantly reduced by methylatropine. In rat isolated thoracic aorta preparations, 1,8-cineole (0.006-2.6 mM) induced a concentration-dependent reduction of the contraction induced by potassium (60 mM). This is the first physiological evidence that i.v. treatment with 1,8-cineole in either anesthetized or conscious rats elicits hypotension; this effect seems related to an active vascular relaxation rather than withdrawal of sympathetic tone.     

Effects of Anesthetics on the Renal Sympathetic Response to Anaphylactic Hypotension in Rats

The autonomic nervous system plays an important role in rat anaphylactic hypotension. It is well known that sympathetic nerve activity and cardiovascular function are affected by anesthetics. However, the effects of different types of anesthesia on the efferent renal sympathetic nerve activity (RSNA) during anaphylactic hypotension remain unknown. Therefore, we determined the renal sympathetic responses to anaphylactic hypotension in anesthetized and conscious rats and the roles of baroreceptors in these responses. Sprague-Dawley rats were randomly allocated to anesthetic groups that were given pentobarbital, urethane, or ketamine-xylazine and to a conscious group. The rats were sensitized using subcutaneously injected ovalbumin. The systemic arterial pressure (SAP), RSNA and heart rate (HR) were measured. The effects of sinoaortic baroreceptor denervation on RSNA during anaphylaxis were determined in pentobarbital-anesthetized and conscious rats. In all of the sensitized rats, the RSNA increased and SAP decreased after antigen injection. At the early phase within 35 min of the antigen injection, the antigen-induced sympathoexcitation in the conscious rats was significantly greater than that in the anesthetized rats. Anaphylactic hypotension was attenuated in the conscious rats compared to the anesthetized rats. The anesthetic-induced suppression of SAP and RSNA was greater in the order ketamine-xylazine >urethane = pentobarbital. Indeed, in the rats treated with ketamine-xylazine, RSNA did not increase until 40 min, and SAP remained at low levels after the antigen injection. The baroreceptor reflex, as evaluated by increases in RSNA and HR in response to the decrease in SAP induced by sodium nitroprusside (SNP), was suppressed in the anesthetized rats compared with the conscious rats. Consistent with this finding, baroreceptor denervation attenuated the excitatory responses of RSNA to anaphylaxis in the conscious rats but not in the pentobarbital-anesthetized rats. RSNA was increased markedly in conscious rats during anaphylactic hypotension. Anesthetics attenuated this antigen-induced renal sympathoexcitation through the suppression of baroreceptor function.     

The antihypertensive properties of a synthetic prostanoid: RS-93427

The antihypertensive activity of RS-93427, a synthetic prostanoid, was evaluated in conscious restrained spontaneously hypertensive rats. RS-93427 possesses potent antihypertensive activity when administered orally, intraduodenally, intravenously, or subcutaneously but not topically. The blood pressure reducing activity of RS-93427 in normotensive rats was comparable to that in hypertensive animals. No signs of tolerance to the antihypertensive effects were observed following fourteen days of oral administration of RS-93427. The synthetic prostanoid minimally enhanced the orthostatic hypotensive responsiveness to vertical, head up, repositioning of the restrained rats. The relative usefulness of the platelet antiaggregatory and antihypertensive properties of RS-93427 will have to be determined by clinical studies.     

Renin release by pentobarbital anesthesia in the rat: A role for vascular mechanisms

Studies were undertaken in intact rats to characterize the renin response to pentobarbital anesthesia and the mechanisms involved in this response. Aortic and peritoneal cavity cannulas were previously implanted to allow drug infusion, blood sampling and anesthesia to be performed without stress. A sustained 2–3- fold increase in plasma renin concentration (PRC) and a 10–15 mm Hg depression of mean arterial pressure were found in pentobarbital anesthesia. Circulating levels of epinephrine and norepinephrine were unchanged. Sympathetic stimulation by tyramine did not decrease and chronic renal denervation did not abolish the PRC rise by pentobarbital. Phenoxybenzamine given to conscious or anesthetized animals elevated PRC to similar levels. Propranolol was effective in suppressing PRC in anesthetized animals, regardless of the presence or absence of phenoxybenzamine. We concluded that the renin response to pentobarbital anesthesia is unrelated to changes in sympatho-adrenal activity. The response appears to be mediated by beta-adrenergic receptors. It is postulated that pentobarbital- induced relaxation of afferent arterioles or JG cells exposes previously concealed beta-receptor sites which increase the signal for the release of renin.     

