Cardiovascular responses to adrenaline and acetylcholine (ACh) were investigated in anesthetized, artificially ventilated cats in control and after induction of acute normovolemic hemodilution. Progressive replacement of blood by high molecular weight dextran was performed in three steps of 20% each of the total estimated blood volume. Hemodynamic responses were recorded at four stages: the control stage and after the 1st, 2nd, and 3rd exchanges of blood for dextran. With the fall in hematocrit (Ht) there was a corresponding significant (p < 0.05) increase in heart rate (HR), cardiac output (CO), and stroke volume (SV), and a decrease in systemic vascular resistance (TPR). However, left ventricular systolic pressure (LVSP), left ventricular contractility (LV dP/dtmax), mean arterial pressure (MAP), and right atrial pressure (RAP) did not show any significant (p > 0.05) change due to hemodilution. The cardiovascular responses of intravenously administered adrenaline and ACh were significantly (p < 0.05) attenuated. Responses to sodium nitroprusside (SNP), a potent vasodilator and an exogenous source of nitric oxide, were also attenuated after hemodilution. The increase in SV and HR seem to be the contributing factors to the CO response. Our results indicate that the cardiovascular responsiveness to adrenaline, ACh and SNP is reduced during acute hemodilution which could be due to inadequate myocardial and vascular O2 supply. The possibility of a modulatory role of an endothelium-dependent mechanism and reflex regulatory responses by arterial baroreceptors during hemodilution also exists.

The synthesis and structure-activity-relationship (SAR) for a series of N-substituted piperazinyl carbamoyl 7-15 and piperazinyl acetyl 18-26 derivatives of tetrahydropapaverine have been carried out. The general synthetic methods of carbamoyl tetrahydropapaverine analogues involve N-substituted piperazines and carbamoyl imidazole tetrahydropapaverine as starting materials. Another route for synthesizing these compounds, involving the formation of carbamoyl imidazole piperazine has also been explored. Acylation of tetrahydropapaverine followed by substitution with various piperazinyl moities afforded the acetyl tetrahydropapaverine derivatives. Variously substituted piperazines have been used to monitor the effect of electron releasing and electron withdrawing substituents upon the antispasmodic activity of the molecules. Effect of varying electron densities on the antispasmodic activity, by altering the position of these groups on the benzene ring has also been monitored. Pharmacological methods involve the in vitro antispasmodic activity studies on a freshly removed guinea pig ileum using a force displacement transducer amplifier connected to a physiograph. Among the analogues synthesized in the present study, a promising compound 7, a potent muscle relaxant as compared to papaverine has been obtained.

Epileptic seizures are accompanied by changes in autonomic function that in turn influence the cardiovascular system (hypertension and bradyarrhythmia). We have studied possible cardioprotective activity (during the ictal state in conscious animals) of valproic acid, nifedipine, and verapamil, alone and in combination, during pentylenetetrazole (PTZ)-induced seizures. Telemetry system was used for recording EEG, blood pressure, and heart rate in conscious, freely moving rats during seizures. We observed that PTZ-induced seizures were accompanied by hypertension and bradyarrhythmia. Pretreatment with valproic acid did not block seizure-induced hypertension and bradyarrhythmia. Nifedipine alone and in combination with valproic acid blocked seizure-induced hypertension and bradyarrhythmia significantly. We also observed that pretreatment with verapamil alone and in combination with valproic acid did not block seizure-induced hypertension and bradyarrhythmia significantly. Our results suggest that pretreatment with nifedipine alone or in combination with valproic acid provides protection against seizure-induced hypertension and bradyarrhythmia.

A reaction of tetrahydropapaverine obtained from homoveratryl amine and homoveratric acid by three step procedure with various aromatic isocyanates or isothiocyanates to give the corresponding aryl substituted N-carbamoyl or N-thiocarbamoyl derivatives of isoquinoline has been achieved. All the compounds have been screened for their antispasmodic activities.