Neurogenic vasodilation in the rat hairy skin measured using a laser Doppler flowmeter

Intradermal stimulation of the saphenous nerve of anesthetized rats at C-fiber strength elicited stimulus-dependent vasodilator responses in saphenous-innervated hairy skin. A laser Doppler flowmeter (Periflux, Pf1d) was used to measure these neurovascular responses non-invasively. Capsaicin pretreatment significantly attenuated the vasodilator response. Furthermore, intraperitoneal administration of atropine or mepyramine significantly reduced the skin vascular responses. The responses of halothane-anesthetized rats were significantly attenuated when compared with rats anesthetized with pentobarbitone. Results of this study suggest the presence of endothelium-dependent vasodilator peptidergic, cholinergic and histaminergic contributions to electrically-evoked axon reflex vasodilation in the rat hairy skin.     

Designing Potent Derivatives of Ovokinin(2-7), an Anti-hypertensive Peptide Derived from Ovalbumin

We obtained a potent anti-hypertensive peptide, RPFHPF, by replacing the amino acid residues of ovokinin(2-7) (RADHPF), an orally active anti-hypertensive peptide derived from ovalbumin. After intravenous administration in anesthetized Wistar rats, the designed peptide [Pro², Phe³]-ovokinin(2-7) had a long-lasting hypotensive activity at a dose of 10 mg/kg, while that of ovokinin(2-7) was only transient even at a dose of 100 mg/kg. After oral administration in conscious spontaneously hypertensive rats (SHRs), [Pro², Phe³]-ovokinin(2-7) significantly lowered the systolic blood pressure in a dose-dependent manner. It is noteworthy that the minimum effective dose of [Pro², Phe³]-ovokinin(2-7) was 0.3 mg/kg, about one-thirtieth of that of ovokinin(2-7). On the other hand, orally administered [Pro², Phe³]-ovokinin(2-7) did not show any significant hypotensive effect in normotensive Wistar-Kyoto rats (WKYs) even at a dose of 3 mg/kg. Taken together, [Pro², Phe³]-ovokinin(2-7) proved to be an ideal, potent anti-hypertensive peptide with little effect on normal blood pressure when given orally.     

U-54,669F: a novel hypotensive agent

U-54,669F, a new antihypertensive agent, administered orally was associated with dose-related hypotensive responses in conscious, spontaneously hypertensive, and normotensive rats (0.015-0.5 mg/kg) and in supine conscious monkeys (1-10 mg/kg). No loss of hypotensive efficacy of U-54,669F was observed after 1 wk of daily repetitive treatment. U-54,669F did not alter electrical postganglionic sympathetic nerve activity or postsynaptic sympathetic function. Hypotensive responses to U-54,669F were blunted in spinal cats. U-54,669F was associated with dose-related decreases in norepinephrine (NE) levels in plasma and in cardiac and splenic tissue, whereas brain NE was unaltered. U-54,669F attenuated vascular responses associated with electrical stimulation of sympathetic nerves. However, at hypotensive doses, U-54,669F did not impair the ability of monkeys to withstand orthostatic stress, or contraction of the nictitating membrane secondary to sympathetic stimulation in the cat. U-54,669F appears to alter peripheral sympathetic neurogenic function, but apparently does not enter the central nervous system and does not impair the ability to withstand orthostatic stress at effective hypotensive doses.     

Hypotensive action of an aqueous extract of Pimenta dioica (Myrtaceae) in rats

The intra-venous (i.v.) hypotensive action of the final aqueous fraction of Pimenta dioica was studied in Spontaneously Hypertensive Rats (SHR). The rats were anaesthetized (sodium pentobarbital 50 mg/kg), the trachea, right carotid artery and jugular vein were cannulated for adequate ventilation, direct blood pressure measurement and intra-venous administration of extracts, solutions and drugs. The arterial line was connected to a pressure transducer (Viggo-Spectramed model P23 XL) and a polygraph (Grass model 7H) and monitored continuously during the first five minutes after plant extract administration and then at 5 and 15 minute intervals for one hour. Responses were taken as the maximum pressure changes observed during this period. Increasing doses of the final aqueous fraction were given i.v. to groups of six SHR each. It produced a dose dependent decrease in blood pressure and the ED50 was 45 mg/kg. To discard that the hypotensive effect of the extracts was due to its ionic composition, a solution containing KCl, NaCl, CaCl2 and MgCl2 equivalent to the ion contents present in a dose of 50 mg/kg of total aqueous extract was injected to Sprague-Dawley rats (SDN) using the same method as described above. It did not produce significant changes in blood pressure. Pharmacological antagonistic studies were done injecting either autonomic ganglion, alpha adrenoceptor, beta adrenoceptor and cholinergic receptor blockers prior to extract administration in SHR rats. Atropine, propranolol and phentolamine did not affect the hypotensive effect of the final aqueous fraction. With hexamethonium (autonomic ganglion blocker) the hypotensive response was diminished in a significant way (p < 0.05). The hypotensive action of the final aqueous extract was not mediated through cholinergic, alpha or beta adrenergic receptors. The extract may posses vasorelaxing activity which could not be evident after autonomic ganglion blockade due to extreme vasodilation present prior to extract administration. Future studies should address the question of a possible direct vasodilating effect of the extracts.     

Increased vasodepressor effect of prostaglandins A1 and E1 in renal hypertensive rabbits.

In order to determine whether cardiovascular reactivity to exogenous prostaglandins is altered in hypertension, the hypotensive effects of increasing intravenous doses of PGA₁ and PGE₁ were assessed in conscious normotensive rabbits and in rabbits made hypertensive by wrapping both kidneys with cellophane. Similar experiments were carried out with nitroglycerin. Depressor responses to the prostaglandins, but not to nitroglycerin, were greater in hypertensive than in normotensive animals. The possibility of this enhanced responsiveness being related to the prostaglandin deficiency believed to exist in hypertension was explored in normotensive rabbits treated acutely with indomethacin. The prostaglandin synthesis inhibitor did not affect blood pressure responses to PGA₁ or PGE₁. Although these experiments do not rule out the possible influence of more prolonged prostaglandin deficiency on cardiovascular reactivity, a more apparent adrenergic inhibitory component of the hypotensive effect of prostaglandins in hypertensive animals was considered a likely alternative explanation for the phenomena observed.     

Variations in the effect of clonidine on arterial pressure in rats in the presence of various anesthetics]

The central hypotensive agent, clonidine (30 microgram/kg i.v.) has been injected in normotensive rats anesthetized with various agents. This dose of clonidine elicits usually a biphasic blood pressure response, i.e. a transient increase due to peripheral vasoconstriction, followed by a long lasting decrease. This has been observed in the animals anesthetized with pentobarbitone as well as with urethane. The hypotensive effect is abolished during chloralose, ketamine or Alfatésine anesthesia. These data emphasize that some anesthetics mays particularly modify the effects of centrally acting cardiovascular drugs.     

L-Name modulates responses to adrenomedullin in the hindquarters vascular bed of the rat

Responses to synthetic human adrenomedullin (ADM), a novel hypotensive peptide recently discovered in human pheochromocytoma cells, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the hintquarters vascular bed of the rat. Under conditions of controlled hintquarters blood flow, intraarterial injections of ADM (0.01–0.3 nmol) and of CGRP (0.03–0.3 nmol) caused dose-related decreases in hindquarters perfusion pressure and decreases in systemic arterial pressure. Following administration of the nitric oxide synthase inhibitor, N^ω-nitro-L-arginine methyl ester (L-NAME), hindquarters vasodilator and systemic depressor responses to ADM were significantly decreased, whereas L-NAME did not significantly decrease the vasodilator response to CGRP in either the hindquarters or systemic vascular beds. Following administration of the cyclooxygenase inhibitor, meclofenamate, vasodilator responses to ADM and to CGRP were not significantly decreased. When the relative vasodilator activity of the two peptides was compared on a nmol basis, responses to ADM were similar to responses with CGRP in the hindquarters vascular bed, whereas ADM was 30–100 fold less potent than CGRP in decreasing systemic arterial pressure. The present data demonstrate that ADM has significant vasodilator activity in the hindquarters vascular bed of the rat, that hindquarters vasodilator and systemic vasodepressor responses to ADM, but not to CGRP, are dependent upon the release of nitric oxide from the endothelium.     

Cardiovascular pharmacological characterization of novel 2,3-dimethyl-2-butylamine derivatives in rats

The electrophysiological properties and pharmacological effects of newly synthesized 2,3-dimethyl-2-butylamine derivatives on the rat cardiovascular system were evaluated both in vitro and in vivo. In conventional whole-cell recordings, 2,3-dimethyl-2-butylamine derivatives with ethyl, isopropyl, allyl, butyl, 1-methyl-propyl or cyclopropylmethyl substituents on the amine side chain had potent effects on the outward potassium currents in isolated rat tail arterial smooth muscle cell membranes. In contrast, the compounds with hydrogen, methyl, propyl or benzyl substituents displayed very low activities, which were not statistically significant. The effects of compounds with pyridine ring substituents were also investigated and their order of potency was (14)>(12)>(13). In addition, the opening activities of these compounds (5), (6), (8) could be prevented by glibenclamide, a highly specific blocker of ATP-sensitive potassium channels. The influences of the compounds on cardiovascular hemodynamics parameters, including mean blood pressure (MBP), heat rate (HR), myocardial contractility and diastolic force, were examined in normotensive anesthetized rats. The derivatives with branched 2-4 carbon alkyl substituents induced long-duration hypotensive effects with modest inhibition of cardiac function. The hypotensive effects of the compound (5) could also be inhibited by glibenclamide. Collectively, these results indicate that 2,3-dimethyl-2-butylamine derivatives, which differ chemically from previously described potassium channel openers, have potassium channel opening activity, hypotensive and cardiac-modulating properties that depend on their amino group substituents.